This is a rare autosomal recessive disorder with a reported prevalence that varies from 1 in 105 in Japan to 1 in 106–107 outside of Japan. There also appears to be an increased incidence in Sardinia. Werner syndrome (WS) is characterized by features of premature senescence and short stature with loss of subcutaneous fat and muscle, stocky trunk and slender limbs, a thin face with beaked nose, and a high-pitched and hoarse voice. The clinical features of senescence develop from the second decade, with premature greying of the hair from the third decade, generalized hair loss, juvenile cataracts from the third decade, premature arteriosclerosis and calcification of blood vessels with coronary heart disease, osteoporosis, metastatic calcification, and scleropoikiloderma of the skin giving an aged appearance. Diabetes mellitus and hypogonadism may be associated. There may be osteoporosis with ankylosis and destruction of joints and muscle atrophy, and hyperkeratosis over bony prominences and on the soles of the feet, which may ulcerate.
There may be areas of hyperpigmentation and hypopigmentation of the skin, with lentigines. The clinical diagnosis is based on the presence of four cardinal signs which are found in more than 95 % of cases. These are cataracts, characteristic skin changes (scleropoikiloderma), short stature, and greying or loss of hair. If all the cardinal signs are present after the age of 10, and two additional signs from the above list (e.g., diabetes, atherosclerosis) are present, then the diagnosis is made clinically. Mutation analysis of WRN is used to confirm the clinical diagnosis (Coppede 2012).
About 10 % of affected individuals develop Tumours, predominantly of types uncommon in the general population, notably of connective tissue or mesenchymal origin, such as soft tissue sarcomas, osteosarcomas, uterine myosarcomas, meningiomas, and adenomas of the thyroid, parathyroid, adrenal cortex, breast, and liver (Epstein et al. 1966; Goto et al. 1996).
Thyroid carcinomas and melanomas have been reported more frequently in Japanese than in Caucasian WS patients. Most WS patients die of atherosclerosis or cancer during the fourth decade of life. Cultured cells from WS patients show chromosome instability and hypersensitivity to DNA cross-linking agents (Moser et al. 2000).
WS is caused by loss-of-function mutations in a gene (WRN, RECQL2) at chromosome 8p12 that encodes a protein, WRN, which is a member of the RECQ DNA helicase family (Yu et al. 1996; Nishijo et al. 2004). In culture, cells from WS patients show increased chromosomal aberrations, premature senescence, and telomere shortening. Defects in DNA replication are observed. Most mutations result in absence of the WRN protein, although some deleterious missense mutations have been reported (Coppede 2012). Chen et al. (2003) found that 20 % of patients referred to an international registry for molecular diagnosis of Werner syndrome had wild-type WRN mutation analysis. Sequence analysis of the LMNA gene (which is mutated in a rare childhood syndrome of premature aging, Hutchinson–Gilford syndrome, and other disorders) in this subset revealed a heterozygous LMNA missense mutation in 15 % of cases. This atypical form of WS typically has an earlier onset of aging phenotypes than RECQL2-associated classical WS cases but lacks cataracts and diabetes.
Experiments in mice suggest that the short stature seen in WS and related progeroid conditions is a result of suppression of the somatotropic axis in response to excessive DNA damage – the so-called survival response. It seems likely that genome maintenance, premature aging, and predisposition to cancer are tightly linked (Hoeijmakers 2009).