Agammaglobulinemia

  • Diagnosis
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  • Background
  • Lab Tests
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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.

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

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

Recommended Use 

Initial test in the workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation

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

Follow-up 

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

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

Recommended Use 

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

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

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 naïve B cells (CD19+/CD27-/IgD+)

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

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

Recommended Use 

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

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

Recommended Use 

Preferred test for initial screening for individuals with clinical suspicion of X-linked agammaglobulinemia/hypogammaglobulinemia   

Limitations 

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

Agammaglobulinemia Panel, Sequencing (9 Genes) and Deletion/Duplication (6 Genes) 2011151
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Recommended Use 

Preferred test for individuals with clinical phenotype of agammaglobulinemia

Genes sequenced – BLNK, BTK, CD79A, CD79B, IGHM, IGLL1, LRRC8A, PIK3R1, SH2D1A

Genes analyzed for deletions/duplications – BLNK, BTK, CD79A, CD79B, IGHM, IGLL1

Clinical sensitivity – ~90%

Analytical sensitivity/specificity – >99% for sequencing and deletion/duplication analysis

Limitations 

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 LRRC8A, PIK3R1, SH2D1A

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of detectable gene mutation does not exclude diagnosis of agammaglobulinemia

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

Recommended Use 

Preferred test for individuals with clinical phenotype of primary antibody deficiency, agammaglobulinemia, hyper IgM syndrome, common variable immunodeficiency (CVID), atypical severe combined immunodeficiency, other related immunodeficiency disorder

Genes sequenced –  ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, IKBKG, LRBA, LRRC8A, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PIK3CD, PIK3R1, PLCG2, PRKCD, PTPRC, RAG2, SH2D1A, TNFRSF13B, TNFRSF13C, UNG, VAV1, XIAP/BIRC4

Genes analyzed for deletions/duplications – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PTPRC, RAG2, TNFRSF13B, TNFRSF13C, UNG, VAV1

Clinical sensitivity –

  • CVID – 20%
  • Hyper IgM syndrome – 75-80%
  • Agammaglobulinemia – 90%

 Analytical specificity/sensitivity – sequencing and deletion/duplication analysis – >99%

Limitations 

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

Delgado, Julio, MD, MS, Head, Histocompatibility and Immunogenetics; Section Chief, Immunology Division at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Heikal, Nahla, MD, MS, Assistant Medical Director, Immunology and Hemostasis/Thrombosis at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Kumanovics, Attila, MD, Assistant Medical Director, Co-Director, Immunology Laboratory, Immunogenetics at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Wittwer, Carl T., MD, PhD, Medical Director and Technical Vice President, General Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Chronic Granulomatous Disease - CGD
Common Variable Immune Deficiency Syndromes - CVID
Complement Deficiency
Congenital Neutrophil Disorders
Immunodeficiency, TLR-Signaling Defects
Immunoglobulin Disorders
Leukocyte Adhesion Deficiency
Severe Combined Immunodeficiencies - SCID
T-Cell Deficiency Disorders, Inherited

Last Update: August 2016

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