• Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Recurrent infections in males during infancy or early childhood

Laboratory Testing

  • Nonspecific testing
    • CBC to rule out congenital neutropenic disorders
      • May observe severe neutropenia in 10-20% of patients if performed when patient has an infection
    • 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
    Specific testing
    • Bruton tyrosine kinase (BTK) protein expression by flow cytometry – if protein expression is absent or reduced, suggests X-linked agammaglobulinemia (XLA) in males
    • Gene mutation analysis
      • Presence of BTK gene mutation is confirmatory
      • Other gene mutations causative for agammaglobulinemia are typically autosomal recessive (eg, BLNK deficiency), but autosomal dominant mutations may be difficult to differentiate from X-linked disease (eg, LRRC8A mutations)

Differential Diagnosis

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


  • 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


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
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.

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


If low IgG, IgM, or IgA, consider ordering B-cell memory and naive panel 

B-Cell Memory and Naive Panel 2008901
Method: Flow Cytometry

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

Bruton Tyrosine Kinase (BTK) Protein Expression by Flow Cytometry 2012002
Method: Qualitative Flow Cytometry


Normal expression of BTK protein

  • Occurs in 20-30% of patients with XLA due to truncated or inactive BTK protein with abnormal function; genetic analysis is recommended
  • Does not exclude mutations or defective protein function
  • Does not rule out XLA in males
  • Does not rule out XLA carrier status in females

Primary Antibody Deficiency Panel, Sequencing (35 Genes) and Deletion/Duplication (26 Genes) 2011156
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray


Not determined or evaluated – mutations in genes not included on the panel; deep intronic and regulatory region mutations; breakpoints for large deletions/duplications; translocations

Deletions/duplications will not be detected in IKBKG, LRBA, LRRC8A, PIK3CD, PIK3R1, PLCG2, PRKCD, SH2D1A, or XIAP/BIRC4 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of primary antibody deficiency

General References

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

Chun J, Lee TJ, Song JW, Linton JA, Kim DS. Analysis of clinical presentations of Bruton disease: a review of 20 years of accumulated data from pediatric patients at Severance Hospital. Yonsei Med J. 2008; 49(1): 28-36. PubMed

Conley M, Howard V. X-Linked Agammaglobulinemia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Nov 2011; Accessed: Nov 2015]

Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Lougaris V, Ferrari S, Cattalini M, Soresina A, Plebani A. Autosomal recessive agammaglobulinemia: novel insights from mutations in Ig-beta. Curr Allergy Asthma Rep. 2008; 8(5): 404-8. PubMed

Medical Reviewers

Last Update: July 2017