Werner syndrome (ORPHA:902)
Werner syndrome (WS) is a rare inherited syndrome characterized by premature aging with onset in the third decade of life and with cardinal clinical features including bilateral cataracts, short stature, graying and thinning of scalp hair, characteristic skin disorders and premature onset of additional age-related disorders.
Epidemiology
The prevalence among Japanese and Sardinian populations is estimated to be 1/50,000 due to the presence of founder mutations. Prevalence in other populations is unknown, but may be around 1/200,000.
Clinical description
WS patients are normal at birth and during childhood, apart from the absence of a pubertal growth spurt. WS presents between the ages of 20 and 30 with major symptoms of early onset bilateral cataracts, thinning and graying of the hair, short stature and skin changes (ankle ulceration, hyperkeratosis, tight skin, age spots, ''bird-like'' facies and subcutaneous atrophy). In most cases, additional age-related disorders are seen and include osteoporosis, diabetes mellitus, mesenchymal neoplasms and atherosclerosis. Voice changes are frequent and flat feet are sometimes present. Patients with WS have a high risk of developing cancer, in particular sarcomas of mesenchymal origin and melanomas that are not due to sun exposure. Death is usually due to malignancies or myocardial infarction caused by extensive atherosclerosis.
Etiology
WS is caused by a mutation in the WRN gene, located on chromosome 8p11-12. WRN codes for one of the five RecQ helicases in humans. Nonsense mutations, insertions and/or deletions or substitutions in the WRN gene all lead to genome instability. Mutations in the WRN gene are found in approximately 90% of clinically diagnosed WS cases. The other 10% are operationally categorized as atypical Werner syndrome (see this term) and are due to other causes (such as a mutation in the LMNA gene).
Diagnostic methods
A clinical diagnosis is based on the presence of all major symptoms (cataracts, skin changes, premature graying/thinning of hair and short stature) and two additional signs (such as osteoporosis or voice change) presenting after adolescence. Molecular analysis can identify most of the mutations in the WRN gene by standard exon sequencing and sequencing of RT-PCR products, in combination with Western blot analysis showing the absence of normal WRN protein.
Differential diagnosis
Differential diagnoses include mandibuloacral dysplasia (MAD), partial lipodystrophy, Rothmund-Thomson syndrome (RTS) and Hutchinson-Gilford progeria syndrome (HGPS; see these terms). Type 2 diabetes mellitus can also share similarities with WS.
Genetic counseling
WS is inherited in an autosomal recessive manner. Once a patient is diagnosed with WS, the patient and family should receive genetic counseling in order to identify those that could develop the disease and those who are carriers. Offspring of a patient with WS are obligate carriers, but unlikely to be affected, given the low likelihood of marrying a carrier unless there is consanguinity.
Management and treatment
There is no cure for WS and treatment involves a multidisciplinary team. Cataracts can be treated with surgery. Regular physical examinations are needed to check for skin ulcers, diabetes, malignancies or cardiovascular disease. Any malignancies should be treated with surgery, chemotherapy and/or radiation. Smoking should be avoided and a healthy lifestyle, including regular exercise and a diet low in fat, should be followed. Psychological counseling may also be beneficial in supporting patients and family members affected by WS.
Prognosis
Patients with WS have a shortened life expectancy but prognosis depends on the age-related diseases present and their severity.

                            Last update: 
                            April 2012


                            - Expert reviewer(s): 
                            Dr Fuki HISAMA  - Dr George MARTIN  - Dr Junko OSHIMA