Bruton Agammaglobulinemia - X-Linked Agammaglobulinemia

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 diptheria 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 severe combined immunodeficiencies
X-linked lymphoproliferative disorder

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

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Assess for neutropenic disorders

Test name: Immunoglobulins (IgA, IgG, IgM), Quantitative

ARUP #: 0050630

Methodology: Quantitative Nephelometry

Use:

Initial test to assess for immunoglobulin deficiency

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

Limitations:

Other X-linked disorders (eg, X-linked hyper IgM syndrome)

Test name: Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies

ARUP #: 0095899

Methodology: Quantitative Flow Cytometry

Use:

Secondary assessment after diagnosis of hypogammaglobulinemia or agammaglobulinemia

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 (suppressor T-cells), CD19 (B-cells ), NK cells, and CD4:CD8 ratio

Test name: B-Cell Immunodeficiency Profile

ARUP #: 0095940

Methodology: Quantitative Flow Cytometry

Use:

Measure surface immunoglobulin on B-cells

Additional Tests Available

Test name: Immunoglobulins, CSF Quantitative

ARUP #: 0050631

Methodology: Quantitative Nephelometry

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