🩺 FCPS Paediatrics TOACS · DiGeorge Syndrome (22q11.2 deletion)
📖 Infant with chronic diarrhoea, hypocalcaemia, absent thymus, severe T‑cell lymphopenia (Chapter 165.3 · Thymic Disorders)
📚 paeds.online – Paeds Online
🩺 OBSERVED/INTERACTIVE STATION · CPSP FORMAT · 8 MINUTES · PRIMARY IMMUNODEFICIENCY / THYMIC APLASIA
🧬 Observed station – “Infant with persistent diarrhoea, nappy rash, FTT and hypocalcaemia”
👶🏽 Clinical scenario (displayed / read to candidate):
A 6‑month‑old male infant presents with watery diarrhoea and nappy rash for the last 1 month. Born by normal vaginal delivery, birth weight 3.2 kg. He is failing to thrive (weight 5.1 kg, <3rd centile). Three maternal uncles died early in childhood (unknown cause, likely infections). On examination: mild oral thrush, no dysmorphic features, normal cardiac exam.
Laboratory results:
• Hb 13 g/dL, Plt 443 x 10⁹/L, WCC 4.3 x 10⁹/L (N 2.9, L 0.9, M 0.3) → severe lymphopenia
• CD3 4% (N ~55-80%), CD4 3%, CD8 3% → all extremely low
• PHA stimulation: No response (severe T‑cell dysfunction)
• Immunoglobulins: IgG 115 g/L (elevated), IgA 7 g/L, IgM 14 g/L
• Electrolytes: Mg 0.6 mmol/L (low), Ca 1.4 mmol/L (severe hypocalcaemia), PO4 1.3 mmol/L
• CXR: Thymic tissue absent
🎯 Task (examiner observed): Recognize the pattern of complete DiGeorge syndrome (22q11.2 deletion) with thymic aplasia and profound T‑cell deficiency. Discuss genetic testing (FISH / CMA), hypoparathyroidism management, avoidance of live vaccines, need for irradiated/CMV‑negative blood products, and options for immune reconstitution (thymus transplantation vs HSCT).
A 6‑month‑old male infant presents with watery diarrhoea and nappy rash for the last 1 month. Born by normal vaginal delivery, birth weight 3.2 kg. He is failing to thrive (weight 5.1 kg, <3rd centile). Three maternal uncles died early in childhood (unknown cause, likely infections). On examination: mild oral thrush, no dysmorphic features, normal cardiac exam.
Laboratory results:
• Hb 13 g/dL, Plt 443 x 10⁹/L, WCC 4.3 x 10⁹/L (N 2.9, L 0.9, M 0.3) → severe lymphopenia
• CD3 4% (N ~55-80%), CD4 3%, CD8 3% → all extremely low
• PHA stimulation: No response (severe T‑cell dysfunction)
• Immunoglobulins: IgG 115 g/L (elevated), IgA 7 g/L, IgM 14 g/L
• Electrolytes: Mg 0.6 mmol/L (low), Ca 1.4 mmol/L (severe hypocalcaemia), PO4 1.3 mmol/L
• CXR: Thymic tissue absent
🎯 Task (examiner observed): Recognize the pattern of complete DiGeorge syndrome (22q11.2 deletion) with thymic aplasia and profound T‑cell deficiency. Discuss genetic testing (FISH / CMA), hypoparathyroidism management, avoidance of live vaccines, need for irradiated/CMV‑negative blood products, and options for immune reconstitution (thymus transplantation vs HSCT).
⚠️ Immediate red flags (examiner expects):
• Severe hypocalcaemia (Ca 1.4 mmol/L) → risk of seizures, prolonged QT → IV calcium gluconate urgently.
• Absent thymus + severe T‑cell lymphopenia → SCID‑like phenotype → No live vaccines (BCG, rotavirus, MMR, varicella).
• Family history of early male deaths suggests X‑linked? But pattern here is autosomal dominant (22q11.2) – but can be inherited.
• Severe hypocalcaemia (Ca 1.4 mmol/L) → risk of seizures, prolonged QT → IV calcium gluconate urgently.
• Absent thymus + severe T‑cell lymphopenia → SCID‑like phenotype → No live vaccines (BCG, rotavirus, MMR, varicella).
• Family history of early male deaths suggests X‑linked? But pattern here is autosomal dominant (22q11.2) – but can be inherited.
🔬 Nelson's Chapter 165.3 – Thymic Disorders:
Complete DiGeorge syndrome (cDGS) is characterised by thymic aplasia → profound T‑cell deficiency (<10% of normal CD3+ cells) + hypoparathyroidism (hypocalcaemia) + cardiac defects (conotruncal). Approximately 1% of 22q11.2 deletions present with complete absence of thymus requiring immune reconstitution.
Complete DiGeorge syndrome (cDGS) is characterised by thymic aplasia → profound T‑cell deficiency (<10% of normal CD3+ cells) + hypoparathyroidism (hypocalcaemia) + cardiac defects (conotruncal). Approximately 1% of 22q11.2 deletions present with complete absence of thymus requiring immune reconstitution.
Clinical features of 22q11.2 deletion syndrome: thymic aplasia, hypocalcaemia, conotruncal heart defects, palatal anomalies, immune deficiency.
💡 Examiner probe: “Why are T cells extremely low but immunoglobulins normal/elevated?” → B‑cell numbers are usually preserved, but T‑cell help is defective; oligoclonal or maternal T‑cell engraftment may produce some IgG. Elevated IgA/IgM can be seen.
🩸 Targeted diagnostic workup – confirming 22q11.2 & immunodeficiency
1 Genetic confirmation
FISH for 22q11.2 (TUPLE1) or chromosomal microarray (CMA) – detects hemizygous deletion in ~90% of DiGeorge. Negative FISH does not exclude atypical deletion.
FISH for 22q11.2 (TUPLE1) or chromosomal microarray (CMA) – detects hemizygous deletion in ~90% of DiGeorge. Negative FISH does not exclude atypical deletion.
2 Immunophenotyping (flow cytometry)
Already shows CD3+ <5%. Further evaluate naïve T cells (CD45RA+), TREC quantification (newborn screen very low). Evaluate B‑cell subsets and NK cells.
Already shows CD3+ <5%. Further evaluate naïve T cells (CD45RA+), TREC quantification (newborn screen very low). Evaluate B‑cell subsets and NK cells.
3 Calcium/ PTH metabolism
Low serum calcium + low PTH → hypoparathyroidism. Also check 25‑OH vitamin D, magnesium (low Mg worsens hypocalcaemia).
Low serum calcium + low PTH → hypoparathyroidism. Also check 25‑OH vitamin D, magnesium (low Mg worsens hypocalcaemia).
4 Cardiac evaluation
Echocardiogram to rule out conotruncal anomalies (tetralogy of Fallot, truncus arteriosus, VSD, interrupted aortic arch).
Echocardiogram to rule out conotruncal anomalies (tetralogy of Fallot, truncus arteriosus, VSD, interrupted aortic arch).
5 Other assessments
Audiology, speech/cleft palate evaluation, renal ultrasound (renal anomalies in 30%), ophthalmology.
Audiology, speech/cleft palate evaluation, renal ultrasound (renal anomalies in 30%), ophthalmology.
📊 Differential diagnosis of T‑cell lymphopenia + hypocalcaemia:
• CHARGE syndrome (CHD7 mutations) – coloboma, choanal atresia, ear anomalies.
• FOXN1 deficiency (nude SCID) – thymic aplasia, alopecia, nail dystrophy.
• Complete DiGeorge syndrome (22q11.2 DS) – most common.
• TBX1 mutations (rare).
• 10p13‑14 deletion syndrome.
• CHARGE syndrome (CHD7 mutations) – coloboma, choanal atresia, ear anomalies.
• FOXN1 deficiency (nude SCID) – thymic aplasia, alopecia, nail dystrophy.
• Complete DiGeorge syndrome (22q11.2 DS) – most common.
• TBX1 mutations (rare).
• 10p13‑14 deletion syndrome.
🧠 Key point: TREC (T‑cell receptor excision circle) screening on newborn dried blood spots is abnormal in most SCID and complete DiGeorge patients. This infant likely missed newborn screening or not performed.
🗨️ Examiner Q&A · Immunology, genetics & parental counseling
❓ Q1 (Examiner): “Based on the lab profile (T cells <5%, PHA no response, absent thymus), how do you classify this DiGeorge syndrome?”
✅ Complete DiGeorge syndrome (cDGS) – also referred to as athymic DiGeorge. Differentiates from partial DGS (some T cells present, PHA response >10% of normal). Complete form requires immune reconstitution. Incidence ~1% of all 22q11.2 deletions.
❓ Q2: “What is the immediate management for severe hypocalcaemia (Ca 1.4 mmol/L) in this infant?”
✅ • IV calcium gluconate 10% (1-2 mL/kg/dose) slow IV push under cardiac monitoring, then continuous infusion (50-75 mg/kg/day elemental calcium).
• Monitor ECG for QT prolongation.
• Replace magnesium (Mg 0.6 → IV Mg sulphate).
• Long‑term: oral calcium + calcitriol (active vitamin D) because hypoparathyroidism leads to low PTH.
• Monitor ECG for QT prolongation.
• Replace magnesium (Mg 0.6 → IV Mg sulphate).
• Long‑term: oral calcium + calcitriol (active vitamin D) because hypoparathyroidism leads to low PTH.
❓ Q3: “Why must we avoid live vaccines? Which specific vaccines are contraindicated?”
✅ Severe T‑cell deficiency → risk of disseminated vaccine strain infection. Contraindicated live vaccines: BCG (already given? in endemic countries risk), rotavirus, MMR, varicella, live attenuated influenza, yellow fever. If already received BCG, monitor for regional or disseminated BCG-itis (needs anti‑mycobacterial therapy).
❓ Q4: “What are the two definitive options for immune reconstitution in complete DiGeorge syndrome?”
✅ 1. Cultured thymus tissue transplantation (thymus transplantation) – preferred in cDGS, restores naïve T cells with good function, no GVHD risk.
2. Hematopoietic stem cell transplantation (HSCT) – from matched sibling or unrelated donor; higher risk of GVHD and requires conditioning. Thymus transplant offers better T‑cell reconstitution without chemotherapy.
2. Hematopoietic stem cell transplantation (HSCT) – from matched sibling or unrelated donor; higher risk of GVHD and requires conditioning. Thymus transplant offers better T‑cell reconstitution without chemotherapy.
❓ Q5 (Counseling scenario): “Parents ask about recurrence risk for future pregnancies. What do you tell them?”
✅ • ~90% of 22q11.2 deletions are de novo; recurrence risk is <1% for unaffected parents.
• 10% inherited from a parent (often mildly affected or with subtle phenotype). Therefore both parents should be tested by FISH/CMA.
• If parent carries deletion → 50% recurrence risk each pregnancy → offer prenatal diagnosis (CVS/amnio) and preimplantation genetic testing.
• Autosomal dominant inheritance pattern.
• 10% inherited from a parent (often mildly affected or with subtle phenotype). Therefore both parents should be tested by FISH/CMA.
• If parent carries deletion → 50% recurrence risk each pregnancy → offer prenatal diagnosis (CVS/amnio) and preimplantation genetic testing.
• Autosomal dominant inheritance pattern.
❓ Q6: “What blood product precautions are required for this infant?”
✅ • All cellular blood products (RBCs, platelets) must be irradiated to prevent transfusion‑associated graft‑versus‑host disease (TA‑GVHD).
• CMV‑negative or leukoreduced products to reduce CMV transmission.
• Family donors should avoid first‑degree relatives because of potential HLA haploidentity.
• CMV‑negative or leukoreduced products to reduce CMV transmission.
• Family donors should avoid first‑degree relatives because of potential HLA haploidentity.
❓ Q7: “What infections are these patients most susceptible to?”
✅ Viral (CMV, EBV, adenovirus, RSV, parainfluenza), Pneumocystis jirovecii (PJP), fungal (Candida, Aspergillus), and atypical mycobacteria. Prophylaxis: PJP prophylaxis (TMP‑SMX); antifungal (fluconazole) for oral thrush; IVIG if hypogammaglobulinemia (though IgG is elevated here, function may be impaired).
❓ Q8 (Examiner): “The chest X‑ray shows absent thymus. What additional anomaly must be ruled out emergently?”
✅ Congenital heart disease – particularly conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch). Echocardiogram is urgent because some defects are ductal‑dependent. Also evaluate for palatal anomalies (submucous cleft, velopharyngeal insufficiency).
❓ Q9: “How does complete DiGeorge differ from typical partial DiGeorge?”
✅ • Partial DGS: residual T cells present (usually >500 CD3+ cells/µL), PHA response often normal, no need for immune reconstitution, may have autoimmune cytopenias later.
• Complete DGS: profound T‑cell lymphopenia (<50 CD3+ cells/µL), PHA unresponsive, thymic aplasia, requires thymus transplant or HSCT to survive.
• Complete DGS: profound T‑cell lymphopenia (<50 CD3+ cells/µL), PHA unresponsive, thymic aplasia, requires thymus transplant or HSCT to survive.
📘 Management algorithm & summary (Nelson's 165.3)
🔄 Immediate
IV calcium gluconate (hypocalcaemia), PJP prophylaxis (TMP-SMX), no live vaccines, irradiated/CMV‑negative blood products.
IV calcium gluconate (hypocalcaemia), PJP prophylaxis (TMP-SMX), no live vaccines, irradiated/CMV‑negative blood products.
🧬 Definitive immunity
Cultured thymus tissue transplantation (preferred) or allogeneic HSCT from matched donor. Refer to specialised immunology centre.
Cultured thymus tissue transplantation (preferred) or allogeneic HSCT from matched donor. Refer to specialised immunology centre.
❤️ Cardiac
Echocardiogram, cardiology referral. Surgical repair if needed. Protect from infection before surgery.
Echocardiogram, cardiology referral. Surgical repair if needed. Protect from infection before surgery.
🍼 Nutrition & FTT
Diarrhoea: consider formula changes, exclude GE reflux. Treat thrush. Caloric supplements, nasogastric feeding if needed. Hypoparathyroidism management with calcitriol + calcium.
Diarrhoea: consider formula changes, exclude GE reflux. Treat thrush. Caloric supplements, nasogastric feeding if needed. Hypoparathyroidism management with calcitriol + calcium.
👨👩👧👦 Family counselling
Genetic counselling, parental FISH testing. Recurrence risk discussion. Psychosocial support for family with previous deaths.
Genetic counselling, parental FISH testing. Recurrence risk discussion. Psychosocial support for family with previous deaths.
💉 IVIG & antimicrobials
IVIG may be used if poor antibody function; but elevated IgG suggests maternal engraftment or oligoclonal expansion. Monitor for autoimmune cytopenias.
IVIG may be used if poor antibody function; but elevated IgG suggests maternal engraftment or oligoclonal expansion. Monitor for autoimmune cytopenias.
📖 Nelson's Textbook of Pediatrics (Chapter 165.3 – Thymic Disorders):
“Complete DiGeorge syndrome is a pediatric emergency. The combination of hypocalcaemic seizures, susceptibility to severe infections, and absent thymus mandates prompt immunologic evaluation. Thymus transplantation provides long‑term T‑cell reconstitution with low morbidity. Family members should be screened for 22q11.2 deletion.”
“Complete DiGeorge syndrome is a pediatric emergency. The combination of hypocalcaemic seizures, susceptibility to severe infections, and absent thymus mandates prompt immunologic evaluation. Thymus transplantation provides long‑term T‑cell reconstitution with low morbidity. Family members should be screened for 22q11.2 deletion.”
⭐ TOACS TAKE‑HOME POINTS (candidate must articulate):
1. Chronic diarrhoea + FTT + hypocalcaemia + absent thymus → complete DiGeorge syndrome until proven otherwise.
2. Severe T‑cell lymphopenia (CD3 <5%, PHA no response) → SCID‑like emergency → no live vaccines, irradiate blood.
3. Hypocalcaemia secondary to hypoparathyroidism – treat with IV calcium, then calcitriol + oral calcium.
4. Definitive treatment: cultured thymus transplantation or HSCT.
5. Genetic diagnosis: FISH/CMA for 22q11.2 deletion, test parents.
6. Prognosis: With immune reconstitution, survival >75%; however neurodevelopmental, psychiatric, and autoimmune issues may arise.
1. Chronic diarrhoea + FTT + hypocalcaemia + absent thymus → complete DiGeorge syndrome until proven otherwise.
2. Severe T‑cell lymphopenia (CD3 <5%, PHA no response) → SCID‑like emergency → no live vaccines, irradiate blood.
3. Hypocalcaemia secondary to hypoparathyroidism – treat with IV calcium, then calcitriol + oral calcium.
4. Definitive treatment: cultured thymus transplantation or HSCT.
5. Genetic diagnosis: FISH/CMA for 22q11.2 deletion, test parents.
6. Prognosis: With immune reconstitution, survival >75%; however neurodevelopmental, psychiatric, and autoimmune issues may arise.
Thymic aplasia in 22q11.2 deletion: third and fourth pharyngeal pouch failure leads to absent thymus and hypoparathyroidism.
🔗 Online resources for FCPS candidates:
• Paeds Online – TOACS station bank & DiGeorge summary
• Immune Deficiency Foundation – 22q11.2 deletion
• Nelson’s Chapter 165.3 – Thymic Disorders
• Paeds Online – TOACS station bank & DiGeorge summary
• Immune Deficiency Foundation – 22q11.2 deletion
• Nelson’s Chapter 165.3 – Thymic Disorders