Wiedemann-Steiner Syndrome

Wiedemann-Steiner syndrome is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in KMT2A (11q23.3), with hypertrichosis cubiti (hairy elbows), short stature, intellectual disability, hypotonia and characteristic facies. Variants are usually de novo.

Pathophysiology. KMT2A encodes a histone methyltransferase that trimethylates histone H3 lysine 4 and regulates gene expression, including HOX genes. Haploinsufficiency disrupts chromatin regulation in many tissues.

KMT2A is also rearranged in some leukaemias, but germline loss-of-function variants do not cause the same malignancy.

Phenotype varies, with some patients showing mild intellectual disability.

• Hypertrichosis cubiti: excess hair on the elbows, especially in childhood
• Short stature, growth delay
• Developmental delay, intellectual disability, speech delay
• Hypotonia and joint laxity
• Facies: thick arched eyebrows with lateral flare, long eyelashes, wide nasal bridge, downslanting palpebral fissures, ptosis
• Behaviour: autism features, anxiety, ADHD, aggression
• Feeding difficulty, constipation and reflux
• Cryptorchidism, cardiac defects, renal anomalies
• Dental problems and vision problems (strabismus, refractive error)
• Seizures in a minority

• KMT2A sequencing with deletion and duplication analysis, or exome sequencing.
• Clinical assessment: hairy elbows, facial features and growth chart.
• Echocardiography and renal ultrasound.
• Vision, hearing and dental assessment.
• Growth evaluation: bone age and endocrine tests if growth is very poor.
• Developmental and behavioural assessment.
• Parental testing to confirm de novo origin.

• Development and communication: early intervention, speech therapy, occupational therapy and an educational support plan.
• Behaviour and mental health: behavioural therapy, methylphenidate 5 mg orally once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily (after cardiac review), and sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for anxiety.
• Growth: monitor height; growth hormone 0.033 mg/kg subcutaneously daily has been tried in short stature with variable response and is a specialist decision.
• Feeding and gastrointestinal care: feeding therapy, macrogol 0.4 to 0.8 g/kg daily (adults 1 to 3 sachets), and omeprazole 0.7 to 1 mg/kg daily for reflux.
• Cardiac and renal care: treat structural defects, and orchidopexy for cryptorchidism.
• Vision and hearing: spectacles, strabismus treatment, and audiology review yearly.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Dental care: regular dental review.
• Genetic counselling: de novo variants carry a low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue mental health and behavioural support, and review for scoliosis and joint problems.

Monitoring. Growth, development and behaviour every 6 to 12 months. Vision and hearing yearly, and cardiac review as advised.

Referral and escalation. Refer to clinical genetics, developmental paediatrics and endocrinology. Urgent for seizures, regression or severe behavioural crisis.