Immunology

Question 1

List the major pediatric primary immunodeficiencies along with their mode of inheritance.

Answer 1

• B-cell (Humoral) Disorders:
  
  • X-linked Agammaglobulinemia (XLA): X-linked recessive
  • Common Variable Immunodeficiency (CVID): Mostly sporadic / Autosomal recessive
  • Selective IgA Deficiency: Sporadic / possibly Autosomal dominant
  • Hyper IgM Syndrome (CD40L defect): X-linked recessive
• T-cell Disorders:
  
  • DiGeorge Syndrome (22q11.2 deletion): Sporadic / Autosomal dominant
• Combined B & T-cell Disorders (SCID spectrum):
  
  • Severe Combined Immunodeficiency (SCID): X-linked (IL2RG) or Autosomal recessive
  • ADA-SCID (Adenosine Deaminase Deficiency): Autosomal recessive
  • Omenn Syndrome: Autosomal recessive
  • Wiskott-Aldrich Syndrome: X-linked recessive
• Phagocytic Defects:
  
  • Chronic Granulomatous Disease (CGD): X-linked recessive (70%) / Autosomal recessive
  • Leukocyte Adhesion Deficiency (LAD): Autosomal recessive
  • Chediak-Higashi Syndrome: Autosomal recessive
• Complement Deficiencies:
  
  • Complement C2, C3, C5–C9 Deficiencies: Autosomal recessive
• Immune Dysregulation Syndromes:
  
  • IPEX Syndrome (FOXP3 mutation): X-linked recessive
• DNA Repair Disorders with Immunodeficiency:
  
  • Ataxia Telangiectasia: Autosomal recessive
• Others:
  
  • Hyper IgE Syndrome (Job Syndrome): Autosomal dominant or recessive

Question 2

List the key clinical features of major pediatric primary immunodeficiencies.

Answer 2

• X-linked Agammaglobulinemia (XLA): Recurrent bacterial infections, absent tonsils/lymph nodes, ↓ Ig levels
• CVID: Sinopulmonary infections, autoimmune diseases, lymphadenopathy
• Selective IgA Deficiency: Recurrent mucosal infections, anaphylaxis to blood products, often asymptomatic
• Hyper IgM Syndrome: Pneumocystis infections, sinopulmonary infections, neutropenia
• SCID: Early onset infections, chronic diarrhea, failure to thrive, absent thymic shadow
• ADA-SCID: Severe infections, neurological deficits, lymphopenia
• Omenn Syndrome: Erythroderma, eosinophilia, hepatosplenomegaly, severe infections
• Wiskott-Aldrich Syndrome: Eczema, thrombocytopenia, recurrent infections
• DiGeorge Syndrome: Cardiac defects, hypocalcemia, absent thymus, facial anomalies
• ZAP-70 Deficiency: Normal CD8+, low/absent CD4+ response, severe viral infections
• IL-12 Receptor Deficiency: Recurrent mycobacterial and Salmonella infections
• IFN-γ Receptor Deficiency: Disseminated BCG or mycobacterial infections
• CGD: Deep abscesses, catalase+ organism infections, granuloma formation
• LAD: Delayed umbilical cord separation, no pus formation, recurrent skin infections
• Chediak-Higashi Syndrome: Partial albinism, neuropathy, giant granules, bleeding
• Complement Deficiencies: Recurrent Neisseria infections, autoimmune diseases
• IPEX Syndrome: Severe autoimmunity (enteropathy, T1DM, dermatitis) in infancy
• ALPS: Chronic lymphadenopathy, hepatosplenomegaly, cytopenias
• Ataxia Telangiectasia: Ataxia, telangiectasia, recurrent infections, ↑ AFP
• Hyper IgE Syndrome (Job): Coarse facies, eczema, retained teeth, lung abscesses

Question 3

What are the characteristic laboratory findings in major pediatric primary immunodeficiencies?

Answer 3

• X-linked Agammaglobulinemia (XLA): Low/absent B cells (CD19+), very low IgG/IgA/IgM, absent tonsils
• CVID: Low IgG with low IgA and/or IgM, normal or reduced B cell numbers, poor vaccine response
• Selective IgA Deficiency: Isolated low IgA, normal IgG/IgM
• Hyper IgM Syndrome: Elevated/normal IgM, low IgG/IgA, defective CD40L (on T cells)
• SCID: Low/absent T cells (CD3+), B and/or NK cell abnormalities (depending on subtype), very low TRECs
• ADA-SCID: Severe lymphopenia, absent T/B/NK cells, ↑ toxic metabolites (adenosine/deoxyadenosine)
• Omenn Syndrome: Elevated eosinophils, high IgE, oligoclonal T cells
• Wiskott-Aldrich Syndrome: Low/normal IgG, ↓ IgM, ↑ IgA/IgE, small platelets with thrombocytopenia
• DiGeorge Syndrome: Low/absent T cells, low calcium, absent thymic shadow on CXR
• CGD: Abnormal neutrophil oxidative burst (NBT or DHR test)
• LAD: High neutrophil count, absent CD18 on leukocytes (flow cytometry)
• Chediak-Higashi Syndrome: Giant granules in neutrophils, partial albinism
• Complement Deficiencies: Specific complement component deficiency (CH50/AP50 low depending on type)
• IPEX Syndrome: ↑ IgE, eosinophilia, ↓ FOXP3+ Tregs
• Ataxia Telangiectasia: ↑ AFP, ↓ IgA/IgE, lymphopenia
• Hyper IgE Syndrome (Job): ↑ IgE (>2000 IU/mL), eosinophilia, poor response to IL-6

Question 4

What are the immunologic defects in major pediatric primary immunodeficiencies?

Answer 4

• X-linked Agammaglobulinemia (XLA): BTK gene mutation → failure of B-cell maturation
• CVID: Unknown cause; impaired B-cell differentiation and defective antibody production
• Selective IgA Deficiency: Unknown defect in IgA class switching
• Hyper IgM Syndrome: CD40L (on T cells) mutation → defective isotype switching in B cells
• SCID (X-linked): IL2RG gene mutation → defective cytokine signaling → absent T/NK cells
• ADA-SCID: ADA enzyme deficiency → toxic purine metabolites → lymphocyte apoptosis
• Omenn Syndrome: RAG1/2 mutation → impaired V(D)J recombination → oligoclonal T cells
• Wiskott-Aldrich Syndrome: WAS gene mutation → defective actin cytoskeleton in immune cells
• DiGeorge Syndrome: 22q11 deletion → defective thymic development → T-cell deficiency
  Th1 differentiation → ↓ IFN-γ
• CGD: NADPH oxidase complex defect → impaired ROS production in phagocytes
• LAD: Defective CD18/β2 integrins → impaired neutrophil adhesion and migration
• Chediak-Higashi Syndrome: LYST gene mutation → impaired lysosomal trafficking
• Complement Deficiencies: Genetic loss of individual complement proteins (C2, C3, etc.)
• IPEX Syndrome: FOXP3 mutation → absence of regulatory T cells
• Ataxia Telangiectasia: ATM gene mutation → defective DNA repair and T-cell development
• Hyper IgE Syndrome (Job): STAT3 mutation → impaired Th17 cell differentiation

Question 5

What are the treatment strategies for major pediatric primary immunodeficiencies?

Answer 5

• X-linked Agammaglobulinemia (XLA): IVIG/SCIG lifelong, prompt antibiotics
• CVID: Regular IVIG/SCIG, monitor for autoimmunity and malignancy
• Selective IgA Deficiency: Usually none; treat infections, avoid IgA-containing blood products
• Hyper IgM Syndrome: IVIG, PCP prophylaxis, hematopoietic stem cell transplant (HSCT) for severe cases
• SCID: Isolation, broad-spectrum antimicrobials, IVIG, urgent HSCT or gene therapy (ADA)
• ADA-SCID: PEG-ADA enzyme replacement, HSCT, or gene therapy
• Omenn Syndrome: Immunosuppression (e.g., steroids), followed by HSCT
• Wiskott-Aldrich Syndrome: IVIG, platelet transfusions, HSCT is curative
• DiGeorge Syndrome: Calcium and vitamin D, thymic transplant (complete forms), avoid live vaccines
• CGD: Prophylactic antibiotics/antifungals, IFN-γ therapy, HSCT in severe cases
• LAD: Antibiotics, HSCT is curative
• Chediak-Higashi Syndrome: HSCT (only improves hematologic/immunologic features), antibiotics
• Complement Deficiencies: Vaccination (especially meningococcal), prophylactic antibiotics
• IPEX Syndrome: Immunosuppression (e.g., steroids, calcineurin inhibitors), HSCT
• Ataxia Telangiectasia: Supportive, IVIG for immunodeficiency, avoid radiation
• Hyper IgE Syndrome (Job): Antibiotics for skin/lung infections, IVIG in some cases

Question 6

What is the prognosis of major pediatric primary immunodeficiencies?

Answer 6

• X-linked Agammaglobulinemia (XLA): Good with IVIG and infection control; normal life expectancy possible
• CVID: Variable; risk of chronic lung disease, autoimmunity, and lymphoma
• Selective IgA Deficiency: Usually excellent; some develop CVID or autoimmunity
• Hyper IgM Syndrome: Moderate to poor without HSCT; improved with early HSCT
• SCID: Fatal in infancy if untreated; excellent prognosis with early HSCT or gene therapy
• ADA-SCID: Good if treated early with gene therapy, PEG-ADA, or HSCT
• Omenn Syndrome: Poor without HSCT; survival improves with early transplant
• Wiskott-Aldrich Syndrome: Poor without HSCT due to infections, bleeding, and malignancies
• DiGeorge Syndrome: Variable; complete form is fatal without thymic transplant
• CGD: Variable; improved with prophylaxis and HSCT
• LAD: Poor without HSCT; high risk of sepsis
• Chediak-Higashi Syndrome: Poor in accelerated phase; HSCT can improve outcome
• Complement Deficiencies: Good with proper vaccination and antibiotic prophylaxis
• IPEX Syndrome: Poor without HSCT; fatal in infancy due to autoimmunity
• Ataxia Telangiectasia: Poor due to progressive neurodegeneration and cancer risk
• Hyper IgE Syndrome (Job): Moderate; recurrent infections and complications reduce quality of life