Learning Objective
Describe primary combined B- and T-cell immunodeficiencies, their genetic or molecular defects, classic clinical presentations, and key laboratory findings.
Severe Combined Immunodeficiency (SCID)
Defect
Multiple types: X-linked IL-2R γ chain defect (most common), ADA deficiency, RAG mutation → VDJ recombination defect
Clinical features
Failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, fungal, and protozoal infections
Key finding/ Lab
↓ T cells, absent thymic shadow, absent germinal centers, ↓ TRECs; newborn screening detects TRECs
Activity
Ataxia-telangiectasia
Defect
ATM gene defect → DNA damage response failure; autosomal recessive
Clinical features
Triad: ataxia (cerebellar defects), spider angiomas (telangiectasia), IgA deficiency
Key finding/ Lab
↑ AFP, ↓ IgA/IgG/IgE, lymphopenia, cerebellar atrophy, ↑ risk of lymphoma/leukemia, ↑ radiation sensitivity
Hyper-IgM syndrome
Defect
Defective CD40L on T-helper cells → class-switching defect; X-linked
Clinical features
Severe pyogenic infections early in life; opportunistic infections (Pneumocystis, Cryptosporidium, CMV)
Key finding/ Lab
Normal/high IgM, ↓ IgG/IgA/IgE; absent germinal centers
Wiskott-Aldrich syndrome (WAS)
Defect
WAS gene mutation → defective actin cytoskeleton in leukocytes/platelets; X-linked
Clinical features
WATER mnemonic: Thrombocytopenia, Eczema, Recurrent infections; ↑ autoimmunity & malignancy risk
Key finding/ Lab
↓/normal IgG, IgM, ↑ IgE, IgA; fewer/smaller platelets
Activity
Summary table
| Disease | Defect | Clinical Features | Key Findings / Lab |
|---|---|---|---|
| Severe Combined Immunodeficiency (SCID) | Multiple types: X-linked IL-2R γ chain defect (most common), ADA deficiency, RAG mutation → VDJ recombination defect | Failure to thrive, chronic diarrhea, thrush, recurrent viral, bacterial, fungal, and protozoal infections | ↓ T cells, absent thymic shadow, absent germinal centers, ↓ TRECs; newborn screening detects TRECs |
| Ataxia-telangiectasia | ATM gene defect → DNA damage response failure; autosomal recessive | Triad: ataxia (cerebellar defects), spider angiomas (telangiectasia), IgA deficiency | ↑ AFP, ↓ IgA/IgG/IgE, lymphopenia, cerebellar atrophy, ↑ risk of lymphoma/leukemia, ↑ radiation sensitivity |
| Hyper-IgM syndrome | Defective CD40L on T-helper cells → class-switching defect; X-linked | Severe pyogenic infections early in life; opportunistic infections (Pneumocystis, Cryptosporidium, CMV) | Normal/high IgM, ↓ IgG/IgA/IgE; absent germinal centers |
| Wiskott-Aldrich syndrome (WAS) | WAS gene mutation → defective actin cytoskeleton in leukocytes/platelets; X-linked | WATER mnemonic: Thrombocytopenia, Eczema, Recurrent infections; ↑ autoimmunity & malignancy risk | ↓/normal IgG, IgM; ↑ IgE, IgA; fewer/smaller platelets |
High-Yield Mnemonics / Tips
- SCID: Severe, early, multiple infections; “bubble baby.”
- Ataxia-telangiectasia: ABC: Ataxia, Blood (IgA ↓), Cancer (lymphoma/leukemia)
- Hyper-IgM syndrome: High IgM → think class switching defect
- Wiskott-Aldrich / WATER: Thrombocytopenia, Eczema, Recurrent infections
