DiGeorge Syndrome

DiGeorge syndrome, now classified as 22q11.2 deletion syndrome, is the commonest microdeletion syndrome, with an incidence of about 1 in 2,000 to 4,000 live births. The usual 3 Mb typical deletion (TBX1 is the principal gene for the cardiac and pharyngeal arch phenotype) is de novo in about 90%, with autosomal dominant inheritance in about 10% from an affected parent.

The disorder arises from abnormal migration of neural crest cells into the third and fourth pharyngeal pouches, causing the CATCH-22 spectrum: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia from parathyroid hypoplasia.

• Cardiac (about 75%): conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, ventricular septal defect, pulmonary atresia with major aortopulmonary collaterals), and vascular ring and aberrant subclavian artery
• Hypoparathyroidism and hypocalcaemia (about 50 to 60% in infancy; may present later with stress, puberty or illness): tetany, seizures, and prolonged QT
• Immunodeficiency: T-cell lymphopenia of variable severity (partial in about 75%, complete DiGeorge with absent thymus and CD3 below 50/microlitre in below 1%), with recurrent infections, autoimmunity (immune thrombocytopenia, autoimmune haemolytic anaemia, juvenile idiopathic arthritis, thyroid disease), and atopy
• Palate abnormalities (velopharyngeal insufficiency, submucous cleft, cleft palate in about 10%), feeding difficulty, and hypernasal speech
• Facies: hooded eyelids, bulbous nasal tip, hypoplastic alae nasi, small ears, micrognathia
• Developmental delay, learning disability, speech delay, and neuropsychiatric disorders (ADHD, autism, anxiety, and schizophrenia in about 25% by adulthood)
• Renal anomalies (about 30%), skeletal anomalies (scoliosis, cervical spine anomalies), hearing loss, ophthalmic findings, short stature, growth hormone deficiency, and an increased risk of leukaemia and hepatoblastoma

• Chromosomal microarray is the first line test; FISH for 22q11.2 or MLPA are alternatives, and FISH is used for rapid detection in neonates with congenital heart disease. Evaluate on diagnosis: echocardiography, serum calcium (ionised), phosphate, magnesium and parathyroid hormone, full blood count with lymphocyte subsets (CD3, CD4, CD8, CD19, CD16/56) and naive T cells, immunoglobulin levels, T-cell receptor excision circles on newborn screening (low in severe cases), renal ultrasound, hearing and speech assessment, and genetic counselling for the parents (test them). Cervical spine films before anaesthesia or intubation in older children.

• Cardiac: surgical repair according to the lesion, with cardiology and cardiac surgery planning, and recognition that these patients require irradiated and CMV-negative blood products if immunodeficient (until T-cell function is proven) because of transfusion associated graft versus host disease risk.
• Hypocalcaemia: acute treatment of symptomatic hypocalcaemia with IV calcium gluconate 10% 0.5 to 1 mL/kg slowly (50 to 100 mg/kg) with ECG monitoring; chronic management with oral calcium 50 to 100 mg/kg/day of elemental calcium in divided doses, calcitriol 0.02 to 0.05 micrograms/kg/day (adjusted to keep calcium low normal, 2.0 to 2.2 mmol/L), and magnesium repletion. Monitor for hypercalciuria and nephrocalcinosis. Avoid triggering factors such as illness and dehydration.
• Immunology: lymphocyte count monitoring, avoid live vaccines until CD4 count above 500/microlitre, CD8 above 200/microlitre, and normal mitogen responses (MMR may be given if CD4 above 500 and CD8 above 200); prophylactic co-trimoxazole 5 mg/kg/day of trimethoprim (3 days per week) for PCP prophylaxis in severe T-cell lymphopenia; immunoglobulin replacement for hypogammaglobulinaemia; thymic tissue transplantation or haematopoietic stem cell transplantation in complete DiGeorge syndrome.
• Palate: speech therapy, palatal surgery, and pharyngeal flap, noting that internal carotid anatomy may be medialised, so imaging is advised before pharyngeal surgery.
• Neuropsychiatric: early developmental and educational support; screening for anxiety, depression, ADHD and psychosis from adolescence; antipsychotics with caution.
• Feeding: specialised bottles and gastrostomy as needed.
• Surveillance: thyroid function annually, calcium every 6 to 12 months, growth, scoliosis, and autoimmune disease screening.
• Genetic counselling: 50% recurrence risk when a parent is affected.