Agammaglobulinemia

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

X-linked hyper IgM syndrome
X-linked severe combined immunodeficiency
X-linked lymphoproliferative disease
HIV

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

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

BTK gene mutation – X-linked inheritance
- 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 pro-B-cell stage to pre-B-cell stage
- Hypogammaglobulinemia results in predisposition to life-threatening infections
  - Encapsulated bacteria
  - Gram-negative bacteria
  - Enteroviruses
  - Giardia duodenalis
  - Unusual pathogens – Helicobacter cinaedi

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
- Otitis media
- Sinusitis
- Pneumonia/empyema
Other common infections
- Conjunctivitis
- Chronic, recurrent diarrhea
- Cellulitis
Life-threatening infections uncommon
- Sepsis
- Meningitis/encephalitis
- Septic arthritis/osteomyelitis

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

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 genetic test for individual with clinical phenotype of primary antibody deficiency (eg, agammaglobulinemia, hyper-IgM syndrome, or common variable immunodeficiency)

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%

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