Bohring-Opitz Syndrome

Bohring-Opitz syndrome is a rare neurodevelopmental disorder caused by de novo truncating variants in ASXL1, with severe intellectual disability, feeding difficulty, trigonocephaly, a distinctive posture and an increased risk of Wilms tumour. Survival into adulthood is now recognised.

Pathophysiology. ASXL1 is a chromatin regulator that works with polycomb repressive complexes and BAP1. Truncating variants in the last exons are thought to act through altered protein function, not simple haploinsufficiency.

Somatic ASXL1 variants are common in clonal haematopoiesis and myeloid neoplasia, but the germline disorder is a developmental condition.

Medical care addresses feeding, airway, seizures and tumour surveillance.

• Trigonocephaly with a prominent metopic ridge, microcephaly, and a glabellar capillary malformation (naevus flammeus)
• Exophthalmos, myopia, hypertelorism, upslanting fissures, and a low nasal bridge
• Characteristic posture in infancy: flexion at the elbows, ulnar deviation of the wrists, flexion of metacarpophalangeal joints
• Severe feeding difficulty, reflux, vomiting, and failure to thrive
• Severe intellectual disability, absent speech, hypotonia then spasticity
• Seizures in about half
• Hirsutism, hypertrichosis and a cleft lip or palate in some
• Airway problems: laryngomalacia, central and obstructive apnoea
• Congenital heart disease, renal anomalies, and hearing loss
• Increased risk of Wilms tumour

• ASXL1 sequencing, or exome or genome sequencing, with deletion and duplication analysis. Truncating variants in the later exons are typical.
• Clinical assessment: facial features, posture and growth.
• Brain MRI: thin corpus callosum, delayed myelination, and Dandy-Walker spectrum features.
• Echocardiography, renal ultrasound, hearing and vision assessment.
• Swallow assessment and sleep study.
• Parental testing to confirm de novo origin.

Differential diagnosis.

• Weaver syndrome and Weaver like syndromes (ASXL3, EZH2)
• Bainbridge-Ropers syndrome (ASXL3)
• Cornelia de Lange syndrome
• Opitz C (trigonocephaly) syndrome
• Kabuki syndrome
• Other causes of metopic craniosynostosis

• Feeding and growth: feeding therapy, gastrostomy for unsafe swallow or growth failure, and omeprazole 0.7 to 1 mg/kg daily for reflux, with fundoplication if severe.
• Airway and respiratory care: sleep study, respiratory support (continuous positive airway pressure) for apnoea, and prompt treatment of chest infection.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with valproate or other agents by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Wilms tumour surveillance: abdominal ultrasound every 3 months until about 8 years of age, with urgent assessment of any mass or haematuria.
• Eye care: correction of myopia and monitoring for exposure keratopathy and retinal changes.
• Hearing, cardiac and renal care: audiology yearly and treatment of structural anomalies.
• Development and posture: early intervention, physiotherapy, orthotics and communication support.
• Palliative care input early for complex needs, planned with the family.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue seizure, airway and gastrointestinal care, and plan transition to adult services.

Monitoring. Growth, feeding and development every 3 to 6 months in childhood. Abdominal ultrasound every 3 months until about 8 years, and eye and hearing review yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology, gastroenterology and ophthalmology. Emergency for apnoea, aspiration, prolonged seizures or an abdominal mass.