Bruton Agammaglobulinemia - X-Linked Agammaglobulinemia

Dx
Background
Lab Tests
Algorithm

Diagnosis

Indications for Testing

Recurrent infections during infancy or early childhood in males

Laboratory Testing

Nonspecific testing – CBC to rule out neutropenic disorders
- May observe severe neutropenia in 10-20% of patients if performed when patient is infected
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
B-cell immunodeficiency profile measures surface immunoglobulin on B-cells – absent in Bruton
Gene mutation analysis
- Presence of BTK mutation is confirmatory
- Not necessary if above tests are positive

Differential Diagnosis

X-linked hyper IgM syndrome
X-linked s evere combined immunodeficiencies
X-linked lymphoproliferative disorder

Clinical Background

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

Epidemiology

Incidence – 1-2/100,000 male births per year
Age
- 50% diagnosed by 2 years
- 80% diagnosed by school age
Sex – >99% male
Ethnicity – most commonly diagnosed in Caucasians

Risk Factors

Genetics
- X-linked recessive inheritance
  - Several mutations in Bruton tyrosine kinase (BTK) gene reported

Pathophysiology

Mutation in BTK gene coding
- Genetic defect 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 caused by encapsulated bacteria and enteroviruses
  - H. influenzae
  - Streptococcus pneumoniae
  - Staphylococcus aureus
  - Gram-negative bacteria
  - Enteroviruses (not prone to severe infection with other viruses)
    - Encapsulated bacteria
    - 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 of disease – infections of upper respiratory airways
- Otitis media
- Sinusitis
- Pneumonia
Other common infections
- Conjunctivitis
- Chronic – recurrent diarrhea
- Skin infections
Life-threatening infections uncommon
- Sepsis
- Meningitis/encephalitis
- Septic arthritis/osteomyelitis

Treatment

Early initiation of therapy is crucial to ensure positive outcome
Intravenous gammaglobulin is mainstay of treatment
Prophylactic antibiotics
Prevention of secondary complications
- Avoid vaccinations with live virus (eg, oral polio vaccine) in affected child and siblings

Indications for Laboratory Testing

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

Test Name and Number	Recommended Use	Follow Up
CBC with Platelet Count and Automated Differential 0040003 Method: Automated Cell Count/Differential	Assess for neutropenic disorders
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630 Method: Quantitative Nephelometry	Initial test in the workup of immunoglobulin disorders Test components include serum quantitative IgA, IgG, IgE, and IgM	If low IgG, IgM or IgA, consider ordering B-cell immunodeficiency profile
B-Cell Immunodeficiency Profile 0095940 Method: Quantitative Flow Cytometry	Useful followup to abnormal immunoglobulins testing Measures surface immunoglobulin on B cells
Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862 Method: Quantitative Flow Cytometry	Preferred lymphocyte subset panel for the investigation of primary 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
Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899 Method: Quantitative Flow Cytometry	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