Werner syndrome (WS), also known as adult-onset progeria, is a multiorgan autosomal recessive disease associated with premature aging of several organs, including the skin, cardiovascular system, and gonads, and increased malignancies, including several rare cancers. It often begins with the absence of a typical adolescence growth spurt. Mesenchymally derived malignancies are much more common than in the general population. Once there is a presumptive diagnosis, a specific gene defect in a helicase (WRN) can be determined. Always closely follow the patient for potentially life-threatening manifestations of the disorder. Median life span is 54 years. The disorder is not increased in those with genetic or acquired immunodeficiency.
The disease has autosomal recessive inheritance and is markedly increased in Japanese individuals, due to a founder mutation in that population, and in Sardinia. All races and ethnic groups are affected, and there is not a significant difference in incidence between sexes. The affected gene WRN is a helicase (RECQL2) involved with DNA replication, recombination, and repair. There are dozens of different causative mutations of WRN, often causing a truncated protein.
During childhood, the patient's voice may be high-pitched or hoarse, but except for familial cases, this diagnosis is rarely made before the third or fourth decade.
In the third decade (20s), graying of the hairs (often at the temples) may be the first sign, followed by generalized hair loss, localized hyperkeratosis over bony prominences, and soft tissue atrophy (on the extremities but not the trunk). Malignancies begin to occur.
In the fourth decade (30s), bilateral postcortical and subcapsular cataracts, testicular atrophy, early menopause, premature atherosclerosis, skin ulcers, and diabetes occur.
Malignancies begin to occur during the third decade and increase during the rest of the patient's life. Tumors in WS often occur at an earlier age than the same tumor in the general population. Frequent neoplasms, often of mesenchymal tissue origin, include thyroid carcinomas, various forms of melanoma (mucosal and acral lentiginous melanoma, more common in the Japanese population), meningiomas, soft tissue sarcoma, hematologic and lymphoid malignancies, and osteosarcomas. Cancer risk for most common malignancies is increased in WS.
Major (cardinal) signs include:
Bilateral cataracts
Short stature
Premature graying, thinning, and loss of hair
Skin changes including tight skin (sclerosis), atrophic skin, pigmentary changes, ulceration, hyperkeratosis, regional subcutaneous atrophy and sclerosis ("birdlike" facies)
Criteria for definite diagnosis include all major signs and 2 additional signs (eg, diabetes, hypogonadism, osteoporosis, premature atherosclerosis, neoplasms, high-pitched voice, and flat feet).
Codes
ICD10CM: E34.8 – Other specified endocrine disorders
SNOMEDCT: 51626007 – Werner syndrome
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Differential Diagnosis & Pitfalls
Progeria – Starts in the first decade, often the first years of life, and signs of premature aging are very prominent before the age of 10. Most patients have abnormal lamin genes.
Lamin heterozygous disease – Very similar to WS but starts in the early 20s and has an accelerated course. Patient usually does not have diabetes or bilateral cataracts.
Mandibuloacral dysplasia – No cataracts. Recessive. Starts in childhood.
Rothmund-Thomson disease – A defect in the RecQ helicase gene. Onset in childhood is contrasted with WS.
Diabetes – Sclerotic changes with mucopolysaccharide deposition.
