Combined Immunodeficiency Syndromes & Immune Dysregulation

DiGeorge anomaly · Wiskott-Aldrich syndrome · X-linked hyper-IgM (CD40L) · X-linked lymphoproliferative disease · Short-limbed dwarfism · DNA repair defects (Ataxia-telangiectasia, Nijmegen) · ALPS · CMC · IPEX syndrome
🧬 Key concepts: DiGeorge (22q11.2 deletion, hypocalcemia, cardiac, T-cell defect). Wiskott-Aldrich (eczema, thrombocytopenia, infections). Hyper-IgM (opportunistic infections). IPEX (enteropathy, endocrinopathy, FOXP3). ALPS (lymphoproliferation, autoimmune cytopenias).

📖 Combined immunodeficiency syndromes & immune dysregulation

🧬 DiGeorge syndrome (22q11.2 deletion)
Cardiac defects (conotruncal), hypocalcemia (parathyroid aplasia), thymic hypoplasia → T-cell deficiency, cleft palate, dysmorphic facies. Variable immune defect.
🩸 Wiskott-Aldrich syndrome (WAS)
X-linked: eczema, thrombocytopenia (small platelets), recurrent infections (encapsulated bacteria). HSCT curative.
⚡ X-linked hyper-IgM (CD40L deficiency)
Low IgG/IgA, normal/elevated IgM. Recurrent pyogenic infections, PCP, Cryptosporidium → sclerosing cholangitis. HSCT.
🧫 Disorders of immune regulation
ALPS (FAS/FASL mutations): lymphoproliferation, autoimmune cytopenias, lymphoma risk. IPEX (FOXP3): enteropathy, type 1 diabetes, eczema, early death. CMC (AIRE, STAT1, IL17F).
⚠️ Red flags: Conotruncal cardiac defect + hypocalcemia → DiGeorge. Eczema + thrombocytopenia + infections → Wiskott-Aldrich. Chronic diarrhea + diabetes + eczema → IPEX.

🩺 Diagnostic approach to syndromic immunodeficiencies & immune dysregulation

1
DiGeorge – Suspicion: conotruncal cardiac defect (tetralogy, interrupted arch), hypocalcemia, dysmorphism. Confirm: FISH for 22q11.2 deletion. Evaluate T-cell count (CD3).
2
Wiskott-Aldrich – Male with eczema, thrombocytopenia (small platelets), recurrent infections. Flow cytometry (WASP protein absent). WAS gene sequencing.
3
Hyper-IgM (CD40L) – Low IgG/IgA, normal/high IgM, recurrent infections (PCP, Cryptosporidium). Lymphocyte subsets: CD40L expression absent on activated T cells.
4
IPEX – Infant with severe enteropathy, type 1 diabetes, eczema, elevated IgE. FOXP3 mutation. Autoantibodies.
📌 Clinical pearl: Any male infant with eczema and thrombocytopenia (small platelets) should have Wiskott-Aldrich syndrome ruled out. Avoid splenectomy.

📋 Stepwise management of syndromic immunodeficiencies & dysregulation

1
DiGeorge syndrome – Correct hypocalcemia (IV calcium). Cardiac surgery as needed. For severe T-cell deficiency: thymic transplantation (complete DiGeorge) or HSCT. Avoid live vaccines.
2
Wiskott-Aldrich syndrome – Definitive: HSCT (best before 2 years). Supportive: IVIG, prophylactic antibiotics (TMP-SMX), eczema management. Avoid splenectomy.
3
Hyper-IgM (CD40L deficiency) – HSCT is curative. IVIG, PCP prophylaxis (TMP-SMX), monitor for Cryptosporidium (avoid contaminated water).
4
IPEX syndrome – Immunosuppression (steroids, tacrolimus, sirolimus). HSCT curative. Supportive: insulin, nutritional support, IVIG.
5
ALPS (autoimmune lymphoproliferative syndrome) – Mycophenolate mofetil, sirolimus. Avoid splenectomy (increased infection risk). Monitor for lymphoma.
🚨 Emergency in IPEX: Severe enteropathy with failure to thrive, electrolyte imbalance, sepsis. Prompt diagnosis and HSCT consideration.

🧠 Reflex prompts: syndromic immunodeficiencies & immune dysregulation

🧬 Newborn with tetralogy of Fallot, hypocalcemia, and absent thymus on imaging. Diagnosis?
DiGeorge syndrome (22q11.2 deletion). Check T-cell count, calcium, FISH.
🩸 6-month-old male with eczema, thrombocytopenia (small platelets), and recurrent otitis media. Diagnosis?
Wiskott-Aldrich syndrome (WAS). HSCT definitive.
⚡ 2-year-old boy with recurrent PCP pneumonia, Cryptosporidium diarrhea, and low IgG, elevated IgM. Diagnosis?
X-linked hyper-IgM syndrome (CD40L deficiency). HSCT curative.
🧫 Infant with severe intractable diarrhea, type 1 diabetes, eczema, and elevated IgE. FOXP3 mutation. Diagnosis?
IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked). HSCT.
🩺 Child with chronic mucocutaneous candidiasis, endocrinopathy (hypoparathyroidism, Addison). Autoimmune regulator gene (AIRE) mutation. Diagnosis?
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).
🧬 Child with lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, and double-negative T cells. Diagnosis?
Autoimmune lymphoproliferative syndrome (ALPS). Sirolimus, mycophenolate.
🧫 X-linked lymphoproliferative disease (XLP) is triggered by which infection?
Epstein-Barr virus (EBV) → fatal infectious mononucleosis, hemophagocytosis.
🧬 Which gene is mutated in DiGeorge syndrome?
22q11.2 deletion (TBX1).
💊 What is the definitive treatment for Wiskott-Aldrich syndrome?
Hematopoietic stem cell transplant (HSCT).
🩺 What is the classic triad of Wiskott-Aldrich syndrome?
Eczema, thrombocytopenia (small platelets), recurrent infections (encapsulated bacteria).