160: Werner Syndrome

Key Points

  • Disease summary:

    • Werner syndrome is an adult-onset genetic disorder characterized by features suggestive of accelerated aging (“segmental progeroid syndrome”) and cancer predisposition.

    • Individuals with Werner syndrome appear to develop normally during the first decade of life. The first sign often recognized retrospectively is the lack of a growth spurt during the early teen years.

    • Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness or high-pitched voice, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers (particularly of the ankles), and osteoporosis in the 30s.

    • Myocardial infarction and cancer are the most common causes of death, at about age 54 years.

  • Hereditary basis:

    • Werner syndrome is caused by mutations in the WRN gene. The WRN gene encodes a helicase that unwinds DNA. Werner syndrome is inherited in an autosomal recessive manner.

  • Differential diagnosis:

    • Atypical Werner syndrome refers to a small subset of individuals with a normal WRN gene sequence, normal WRN protein, and some signs and symptoms that sufficiently overlap with the Werner syndrome such that clinicians submit these cases to the International Registry. These individuals may give a history of comparatively early age of onset and a faster rate of progression than those with typical Werner syndrome. Among this group, 4 of 26 individuals so far investigated (15%) had novel heterozygous missense mutations in LMNA, which encodes the nuclear intermediate filament lamin A/C. These mutations are N-terminal to the canonical C-terminal mutations of the classical Hutchinson-Gilford progeria syndrome (HGPS) (see later).

    • Mandibuloacral dysplasia (MAD) is characterized by short stature; thin, hyperpigmented skin; partial alopecia, prominent eyes, beaked nose, tooth loss, small recessed chin, and short fingers. The Arg527His mutation in the C-terminal region of lamin A/C accounts for approximately 90% of the recessive MAD caused by LMNA mutations. A small subset of MAD is caused by mutations in the ZMPSTE24 gene, whose gene product is involved in the processing of lamin A.

    • The HGPS or progeria of childhood, like Werner syndrome, affects multiple organs with presentations suggestive of accelerated aging. Newborns with HGPS usually appear normal, but profound failure to thrive occurs during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the second to third year. Motor and mental development is normal. Individuals with HGPS develop severe atherosclerosis. Death usually occurs as a result of complications of cardiac or cerebrovascular disease generally between age 6 and 20 years. Average life span is approximately 13 years. About 90% of individuals with HGPS have the same p.Gly608Gly in exon 11 of the LMNA gene, a mutation that creates a cryptic splice site. Inheritance is autosomal dominant. All individuals with HGPS have a de novo mutation, although inheritance via a mosaic testicular mutation is a potential mechanism.

    • Early-onset type 2 diabetes with secondary complications of vascular disease and skin complications could mimic some features of Werner syndrome.

    • Though bilateral ocular cataracts (probably presenting as posterior subcapsular cataracts) are one of the most commonly observed features of Werner syndrome, the age of onset is typically in the second decade when graying of hair and skin findings would likely be present. Isolated juvenile cataracts are therefore not likely to be a feature of Werner syndrome. Myotonic dystrophy type 1 or myotonic dystrophy type 2 could be a consideration with young adult-onset cataracts; there may be muscle wasting, although other manifestations (myotonia, cardiac conduction abnormalities) are quite different and onset is usually in adulthood.

    • Scleroderma, mixed connective tissue disorders, and lipodystrophy may present skin features similar to those of Werner syndrome. Distal atrophy and skin ulcerations in the absence of other manifestations characteristic of Werner syndrome could raise the possibility of Charcot-Marie-Tooth disease or familial leg ulcers of juvenile onset.

    • Other cancer-prone syndromes, including Rothmund-Thomson syndrome (RTS), caused by mutations in a member of the same family of helicases, and Bloom syndrome, caused by mutations in a related helicase, (BLM) may be considered if cancer is the presenting symptom. However, RTS and Bloom syndrome are childhood-onset disorders. Werner syndrome cells do not exhibit the increased sister chromatid exchange typical of Bloom syndrome. Li-Fraumeni syndrome (caused by mutations in TP53) may present multiple cancers, including nonepithelial cancers similar to those observed in Werner syndrome, but juvenile-onset cataracts and other manifestations of Werner syndrome are not part of Li-Fraumeni syndrome.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for Werner Syndrome

  • Cardinal signs and symptoms (onset after age 10 years)

    • Bilateral cataracts

    • Characteristic skin (tight skin, atrophic skin, pigmentary alterations, ulceration, hyperkeratosis, regional subcutaneous atrophy)

    • Characteristic facies, described as “bird-like” (ie, the nasal bridge appears pinched and subcutaneous tissue is diminished)

    • Short stature

    • Premature graying and/or thinning of scalp hair

    • Parental consanguinity (third cousin or closer) or affected sibling

  • Further signs and symptoms

    • Type 2 diabetes mellitus

    • Hypogonadism (secondary sexual underdevelopment, diminished fertility, testicular or ovarian atrophy)

    • Osteoporosis

    • Radiographic evidence of osteosclerosis of distal phalanges of fingers and/or toes

    • Soft tissue calcification

    • Evidence of premature atherosclerosis (eg, history of myocardial infarction)

    • Neoplasms, especially mesenchymal (eg, meningiomas, sarcomas), rare neoplasms (eg, unusual sites of melanomas and osteosarcomas, and multiple neoplasms)

    • Abnormal voice (high pitched, squeaky, or hoarse)

    • Flat feet

The International Registry of Werner syndrome uses the above findings to establish a “definite,” “probable,” or “possible” diagnosis pending molecular genetic confirmation:

  • Definite diagnosis: all of the cardinal signs and two others

  • Probable diagnosis: the first three cardinal signs and any two others

  • Possible diagnosis: either cataracts or dermatologic alterations and any four others

  • Exclusion of the diagnosis: onset of cardinal signs and further symptoms before age 10 years, except for short stature, which is typically caused by lack of the usual adolescent growth spurt

Clinical Characteristics

Werner syndrome is characterized clinically by the premature appearance of some (but not all) features associated with normative aging, and cancer predisposition.

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Jun 2, 2016 | Posted by in HUMAN BIOLOGY & GENETICS | Comments Off on 160: Werner Syndrome

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