Bruton Agammaglobulinemia - X-Linked Agammaglobulinemia

Diagnostic Algorithm

Clinical Background

Bruton agammaglobulinemia or X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by recurrent bacterial infections in affected males.

Epidemiology

• Incidence – 1-2/100,000 male births per year
• Age  
  • 50% diagnosed by 2 years
  • 80% are diagnosed by school age
• Sex – male, >99%
• Ethnicity – most commonly diagnosed in Caucasians

Risk Factors

• Genetics
  • X-linked recessive inheritance
    • Several mutations in the Bruton tyrosine kinase (BTK) gene have been reported

Pathophysiology

• Mutation in gene coding for BTK
  • Genetic defect leads to deficient development of B-cell lymphocytes and marked reduction in all classes of immunoglobulins
    • B-cell development in bone marrow is blocked at the pro-B-cell stage to the pre-B-cell stage
  • Hypogammaglobulinemia results in predisposition to life-threatening infections caused by encapsulated bacteria and enteroviruses
    • H. influenzae
    • Streptococcus pneumoniae
    • Staphylococcus aurens
    • Gram-negative bacteria
    • Enteroviruses (not prone to severe infection with other viruses)
      • Encapsulated bacteria
      • Giardia lamblia
      • Unusual pathogens – Helicobacter cinaedi

Clinical Presentation

• Infants are usually asymptomatic during the first 3 months of life due to passive transfer of immunoglobulins by their mothers
• Most common clinical presentation of disease – infections of the upper respiratory airways
  • Otitis media
  • Sinusitis
  • Pneumonia
• Other common infections
  • Conjunctivitis
  • Chronic – recurrent diarrhea
  • Skin infections
• Life-threatening infections are uncommon
  • Sepsis
  • Meningitis/encephalitis
  • Septic arthritis/osteomyelitis

Treatment

• Early initiation of therapy is crucial to ensure good outcomes
• Intravenous gammaglobulin is mainstay of treatment
• Prophylactic antibiotics
• Prevention of secondary complications
  • Avoid vaccinations with live virus (eg, oral polio vaccine [OPV]) in affected child and siblings

Diagnosis

• Indications for testing – recurrent infections in infancy or early childhood of males
• Laboratory testing
  • Nonspecific testing – CBC to rule out neutropenic disorders
    • If performed when patient is infected, may note severe neutropenia in 10-20%
  • Immunoglobulin testing – quantitative
    • IgG typically <200 mg/dL; most between 100-200 mg/dL; 10% ≥200 mg/dL
    • IgM and IgA typically <20 mg/dL
    • Antibody titers to vaccination – typically none found
  • Lymphocyte cell surface markers – significantly decreased CD19+ cells (B lymphocytes) <1% in circulation
  • B-cell immunodeficiency profile measures surface immunoglobulin on B-cells, which is absent in Bruton
  • Gene mutation analysis
    • Presence of BTK mutation is confirmatory 
    • Not necessary if the above tests are positive

Differential Diagnosis

• X-linked hyper IgM syndrome
• X-linked severe combined immunodeficiencies
• X-linked lymphoproliferative disorder

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

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Test Name and Number	Comments
Immunoglobulins, CSF Quantitative 0050631 Method: Nephelometry

Guidelines

General References