DiGeorge Syndrome

Notes

Immunodeficiency Disorders | Immunology | Paediatrics | Primary Immunodeficiency | Primary Immunodeficiency Disorders

Overview

DiGeorge syndrome (22q11.2 deletion syndrome) is a congenital immunodeficiency and multisystem disorder caused by a microdeletion on chromosome 22. It leads to defective development of the third and fourth pharyngeal pouches, resulting in thymic hypoplasia/aplasia, hypocalcaemia due to parathyroid hypoplasia, and congenital heart defects. Prevalence is estimated at 1 in 4000 live births. Clinical presentation varies from severe neonatal disease with immunodeficiency and cardiac defects to milder phenotypes presenting later in life.

Definition

Microdeletion: A chromosomal deletion too small to be detected on standard karyotype; detected by FISH/array.
Pharyngeal pouch: Embryological structure; 3rd → thymus & inferior parathyroids; 4th → superior parathyroids.
Hypocalcaemia: Low serum calcium, often symptomatic with tetany or seizures.
Congenital heart defect: Structural abnormality present at birth, common in DiGeorge (e.g., conotruncal anomalies).

Anatomy & Physiology

Thymus: Site of T-cell maturation (positive/negative selection).
Parathyroid glands: Regulate calcium via parathyroid hormone (PTH).
3rd and 4th pharyngeal pouches: Embryological precursors to thymus, parathyroids, parts of cardiac outflow tract.
Defect in pouch development → thymic aplasia, parathyroid hypoplasia, cardiac outflow tract malformations.

Remember

“CATCH-22” → hallmark features of DiGeorge (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia; Chromosome 22q11.2).

Aetiology and Risk Factors

Cause: 22q11.2 microdeletion (most due to de novo deletion; ~10% inherited).

Family history of 22q11.2 deletion.
Parental balanced translocation (rare).

Pathophysiology

22q11.2 deletion → abnormal neural crest migration and pharyngeal pouch development.
Thymic hypoplasia → impaired T-cell maturation → variable immunodeficiency.
Parathyroid hypoplasia → ↓ PTH → hypocalcaemia.
Abnormal aortic arch / conotruncal development → congenital heart disease.
Craniofacial anomalies due to neural crest migration defects.

Think

Severity depends on extent of thymic dysfunction → partial DiGeorge (mild T-cell dysfunction) vs complete (SCID-like).

Clinical Manifestations

Immunodeficiency: Recurrent viral, fungal, opportunistic infections (T-cell defect).
Hypocalcaemia: Neonatal tetany, seizures, muscle cramps.
Congenital heart disease: Conotruncal anomalies (Tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, VSD).
Craniofacial anomalies: Low-set ears, micrognathia, cleft palate, hypertelorism.
Neurodevelopmental/psychiatric: Learning difficulties, increased risk of schizophrenia.

Remember

Tetany in neonate + congenital heart disease + recurrent infections = DiGeorge until proven otherwise.

Diagnosis

Genetic testing: FISH or chromosomal microarray for 22q11.2 deletion.
Labs: Low/absent T-cells, reduced PHA (phytohaemagglutinin) response, hypocalcaemia (↓ PTH).
Imaging: CXR → absent thymic shadow.
Differentials:
- SCID (but usually earlier severe infections, absent both T & B function).
- Hypoparathyroidism (isolated, without thymic/heart defects).
- Other syndromic congenital heart diseases.

Treatment

Cardiac surgery: Repair congenital heart defects.
Calcium & vitamin D supplementation: For hypocalcaemia.
Infection management: Prophylactic antibiotics, antifungals as needed.
Immune restoration: Thymic transplant or HSCT in complete DiGeorge.
Avoid live vaccines if severe T-cell deficiency.
Speech therapy, psychological support for craniofacial/learning issues.

Think

Tailor treatment to severity — complete DiGeorge may require thymic or stem cell transplant, partial often managed supportively.

Complications & Prognosis

Severe infections in infancy if untreated.
Congenital heart disease → morbidity and mortality.
Chronic hypocalcaemia → seizures, neuromuscular irritability.
Increased risk of autoimmune disease and psychiatric disorders later in life.
Prognosis variable: partial form survivable into adulthood; complete form fatal without intervention.

References

McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.
Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010;135(2):236–46.
Jawad AF, McDonald-McGinn DM, Zackai EH, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome. J Pediatr. 2001;139(5):715–23.
Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions. J Med Genet. 1997;34(10):798–804.
Sullivan KE. Chromosome 22q11.2 deletion syndrome: DiGeorge syndrome/velocardiofacial syndrome. Immunol Allergy Clin North Am. 2008;28(2):353–66.