Syndrome de Werner

Synonyms: adult premature ageing syndrome, adult progeria

What is Werner's syndrome?

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).

Pathogenèse

Interest in Werner's syndrome (WS) is fuelled in part by the observation that transcription aberrations in WS are similar to those found in normal ageing.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.

How common is Werner's syndrome? (Epidemiology)

• It is extremely rare, with only approximately 1,300 cases reported worldwide since 1916, with 1,000 of those coming from Japan.⁴

• A prevalence of 1/200,000 US population is contrasted with 1/20-40,000 Japanese population (ie 10-20 x more common).

• In Japan the frequency of heterozygote carriers of the condition within the general population is estimated as 1/180.³

Symptoms of Werner's syndrome (presentation)

• Typically, individuals grow normally until puberty.⁵

• The first symptom is the lack of a teen growth spurt.

• Early findings (observed in the 20s) are loss and greying of hair, hoarseness and sclérodermie-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.

Typical signs and symptoms

Suggested diagnostic criteria:⁶

• Bilateral cataracts.

• Characteristic skin: tight, atrophic, pigmentary changes, ulceration, hyperkeratosis.

• 'Bird-like' facies.

• Petite taille.

• Premature greying and/or balding.

Autres signes et symptômes

• Type 2 diabetes mellitus.

• Hypogonadism and decreased fertility.

• Ostéoporose.

• 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.

Diagnostic différentiel⁷

• Atypical Werner's syndrome (WS) - small subset with normal WRN protein. Earlier age of onset and faster progression compared with classic WS.

• Hutchinson-Gilford progeria syndrome most closely resembles WS. Neonates with WS appear normal but fail to thrive during their first year, with connective tissue abnormalities becoming apparent in the second and third year, and 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 et Syndrome de Charcot-Marie-Tooth have some skin features similar to WS.

Diagnosing Werner's syndrome (investigations)⁷

• 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.

Maladies associées

Werner's syndrome (WS) is associated with several diseases of old age including:

• Infarctus du myocarde.

• Cancers - x 10 risk of epithelial cancers and mesenchymal sarcomas compared with the general population.⁴

• Cerebral infarction.

• Diabète sucré.

• Hyperuricémie.

• Osteoporosis.

Management of Werner's syndrome

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 (WS), although surgical intervention and hyperbaric oxygen therapy may be of use in the treatment of refractory skin ulcers.⁵

Médical

• Treatment of diabetes - glitazones are thought to be particularly effective.⁸

• Cholesterol lowering where lipid profile is abnormal.⁹

• Standard treatments for malignancies and ischaemic heart disease.

• Preliminary mouse studies suggest vitamin C supplementation may be beneficial.¹⁰

• New studies have demonstrated involvement of particular genes and considered activation of P13K/AKT activation to improve the possible future benefits of stem cell based therapy. ¹¹

Chirurgical

• Specific surgical procedures may be required to treat complications such as cataracts and contractures.

Conseil génétique

Fertility is much reduced but there are recorded instances of individuals of both sexes having children.

• Obligate carrier status of all affected individual's 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 a sibling.

• Relatives of affected individuals should have increased cancer surveillance.³

Pronostic

The life span of individuals with Werner's syndrome (WS) is reduced. Death previously occurred on average in the mid-40s, commonly as a result of malignancy or myocardial infarction.⁴

However, recent studies suggest an increase in the average age of death to the late 50s with fewer dying from vascular events. ¹²

Prevention of Werner's syndrome

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