DiGeorge sequence

**Genetics/Pathophysiology** - Most common cause: de novo (~90%) or AD-inherited 22q11.2 microdeletion (detected by FISH or chromosomal microarray). TBX1 haploinsufficiency is the major contributor. - Defective migration of neural crest cells and abnormal development of the 3rd and 4th pharyngeal pouches (plus arch/cleft derivatives). - 3rd pouch: thymus and inferior parathyroids -> thymic aplasia/hypoplasia and hypoparathyroidism. - 4th pouch: superior parathyroids (also contributes to the thymus and ultimobranchial body). - Neural crest also drives outflow tract/aortic arch formation and facial structures.

**Clinical features (CATCH-22)** - Cardiac anomalies: conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, VSD) - Abnormal facies: micrognathia, low-set/notched ears, hypertelorism, short philtrum, bulbous nasal tip - Thymic aplasia: T-cell deficiency -> recurrent viral/fungal infections (Candida, PJP), failure to thrive - Cleft palate / velopharyngeal insufficiency - Hypocalcemia (hypoparathyroidism): neonatal tetany, seizures, prolonged QT, positive Chvostek/Trousseau signs - Chromosome 22 deletion - Later associations: psychiatric illness (schizophrenia, anxiety, ADHD), learning difficulties, autoimmune disease

**Diagnosis/Labs** - Low PTH and low calcium, high phosphate - Absent thymic shadow on CXR in infants - Low T-cell counts (CD3+, CD4+, CD8+) with absent TRECs on newborn screening (SCID screen); B-cell numbers are usually normal, though antibody function may be impaired. Immunoglobulins are usually normal or may be low. - Echocardiogram; FISH/microarray for 22q11.2 deletion

**Management** - Calcium and vitamin D supplementation for hypocalcemia - Surgical repair of cardiac defects - Immune: usually partial DiGeorge (some residual thymic tissue) with mild immune dysfunction; complete DiGeorge needs thymic tissue transplantation or HSCT. - Give irradiated, CMV-negative blood products and avoid live vaccines (e.g., MMR, rotavirus, varicella) until T-cell function is confirmed, to prevent transfusion-associated graft-versus-host disease and vaccine-strain infection.

**High-yield board points** - Newborn with congenital heart disease + hypocalcemic seizures + recurrent infections -> think DiGeorge. - Differentiate from other T-cell disorders: SCID (absent thymic shadow, but no hypocalcemia/cardiac defects; thymus is present though underdeveloped), Ataxia-telangiectasia, Wiskott-Aldrich (eczema, thrombocytopenia, infections). - Lymph node paracortex and the periarteriolar lymphoid sheath (PALS) of the spleen (T-cell zones) are depleted. - Velocardiofacial syndrome (Shprintzen) is a related phenotype from the same deletion, with more prominent palatal and facial features. - "Sequence" refers to a cascade of developmental defects stemming from a single initial abnormality (here, abnormal pharyngeal pouch development).