Werner Syndrome
Werner syndrome (ORPHA:902; MIM #277700) is a rare genetic disorder characterized by premature signs of normal aging (also defined as “progeria”) and tumour predisposition. Typical signs of aging usually appear in adolescence or early adulthood and include short stature, premature greying and thinning of hair, characteristic skin changes which are reminiscent of those seen in the rheumatic disorder scleroderma, and bilateral cataracts (clouding of the lens in the eye). Frequent complications are osteoporosis, type 2 diabetes and an early decline in fertility, and there is also an increased risk of developing atherosclerosis and subsequent myocardial infarction. Chronic skin ulcers around the ankles are typical of the disease. Patients can also present with typical facial features, which are sometimes described as pinched and a high-pitched voice.
Patients with Werner syndrome are at increased risk of certain cancers, including sarcomas, melanomas, leukaemias, and thyroid carcinomas, but other cancers have also been described. Cardiovascular disease and cancer are the leading causes of death in these patients.
Although some studies suggest it is underdiagnosed, Werner syndrome is rare globally, but is more common in some regions, such as Japan, where it affects 1 in 20,000 to 1 in 40,000 individuals, and in Sardinia, with an estimated frequency of 1 in 50,000 individuals.
Werner syndrome is caused by pathogenic variants in the WRN gene, which codes for a protein called WRN helicase, a protein that has several different functions: it can unwind and digest abnormal DNA structures, and is involved in DNA repair, replication and transcription. In general, the protein appears to be important for maintaining genome stability.
Werner syndrome is inherited in an autosomal recessive manner. Affected patients carry a pathogenic variant in both copies of the WRN gene, which they typically inherited from their parents. The parents are usually healthy carriers of the disease, with one normal and one affected copy of the WRN gene. If both parents are carriers, they have a 25% chance of having a child with Werner syndrome in each pregnancy.
As carriers of WRN pathogenic variants are rare in most populations, a patient with Werner syndrome is unlikely to have a child with the same diagnosis, unless there is consanguinity with the partner.
Patients with Werner syndrome who are planning to start a family can be referred for preconception genetic counselling. If the causative WRN variants are known, they can opt for prenatal or preimplantation genetic testing.
To date, there are no official guidelines for clinical management of patients with Werner syndrome, and all recommendations are based on expert opinion.
Patients are advised to undergo yearly eye and skin examinations, and monitoring for diabetes, high blood pressure, osteoporosis and signs and symptoms of various malignancies. Surveillance and treatment should involve a multidisciplinary team and psychosocial support should also be provided. It is advisable to avoid smoking, alcohol and excessive sun exposure and prevent any trauma (such as falls) and/or formation of skin ulcers.
More information regarding Werner Syndrome can be found on:
GeneReviews® - Werner Syndrome
Orphanet: Werner Syndrome
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A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.