DiGeorge Syndrome (22q11.2 Deletion Syndrome)

Introduction and Epidemiology

DiGeorge syndrome is a classic microdeletion syndrome caused by a heterozygous deletion of the chromosome 22q11.2 region.
Incidence is approximately 1 in 4000 live births, making it the most common microdeletion syndrome.
The condition exhibits equal male-to-female ratio and highly variable expressivity, even within affected families.
It is part of the broader 22q11.2 deletion syndrome spectrum, which encompasses velocardiofacial syndrome and conotruncal anomaly face syndrome.

Approximately 90% of cases arise from a de novo deletion.
Remaining 10% of cases are inherited from a mildly affected parent in an autosomal dominant pattern with variable penetrance.
The typical microdeletion spans 3 Mb and includes approximately 30 to 40 genes.
Deletions are mediated by non-allelic homologous recombination involving low-copy repeats.

TBX1 (T-box transcription factor 1) is the critical gene involved in the syndrome.
Haploinsufficiency of TBX1 disrupts normal neural crest cell migration.
Defective neural crest migration leads to abnormal development of the third and fourth pharyngeal pouches.
Pharyngeal pouch defects result in thymic aplasia or hypoplasia (causing T-cell deficiency), parathyroid agenesis or hypoplasia (causing hypocalcemia), and conotruncal cardiac anomalies.

Feature Category	Clinical Findings
Cardiac (70-75%)	Conotruncal anomalies including Tetralogy of Fallot, interrupted aortic arch type B, truncus arteriosus, and ventricular septal defect with pulmonary atresia.
Abnormal Facies	Hypertelorism, low-set ears, hooded eyelids, bulbous nose with squared tip, micrognathia, and short philtrum.
Thymic Hypoplasia	Variable T-cell immunodeficiency resulting in recurrent viral and fungal infections. Complete DiGeorge presents similarly to severe combined immunodeficiency.
Cleft Palate (70%)	Submucous cleft palate, velopharyngeal incompetence, and hypernasal speech.
Hypocalcemia (50-60%)	Parathyroid hypoplasia leading to neonatal seizures and tetany. Can be transient or permanent.
Neurodevelopmental	Mild to moderate intellectual disability, learning disabilities, speech delay, and psychiatric disorders (schizophrenia in 25% of adults, autism spectrum, ADHD).
Renal and Skeletal	Renal agenesis, hydronephrosis, scoliosis, and vertebral anomalies.

Chromosomal microarray is the gold standard investigation, detecting atypical or smaller copy number variants with higher yield.
Fluorescence in situ hybridization using the HIRA probe is a rapid test that detects 90% of typical deletions within 24 to 48 hours.
Multiplex ligation-dependent probe amplification provides a targeted, cost-effective alternative.
Conventional karyotyping is typically normal because the 22q11.2 deletion is submicroscopic.

Urgent echocardiography is mandated for all suspected cases.
Serum calcium, parathyroid hormone, and phosphate levels require neonatal and periodic monitoring.
Immunological evaluation includes lymphocyte subsets (CD3/CD4/CD8), T-cell function via mitogen proliferation, and immunoglobulin levels.
Renal ultrasound, hearing screen, and palatal evaluation via nasopharyngoscopy are necessary baseline investigations.

Urgent cardiac evaluation and surgical repair of conotruncal defects are prioritized.
Symptomatic hypocalcemia with seizures requires intravenous calcium gluconate.
Permanent hypocalcemia necessitates lifelong oral calcium and calcitriol supplementation.
Immunodeficiency management includes using irradiated, cytomegalovirus-negative blood products.
Live vaccines are contraindicated in severe T-cell deficiency.
Prophylaxis for Pneumocystis pneumonia using cotrimoxazole is indicated if T-cell counts are low.
Thymus transplantation is reserved for rare cases of complete DiGeorge syndrome.
Nasogastric feeding support and cleft palate repair by 12 months address significant feeding difficulties.

Early developmental intervention and speech therapy are critical for managing velopharyngeal insufficiency and learning disabilities.
Annual immunological reviews monitor for hypogammaglobulinemia and autoimmune disease emergence.
Psychiatric screening is essential during adolescence due to high risk of schizophrenia and anxiety.
Killed vaccines are safe, while live vaccines are administered only following documented immune reconstitution.

Survival exceeds 90% beyond infancy with optimal multidisciplinary care, largely dependent on cardiac severity.
Recurrence risk for de novo deletions is less than 1%.
Recurrence risk for cases inherited from an affected parent is 50%.
Parental genetic testing is routinely offered to differentiate de novo from inherited forms.