Werner Syndrome (WS) is a rare genetic condition. The main feature of WS is the appearance of premature aging.^[1] People with this condition usually develop normally until puberty, where they may start showing signs of aging and develop “old age” related features. The average age for diagnosis is about 24 years old as the lack of growth spurt is recognized.^[2] People with this condition usually live into their forties to mid-fifties, with the cause of death most commonly being either a heart attack or cancer.^[1]^[3]

Characteristics

The characteristics of WS are split into two categories. Cardinal signs are those that are seen in all cases of WS, and additional signs are those that may or may not occur, depending on how severe it is in a specific person.^[4] Not all individuals with WS will develop all of these signs.

Cardinal Signs

Cataracts in both eyes
Early greying and thinning of the scalp hair
Skin changes, such as tightening or development of ulcers
Short height

Additional Signs

Thin arms and legs
Brittle bones that are prone to breaking (Osteoporosis)
Changes in the voice
Small penis/testicles or ovaries (Hypogonadism)
Type 2 diabetes
Calcium build ups in the soft tissue
Specific types of cancer (Neoplasms)
Hardening of the arteries (Atherosclerosis)

Diagnosis

An individual has a definite diagnosis of Werner Syndrome if they have all four cardinal signs and at least two additional signs.^[4] An individual has a probable diagnosis of Werner Syndrome if they have three cardinal signs and at least two additional signs.^[4] A diagnosis can also be made or clarified through genetic testing of the WRN gene.^[4] If mutations are found in both WRN genes, a person will be diagnosed with WS regardless of how many cardinal and additional signs they show.

Treatment

There are currently no treatments for WS, although it is possible to treat some of the associated conditions.^[1] Individuals with WS should undergo regular screening and follow-up by the appropriate physicians to look for any development of diabetes, cataracts, cancers, and/or heart problems. Someone who is affected with WS would be treated accordingly depending on which signs and symptoms they specifically had.^[4]

Medication may be prescribed to help control cholesterol levels to prevent the hardening of arteries (atherosclerosis). There are also lifestyle changes such as regular exercise, weight control, and smoking avoidance that can reduce the risk of atherosclerosis.^[5]

Cataracts can lead to complete loss of vision and can be treated surgically by a specialized eye doctor. There are topical treatments that can be used to treat skin ulcers. People who develop type 2 diabetes, brittle bones (osteoporosis), or cancer would be treated similarly to other people who would develop these conditions that don't also have WS.

Incidence

This condition is very rare and is found in about 1/200 000 people.^[3]

Some conditions are found more often within certain ethnic groups. Werner syndrome is more common in Japanese and Sardinian populations, and is found in about 1/50 000 people from these specific areas.^[3] Werner syndrome is a condition that affects both females and males equally.

Genetics and Inheritance

Background

There are about 25 000 genes in the human body. Genes are a string of letters made from DNA and they provide instructions for proteins. Proteins are used by the body to grow, develop and function normally.

If there is an error in the DNA code, known as a mutation, then the protein that is made from those instructions may not be able to be formed or may not work as well as it should. Depending on what the function of the protein is, a missing or non-working protein may cause issues and may lead to someone developing a genetic condition.

All of our genes come in pairs and we get one gene from each pair from each of our parents.

Genetics of Werner Syndrome

Autosomal recessive pattern of inheritance

Werner syndrome is caused by mutations in the WRN gene.^[1] When the WRN protein is functioning normally, it is thought to help fix damaged DNA. ^[3]

This condition is inherited in an autosomal recessive pattern. This means that a person must inherit two mutated copies of the WRN gene (one from each parent) in order to have WS.^[1] A person may get two of the same mutation (homozygous) or two different mutations (compound heterozygous), and in either situation it would cause WS to develop. In 90% of individuals affected with WS, a mutation can be found in the WRN gene.^[3]

A person with a mutation in only one copy of the WRN gene is called a carrier. Carriers usually do not show any symptoms and are not expected to develop WS as they still have one "working copy" of the WRN gene. The siblings of a carrier have a 50% chance of also being a carrier.

When both parents are carriers for a WRN gene mutation, there are the following possible outcomes:

25% chance of having an affected child
50% chance of having a child that is an asymptomatic carrier
25% chance of having an unaffected child

A carrier child will have the same possible outcomes when they go to have children of their own. An unaffected child has two "working copies" of the WRN gene and therefore will not be at risk of passing on any mutations to their own children.

Genetic Counselling

If you or someone in your family is affected with Werner Syndrome, you may want to speak with your doctor for a referral to your local genetics clinic where you would meet with a genetic counsellor or a geneticist. Meeting with a genetic specialized health care provider can help you better understand how this condition runs in families and help facilitate genetic testing, if it is applicable for your family.

Genetic Testing

If you or a family member are affected with Werner Syndrome, you may wish to meet with a genetic counsellor to try to identify the exact genetic cause of the condition. A genetic test can be done to look at the WRN gene to determine if there is any mutation, and if so, what kind of mutation is present. This information may be useful for you to know for your own family planning purposes and may also be helpful for other family members to figure out if their risks of having WS or having children with WS. Genetic testing is usually done through a blood draw. There are a variety of pros and cons for genetic testing, and they should be thoroughly explored with a genetic counsellor before genetic testing is done.

Prenatal Genetic Testing

If both parents are carriers of the mutated WRN gene, they are at risk of having a child who may be affected. During pregnancy, carrier parents may choose to have prenatal genetic testing done. Genetic testing during pregnancy will inform parents if their child will be affected and have WS. A GC can explain to the parents the prenatal genetic testing options that are available. They will outline to parents when testing is done and what are the potential risks to the pregnancy.

DNA from placenta or amniotic fluid is needed for testing. The placenta is an organ that forms during pregnancy that helps connect baby to uterus. The amniotic fluid is liquid that surrounds the baby during pregnancy.

There are two different ways to collect this DNA:

Chorionic Villus Sampling (CVS)
- Needle is carefully used to take a piece of tissue from the placenta
- Test is done between 11 to 13 weeks during a person's pregnancy
- There is a 1% chance of having a miscarriage because of CVS
Amniocentesis
- Needle is carefully used to take some amniotic fluid
- Test is done starting at 15 weeks during pregnancy
- There is a 0.5% chance of having a miscarriage because of Amniocentesis

When prenatal genetic testing is done, a GC will explain the test results to the parents. If results show that their child will be affected, parents may need to decide if they want to keep or end their pregnancy. This decision may not be easy for parents to make. As a result, the GC will provide more information and resources to the parents that may help them decide. A GC will provide emotional support throughout the decision-making process.

If parents choose to keep the pregnancy, parents might have the following questions:

What will my child's life look like with WS?
What resources are available for people with WS?
What can I do to prepare or plan for my child's life?

If parents choose to end the pregnancy, parents may want more information on this process.

GCs are prepared to discuss all the possible options with parents. GCs will listen to the thoughts and feelings of the parents as they make their decision.

IVF

Individuals with WS may benefit from having a consultation with a fertility clinic.There is a quick decline in fertility in individuals with WS for both genders, but there have been reports of successful pregnancies. Females with WS who are pregnant, or are planning a pregnancy, should be followed by a obstetrician as there is a risk of pre-term delivery and complications during pregnancy.^[3]

Additional Resources

If you wanted to get some more information here are some more resources about Werner Syndrome and genetics. Please note that these resources are just for your reference and are not a substitute for medical advice. There is no guarantee that the information in these resources is completely accurate and up to date. If you have any questions or health concerns, please talk to your doctor.

Genetics Home Reference: Werner Syndrome

International Registry of Werner Syndrome

Understanding Genetics

Video on Autosomal Recessive Inheritence

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 Yokote., K., Chanprasert, S., Lee, L., Eirich, K., Takemoto, M., Watanabe, A., ... Oshima, J. (2016). WRN Mutation Update: Mutation spectrum, patient registries and translational prospects. Human Mutation. 38(1): 7-15.
↑ Epstein CJ, Martin GM, Schultz AL, Motulsky AG (1966). "Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process". Medicine (Baltimore). 45 (3): 177–221.
↑ ^3.0 ^3.1 ^3.2 ^3.3 ^3.4 ^3.5 Oshima, J., Martin, G., Hisama, F. GeneReviews: Werner Syndrome. Last Updated: September 29, 2016. Last Accessed: January 12, 2017. https://www.ncbi.nlm.nih.gov/books/NBK1514/
↑ ^4.0 ^4.1 ^4.2 ^4.3 ^4.4 Huang, S., Lee, L., Hanson, NB., Lenaerts, C., Hoehn, H., Poot, M., ... Oshima, J. (2006). The spectrum of WRN mutations in Werner syndrome patients. Human Mutation. 27(6): 558-567.
↑ Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet. 2008;124(4):369–377. doi:10.1007/s00439-008-0562-0

[Spectrum-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 Yokote., K., Chanprasert, S., Lee, L., Eirich, K., Takemoto, M., Watanabe, A., ... Oshima, J. (2016). WRN Mutation Update: Mutation spectrum, patient registries and translational prospects. Human Mutation. 38(1): 7-15.

[2] Epstein CJ, Martin GM, Schultz AL, Motulsky AG (1966). "Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process". Medicine (Baltimore). 45 (3): 177–221.

[GeneReview-3] 3.0 ^3.1 ^3.2 ^3.3 ^3.4 ^3.5 Oshima, J., Martin, G., Hisama, F. GeneReviews: Werner Syndrome. Last Updated: September 29, 2016. Last Accessed: January 12, 2017. https://www.ncbi.nlm.nih.gov/books/NBK1514/

[Huang-4] 4.0 ^4.1 ^4.2 ^4.3 ^4.4 Huang, S., Lee, L., Hanson, NB., Lenaerts, C., Hoehn, H., Poot, M., ... Oshima, J. (2006). The spectrum of WRN mutations in Werner syndrome patients. Human Mutation. 27(6): 558-567.

[5] Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet. 2008;124(4):369–377. doi:10.1007/s00439-008-0562-0

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