Agammaglobulinemia

Agammaglobulinemia, also known as Bruton agammaglobulinemia, X-linked agammaglobulinemia (XLA), or Bruton tyrosine kinase (BTK) deficiency, is a primary immunodeficiency characterized by recurrent bacterial infections in affected males. Laboratory testing includes nonspecific tests, such as immunoglobulin testing, and more specific testing, such as gene variant analysis.

Quick Answers for Clinicians

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

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

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
  • Other common infections
    • Conjunctivitis
    • Chronic, recurrent diarrhea
    • Cellulitis
  • Life-threatening infections uncommon

ARUP Lab Tests

Primary Tests

Initial test in the workup of immunoglobulin disorders

Order in conjunction with serum protein electrophoresis and immunofixation to rule out plasma cell dyscrasia in adults and older children (>15 years) with suspected hypogammaglobulinemia

Test components include serum quantitative IgA, IgG, and IgM

Assess B-cell subsets in immunodeficiencies (eg, common variable immunodeficiency [CVID], B-cell reconstitution after bone marrow or hematopoietic stem cell transplantation)

Supports the diagnosis of CVID and may help predict the clinical phenotype

Assess B-cell reconstitution after bone marrow or hematopoietic stem cell transplantation

Measures B cells (CD19+), total memory B cells (CD19+/CD27+), class-switched memory B cells (CD19+/CD27+/IgD-), nonswitched/marginal-zone memory B cells (CD19+/CD27+/IgD+), and naive B cells (CD19+/CD27-/IgD+)

Not recommended for rituximab monitoring; refer to B-cell CD20 expression test

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

Panel 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

Determine the genetic etiology of a primary antibody deficiency (eg, agammaglobulinemia, hyper IgM syndrome, CVID, atypical severe combined immunodeficiency, or other related immunodeficiency disorders) in affected individuals

Refer to the Test Fact Sheet for a list of genes tested

Refer to the Test Fact Sheet for a list of limitations

Related Tests

Initial screening for immunodeficiency

Rule out congenital neutropenic disorders

Assess 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

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Professor of Clinical Pathology, University of Utah
Chief, Division of Clinical Pathology, University of Utah and ARUP Laboratories
Chief Medical Officer and Director of Laboratories at ARUP Laboratories
Contributor

References

Additional Resources