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
- IgG typically <200 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
- CBC with white blood cell differential
- 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
- Gene variant analysis
Differential Diagnosis
- X-linked hyper IgM syndrome
- X-linked severe combined immunodeficiency
- X-linked lymphoproliferative disease
- HIV
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
- Encapsulated bacteria
- Haemophilus influenzae
- Streptococcus pneumoniae
- Staphylococcus aureus
- Gram-negative bacteria
- Enteroviruses
- Giardia duodenalis
- Unusual pathogens – Helicobacter cinaedi
- Encapsulated bacteria
- Leads to impaired development of mature B-cell lymphocytes
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
ARUP Laboratory 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
Quantitative Immunoturbidimetry
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
Flow Cytometry
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
Quantitative Flow Cytometry
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
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Initial screening for immunodeficiency
Rule out congenital neutropenic disorders
Automated Cell Count/Differential
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
Quantitative Flow Cytometry
Medical Experts
Delgado

Wittwer

References
24795713
Al-Herz W, Bousfiha A, Casanova JL, et al. 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.
18306466
IDF - Diagnostic & Clinical Care Guidelines for Primary Immunodeficiencies
24569953
Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014;46(2):154-168.
18682105
GeneReviews - X-linked Agammaglobulinemia
Smith CIE, Berglöf A. X-linked agammaglobulinemia. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Aug 2016; Accessed: Feb 2020]
Test components include serum quantitative IgA, IgG, and IgM