Werner's Syndrome

Synonyms: Adult premature aging syndrome, adult progeria.

Werner's syndrome (WS) is an extremely rare, autosomal recessive, systemic disease which is associated with features of premature aging and cancer predisposition. The syndrome is named after C.W. Otto Werner, a German physician (1879-1936).

Interest in WS is fuelled in part by the observation that transcription aberrations in WS are similar to those found in normal aging.¹ In WS, the gene defect is known to affect WRN (found on chromosome 8) encoding Werner protein, a nuclear protein with helicase and exonuclease activity important in maintaining and repairing DNA, particularly where double strand breaks occur.^2,3 WRN gene mutations encode an abnormally shortened Werner protein.
More than 50 different disease-causing mutations in the WRN gene have been identified in WS patients.

• It is extremely rare, with only approximately 1300 cases reported worldwide since 1916, with 1000 of those coming from Japan.⁴
• A prevalence of 1/200,000 US population is contrasted with 1/20-40,000 Japanese population (i.e. 10-20x more common).
• In Japan, the frequency of heterozygote carriers of the condition within the general population is estimated as 1/180.³

• Typically individuals grow normally until puberty.
• The first symptom is the lack of a teen growth spurt.
• Early findings (observed in the 20s) are loss and graying of hair, hoarseness and scleroderma-like skin changes.
• This is followed (typically in the 30s) by bilateral cataracts, type 2 diabetes mellitus, hypogonadism, refractory skin ulcers and osteoporosis.
• Most will present to dermatologists or ophthalmologists in the first instance.

Further signs and symptoms

• Type 2 Diabetes mellitus
• Hypogonadism and decreased fertility
• Osteoporosis
• Osteosclerosis of distal phalanges of fingers and/or toes
• Soft tissue calcification
• Premature arteriosclerosis
• Neoplasms: mesenchymal (sarcomas), unusual or multiple types or sites
• High-pitched, squeaky or hoarse voice
• Flat feet

• Atypical Werner syndrome - small subset with normal WRN protein. Earlier age of onset and faster progression compared to classic WS.
• Hutchinson-Gilford progeria syndrome most closely resembles WS. Neonates with NS appear normal but fail to thrive during first year with connective tissue abnormalities becoming apparent in the second and third year, with death usual between 6-20 years.
• Early onset type 2 diabetes mellitus with secondary vascular and skin complications.
• Myotonic dystrophy - in view of the young adult onset cataracts but other features are different and onset is usually in adulthood.
• Scleroderma, mixed connective tissue disorders, lipodystrophy and Charcot-Marie-Tooth have some skin features similar to WS.

• Urinary and serum hyaluronic acid is increased in most individuals.
• Sequence analysis of the WRN coding region detects mutations in both alleles for approximately 90%.
• Western blot - usually absent Werner protein.

WS is associated with several diseases of old age including:

• Myocardial infarction
• Cancers - x10 risk of epithelial cancers and mesenchymal sarcomas compared to general population⁴
• Cerebral infarction
• Diabetes mellitus
• Hyperuricaemia
• Osteoporosis

• Early recognition of the syndrome is helpful, as screening for malignancies and associated diseases such as diabetes may then be performed on a regular basis.
• There is no specific treatment available for Werner's syndrome, although surgical intervention and hyperbaric oxygen therapy may be of use in the treatment of refractory skin ulcers.
• Specific surgical procedures may be required to treat complications such as cataracts and contractures.
• Treatment of diabetes - glitazones thought to be particularly effective.⁷
• Standard treatments for malignancies and ischaemic heart disease.
• Genetic counselling for individual and family:
  • Obligate carrier status of all affected individual's children. Fertility is much reduced but there are recorded instances of individuals of both sexes having children.
  • For siblings of an affected individual, there is a 1 in 4 risk of having the disease and a 1 in 2 risk of carrier status as sibling.
• Relatives of affected individuals should have increased cancer surveillance.³

The life span of individuals with Werner's syndrome is reduced, with death occurring on average in the mid 40s, most commonly as a result of malignancy or myocardial infarction.⁴

Pre-natal screening may be available to parents who are considered at high risk of having an affected child.