Bruton Agammaglobulinemia - X-Linked Agammaglobulinemia

Diagnosis

Indications for Testing

  • Recurrent infections during infancy or early childhood in males

Laboratory Testing

  • Nonspecific testing – CBC to rule out neutropenic disorders
    • May observe severe neutropenia in 10-20% of patients if performed when patient is infected
  • 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
    • Response to vaccination (polyvalent pneumococcal or diphtheria toxoid) – typically no response
  • Lymphocyte cell surface markers – significantly decreased CD19+ cells (B lymphocytes); <1% in circulation
  • B-cell immunodeficiency profile measures surface immunoglobulin on B-cells – absent in Bruton
  • Gene mutation analysis
    • Presence of BTK mutation is confirmatory 
    • Not necessary if above tests are positive

Differential Diagnosis

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% diagnosed by school age
  • Sex – >99% male
  • Ethnicity – most commonly diagnosed in Caucasians

Risk Factors

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

Pathophysiology

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 of disease – infections of upper respiratory airways
  • Other common infections
    • Conjunctivitis
    • Chronic – recurrent diarrhea
    • Skin infections
  • Life-threatening infections uncommon

Treatment

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

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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Assess for neutropenic disorders

   
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Initial test in the workup of immunoglobulin disorders

Test components include serum quantitative IgA, IgG, IgE, and IgM

 

If low IgG, IgM or IgA, consider ordering B-cell immunodeficiency profile

B-Cell Immunodeficiency Profile 0095940
Method: Quantitative Flow Cytometry

Useful in supporting diagnosis of primary B-cell immunodeficiency disorders, including bare lymphocyte syndrome and agammaglobulinemia

Measures circulating B-cells (CD19), their surface immunoglobulins (Total Ig, IgG, IgD, IgM, and IgA) and a common HLA class II antigen

   
Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Useful for assessing primary T-cell immunodeficiency disorders

Measures percentage and absolute numbers of CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4: CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells

   
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

Test includes percentage and absolute counts for CD2, CD3 (total T cells), HLA-DR, CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD19 (B cells ), NK cells, and  CD4:CD8 ratio

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Immunoglobulins, CSF Quantitative 0050631
Method: Quantitative Nephelometry