Werner syndrome
WS; "adult progeria"; progeria of the adult; one of the RecQ-helicase / "premature ageing" / cancer-predisposition disorders alongside Bloom and Rothmund-Thomson
Werner syndrome is a rare autosomal recessive RecQ-helicase deficiency syndrome — a sister disorder to Bloom syndrome and Rothmund-Thomson syndrome. Caused by biallelic loss-of-function mutations of the WRN gene encoding the WRN (RecQL2) helicase, the syndrome produces a striking adult-onset "premature ageing" (segmental progeria) phenotype — with onset in the teens or twenties, patients develop greying / loss of hair, scleroderma-like skin atrophy, bilateral cataracts, type 2 diabetes, atherosclerosis, hypogonadism, osteoporosis, recalcitrant lower-limb ulceration and an elevated lifetime risk of soft-tissue sarcoma, melanoma, thyroid carcinoma, meningioma and haematological malignancy. The disease is over-represented in Japanese populations (~1 in 100,000) due to founder mutations. Recognition by the dermatologist of the scleroderma-like skin and chronic lower-limb ulceration in a young adult with cataracts and short stature is frequently the diagnostic clue.
Genetics
- Biallelic loss-of-function mutations of WRN on chromosome 8p12 — encodes the WRN (RecQL2) helicase, a member of the RecQ family essential for DNA replication, repair, telomere maintenance and resolution of stalled replication forks.
- Autosomal recessive.
- Founder mutations — over-represented in Japanese populations (~1 in 100,000) and Sardinian populations.
- Some milder "atypical Werner syndrome" patients harbour mutations in LMNA (lamin A/C) — overlapping with Hutchinson-Gilford progeria.
- Diagnosis confirmed by germline WRN sequencing.
Cardinal clinical features
- Cardinal triad / pentad:
- Bilateral juvenile cataracts — usually presenting feature; develop in the second / third decade.
- Scleroderma-like skin changes — taut, atrophic, indurated skin particularly over the face, hands and feet; "bird-like" facial appearance.
- Premature greying / hair loss from teens.
- Short stature.
- Hoarse / high-pitched voice.
- Cutaneous:
- Pigmented patches (leopard-skin appearance) on the face and limbs.
- Recalcitrant non-healing leg ulcers, especially around the ankles and Achilles tendon.
- Soft-tissue calcification.
- Endocrine — type 2 diabetes (~70%), hypogonadism, osteoporosis.
- Cardiovascular — premature atherosclerosis, ischaemic heart disease — leading cause of mortality.
- Reproductive — infertility / subfertility.
- Cancer — see next section.
- Median life expectancy ~50–60 years; mortality from atherosclerotic cardiovascular disease and malignancy.
Cancer risk
- Lifetime cancer risk substantially elevated; cancers tend to develop a decade or more earlier than sporadic equivalents.
- Soft-tissue sarcoma — strikingly over-represented; soft-tissue sarcomas, osteosarcoma; sometimes multifocal.
- Cutaneous melanoma — particularly of unusual sites (acral / mucosal melanoma over-represented).
- Thyroid carcinoma — particularly follicular thyroid carcinoma.
- Meningioma.
- Haematological malignancy — myelodysplastic syndrome, AML.
- Other — gastric, colorectal, breast, hepatocellular carcinoma.
- Multiple primaries common.
Surveillance & management
- Multidisciplinary care — dermatology, ophthalmology, endocrinology, cardiology, oncology, clinical genetics; lifelong.
- Skin — annual full-skin examination; lifelong photoprotection; lower threshold for biopsy of any new or changing lesion (especially acral / mucosal sites for melanoma, soft-tissue lump for sarcoma).
- Eye — annual ophthalmology review; cataract surgery as needed.
- Cardiovascular — annual blood pressure, lipids; aggressive primary prevention with statins, antihypertensives.
- Diabetes — annual screening from second decade.
- Cancer surveillance — clinical examination for soft-tissue lump; thyroid examination; consider whole-body MRI in selected centres (no consensus); biopsy of any change.
- Wound care — multidisciplinary management of recalcitrant lower-limb ulcers (vascular surgery, wound nurse, plastic surgery for grafting / flaps).
- Genetic counselling and cascade testing.
- Cancer treatment — markedly enhanced normal-tissue radiosensitivity / chemotherapy toxicity due to defective DNA repair; reduced doses with specialist input.
References
- Oshima J et al. Werner syndrome — clinical features, pathogenesis and potential therapies. Ageing Res Rev; 2017.
- Goto M et al. Werner syndrome — a changing pattern of clinical manifestations in Japan. Biosci Trends; 2013.
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