Werner Syndrome

Werner syndrome is a rare autosomal recessive progeroid disorder caused by biallelic variants in WRN, with premature ageing from the third decade, including cataracts, greying, skin atrophy, diabetes, atherosclerosis and unusual cancers. Median life expectancy is about 54 years, and death results from cancer or cardiovascular disease.

Pathophysiology. WRN encodes a RecQ helicase and exonuclease needed for DNA repair, replication and telomere maintenance. Loss of function causes genomic instability, telomere dysfunction and accelerated cellular ageing.

Growth is normal until puberty, when the expected growth spurt fails.

Cancer types include mesenchymal tumours, thyroid cancer, melanoma (including acral and mucosal forms) and myeloid neoplasms.

• Short stature and absent pubertal growth spurt
• Premature greying and hair loss
• Bilateral juvenile cataracts
• Thin atrophic skin of the limbs, with scleroderma like change, and chronic ulcers around the ankles and heels
• Beaked nose, bird like facies, and a hoarse high pitched voice
• Type 2 diabetes mellitus with insulin resistance, hypertriglyceridaemia, and fatty liver
• Osteoporosis, soft tissue calcification, and early atherosclerosis
• Hypogonadism with reduced fertility
• Cancers: osteosarcoma and soft tissue sarcoma, thyroid cancer, acral lentiginous melanoma, meningioma, myelodysplastic syndrome

• Clinical diagnosis: cataracts, characteristic skin changes, short stature, premature greying and hair loss, and typical facies, in a person of 20 to 40 years.
• Genetic testing of WRN with deletion and duplication analysis.
• Metabolic and cardiovascular assessment: fasting glucose or HbA1c, lipids, liver ultrasound, carotid imaging and coronary risk assessment.
• Endocrine and bone assessment: gonadal function, DXA scan.
• Cancer assessment: thyroid ultrasound, skin examination, and imaging as symptoms dictate.
• Eye examination for cataracts and glaucoma.

• Cardiovascular risk control: high intensity statin such as atorvastatin 20 to 40 mg orally once daily, blood pressure control (target under 130/80 mmHg), antiplatelet therapy for established disease, and smoking cessation.
• Diabetes: pioglitazone 15 to 45 mg orally once daily is useful for insulin resistance. Metformin 500 mg increasing to 1000 mg twice daily (maximum 2000 mg daily, reduced at eGFR under 45 mL/min) is an alternative. Monitor for heart failure and fractures with pioglitazone.
• Skin ulcers: offloading, moist wound dressings, treatment of infection, and vascular assessment. Surgical grafting is tried in refractory ulcers.
• Cataract surgery when vision is impaired, usually in the third decade.
• Bone health: calcium 1000 mg and vitamin D 800 to 1000 units daily, with a bisphosphonate (alendronic acid 70 mg weekly) for osteoporosis.
• Cancer surveillance: yearly thyroid ultrasound and skin check, targeted imaging for pain or masses, and prompt biopsy. Sarcomas and melanomas need specialist oncology care.
• Endocrine care: sex hormone replacement for hypogonadism.
• Genetic counselling: each sibling has a 25% chance of being affected, and consanguinity is common.

Special groups.

• Patients with ankle ulcers: consider osteomyelitis and arterial disease before attributing to venous causes.

Monitoring. Clinical review every 6 months. Glucose or HbA1c, lipids and liver tests every 3 to 6 months. Annual eye, thyroid, skin and bone assessment.

Referral and escalation. Refer to clinical genetics, endocrinology, cardiology and oncology. Urgent for chest pain, a limb mass, a changing pigmented lesion on the palms, soles or nails, or a non-healing ulcer with infection.