Opitz G/BBB Syndrome

Opitz G/BBB syndrome is a midline malformation syndrome with hypertelorism, hypospadias and swallowing and airway problems from laryngotracheoesophageal clefts. The X-linked form is due to variants in MID1 (Xp22.2) and affects males mostly; an autosomal dominant form is linked to 22q11.2 deletion.

Pathophysiology. MID1 encodes a microtubule associated E3 ubiquitin ligase that regulates the catalytic subunit of protein phosphatase 2A. Loss of function disturbs midline development in the first weeks of gestation.

Expression is variable, even within a family.

Aspiration and recurrent chest infection drive early morbidity.

• Hypertelorism, a broad nasal bridge, and a prominent forehead
• Hypospadias, cryptorchidism and bifid scrotum in males
• Laryngotracheoesophageal cleft with hoarse or weak cry, stridor, choking with feeds and recurrent aspiration
• Cleft lip and palate
• Anal anomalies (anterior anus, imperforate anus)
• Mild intellectual disability or developmental delay in about 40% of males, and agenesis or hypoplasia of the corpus callosum
• Congenital heart disease in some
• Hypotonia, and in some a Dandy-Walker malformation or cerebellar vermis hypoplasia
• Females: mild hypertelorism and, rarely, other midline features

• MID1 sequencing with deletion and duplication analysis in males with the X-linked phenotype.
• Chromosomal microarray or FISH for 22q11.2 deletion in either sex, in families with autosomal dominant inheritance, and when cardiac or immune features are present.
• Airway endoscopy and contrast swallow to define the laryngotracheoesophageal cleft.
• Echocardiography, renal ultrasound and brain MRI.
• Carrier testing of the mother and female relatives for MID1 variants.

Differential diagnosis.

• 22q11.2 deletion syndrome
• Smith-Lemli-Opitz syndrome
• Opitz-Kaveggia FG syndrome
• Isolated laryngotracheoesophageal cleft
• Other hypospadias with hypertelorism syndromes (for example Aarskog-Scott syndrome)

• Airway and feeding: keep nil by mouth when aspiration is suspected, give enteral feeds by nasogastric or gastrostomy tube, and arrange endoscopic or open repair of the cleft by an airway team. Type of repair depends on the length and depth of the cleft.
• Chest infection: physiotherapy and prompt antibiotics. Use amoxicillin with clavulanic acid 25 mg/kg (amoxicillin component) twice daily for 7 days for aspiration pneumonia.
• Cleft lip and palate: repair of the lip at 3 to 6 months and the palate at 6 to 12 months by a cleft team.
• Genitourinary care: hypospadias repair at 6 to 18 months, and orchidopexy for undescended testes.
• Anal anomalies: colorectal surgery and bowel management.
• Reflux: omeprazole 0.7 to 1 mg/kg daily.
• Development and education: early intervention, speech therapy and special education.
• Genetic counselling: in the X-linked form a carrier mother has a 50% chance of transmitting the variant to each child; sons are affected and daughters are carriers. The 22q11.2 deletion form is dominant with a 50% risk when a parent carries it.

Special groups.

• Infants with weak cry, stridor or choking on feeds: suspect a cleft and arrange airway endoscopy before oral feeding continues.

Monitoring. Growth, feeding, chest infections and development every 3 months in infancy. Airway review after repair, and renal and cardiac follow up as advised.

Referral and escalation. Refer to clinical genetics, paediatric surgery, ENT and a cleft team. Emergency for respiratory distress, apnoea or aspiration.