High-Yield Primary Immunodeficiency Disorders

High-Yield Primary Immunodeficiency Disorders

Overview

Primary immunodeficiencies (PIDs) are inherited disorders of immune function characterized by:

• Recurrent, severe, or unusual infections
• Autoimmune manifestations
• Increased risk of malignancy

Classification

1.     B-cell (humoral) deficiencies

2.     T-cell (cell-mediated) deficiencies

3.     Combined B and T cell deficiencies

4.     Phagocytic defects

5.     Complement deficiencies

I. Combined T and B Cell Deficiencies

1. Severe Combined Immunodeficiency (SCID)

1.     Genetics:
A. X-linked: IL2RG (common γ-chain) mutation (most common)
B. AR: ADA deficiency, RAG1/2 mutations, others

2.     Defect: Severe T-cell deficiency → impaired B-cell function (B cells may be present but nonfunctional)

3.     Immune Profile:
A. T cells ↓↓↓
B. B cells variable
C. NK cells variable

4.     Clinical Features:
A. Early infancy: severe infections (viral, bacterial, fungal, protozoal)
B. Failure to thrive, chronic diarrhea
C. May have absent or small thymic shadow (not universal)
D. Scant lymphoid tissue

5.     Labs: ↓ T cells, ↓ TRECs (newborn screening), hypogammaglobulinemia

6.     Management:
A. HSCT (curative)
B. IVIG + antimicrobial prophylaxis

7.     Key Pearls:
A. Avoid live vaccines
B. Medical emergency

2. Hyper IgM Syndrome

1.     Genetics: CD40L deficiency (X-linked most common)

2.     Defect: Failure of immunoglobulin class switching (CD40–CD40L interaction)

3.     Immune Profile: Normal B-cell number, impaired function

4.     Clinical Features:
A. Recurrent pyogenic infections
B. Opportunistic infections (Pneumocystis jirovecii, Cryptosporidium)

5.     Labs: ↑ IgM, ↓ IgG/IgA/IgE

6.     Management:
A. IVIG
B. Antimicrobial prophylaxis
C. ± HSCT

7.     Pearls:
A. Absent germinal centers
B. Combined immunodeficiency phenotype

3. Omenn Syndrome (SCID Variant)

1.     Genetics: RAG1/RAG2 mutation (AR)

2.     Defect: Oligoclonal autoreactive T cells + defective B cells

3.     Clinical Features:
A. Erythroderma, alopecia
B. Hepatosplenomegaly
C. Chronic diarrhea

4.     Labs: Hypogammaglobulinemia, eosinophilia

5.     Management:
A. HSCT

II. B-Cell (Humoral) Deficiencies

4. X-linked Agammaglobulinemia (Bruton)

1.     Genetics: BTK mutation

2.     Inheritance: X-linked

3.     Defect: Arrest of B-cell maturation

4.     Clinical Features:
A. Male infant
B. Recurrent bacterial infections after ~6 months
C. Absent tonsils/lymph nodes

5.     Labs: ↓ all immunoglobulins, ↓/absent B cells

6.     Management:
A. IVIG

7.     Pearls:
A. Enteroviral infections (e.g., polio)
B. No germinal centers

5. Selective IgA Deficiency

1.     Genetics: Heterogeneous; usually sporadic (familial clustering may occur)

2.     Defect: Impaired mucosal immunity

3.     Clinical Features:
A. Recurrent sinopulmonary infections
B. Giardia infections
C. Atopy and autoimmune disease

4.     Labs: ↓ IgA, normal IgG/IgM

5.     Management:
A. Supportive

6.     Pearls:
A. False-negative IgA-based celiac serology
B. Risk of transfusion anaphylaxis

6. Common Variable Immunodeficiency (CVID)

1.     Genetics: Heterogeneous (AD/AR or sporadic)

2.     Defect: Impaired B-cell differentiation → ↓ plasma cells

3.     Clinical Features:
A. Adolescents/adults with recurrent infections
B. Autoimmune disease, lymphadenopathy

4.     Labs: ↓ IgG ± ↓ IgA/IgM; B-cell number often normal

5.     Management:
A. IVIG

6.     Pearls:
A. ↑ lymphoma risk
B. Variable presentation

III. T-Cell (Cell-Mediated) Deficiencies

7. DiGeorge Syndrome (22q11 Deletion)

1.     Defect: Failure of 3rd/4th pharyngeal pouch → thymic hypoplasia

2.     Clinical Features:
A. Hypocalcemia → tetany (low PTH)
B. Conotruncal cardiac defects (TOF, truncus arteriosus)
C. Cleft palate, facial dysmorphism

3.     Labs: ↓ T cells, normal immunoglobulins

4.     Management:
A. Calcium + vitamin D replacement
B. Cardiac and structural anomaly management
C. Management depends on severity
D. Complete athymia: thymus transplantation (HSCT is not effective for absent thymus)

5.     Pearls:
A. Variable severity
B. Vaccine decisions depend on T-cell function

8. Chronic Mucocutaneous Candidiasis (CMC)

1.     Genetics: Heterogeneous (e.g., STAT1 GOF, AIRE/APECED)

2.     Defect: Impaired IL-17–mediated immunity

3.     Clinical Features:
A. Chronic Candida infections (skin, nails, mucosa)
B. Autoimmune endocrinopathies (subtype-dependent, e.g., AIRE/APECED)

4.     Management:
A. Antifungals

5.     Pearls:
A. Not a single disease entity

9. Ataxia-Telangiectasia

1.     Genetics: ATM mutation (AR)

2.     Defect: Impaired DNA double-strand break repair

3.     Clinical Features:
A. Cerebellar ataxia
B. Telangiectasias
C. Recurrent infections

4.     Labs: ↑ AFP, lymphopenia, ↓ IgA (common)

5.     Pearls:
A. Radiation sensitivity
B. ↑ malignancy risk

IV. Phagocytic Defects

10. Chronic Granulomatous Disease (CGD)

1.     Defect: NADPH oxidase deficiency → impaired respiratory burst

2.     Inheritance: X-linked most common

3.     Clinical Features:
A. Recurrent abscesses
B. Granuloma formation

4.     Pathogens: Catalase-positive organisms (examples):
A. Staph aureus
B. Serratia
C. Aspergillus

5.     Labs: Abnormal DHR test

6.     Management:
A. Antibacterial + antifungal prophylaxis
B. ± IFN-γ
C. HSCT (selected cases)

7.     Pearls:
A. “Catalase-positive infections” = key clue

11. Myeloperoxidase (MPO) Deficiency

1.     Defect: Impaired HOCl production

2.     Inheritance: AR

3.     Clinical Features:
A. Usually asymptomatic

4.     Pathogens:
A. Occasionally Candida

5.     Pearls:
A. Often incidental finding

12. Wiskott–Aldrich Syndrome

1.     Genetics: WAS gene

2.     Inheritance: X-linked

3.     Defect: Cytoskeletal dysfunction → combined immunodeficiency

4.     Clinical Features:
A. Eczema
B. Recurrent infections (bacterial, viral, opportunistic)
C. Thrombocytopenia (small platelets)

5.     Labs: ↑ IgA/IgE, ↓ IgM

6.     Management:
A. HSCT

7.     Pearls:
A. Classic triad

13. Leukocyte Adhesion Deficiency (LAD)

1.     Defect: CD18 integrin deficiency → impaired leukocyte adhesion/extravasation

2.     Clinical Features:
A. Delayed umbilical cord separation
B. Recurrent infections
C. Absent pus formation

3.     Labs: Marked leukocytosis

4.     Management:
A. HSCT

14. Chediak–Higashi Syndrome

1.     Genetics: LYST mutation

2.     Defect: Defective lysosomal trafficking → impaired phagolysosome fusion

3.     Clinical Features:
A. Partial albinism
B. Recurrent infections
C. Neurologic dysfunction

4.     Labs: Giant granules in leukocytes

5.     Management:
A. HSCT

6.     Pearls:
A. “Giant granules” = hallmark

V. Complement Deficiency

15. Terminal Complement Deficiency (C5–C9)

1.     Defect: Impaired membrane attack complex (MAC) formation

2.     Clinical Features:
A. Recurrent Neisseria infections

3.     Management:
A. Vaccination
B. Prophylactic antibiotics

4.     Pearls:
A. Recurrent meningococcemia

VI. Other Immunodeficiencies

16. IL-12 Receptor Deficiency (MSMD Spectrum)

1.     Inheritance: AR

2.     Defect: Impaired Th1 → ↓ IFN-γ → defective macrophage activation

3.     Clinical Features:
A. Mycobacterial infections (TB, BCG, NTM)
B. Salmonella infections

4.     Management:
A. Antimicrobials
B. ± IFN-γ

5.     Pearls:
A. Defective Th1–macrophage axis

17. Hyper-IgE Syndrome (Job Syndrome – STAT3)

1.     Genetics: STAT3 mutation (AD)

2.     Defect: Impaired Th17 differentiation

3.     Clinical Features:
A. Eczema
B. Cold (non-inflammatory) abscesses
C. Retained primary teeth
D. Characteristic facies

4.     Labs: ↑ IgE, eosinophilia

5.     Pearls:
A. “FATED” mnemonic
B. Distinct from other Hyper-IgE syndromes