DiGeorge syndrome

Autosomal dominant microdeletion of chromosome 22q11.2 (usually de novo) causing defective development of the 3rd & 4th pharyngeal pouches. Results in thymic & parathyroid hypoplasia (T-cell immunodeficiency, hypocalcemia) along with conotruncal cardiac defects and craniofacial abnormalities.

• It's the most common microdeletion syndrome (~1 in 4,000 births) and exemplifies how a single genetic defect can disrupt multiple systems (heart, immune, endocrine). Classic for exams due to the triad of cardiac defect, immune deficiency, and hypocalcemia. Early recognition allows life-saving interventions (calcium for seizures, infection precautions).

• Severe neonatal presentation: conotruncal heart defect (e.g., truncus arteriosus, tetralogy of Fallot) with hypocalcemic seizures in the first days of life (neonatal tetany from parathyroid aplasia). Dysmorphic facial features (e.g., low-set ears, micrognathia) may be noted at birth.
• Recurrent infections starting in infancy due to T-cell deficiency from thymic hypoplasia (often manifesting after 3–6 months when maternal antibodies wane). Chest X-ray can show an absent thymic shadow (if thymus is very small).
• Craniofacial and palate anomalies: cleft palate or velopharyngeal insufficiency (leading to feeding difficulties and nasal-sounding speech), hooded eyelids, bulbous nasal tip, and an elongated face. Many patients have developmental delays or learning disabilities.
• Adolescents and adults: increased risk of psychiatric disorders (anxiety, ADHD, depression) – notably about 25% develop schizophrenia in adulthood.

1. Think of 22q11.2 deletion (DiGeorge) in any infant with the combination of heart defect, immunodeficiency, and hypocalcemia.
2. Confirm the diagnosis with genetic testing: fluorescence in situ hybridization (FISH) or chromosomal microarray to detect the 22q11.2 deletion.
3. Evaluate the extent of organ involvement: perform an echocardiogram for cardiac anomalies; check serum calcium and parathyroid hormone levels; obtain T-lymphocyte counts (flow cytometry) to assess immune function.
4. If T-cell counts are extremely low (complete DiGeorge syndrome), manage like severe combined immunodeficiency: protective isolation, no live vaccines, and consider thymus transplant or hematopoietic stem cell transplant.
5. For partial DiGeorge (most cases), immune function often improves with time. Provide infection prophylaxis (e.g., appropriate antibiotics, IVIG if needed) and monitor immune recovery while treating other issues.

1. Cardiac & palate: Early surgical repair of cardiac defects (e.g., TOF repair in infancy) and of cleft palate/velopharyngeal anomalies to improve feeding and speech.
2. Calcium: Calcium supplementation (often with calcitriol, active vitamin D) to maintain normal calcium levels and prevent tetany/seizures. Monitor serum calcium regularly, especially in infancy and around surgeries or growth spurts.
3. Immune support: For significant T-cell deficiency, prevent infections with prophylactic antibiotics and/or IVIG. Avoid live vaccines until an immunologist confirms sufficient T-cell function. In the rare complete DiGeorge, pursue thymus transplant or bone marrow transplant.
4. Developmental and psychosocial: Provide early intervention for speech and developmental delays (speech therapy, PT/OT, special education). Monitor and treat psychiatric conditions (e.g., counseling, medications for schizophrenia or anxiety) as the patient ages.

• Mnemonic CATCH-22: Cardiac (conotruncal defects), Abnormal facies, Thymic hypoplasia (T-cell deficiency), Cleft palate, Hypocalcemia (due to absent parathyroids) — all due to 22q11 deletion.
• Embryology tie-in: failure of the 3rd and 4th pharyngeal pouches to develop → thymic and parathyroid aplasia, explaining the immunodeficiency and hypocalcemia.
• Genetics: ~3 Mb deletion (~40 genes, including TBX1 which drives many features). ~90% of cases are de novo; if inherited, it follows autosomal dominant transmission (50% chance to each offspring).

• Neonate with hypocalcemic seizure or arrhythmia – requires immediate IV calcium; undiagnosed DiGeorge is a common cause of life-threatening neonatal hypocalcemia.
• Infants with known or suspected T-cell immunodeficiency (DiGeorge) should not receive live vaccines (e.g., rotavirus, MMR, varicella) until immune status is verified, due to risk of vaccine-strain infections.

1. Clinical features (congenital heart defect, hypocalcemia, dysmorphic facies, infections) → suspect DiGeorge syndrome.
2. Initial workup: check electrolytes (calcium), obtain a CBC with differential and lymphocyte subset panel (T-cell count), and perform a cardiac evaluation (echo). Consider chest X-ray for thymic shadow.
3. Confirm the diagnosis with genetic testing (FISH or microarray for 22q11.2 deletion). Offer parents genetic counseling (recurrence risk).
4. Acute management: correct hypocalcemia (IV calcium for neonates with seizures), treat any infections promptly, and withhold live vaccines pending immune evaluation.
5. Long-term management: coordinate multidisciplinary care (cardiology, immunology, endocrinology, speech therapy). Schedule definitive repairs (cardiac surgery, palate repair), maintain calcium supplementation, and regularly monitor immune function and development.

• Newborn with truncus arteriosus, craniofacial anomalies, and tetany (seizures) from hypocalcemia → DiGeorge syndrome (22q11.2 deletion).
• Infant with cleft palate, recurrent viral/fungal infections, and congenital heart murmur (Tetralogy of Fallot) → suspect 22q11 deletion (DiGeorge).
• Young adult with a history of conotruncal heart defect repair and learning difficulties develops schizophrenia → consider an undiagnosed 22q11.2 deletion syndrome.