UBC Wiki - User contributions [en]

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T06:19:26Z

KINGHENGWONG: /* Diagnosing Noonan Syndrome */

Noonan syndrome (NS) is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have NS <ref name="Romano"/>, and both males and females are affected by this condition.

==Clinical Features==

NS is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect seen in NS, and is found in 20%-50% of individuals with NS. <ref name = "PVstenosis"> Bertola DR, Kim CA, Sugayama SM, et al. Cardiac Findings in 31 Patients with Noonan's Syndrome. Arq Bras Cardiol. 2000; 75(5): 409-23. </ref> The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. <ref name = "HCM"> Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442–8. </ref>

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

'''<big>Prenatal Diagnosis</big>'''

Prenatal diagnosis can be considered in cases where the mutation in the specific gene is known in the family. This involves looking at the baby’s DNA to see if it carries the same change found in the affected parent. In addition, there are certain features that can be seen in an ultrasound that may raise the suspicion that a baby may be born with NS. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

Parents may want to consider being referred to a genetic counsellor if there is a known family history of NS. Genetic counsellors are trained health professionals that help parents decide which prenatal genetic test they are suitable for, and also provide more information about the condition. <ref>National Society of Genetic Counselors : Who are Genetic Counselors?. Nsgc.org (2017). at <http://www.nsgc.org/page/whoaregcs></ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T05:06:50Z

KINGHENGWONG:

Noonan syndrome (NS) is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have NS <ref name="Romano"/>, and both males and females are affected by this condition.

==Clinical Features==

NS is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect seen in NS, and is found in 20%-50% of individuals with NS. <ref name = "PVstenosis"> Bertola DR, Kim CA, Sugayama SM, et al. Cardiac Findings in 31 Patients with Noonan's Syndrome. Arq Bras Cardiol. 2000; 75(5): 409-23. </ref> The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. <ref name = "HCM"> Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442–8. </ref>

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T05:05:48Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

NS is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect seen in NS, and is found in 20%-50% of individuals with NS. <ref name = "PVstenosis"> Bertola DR, Kim CA, Sugayama SM, et al. Cardiac Findings in 31 Patients with Noonan's Syndrome. Arq Bras Cardiol. 2000; 75(5): 409-23. </ref> The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. <ref name = "HCM"> Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442–8. </ref>

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T05:05:20Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect seen in NS, and is found in 20%-50% of individuals with NS. <ref name = "PVstenosis"> Bertola DR, Kim CA, Sugayama SM, et al. Cardiac Findings in 31 Patients with Noonan's Syndrome. Arq Bras Cardiol. 2000; 75(5): 409-23. </ref> The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. <ref name = "HCM"> Wilkinson JD, Lowe AM, Salbert BA, et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442–8. </ref>

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:59:10Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. <ref name = "HCM"> Wilkinson J.D., Lowe A.M., Salbert B.A., et al. Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2012;164:442–8. </ref>

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:56:23Z

KINGHENGWONG: /* Patient Resources */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:55:50Z

KINGHENGWONG: /* Diagnosing Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:54:45Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS. <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:53:25Z

KINGHENGWONG: /* Diagnosing Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref> It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered.

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:51:36Z

KINGHENGWONG: /* Patient Resources */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

Noonan syndrome can be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:51:07Z

KINGHENGWONG: /* Patient Resources */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals or parents with a recent child diagnosed with NS to join support groups and meet individuals living with the same condition.

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

[http://www.thesweetone.ca/index.html Living with Noonan Syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:40:35Z

KINGHENGWONG: /* Patient Resources */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], as a result of similar clinical features overlapping with these conditions. This may cause families with an NS individual to feel unheard. It may be beneficial for NS individuals to join support groups and meet individuals living with the same condition. Parent guides are also a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

[http://www.teamnoonan.org/help/#support-systems The Noonan Syndrome Foundation]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:24:45Z

KINGHENGWONG: /* Diagnosing Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. It is important to perform genetic testing to see if the affected individual truly has NS, so that the appropriate treatment is offered. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is known to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:22:15Z

KINGHENGWONG: /* Diagnosing Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

A gene panel (which looks at several different genes at once) may be ordered when testing for NS, as more than one gene is know to cause the condition. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

An individual with NS may sometimes be mistaken for other conditions such as, Leopard Syndrome, Neurofibromatosis Type 1, Costello Syndrome, and Cardiofaciocutaneous syndrome. This is because the genes that cause NS participate in the same biological pathway ('''RAS pathway''') as the genes causing the other listed diseases. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T04:00:27Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries one working copy and one non-working copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T01:04:17Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by heart specialist, including electrocardiogram and echocardiogram
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-03T01:03:41Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

Based on the known symptoms that occur in individuals with NS, a patient may be required to undergo the following examinations: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism (lack of thyroid hormone) such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Blood clotting tests
*Eye evaluation
*Complete blood count to assess for various blood disorders
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:28:04Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:22:35Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:21:44Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Congenital Heart Disease'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease (the presence of different types of heart defects) at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:19:14Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Heart Abnormalities'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood.

Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:18:56Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability.

<big>'''Heart Abnormalities'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include '''Atrial''' and '''Ventricular Septal Defects''' (holes in the walls separating the heart chambers), '''Branch Pulmonary Artery Stenosis''', and '''Tetralogy of Fallot''' (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:16:07Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

<big>'''Heart Abnormalities'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis (the narrowing of the pulmonary heart valve) is the most common heart defect and is present in 20%-50% of individuals with NS. The function of the pulmonary valve is to allow blood to flow out of the heart. When this heart valve narrows, individuals can develop a heart condition called '''Hypertrophic cardiomyopathy''' (thickened muscle in the heart), leading to complications. This is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include Atrial and Ventricular Septal Defects (holes in the walls separating the heart chambers), Branch Pulmonary Artery Stenosis, and Tetralogy of Fallot (a group of four different heart defects). <ref name = "Roberts"/> If there is a major structural defect or blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T06:04:26Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

<big>'''Facial features'''</big>
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

<big>'''Other features'''</big>
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects

Most children with NS may initially display signs of developmental delay, although most have normal intelligence. Some individuals may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

<big>'''Heart Abnormalities'''</big>

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:58:37Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

'''Facial features'''
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

'''Other features'''
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:58:19Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

'''Facial features'''
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

'''Other features'''
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%. Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Genetic testing can help identify which gene is causing the condition in NS, and can also help identify whether the mutation was inherited or de novo. <ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:53:14Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

'''Facial features'''
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

'''Other features'''
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: '''SOS1, RAF1, KRAS, NRAS, BRAF, MAP2K1'''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref>

Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:52:05Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

'''Facial features'''
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

'''Other features'''
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref>

Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:51:13Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

'''Facial features'''
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

'''Other features'''
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref>

Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for NS. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range. As such, an early evaluation is important after a diagnosis of NS.

The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:48:58Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

'''Facial features'''
* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears

'''Other features'''
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref>

Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for Noonan syndrome. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range.

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:46:34Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the gene mutation is not inherited from the parents but is '''de novo''', meaning it arose newly in the individual. In this scenario, both parents are unaffected, and the risk of having another affected child is less than 1%.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref>

Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for Noonan syndrome. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range.

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:40:59Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the mutations are not inherited from the parents but rather occur newly in the individual.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for Noonan syndrome. However, many symptoms as a result of the condition can be managed through surgery, medication, or other therapies and technologies. Provided that there are no severe heart abnormalities in individuals with NS, the life expectancy is expected to be in the normal range.

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:38:22Z

KINGHENGWONG: /* Management */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the mutations are not inherited from the parents but rather occur newly in the individual.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==
There is currently no cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:37:57Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Alternatively, the mutations are not inherited from the parents but rather occur newly in the individual.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/>

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:33:20Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

<big>'''Genetic Counselling'''</big>

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:32:28Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
NS can be inherited, meaning it is a condition that can be passed down from parents to their children through their genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

Mutations have been found in several genes that can lead to NS. Majority of individuals with NS have mutations in the gene called '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

'''Genetic Counselling'''

[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:28:59Z

KINGHENGWONG: /* Diagnosing Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

NS can be inherited, meaning it is a condition that can be passed down from parents to their children through genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Mutations have been found in several genes that can lead to NS. Many individuals with NS have mutations in the gene '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T05:27:48Z

KINGHENGWONG:

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

NS can be inherited, meaning it is a condition that can be passed down from parents to their children through genes. Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS. In a couple where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Mutations have been found in several genes that can lead to NS. Many individuals with NS have mutations in the gene '''PTPN11'''. Although less frequently, mutations in the following genes can also cause NS: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing can help identify which gene is causing the condition in the individual.

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

==Diagnosing Noonan Syndrome==

Making a diagnosis of NS in an individual relies on the observation of clinical features followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that is most notable during infancy and childhood. This commonly includes: a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Because NS can be caused by more than one gene, a gene panel (which looks at several different genes at once) can be considered. A positive genetic testing result can confirm a NS clinical diagnosis. However, a negative result (meaning no mutation was found in the genes that were examined) does not rule out the possibility of NS. In fact, a small proportion of individuals with NS will have a negative result, as there are likely other genes that can cause NS but have not yet been discovered. <ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T04:43:11Z

KINGHENGWONG: /* Genetics of Noonan Syndrome */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==How is Noonan Syndrome inherited?==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

NS can be inherited, meaning it is a condition that is passed down from parents to their children. The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS.

==How is Noonan Syndrome Diagnosed?==

Making a diagnosis of NS in an individual relies on identifying characteristic features associated with the condition followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that's most notable during infancy and childhood, which commonly includes a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Mutations have been found in several genes that can lead to NS. Many individuals with NS have mutations in the gene '''PTPN11'''. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing to identify the mutation can help determine which gene is causing NS in the individual.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

As mentioned above, NS is passed down in an autosomal dominant manner. In a couple, where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-02-02T04:41:49Z

KINGHENGWONG:

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations (errors in the genes) that prevent them from working properly, resulting in the features of NS.

NS can be inherited, meaning it is a condition that is passed down from parents to their children. The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS.

==How is Noonan Syndrome Diagnosed?==

Making a diagnosis of NS in an individual relies on identifying characteristic features associated with the condition followed by confirmatory genetic testing. An individual with NS has a distinctive facial appearance that's most notable during infancy and childhood, which commonly includes a large cranium (the part of the skull that encloses the brain), tall forehead, and downslanting eyes, and abnormal positioning of the ears.

'''<big>Genetic Testing</big>'''

Mutations have been found in several genes that can lead to NS. Many individuals with NS have mutations in the gene '''PTPN11'''. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''. Genetic testing to identify the mutation can help determine which gene is causing NS in the individual.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

As mentioned above, NS is passed down in an autosomal dominant manner. In a couple, where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-27T05:59:41Z

KINGHENGWONG: /* Genetic Counselling */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
------
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations, or errors in the genes that prevent them from working properly, resulting in the features of NS.

NS can be inherited, meaning it is a condition that is passed down from parents to their children. The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS.

There are several genes that when mutated, can cause NS. The most common one is called '''PTPN11''', and 50% of individuals with NS have mutations in this gene. Genetic testing to identify the mutation can help determine which gene is causing NS in the individual.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

As mentioned above, NS is passed down in an autosomal dominant manner. In a couple, where one has NS and carries a bad copy of the gene, while the other partner carries two normal copies of the gene:
* There is a '''50%''' chance that their future child will have NS (if the affected individual passes the bad copy)
* There is a '''50%''' chance that their future child will be unaffected (if both passed down the normal copy)

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-27T05:52:35Z

KINGHENGWONG: /* Inheritance */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
------
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

==Genetics of Noonan Syndrome==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

Every individual has two copies of a particular gene, because we receive one each from our mother and father. Our genes are important for providing the instructions to make sure our body is undergoing proper growth and development. In NS individuals, they have mutations, or errors in the genes that prevent them from working properly, resulting in the features of NS.

NS can be inherited, meaning it is a condition that is passed down from parents to their children. The pattern in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his/her mother or father is enough to cause NS.

There are several genes that when mutated, can cause NS. The most common one is called '''PTPN11''', and 50% of individuals with NS have mutations in this gene. Genetic testing to identify the mutation can help determine which gene is causing NS in the individual.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-27T05:29:22Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
------
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

== Inheritance==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

NS is inherited, meaning it is a condition that is passed down from parents to their children. The way in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his or her mother or father is enough to cause NS.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-27T00:47:20Z

KINGHENGWONG: /* Inheritance */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is a multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
------
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

== Inheritance==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]

NS is inherited, meaning it is a condition that is passed down from parents to their children. The way in which NS is passed down is called '''autosomal dominant'''. This means that just one non-working copy of a gene that an individual inherits from either his or her mother or father is enough to cause NS.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-27T00:10:02Z

KINGHENGWONG: /* Clinical Features */

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is a multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
------
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay

Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Congenital heart disease, or the presence of heart defects at birth is a common feature observed in approximately 50% to 80% of NS individuals.

Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

== Inheritance==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]
Because it is inherited in an autosomal dominant manner, heterozygotes, or individuals who receive just one copy of the gene mutation, will be affected.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-27T00:05:24Z

KINGHENGWONG:

Noonan syndrome is a genetic condition that causes abnormal development in several parts of the body. It is estimated that 1 in 1000-2500 people have Noonan syndrome, <ref name="Romano"/> and both males and females are affected by this condition.

==Clinical Features==

Noonan syndrome (NS) is a multisystemic, which means the condition affects several different parts of the body. Individuals with NS have recognizable features which includes:<ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref>

* wide-set eyes
* a downward eye slant
* low-set posteriorly rotated ears,
------
* webbed neck
* unusual chest shape
* widely shaped nipples
* undescended testicles
* short stature
* congenital heart defect
* kidney anomalies
* eye abnormalities
* skin abnormalities
* lymphatic malformations
* varied bleeding defects
* developmental delay <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref> Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Noonan syndrome is the second most common syndromic cause of congenital heart disease, exceeded in prevalence only by Down syndrome. Congenital heart disease occurs in 50%-80% of individuals with Noonan syndrome. Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

== Inheritance==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]
Because it is inherited in an autosomal dominant manner, heterozygotes, or individuals who receive just one copy of the gene mutation, will be affected.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-26T23:48:56Z

KINGHENGWONG:

Noonan syndrome is an inherited condition that causes abnormal development in several parts of the body. It has an estimated prevalence of 1 in 1000-2500 <ref name="Romano"/> and it affects males and females equally.

==Clinical Features==

Noonan syndrome (NS) is a multisystem disorder characterized by wide-set eyes, a downward eye slant, low-set posteriorly rotated ears, <ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> webbed neck, unusual chest shape, widely shaped nipples, undescended testicles, short stature, congenital heart defect, kidney anomalies, eye abnormalities, skin abnormalities, lymphatic malformations, varied bleeding defects, and developmental delay of varying degree. <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref> Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Noonan syndrome is the second most common syndromic cause of congenital heart disease, exceeded in prevalence only by Down syndrome. Congenital heart disease occurs in 50%-80% of individuals with Noonan syndrome. Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

== Inheritance==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]
Because it is inherited in an autosomal dominant manner, heterozygotes, or individuals who receive just one copy of the gene mutation, will be affected.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Noonan Syndrome

2017-01-26T23:46:13Z

KINGHENGWONG:

Noonan syndrome is an inherited condition that causes abnormal development in several parts of the body. It has an estimated prevalence of 1 in 1000-2500 <ref name = "Romano"> Roberts, A., et al., Noonan syndrome. Clinical Features, Diagnosis and Management Guidelines. Pediatrics, 2010. 126: 746-59.</ref> and it affects males and females equally.

==Clinical Features==

Noonan syndrome (NS) is a multisystem disorder characterized by wide-set eyes, a downward eye slant, low-set posteriorly rotated ears, <ref name = "OMIM"> Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/ </ref> webbed neck, unusual chest shape, widely shaped nipples, undescended testicles, short stature, congenital heart defect, kidney anomalies, eye abnormalities, skin abnormalities, lymphatic malformations, varied bleeding defects, and developmental delay of varying degree. <ref name = "Roberts"> Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.</ref> Most children with NS have normal intelligence, although some may have learning disabilities or intellectual disability. NS has alternatively been called male Turner syndrome, Female Pseudo-Turner syndrome, and Turner syndrome with Normal Karyotype because of the similarity of features in the two conditions.

[[File:Pulmonary valve stenosis.png|thumb|Pulmonary valve stenosis]]

Noonan syndrome is the second most common syndromic cause of congenital heart disease, exceeded in prevalence only by Down syndrome. Congenital heart disease occurs in 50%-80% of individuals with Noonan syndrome. Pulmonary valve stenosis is the most common heart defect and is found in 20%-50% of individuals with Noonan syndrome. Pulmonary valve stenosis is caused by an obstruction on the pulmonary valve, which causes reduction of the blood flow from the heart to the lungs. Hypertrophic cardiomyopathy (thickened muscle in the heart), is found in 20%-30% of individuals, and may be present at birth or develop in infancy or childhood. Other structural heart defects include atrial and ventricular septal defects (holes in the walls separating the heart chambers), branch pulmonary artery stenosis, and tetralogy of Fallot. <ref name = "Roberts"/> If there is a major structural defect of blockage, heart surgery may be required.

== Inheritance==
[[File:AD inheritance Noonan.png|thumb|Autosomal dominant inheritance. One gene with a mutation is enough to cause the condition. An individual with an autosomal dominant condition has 50% chance of having a child with the condition.]]
Because it is inherited in an autosomal dominant manner, heterozygotes, or individuals who receive just one copy of the gene mutation, will be affected.

While initially diagnosed on clinical grounds by observation of key features, molecular genetic testing identifies a mutation in the ''PTPN11'' gene in 50% of affected individuals. Less frequent mutations are found in the following genes: ''SOS1, RAF1, KRAS, NRAS, BRAF,'' and ''MAP2K1''.

Multigene panels can be used for simultaneous analysis of some or all of the genes associated with NS. Positive gene testing can confirm an NS diagnosis. The inability of genetic testing to identify a mutation in one of the known genes associated with Noonan syndrome does not rule out the possibility of the disorder. In roughly 15% of individuals with NS, no mutation will be detected, as there are likely other genes involved that are not yet well-understood.<ref name = "GeneReviews"> GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013] </ref>

== Management ==

Early evaluation is important after a diagnosis of Noonan syndrome. The following should be considered to help guide management: <ref name = "Allanson"> Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138 </ref> <ref name = "Romano"> Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </ref>
*Physical and neurological examination
*Weight and height measurements plotted on appropriate growth curve
*Cardiac evaluation by cardiologist, including electrocardiogram and echocardiogram (if nothing detected, re-evaluation every 5 years)
*Thyroid-function tests and antibodies if symptoms or hypothyroidism such as fatigue, constipation, poor growth
*Kidney ultrasound
*Brain and cervical spine MRI if presenting with neurologic signs
*Developmental screening
*Hearing evaluation
*Coagulation screen
*Ophthalmologic evaluation
*Complete blood count with differential count for assessing various hematology issues
*X-ray of spine and rib cage

== Genetic Counselling ==

Although many individuals with NS have a new mutation which occurs sporadically, there is an affected parent in 30%-75% of families. Transmission of NS is mostly maternal, most likely because cryptorchidism leads to reduced fertility in males.<ref name = "Elsawi"> Elsawi, MM, Pryor, JP, Kliflo, G, Barnes, C, Patton, MA Genital tract function in men with Noonan syndrome. J Med Genet. 1994 Jun;31(6):468-70. </ref> The risk to siblings of an affected child depends on the genetic status of the parents. If a parent is affected, the risk of having a child with NS is 50%. When the parents are clinically unaffected, the risk to the siblings of an affected child is less than 1%. Each child of an individual with Noonan syndrome has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing allele has been identified in an affected family member.<ref name = "GeneReviews"/> There is not a cure for Noonan syndrome, however many aspects of the condition are able to be treated with surgery, medication, or other therapies and technologies. Provided that there is not a serious heart defect that is untreatable, the life expectancy for individuals with NS is in the normal range.

Prenatal features suggestive of Noonan syndrome include: increased nuchal translucency, cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis. Prenatal diagnosis is possible by analysis of DNA following amniocentesis or chorionic villus sampling (CVS) at approximately 10 to 12 weeks gestation. The disease-causing allele of an affected family member must be identified in the family before prenatal testing can be performed. <ref name = "GeneReviews"/> There is currently momentum to perform molecular testing for Noonan syndrome in a pregnancy with an increased nuchal translucency thickness and a normal chromosome study. Although prenatal diagnosis may be able to diagnosis NS, it will not be able to determine how severely affected the child will be.

NS should be distinguished from other syndromes/conditions with similar features, especially Leopard syndrome, Neurofibromatosis type 1 (NF1), Costello syndrome and cardiofaciocutaneous syndrome because all of these disorders are caused by mutations at certain points along the same biological pathway: the RAS pathway. <ref name = "Bitton"> Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147.</ref>

==Patient Resources==

A diagnosis of Noonan Syndrome can be confusing, as the diagnosis can be mostly clinical with the physician making the diagnosis if there are enough features, despite there being known genetic causes for ~60%.

Noonan syndrome can also be confused with [http://ghr.nlm.nih.gov/condition/turner-syndrome Turner's syndrome] and [http://www.nofas.org/ Fetal Alcohol Syndrome], due to some clinical features overlapping.

Due to this, many families which experience Noonan Syndrome may feel unheard. Support groups and parent guides are a way for families to exchange stories and relate.

[http://www.noonansyndrome.org/NSLay_Summary2-7-13.pdf Parent's Guide to Noonan syndrome]

== References ==

<references>
# Bitton, N., et al., Case report: Noonan-like multiple central giant cell granuloma syndrome. Pediatric dentistry, 2012. 34(5): p. 144-147
# GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2013. Available at http://www.genetests.org. Accessed [March 6, 2013].
# Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: http://omim.org/
# Roberts, A., et al., Noonan syndrome. Lancet, 2013. 381(9863): p. 333-342.
# Allanson, J.E. (2007). Noonan Syndrome. American Journal of Medical Genetics, 145C, 274-279. DOI: 10.1002/ajmg.c.30138
# Romano, A. A., Allanson, J. E., Dahlgren, J., Gelb, B. D., Hall, B., Pierpont, M. E., ... & Noonan, J. A. (2010). Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics, 126(4), 746-759. </references>

Course:MEDG550/Student Activities/Fabry Disease

2017-01-13T19:05:16Z

KINGHENGWONG: /* Resources */

=Fabry Disease=
'''Fabry Disease''' ('''FD'''), also called '''alpha-galactosidase A deficiency''', is a rare and inherited lysosomal storage disease. Inherited means being passed down from parent to child. Lysosomes are molecules in the cells of our body that play an important job in breaking down waste and nutrients in the cell. For the lysosome to work properly, it requires different molecules called enzymes to help it participate in its function.

Patients with FD produce a lower amount of a specific enzyme called '''alpha-galactosidase A''' ('''α-Gal'''), resulting in the buildup of a type of fat substance called globotriaosylceramide and other related compounds in the lysosome. The improper clearance of these fat substances in the cells of the body results in a range of symptoms and causes progressive damage to several organs in the body, including the heart, kidney and brain.<ref name="Germain 2010">Germain DP. (2010). Fabry Disease. Orphanet J Rare Dis. 5:30.</ref>

==Clinical Characteristics==
Patients may not present with every symptom listed, and the symptoms observed also can vary between patients. FD is classified into two types depending on when and which symptoms appear in affected individuals.

[[File:Angiokeratoma 01.jpg|thumb|Angiokeratoma seen in various parts of the body]]

[[File:Morbus Fabry Cornea verticillata 01.jpg|thumb|Cornea verticillata]]

'''<big>Classic Fabry Disease</big>''' <ref name="Hopkin et al (2016)">Hopkin RJ, Jefferies JL, Laney DA, et al. (2016). The management and treatment of children with Fabry disease: A United States-based perspective. Mol Genet Metab. 117: 104-13.</ref><ref name="Laney 2015">Laney DA, Peck DS, Atherton AM, et al. (2015). Fabry disease in infancy and early childhood: A systematic literature review. Genet Med. 17: 323-30.</ref>

The classic form of FD begins in infancy/childhood and is considered to be more severe than the atypical type. The average age when symptoms appear is from 6-9 years old. <ref name="Hopkin et al (2008)">Hopkin RJ, Bissler J, Banikazemi M, et al. (2008). Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 64: 550–555.</ref> Distinct symptoms may include:
* Small dark red/purple raised spots that are present throughout the body ('''angiokeratoma''')
* Distinctive starburst pattern in the eyes ('''cornea verticillata''')
* Immense pain in the hands and feet that can be chronic or periodic ('''neuropathic pain''')
* Reduced/Absence of sweating ('''anhidrosis/hypohidrosis''')

Other non-specific symptoms may also be seen:

* Gastrointestinal problems (abdominal pain, nausea, vomiting, diarrhea, constipation)
* Heat/cold intolerance
* Cardiac abnormalities (heart valve problems, heart rhythm abnormalities, thickening of the left ventricle)
* Poor growth (height/weight gain) in boys

In adulthood, when irreversible damage has been done to different organs, more severe symptoms may occur in the heart, brain and kidneys and lead to death:

* Cardiac disease
* Stroke
* End stage kidney failure

'''<big>Atypical Fabry Disease</big>''' <ref>Nakao S, Kodama C, Takenaka T, et al. (2003). Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int. 64: 801–7</ref><ref>Sawada K, Mizoguchi K, Hsihida A, et al. (1996). Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy. Clin Nephrol. 45: 289-94.</ref>

The atypical type appears later on in adulthood and is less severe, as symptoms are usually only seen in one organ. For example, some patients have an '''atypical renal FD''', which only presents with kidney related symptoms (such as end stage kidney failure) and not the other characteristic features of FD.

==Genetics==

[[File:Xlinkrecessivefather.jpg|thumb|X-linked inheritance. The father is affected and will never pass the mutation to his son, but will always pass it to his daughters, making them "carriers" for the mutation.]]

[[File:XlinkRecessive.jpg|thumb|X-linked inheritance. The mother is a carrier for the mutation, and can pass the mutation to either her son or daughter. If the son receives the mother's X-chromosome that carries the mutation, he will be affected, whereas the daughter becomes a carrier.]]

DNA is what makes us who we are, and consequently provides instructions for cells in our body to make different molecules. Our DNA are packaged into genes, which are located on chromosomes. Everyone has 23 pairs of chromosomes (22 numbered pairs, and 1 pair of sex chromosomes). Males have an XY pair of sex chromosomes, while females have XX.

The gene that instructs our cells to make α-Gal is called '''GLA''', and is located on the X-chromosome. All patients with FD have mutations, which are genetic changes in this gene that leads to a drastic reduction in the amount of α-Gal enzyme being produced.<ref name="Germain 2010"/>

Mutations in GLA are extremely diverse, and majority of mutations are unique to individual families.<ref>Desnick RJ, Iouannou YA, & Eng ME. (2007). a-Galactosidase A deficiency: Fabry disease. OMBIDD. p3733-74.</ref> The type of mutation and where it occurred in the gene determines the severity and types of symptoms observed in affected individuals. Thus, individuals with FD are likely to show differences in the progression of their disease.

<big>'''Inheritance Pattern of Fabry Disease'''</big>

The pattern of inheritance for FD occurs in a '''X-linked''' manner. Males who inherit the mutated copy of GLA from their parents will be affected with Fabry disease. This is because males only have one X-chromosome. In contrast, females that inherit the mutated copy of GLA are called '''carriers''' because they still have a normal copy of GLA on the other X chromosome.

When an affected father carries the FD causing mutation:
* Daughters have a '''100%''' chance of receiving the mutation, making them carriers (the father will only pass the X chromosome to females)
* Sons have a '''0%''' chance of receiving the mutation and being affected with FD (the father will only pass the Y chromosome to males)

When a mother is a carrier for the FD causing mutation:
* Daughters have a '''50%''' chance of receiving the mutation, making them carriers
* Sons have a '''50%''' chance of receiving the mutation and being affected with FD

It was previously believed that female carriers are not affected with FD as they still have a normal functioning copy of the GLA gene to make normal α-Gal. However, it is now known that some female carriers may have reduced levels of α-Gal, and also the clinical symptoms seen in males with FD.<ref name= "Laney et al (2013)"/>

==Diagnosis==

<big>'''Biochemical Testing'''</big> <ref name= "Gal et al (2011)">Gal S, Hughes DA, & Winchester B. (2011). Towards a consensus in the laboratory diagnostics of Fabry disease – recommendations of a European expert group. J Inherit Metab Dis. 34: 509-14.</ref><ref name= "Laney et al (2013)">Laney DA, Bennett RL, Clarke V, et al. (2013). Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 22: 555-64.</ref>

Biochemical testing for FD involves looking at the level of α-Gal circulating in the blood. Males affected with FD will have decreased levels of α-Gal. FD females however, may have normal or decreased levels of α-Gal, and would require further confirmatory genetic testing.

<big>'''Genetic Testing'''</big> <ref name= "Gal et al (2011)"/><ref name= "Laney et al (2013)"/>

Genetic testing involves reading the DNA to see if a mutation can be found in the GLA gene. As mentioned above, females suspected to have FD will need to have genetic testing for a definitive diagnosis.

==Genetic Counselling==
Individuals may want to consider genetic counselling if there is a family history of individuals with FD, or have had a previous child that has been diagnosed. Genetic counsellors are trained health professionals that can help individuals assess if there are any other family members or relatives that maybe at risk for the disease and coordinate testing options. In addition, genetic counsellors can provide a better understanding of living with the disease and explore reproductive options. <ref>National Society of Genetic Counselors : Who are Genetic Counselors?. Nsgc.org (2017). at <http://www.nsgc.org/page/whoaregcs></ref>

<big>'''Reproductive Options'''</big> <ref name= "Laney et al (2013)"/>

'''Prenatal diagnosis''' is an option for parents who have confirmed the specific mutation in the GLA gene. This involves looking at the baby’s DNA to see if it has the same genetic change as identified in its parents.

Parents may want to explore the option of '''pre-implantation genetic diagnosis''' ('''PGD''') at an assisted reproduction center. PGD is a technique performed during an in-vitro fertilization (IVF) process to select for healthy embryos that do not carry the known GLA mutation identified in the parents.

Alternatively, parents may want to consider pursuing IVF through an egg or sperm donor.

<big>'''Psychological and Social Aspects of Living with Fabry Disease'''</big>

FD patients may have lower psychological wellbeing as a result of living with the symptoms of the disease, such as an increased risk of depression and anxiety.<ref>Cole AL, Lee PJ, Hughes DA, et al. (2007). Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 30: 943-51.</ref><ref>Boisover FE, Murphe E, Cipolotti L, et al. (2014). Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis. 37: 177-87.</ref> Some other feelings may include: <ref name= "Laney et al (2013)"/>
* Isolation from peers for being unable to participate in activities as a result of pain symptoms
* Embarrassment and issues of intimacy arising from physical appearance due to presence of angiokeratomas
* Anger, grief, blame, hopelessness, which are all feelings that commonly are experienced in patients with chronic illnesses

==Clinical and Medical Management==
Fabry disease patients should be managed by a multidisciplinary specialty team as symptoms can occur in multiple organs. This could comprise a medical geneticist, genetic counsellor, pediatric cardiologist, pain specialist, psychologist and others depending on the specific symptoms that arises. <ref name= "Laney et al (2013)"/>

<big>'''Neuropathic Pain Management'''</big><ref name="Hopkin et al (2016)"/>

There are different types of pain medications that may be prescribed for patients, depending on whether the pain is chronic or episodic, and whether the pain is throughout the body or localized to certain areas, and the severity.

<big>'''Enzyme Replacement Therapy'''</big> <ref name="Biegstratten et al (2015)">Biegstraaten M, Arngrimsson R, Barbey F, et al. (2015). Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. 10: 36.</ref><ref name="Hopkin et al (2016)"/>

There is currently no cure for FD. However, a treatment called enzyme replacement therapy (ERT) can be used to reduce the severity of symptoms that progress overtime. This involves delivery of the medication directly to the veins, that will help the lysosome break down the buildup of fat substances that causes organ damage.

Not all patients with FD may need ERT, and it is important that patients discuss this option with their doctor. In general, patients that begin presenting with symptoms should consider ERT to prevent the progression of the disease and causing irreversible organ damage. However, asymptomatic patients should discuss with their doctor about the optimal time to start ERT, as there has not been a consensus among doctors for managing this subset of FD patients.

==Resources==
Patients may find it helpful to review other resources for information regarding FD, or to connect with other individuals or families that are living with the disease. Some starting places are listed below:

[http://www.fabrycanada.com/home.php Canadian Fabry Association]

[http://www.fabrydisease.org National Fabry Disease Foundation]

[http://www.fabrynetwork.org/members/ Fabry International Network]

==References==

<references/>

Course:MEDG550/Student Activities/Fabry Disease

2017-01-13T19:04:46Z

KINGHENGWONG: /* Resources */

=Fabry Disease=
'''Fabry Disease''' ('''FD'''), also called '''alpha-galactosidase A deficiency''', is a rare and inherited lysosomal storage disease. Inherited means being passed down from parent to child. Lysosomes are molecules in the cells of our body that play an important job in breaking down waste and nutrients in the cell. For the lysosome to work properly, it requires different molecules called enzymes to help it participate in its function.

Patients with FD produce a lower amount of a specific enzyme called '''alpha-galactosidase A''' ('''α-Gal'''), resulting in the buildup of a type of fat substance called globotriaosylceramide and other related compounds in the lysosome. The improper clearance of these fat substances in the cells of the body results in a range of symptoms and causes progressive damage to several organs in the body, including the heart, kidney and brain.<ref name="Germain 2010">Germain DP. (2010). Fabry Disease. Orphanet J Rare Dis. 5:30.</ref>

==Clinical Characteristics==
Patients may not present with every symptom listed, and the symptoms observed also can vary between patients. FD is classified into two types depending on when and which symptoms appear in affected individuals.

[[File:Angiokeratoma 01.jpg|thumb|Angiokeratoma seen in various parts of the body]]

[[File:Morbus Fabry Cornea verticillata 01.jpg|thumb|Cornea verticillata]]

'''<big>Classic Fabry Disease</big>''' <ref name="Hopkin et al (2016)">Hopkin RJ, Jefferies JL, Laney DA, et al. (2016). The management and treatment of children with Fabry disease: A United States-based perspective. Mol Genet Metab. 117: 104-13.</ref><ref name="Laney 2015">Laney DA, Peck DS, Atherton AM, et al. (2015). Fabry disease in infancy and early childhood: A systematic literature review. Genet Med. 17: 323-30.</ref>

The classic form of FD begins in infancy/childhood and is considered to be more severe than the atypical type. The average age when symptoms appear is from 6-9 years old. <ref name="Hopkin et al (2008)">Hopkin RJ, Bissler J, Banikazemi M, et al. (2008). Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 64: 550–555.</ref> Distinct symptoms may include:
* Small dark red/purple raised spots that are present throughout the body ('''angiokeratoma''')
* Distinctive starburst pattern in the eyes ('''cornea verticillata''')
* Immense pain in the hands and feet that can be chronic or periodic ('''neuropathic pain''')
* Reduced/Absence of sweating ('''anhidrosis/hypohidrosis''')

Other non-specific symptoms may also be seen:

* Gastrointestinal problems (abdominal pain, nausea, vomiting, diarrhea, constipation)
* Heat/cold intolerance
* Cardiac abnormalities (heart valve problems, heart rhythm abnormalities, thickening of the left ventricle)
* Poor growth (height/weight gain) in boys

In adulthood, when irreversible damage has been done to different organs, more severe symptoms may occur in the heart, brain and kidneys and lead to death:

* Cardiac disease
* Stroke
* End stage kidney failure

'''<big>Atypical Fabry Disease</big>''' <ref>Nakao S, Kodama C, Takenaka T, et al. (2003). Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype. Kidney Int. 64: 801–7</ref><ref>Sawada K, Mizoguchi K, Hsihida A, et al. (1996). Point mutation in the alpha-galactosidase A gene of atypical Fabry disease with only nephropathy. Clin Nephrol. 45: 289-94.</ref>

The atypical type appears later on in adulthood and is less severe, as symptoms are usually only seen in one organ. For example, some patients have an '''atypical renal FD''', which only presents with kidney related symptoms (such as end stage kidney failure) and not the other characteristic features of FD.

==Genetics==

[[File:Xlinkrecessivefather.jpg|thumb|X-linked inheritance. The father is affected and will never pass the mutation to his son, but will always pass it to his daughters, making them "carriers" for the mutation.]]

[[File:XlinkRecessive.jpg|thumb|X-linked inheritance. The mother is a carrier for the mutation, and can pass the mutation to either her son or daughter. If the son receives the mother's X-chromosome that carries the mutation, he will be affected, whereas the daughter becomes a carrier.]]

DNA is what makes us who we are, and consequently provides instructions for cells in our body to make different molecules. Our DNA are packaged into genes, which are located on chromosomes. Everyone has 23 pairs of chromosomes (22 numbered pairs, and 1 pair of sex chromosomes). Males have an XY pair of sex chromosomes, while females have XX.

The gene that instructs our cells to make α-Gal is called '''GLA''', and is located on the X-chromosome. All patients with FD have mutations, which are genetic changes in this gene that leads to a drastic reduction in the amount of α-Gal enzyme being produced.<ref name="Germain 2010"/>

Mutations in GLA are extremely diverse, and majority of mutations are unique to individual families.<ref>Desnick RJ, Iouannou YA, & Eng ME. (2007). a-Galactosidase A deficiency: Fabry disease. OMBIDD. p3733-74.</ref> The type of mutation and where it occurred in the gene determines the severity and types of symptoms observed in affected individuals. Thus, individuals with FD are likely to show differences in the progression of their disease.

<big>'''Inheritance Pattern of Fabry Disease'''</big>

The pattern of inheritance for FD occurs in a '''X-linked''' manner. Males who inherit the mutated copy of GLA from their parents will be affected with Fabry disease. This is because males only have one X-chromosome. In contrast, females that inherit the mutated copy of GLA are called '''carriers''' because they still have a normal copy of GLA on the other X chromosome.

When an affected father carries the FD causing mutation:
* Daughters have a '''100%''' chance of receiving the mutation, making them carriers (the father will only pass the X chromosome to females)
* Sons have a '''0%''' chance of receiving the mutation and being affected with FD (the father will only pass the Y chromosome to males)

When a mother is a carrier for the FD causing mutation:
* Daughters have a '''50%''' chance of receiving the mutation, making them carriers
* Sons have a '''50%''' chance of receiving the mutation and being affected with FD

It was previously believed that female carriers are not affected with FD as they still have a normal functioning copy of the GLA gene to make normal α-Gal. However, it is now known that some female carriers may have reduced levels of α-Gal, and also the clinical symptoms seen in males with FD.<ref name= "Laney et al (2013)"/>

==Diagnosis==

<big>'''Biochemical Testing'''</big> <ref name= "Gal et al (2011)">Gal S, Hughes DA, & Winchester B. (2011). Towards a consensus in the laboratory diagnostics of Fabry disease – recommendations of a European expert group. J Inherit Metab Dis. 34: 509-14.</ref><ref name= "Laney et al (2013)">Laney DA, Bennett RL, Clarke V, et al. (2013). Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 22: 555-64.</ref>

Biochemical testing for FD involves looking at the level of α-Gal circulating in the blood. Males affected with FD will have decreased levels of α-Gal. FD females however, may have normal or decreased levels of α-Gal, and would require further confirmatory genetic testing.

<big>'''Genetic Testing'''</big> <ref name= "Gal et al (2011)"/><ref name= "Laney et al (2013)"/>

Genetic testing involves reading the DNA to see if a mutation can be found in the GLA gene. As mentioned above, females suspected to have FD will need to have genetic testing for a definitive diagnosis.

==Genetic Counselling==
Individuals may want to consider genetic counselling if there is a family history of individuals with FD, or have had a previous child that has been diagnosed. Genetic counsellors are trained health professionals that can help individuals assess if there are any other family members or relatives that maybe at risk for the disease and coordinate testing options. In addition, genetic counsellors can provide a better understanding of living with the disease and explore reproductive options. <ref>National Society of Genetic Counselors : Who are Genetic Counselors?. Nsgc.org (2017). at <http://www.nsgc.org/page/whoaregcs></ref>

<big>'''Reproductive Options'''</big> <ref name= "Laney et al (2013)"/>

'''Prenatal diagnosis''' is an option for parents who have confirmed the specific mutation in the GLA gene. This involves looking at the baby’s DNA to see if it has the same genetic change as identified in its parents.

Parents may want to explore the option of '''pre-implantation genetic diagnosis''' ('''PGD''') at an assisted reproduction center. PGD is a technique performed during an in-vitro fertilization (IVF) process to select for healthy embryos that do not carry the known GLA mutation identified in the parents.

Alternatively, parents may want to consider pursuing IVF through an egg or sperm donor.

<big>'''Psychological and Social Aspects of Living with Fabry Disease'''</big>

FD patients may have lower psychological wellbeing as a result of living with the symptoms of the disease, such as an increased risk of depression and anxiety.<ref>Cole AL, Lee PJ, Hughes DA, et al. (2007). Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 30: 943-51.</ref><ref>Boisover FE, Murphe E, Cipolotti L, et al. (2014). Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis. 37: 177-87.</ref> Some other feelings may include: <ref name= "Laney et al (2013)"/>
* Isolation from peers for being unable to participate in activities as a result of pain symptoms
* Embarrassment and issues of intimacy arising from physical appearance due to presence of angiokeratomas
* Anger, grief, blame, hopelessness, which are all feelings that commonly are experienced in patients with chronic illnesses

==Clinical and Medical Management==
Fabry disease patients should be managed by a multidisciplinary specialty team as symptoms can occur in multiple organs. This could comprise a medical geneticist, genetic counsellor, pediatric cardiologist, pain specialist, psychologist and others depending on the specific symptoms that arises. <ref name= "Laney et al (2013)"/>

<big>'''Neuropathic Pain Management'''</big><ref name="Hopkin et al (2016)"/>

There are different types of pain medications that may be prescribed for patients, depending on whether the pain is chronic or episodic, and whether the pain is throughout the body or localized to certain areas, and the severity.

<big>'''Enzyme Replacement Therapy'''</big> <ref name="Biegstratten et al (2015)">Biegstraaten M, Arngrimsson R, Barbey F, et al. (2015). Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. 10: 36.</ref><ref name="Hopkin et al (2016)"/>

There is currently no cure for FD. However, a treatment called enzyme replacement therapy (ERT) can be used to reduce the severity of symptoms that progress overtime. This involves delivery of the medication directly to the veins, that will help the lysosome break down the buildup of fat substances that causes organ damage.

Not all patients with FD may need ERT, and it is important that patients discuss this option with their doctor. In general, patients that begin presenting with symptoms should consider ERT to prevent the progression of the disease and causing irreversible organ damage. However, asymptomatic patients should discuss with their doctor about the optimal time to start ERT, as there has not been a consensus among doctors for managing this subset of FD patients.

==Resources==
Patients may find it helpful to review other resources for information regarding FD, or to connect with other individuals or families that are living with the disease. Some starting places are listed below:

[http://www.fabrycanada.com/home.php Canadian Fabry Association] - Canada

[http://www.fabrydisease.org National Fabry Disease Foundation]

[http://www.fabrynetwork.org/members/ Fabry International Network]

==References==

<references/>