Agammaglobulinemia

Diagnosis

Indications for Testing

• Recurrent infections in males during infancy or early childhood
  • Respiratory tract (lungs, ears, sinuses)
  • Meningitis
  • Sepsis
  • Gastrointestinal
  • Cutaneous infections

Laboratory Testing

• Nonspecific testing
  • CBC with white blood cell differential
    • Severe neutropenia seen in 10-20% of patients if performed when patient has an infection  
  • Immunoglobulin testing – quantitative IgG, IgM, IgA, and IgE
    • IgG typically <200 mg/dL
      • Most between 100-200 mg/dL
      • 10% ≥200 mg/dL
    • IgM and IgA typically <20 mg/dL
  • Measurement of specific antibodies to vaccine
    • Test protein and polysaccharide vaccines (polyvalent pneumococcal or diphtheria toxoid)
    • Typically no response to vaccination
  • Isohemagglutinin testing
    • Absent in all but type AB individuals
    • Presence is suggestive of antibody deficiency disorder
  • Lymphocyte cell surface markers
    • Significantly decreased CD19+ cells (B lymphocytes)
    • <1% in circulation
• Specific testing
  • Gene variant analysis
    • Presence of BTK gene variant is confirmatory
    • Other gene variants causative for agammaglobulinemia are typically autosomal recessive (eg, BLNK deficiency), but autosomal dominant variants may be difficult to differentiate from X-linked disease (eg, LRRC8A variants)
  • Bruton tyrosine kinase (BTK) protein expression by flow cytometry – if protein expression is absent or reduced, suggests X-linked agammaglobulinemia (XLA) in males

Differential Diagnosis

• X-linked hyper IgM syndrome
• X-linked severe combined immunodeficiency
• X-linked lymphoproliferative disease
• HIV

Background

Epidemiology

• Incidence – estimated 1/250,000-700,000 male births
• Age
  • 50% diagnosed by 2 years
  • 80% diagnosed by 5 years
• Sex – >99% male
• Ethnicity – most commonly diagnosed in Caucasians

Pathophysiology

• BTK gene mutation – X-linked inheritance
  • Leads to impaired development of mature B-cell lymphocytes
    • B-cell development in bone marrow is blocked at pro-B-cell stage to pre-B-cell stage
  • Results in marked reduction in all classes of immunoglobulins (B-cell products)
  • Hypogammaglobulinemia results in predisposition to life-threatening infections, especially
    • Encapsulated bacteria
      • Haemophilus influenzae
      • Streptococcus pneumoniae
      • Staphylococcus aureus
    • Gram-negative bacteria
    • Enteroviruses
    • Giardia duodenalis
    • Unusual pathogens – Helicobacter cinaedi

Clinical Presentation

• Infants are usually asymptomatic during first 3 months of life due to passive transfer of immunoglobulins by their mothers
• Most common clinical presentation is respiratory infections with encapsulated organisms
  • Otitis media
  • Sinusitis
  • Pneumonia/empyema
• Other common infections
  • Conjunctivitis
  • Chronic, recurrent diarrhea
  • Cellulitis
• Life-threatening infections uncommon
  • Sepsis
  • Meningitis/encephalitis
  • Septic arthritis/osteomyelitis