Koolen-de Vries Syndrome

Koolen de Vries syndrome is a neurodevelopmental disorder caused by deletion of the 17q21.31 region or variants in KANSL1, with a friendly, sociable personality, hypotonia, intellectual disability, epilepsy and characteristic facies. It occurs in about 1 in 16000 births.

Pathophysiology. KANSL1 is a component of the histone acetyltransferase complex (NSL) involved in chromatin regulation. Haploinsufficiency of KANSL1, through a 17q21.31 microdeletion or a loss-of-function variant, causes the syndrome.

Most cases are de novo. A common inversion polymorphism of the region (H2 haplotype) in a parent predisposes to the microdeletion.

Severity varies, but speech delay is typical and seizures affect about a third.

• Neonatal and infant hypotonia, feeding difficulty
• Developmental delay and intellectual disability, with severe speech delay
• Friendly, sociable behaviour
• Epilepsy (about 30% to 50%), including febrile and focal seizures
• Characteristic face: long face, tubular or pear shaped nose with bulbous tip, upslanting palpebral fissures, ptosis, sparse medial eyebrows
• Congenital heart disease, renal and urinary tract anomalies
• Cryptorchidism in males
• Hip dysplasia, joint hypermobility and scoliosis
• Hyperopia and strabismus, hearing loss

• Chromosomal microarray showing a 17q21.31 deletion (about 500 to 650 kb) including KANSL1.
• KANSL1 sequencing if microarray is normal and the phenotype is typical.
• Parental testing for inheritance (de novo in most).
• Echocardiography, renal and bladder ultrasound, and hip imaging.
• EEG if seizures are suspected.
• Developmental assessment, vision and hearing tests.

• Epilepsy: levetiracetam 10 mg/kg orally twice daily increasing to 30 mg/kg twice daily, valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, or lamotrigine titrated slowly (avoid with valproate unless dose is reduced). Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and growth: feeding therapy, omeprazole 0.7 to 1 mg/kg daily for reflux, and gastrostomy if unsafe.
• Cardiac and renal care: treat structural defects, and monitor for urinary tract infection with prophylaxis (trimethoprim 2 mg/kg at night) for vesicoureteric reflux.
• Orthopaedic care: hip ultrasound in infancy, bracing for dysplasia, physiotherapy, and scoliosis surveillance.
• Vision and hearing: spectacles for hyperopia, treatment of strabismus, and hearing aids.
• Development and communication: early intervention, speech therapy with augmentative communication, occupational therapy and school support.
• Behaviour: behavioural support, and treatment of anxiety or ADHD as needed.
• Genetic counselling: de novo deletions carry low recurrence risk, while a parent who carries an inversion may have a higher risk.

Special groups.

• Adults: continue epilepsy care and plan supported living and transition.

Monitoring. Seizure review every 3 to 6 months, development every 6 to 12 months, cardiac and renal follow up as indicated, and vision and hearing yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology and developmental services. Emergency for prolonged seizures, and urgent for febrile urinary infection or heart failure.