Course:MEDG550/Student Activities/Williams Syndrome

From UBC Wiki

Williams syndrome (WS; also Williams–Beuren syndrome or WBS) (OMIM# 194050) is a neurodevelopmental disorder caused by a deletion on chromosome 7[1][2]. People with Williams syndrome have cardiovascular problems, a distinctive facial appearance, intellectual disability, and a strikingly friendly personality[2]. This condition is rare, affecting roughly 1 in 7,500 - 10,000[3].

History

In 1961, cardiologist John C.P. Williams and his colleagues identified four patients with a similar set of characteristics. These patients all had heart problems, "mental deficiency," and similar facial features. They published a paper proposing that these features comprised a specific syndrome[4]. The next year, another group reported three more patients with the same features[5]. Together, these reports lead to calling this condition "Williams-Beuren Syndrome" after the authors. By 1999, the condition shortened to Williams Syndrome, and a wider range of symptoms defined[6].

Stellate pattern in the iris is commonly seen in Williams syndrome.

Clinical Features

Williams syndrome is a collection of symptoms, with no single feature responsible for the diagnosis[7]. It is suspected in individuals with the following characteristics:

Cardiovascular Disease

Supravalvular aortic stenosis (SVAS) is the most common and most significant cardiovascular finding. It occurs in approximately 75% of affected individuals[7]. SVAS is a narrowing of the large blood vessel (the aorta) that carries blood from the heart to the rest of the body[7]. Individuals with SVAS may have an abnormal heartbeat (murmur) during a chest exam. If this is left untreated, it can cause shortness of breath, chest pain and heart failure[7].

Facial Features

Facial features of Williams syndrome typically include[7]:

  • A broad forehead
  • Full cheeks
  • Stellate pattern in the iris
  • Flat nasal bridge
  • Short upturned nose
  • Wide mouth
  • Full lips
  • Small jaw

Intellectual Disability And Cognition

Most people with Williams syndrome experience intellectual disability, ranging from severe to mild. Regardless, there is usually strong short and long-term memory, as well as a robust vocabulary. Poor visuospatial skills are also frequently recorded[8]. Some research has identified improved musical skills among children Williams Syndrome. Amusia, the ability to recognize and reproduce musical notes, has been reported.[9]

Unique Personality[7]

  • Outgoing social nature
  • Overfriendliness & enthusiasm
  • Increased sensitivity to sounds[10]
  • Generalized anxiety
  • Specific phobias
  • Attention deficit disorder (ADD/ADHD)

Other Common Abnormalities and Medical Features

Individuals with Williams Syndrome may also have the abnormalities in the following:

  • Connective Tissue: Joint problem's and soft, loose skin.[7]
  • Oral/Dental: May have small and/or sparse teeth, some of their permanent teeth may not grow in[11], and they may have a high arched palate[12].
  • Vision: more likely to develop strabismus (where one eye is focused and the other wanders) and nearsightedness or farsightedness[1]
  • Digestive Tract: chronic abdominal pain [7]
  • Urinary tract: increased urination frequency, involuntary urination, and may have structural differences in their urinary tract[1] [7]
  • Growth: typically have growth deficiency as a baby and poor growth in childhood, resulting in short height as an adult. [7]
  • Sleep disruptions: greater difficulty falling asleep, irregular sleep cycles, more restlessness and rapid-eye-movement, and more respiratory-related sleep arousals (like sleep apnea), all leading to decreased sleep time.[13][14]
  • Endocrine[1]: Problems with their glands secreting hormones, which can lead to:
    • hypercalcemia: high levels of calcium in the blood (can affect kidneys)
    • hypercalciuria: high levels of calcium in the urine (can lead to kidney stones)
    • hypothyroidism: underactive or low thyroid functioning (may lead to fatigue, weight gain, and low cold tolerance)
    • Diabetes mellitus Type II: acquired diabetes, due to dysregulation of blood sugars
    • Early puberty

Child Development

Due to a number of the features mention above, there are a few developmental differences to note in growing children:

  1. Most babies with Williams Syndrome begin having growth problems in the womb, and as infants, have feeding difficulties and failure to thrive (about 70% of cases). They may also have poor growth in childhood, overall leaving them smaller then their peers.
  2. Their language development is nearly always delayed[15]: Though even as infants they are likely to be quite social, they don't start using single words to communicate until around 18 months, and talking in sentences until around 3 years[16]. After this delay, language begins to be a strength for these children.
  3. Adaptive skills may also be delayed, such as toilet training, feeding themselves and dressing[17].

Evaluation, Management & Diagnosis

Evaluation

Because of the variability of the clinical features of Williams syndrome the extent of the condition and the individual needs of the patient need to be evaluated. The following are recommendations regarding evaluation[7]:

  • Physical exam and neurological evaluation
  • Growth evaluation
  • Cardiology (heart) assessment
  • Urinary system assessment
  • Calcium determinations
  • Thyroid function tests
  • Ophthalmologic (vision) evaluation
  • Hearing assessment
  • Medical genetics consultation

Management

There is no cure for Williams syndrome, but management focuses on treatment of manifestations and surveillance and prevention of secondary complications. Treatment and surveillance includes[7]:

  • Surgery to correct heart problems such as SVAS
  • Medication to manage high blood pressure
  • Adjusted diet to manage high calcium levels in blood and urine
  • Tympanostomy tubes to treat recurrent inflammation in the middle ear
  • Medication may be used to treat early puberty (Gonadotropin releasing hormone agonist)
  • Addressing cognitive and behavioural challenges with:
    • Speech/language therapy
    • Physical therapy
    • Occupational therapy
    • Sensory therapy
    • Feeding programs
    • Psychological counselling
    • Psychiatric Medication
    • Self-calming techniques to manage anxiety

Genetics

Williams Syndrome genes[2]
ABHD11 · BAZ1B · BCL7B · CLDN3 · CLDN4 · CLIP2 · DNAJC30 · EIF4H · ELN · FKBP6 · FZD9 · GTF2I · GTF2IRD1 · GTF2IRD2 · LAT2 · LIMK1 · MLXIPL · NCF1 · NSUN5 · RFC2 · STX1A · TBL2 · TRIM50 · VPS37D · WBSCR22 · WBSCR23 · WBSCR27 · WBSCR28

Every cell in the human body contains "genes", the instruction manual for the human body. These instructions are organized into structures called chromosomes. At birth, every human has 46 chromosomes[18]. These chromosomes exist in pairs, numbered 1 through 22 plus one set of sex chromosomes (XX, or XY). We get these chromosomes from our parents: one set comes from the egg, and one comes from the sperm. Genes are made up of DNA and provide the information to our cells to make proteins that are involved in various functions for our bodies to grow and develop[18]. A change in the genes (or many genes) can have an effect on how the body grows and develops[18]. Williams syndrome is caused by a deletion from a specific region of chromosome 7 which includes 26-28 genes[19]. When a condition that is the result of a deletion that removes several genes lying close to each other, it is called a contiguous gene syndrome[7]. Of the genes involved in the deletion, the most widely studied gene is called elastin (ELN). ELN is important for elasticity in arteries, lungs and skin. Loss of an ELN allele is associated with arteriopathy, including vascular stenoses and hypertension, and is likely the cause of the major cardiac features of Williams syndrome[20] [7]. The behavioural characteristics and other cognitive difficulties may be due to the loss of genes like CLIP2, GTF2I, GTF2IRD1 and LIMK1. GF2IRD1 may also contribute to the unique facial features[19].

Williams syndrome shows complete penetrance and variable expressivity. This means that everyone with the deletion will have the syndrome, but the symptoms might be different.[1].

Inheritance

Autosomal dominant inheritance: an affected individual has a 50% chance of passing on the deletion, which would result in an affected child.

Williams syndrome is inherited in an autosomal dominant manner, meaning that only one copy of the deletion is needed to cause Williams syndrome[19]. Most cases occur de novo, meaning that the genetic change is a new random event in the child with both parents being unaffected [19]. When this genetic change is new in the family, the recurrence risk for a couple to have another child with Williams syndrome is very low. Rarely individuals with Williams syndrome inherited the chromosomal deletion from an affected parent [19].

Genetic Testing

When features of Williams syndrome are clinically recognized, genetic testing (such as fluorescence in situ hybridization; FISH) and/or deletion/duplication analysis for a deletion of the Williams-Beuren syndrome critical region (WBSCR) can be done to confirm diagnosis. Over 99% of individuals with a clinical diagnosis of Williams syndrome have this deletion[1].

Genetic Counselling

Parents of a child who is suspected of having Williams syndrome or an affected individual with Williams syndrome may benefit from genetic counselling. Genetic counsellors are healthcare professionals trained to provide patients with information regarding genetic disorders and guide them in their process of making informed medical and personal decisions[21]. A genetic counsellor will work with the individual to help them understand complex genetic information along with providing emotional support as the patient makes decisions[21]. Genetic counsellors can assist in providing information about as well as facilitating pre-conception options, prenatal options and genetic testing[21].

Preconception Counselling and Prenatal Diagnosis

People who have Williams syndrome have normal reproductive capabilities; however, if someone with Williams syndrome has a child, there is a 50% chance of passing the deletion to a child, who would then also be affected[19]. Preconception genetic counselling may be offered to individuals with Williams syndrome. Due to the chance of someone with Williams syndrome passing the deletion to a child, prenatal diagnosis could be performed on fetal cells collected by chorionic villus sampling (CVS) or amniocentesis to determine if the fetus has Williams syndrome. Williams syndrome is not otherwise screened for in pregnancies with a low risk of Williams syndrome.

In the Media

The award-winning foreign language film, Gabrielle, depicts a young woman with Williams syndrome as she explores her independence and romantic interests.

Resources

Below are resources for information and support regarding Williams syndrome, understanding genetics in general as well as genetic counselling.

  • Williams Syndrome Association 570 Kirts Boulevard, Ste. 223
    Troy, MI 48084-4156
    USA
    Phone: 248-244-2229, 800-806-1871
    Email: info@williams-syndrome.org
    https://williams-syndrome.org
Williams Syndrome
https://ghr.nlm.nih.gov/williams-syndrome
  • Genetic Counselling
Find a Clinic - Canada
https://www.cagc-accg.ca/?page=225

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Morris, C.A. (1999) Williams Syndrome. [Updated 2013 Jun 13]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK1249/
  2. ↑ 2.0 2.1 2.2 Pober, B.R. (2010) Williams-Beuren syndrome. N Engl J Med, 362(3):239-252. http://www.ncbi.nlm.nih.gov/pubmed/20089974
  3. ↑ Strømme, P., Bjørnstad, P.G., & Ramstad, K. (2002) Prevalence estimation of Williams syndrome. J Child Neurol, 17(4):269-271. http://www.ncbi.nlm.nih.gov/pubmed/12088082
  4. ↑ Williams, J.C.P., Barratt-Boyes, B.G., & Lowe, J.B. (1961) Supravalvular aortic stenosis. Circulation, 24(6):1311-1318. http://www.ncbi.nlm.nih.gov/pubmed/14007182
  5. ↑ Beuren, A.J., Apitz, J., & Harmjanz, D. (1962) Supravalvular aortic stenosis in association with mental retardation and a certain facial appearance. Circulation, 26:1235-1240.http://www.ncbi.nlm.nih.gov/pubmed/13967885
  6. ↑ Lashkari, Ashkan; Smith, Andrew; Graham, John (May 1999). "Williams-Beuren Syndrome: An Update and Review for the Primary Physician". Clinical Pediatrics. 38: 189–257.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 Morris, C. A. (2013, June 13). Williams Syndrome. Retrieved January 23, 2017, from https://www.ncbi.nlm.nih.gov/books/NBK1249/
  8. ↑ Greer, M.K., Brown, F.R., Pai, G.S., Choudry, S.H., & Klein, A.J. (1997) Cognitive, adaptive, and behavioral characteristics of Williams syndrome. Am J Med Genet, 74:521-525. http://www.ncbi.nlm.nih.gov/pubmed/9342204
  9. ↑ Lense, Miriam D.; Shivers, Carolyn M.; Mykens, Elisabeth M. (2013). "(A)musicality in Williams syndrome: examining relationships among auditory perception, musical skill, and emotional responsiveness to music". Frontiers Psychology. 4: 525.
  10. ↑ Gothelf, D; Farber, N; Apter, A; Attias, J (2006). "Hyperacusis in Williams syndrome: characteristics and associated neuroaudiologic abnormalities". Neurology. 66 (3): 390–395.
  11. ↑ Axelsson, Stefan; Bjornland, Tore; Kjaer, Inger; Heiberg, Arvid; Storhaug, Kari (2003). "Dental characteristics in Williams syndrome: a clinical and radiographic evaluation". Acta Odontologica Scandinavica. 61 (3): 129–136.
  12. ↑ Ferreira, Shirlene-Bardbosa-Pimentel; Viana, Melissa-Machado; Maia, Naiara-Goncalves-Fonseca; Leao, Leticia-Lima; Machado, Renato-Assis; Coletta, Ricardo-Della; de Aguiar, Marcos-Jose-Burle; Martelli-Junior, Hercillio (2017). "Oral findings in Williams-Beuren syndrome". Med Oral Patol Oral Cir Bucal. 23 (1): e1–e6.
  13. ↑ Mason, Thorton B.A.; Arens, Raanan; Sharman, Jaclyn; Blintliff-Janisak, Brooke; Shultz, Brian; Walters, Arthur S.; Cater, Jacqueline R.; Kaplan, Paige; Pack, Allan I. (2011). "Sleep in children with Williams Syndrome". Sleep Medicine. 12 (9): 892–897.
  14. ↑ Gombos, F; Bodizs, R; Kovacs, I (2011). "Atypical sleep architecture and altered EEG spectra inWilliams syndrome". Journal of Intellectual Disability Research. 55: 255–262.
  15. ↑ Mervis, Carolyn B.; Velleman, Shelley L. (2011). "Children with Williams Syndrome: Language, Cognitive, and Behavioral Characteristics and their Implications for Intervention". Perspect Lang Learn Educ. 18 (3): 98–107.
  16. ↑ Krishnan, Saloni; Bergstrom, Lina; Alcock, Katherine J.; Dick, Frederic; Karmiloff-Smith, Annette (2015). "Williams syndrome: A surprising deficit in oromotor praxis in a population with proficient language production". Neuropsychologia. 67: 82–90.
  17. ↑ Kirchner, Rebecca M.; Martens, Marilee A.; Andridge, Rebecca r. (2016). "Adaptive Behavior and Development of Infants and Toddlers with Williams Syndrome". Frontiers in Psychology. 7: 598.
  18. ↑ 18.0 18.1 18.2 "Help Me Understand Genetics - Genetics Home Reference." U.S. National Library of Medicine. National Institutes of Health, n.d. Web. 12 Jan. 2017, https://ghr.nlm.nih.gov/primer#
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 Williams syndrome - Genetics Home Reference. (n.d.). Retrieved January 23, 2017, from https://ghr.nlm.nih.gov/condition/williams-syndrome
  20. ↑ Ewart, A.K., Morris, C.A., Atkinson, D., et al., (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet, 5(1):11-16.http://www.ncbi.nlm.nih.gov/pubmed/7693128
  21. ↑ 21.0 21.1 21.2 How A Genetic Counselor Could Help You or Your Family. (n.d.). Retrieved January 12, 2017, from http://www.nsgc.org/page/patients
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