Mowat-Wilson Syndrome

Mowat-Wilson syndrome is an autosomal dominant disorder caused by heterozygous loss of ZEB2, with Hirschsprung disease, intellectual disability, seizures, congenital heart disease and a distinct facial appearance.

It is usually de novo.

Pathophysiology

ZEB2 is a transcription factor for neural crest migration, enteric neuron formation and cortical development. Haploinsufficiency, through deletions or truncating variants, disrupts these processes.

Speech is very limited, but comprehension and social engagement are often better than expected.

Gastrointestinal, cardiac and neurological care together determine outcome.

• Hirschsprung disease or severe constipation (about half)
• Moderate to severe intellectual disability, with absent or very limited speech
• Epilepsy (about 75%), often starting in the first years, with a range of seizure types
• Facies: widely spaced eyes, medially flared eyebrows, prominent columella, pointed chin, and uplifted earlobes with a central depression
• Microcephaly, corpus callosum hypoplasia or agenesis
• Congenital heart disease (pulmonary artery sling, septal defects, pulmonary stenosis)
• Genitourinary anomalies: hypospadias, cryptorchidism, renal anomalies
• Eye anomalies: strabismus, optic nerve hypoplasia, coloboma
• Hypotonia, short stature, and a happy demeanour

• ZEB2 sequencing with deletion and duplication analysis, and chromosomal microarray for 2q22.3 deletions.
• Gastrointestinal assessment: contrast enema, anorectal manometry and rectal suction biopsy when Hirschsprung disease is suspected.
• Brain MRI and EEG.
• Echocardiography and renal ultrasound, and eye and hearing assessment.
• Developmental assessment.
• Parental testing to confirm de novo origin.

Differential diagnosis.

• Other syndromic Hirschsprung disease (Down syndrome, Waardenburg-Shah syndrome)
• Pitt-Hopkins syndrome and Angelman syndrome
• Smith-Lemli-Opitz syndrome
• Goldberg-Shprintzen syndrome
• Non-syndromic Hirschsprung disease (RET)
• Kabuki syndrome

• Hirschsprung disease: surgical resection of the aganglionic segment with a pull through operation (often laparoscopic) in infancy, then bowel management. Observe for enterocolitis (fever, abdominal distension, diarrhoea): treat with fluids, rectal washouts, and metronidazole 7.5 mg/kg intravenously every 8 hours with a second agent.

• Constipation: macrogol 0.4 to 0.8 g/kg daily (adults 1 to 3 sachets), with stimulant laxatives such as senna or sodium picosulfate when needed.

• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, or valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, with 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.

• Cardiac and renal care: surgical repair of significant cardiac defects, and treatment of renal and genital anomalies.

• Eye and hearing care: ophthalmology and audiology review yearly.

• Development and communication: early intervention, speech therapy with augmentative communication, physiotherapy and special education.

• Feeding and reflux: feeding therapy and omeprazole 0.7 to 1 mg/kg daily for reflux.

• Genetic counselling: de novo variants carry a low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Newborns with delayed passage of meconium or abdominal distension: assess urgently for Hirschsprung disease.

Monitoring. Seizure control, growth and development every 3 to 6 months in childhood. Bowel function at each visit, and cardiac, renal, eye and hearing review as advised.