Definition/General
Introduction:
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder characterized by absence of mature B cells and profound hypogammaglobulinemia
It results from mutations in the BTK gene encoding Bruton tyrosine kinase
Patients develop recurrent bacterial infections due to antibody deficiency.
Origin:
Results from mutations in BTK gene (Xq22.1) encoding Bruton tyrosine kinase
BTK is essential for B cell development and maturation
Mutations cause developmental arrest at pre-B cell stage
T cells and other lineages develop normally
Antibody production severely impaired.
Classification:
Classified as primary antibody deficiency
X-linked form (XLA, BTK mutations)
Autosomal recessive forms (μ heavy chain, λ5, Igα, Igβ, BLNK)
Classical XLA (complete B cell absence)
Atypical XLA (some residual B cells).
Epidemiology:
Incidence approximately 1 in 190,000 male births
X-linked inheritance affects only males
Carrier females typically asymptomatic
Early onset infections (6-18 months)
Good prognosis with immunoglobulin replacement.
Clinical Features
Presentation:
Recurrent bacterial infections (sinopulmonary)
Absence of lymphadenopathy and tonsils
Normal growth initially
Chronic diarrhea (enteroviral)
Arthritis (mycoplasma, enterovirus)
No allergies or autoimmunity.
Symptoms:
Recurrent pneumonia and sinusitis
Otitis media
Skin and soft tissue infections
Meningoencephalitis (enteroviral)
Chronic conjunctivitis
Growth retardation (if untreated).
Risk Factors:
X-linked inheritance (maternal transmission)
Family history of immunodeficiency
Male gender
Early onset infections
Absent B cells
Hypogammaglobulinemia.
Screening:
Immunoglobulin levels (markedly low)
B cell enumeration (absent CD19+ cells)
Vaccine responses (absent)
BTK protein expression
Genetic testing
Family screening.
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Gross Description
Appearance:
Bone marrow aspirate shows normal cellularity
Absent mature B cells
Pre-B cells may be present
Normal T cells, granulocytes, erythroid cells
No plasma cells.
Characteristics:
Selective B cell lineage defect
Normal other hematopoietic lineages
Absent lymphoid follicles
Normal bone marrow architecture
No hypoplastic changes.
Size Location:
Absent/rudimentary lymph nodes
Small spleen
Absent tonsils
Normal bone marrow distribution
Thymus normal.
Multifocality:
Systemic B cell absence
All lymphoid organs affected
Preserved T cell areas
Consistent findings across sites
Stable over time.
Microscopic Description
Histological Features:
Absent mature B cells (CD19+, CD20+)
Pre-B cells present but reduced
Normal T cell numbers
Normal granulopoiesis and erythropoiesis
Absent plasma cells.
Cellular Characteristics:
Developmental arrest at pre-B to immature B cell transition
Normal early B cell precursors
Morphologically normal T cells
Normal other lineages
No dysplastic changes.
Architectural Patterns:
Preserved bone marrow architecture
Normal cellular distribution
Absent B cell zones in lymphoid organs
Normal T cell areas
No inflammatory infiltrates.
Grading Criteria:
Severity by B cell count: Severe (<2% of normal)
Immunoglobulin levels: IgG <200 mg/dL
BTK expression absent/reduced
Vaccine responses absent
Infections frequency high.
Immunohistochemistry
Positive Markers:
CD3 shows normal T cells
MPO highlights granulopoiesis
Glycophorin A shows erythropoiesis
CD34 shows stem cells
Early B cell markers (CD10, TdT) may be present.
Negative Markers:
CD19 and CD20 (mature B cells absent)
CD138 (plasma cells absent)
BTK protein absent/reduced
Immunoglobulin heavy chains absent
Memory B cell markers absent.
Diagnostic Utility:
Demonstrates B cell absence
Shows normal T cells
Confirms BTK deficiency
Identifies developmental arrest
Excludes other immunodeficiencies
Monitors treatment response.
Molecular Subtypes:
Classical XLA (complete BTK deficiency)
Variant XLA (partial function)
Atypical presentations
Late-onset XLA
Different mutation types.
Molecular/Genetic
Genetic Mutations:
BTK gene mutations (Xq22.1)
Missense mutations (65% cases)
Nonsense mutations (15% cases)
Splice site mutations (10% cases)
Deletions and insertions (10% cases)
Over 600 mutations described.
Molecular Markers:
Absent or reduced BTK protein
Defective B cell signaling
Arrested B cell development
Normal T cell function
Absent antibody responses
Normal cellular immunity.
Prognostic Significance:
Good prognosis with treatment
Normal life expectancy with IVIG
Risk of chronic complications
Enteroviral infections problematic
Pulmonary complications long-term
Gene therapy promising.
Therapeutic Targets:
Immunoglobulin replacement (IVIG/SCIG)
Antimicrobial prophylaxis
Vaccination (killed vaccines only)
Gene therapy (experimental)
Supportive care
Infection monitoring.
Differential Diagnosis
Similar Entities:
Common variable immunodeficiency
Transient hypogammaglobulinemia
Severe combined immunodeficiency
Hyper-IgM syndrome
Good syndrome
Autosomal agammaglobulinemia.
Distinguishing Features:
XLA: X-linked inheritance
XLA: Absent B cells
XLA: BTK mutations
CVID: Variable B cells
CVID: Later onset
SCID: T cell deficiency
HIGM: IgM elevated
THI: Transient nature.
Diagnostic Challenges:
Confirming BTK deficiency
Distinguishing from other antibody deficiencies
Carrier detection
Prenatal diagnosis
Genetic counseling
Treatment monitoring.
Rare Variants:
Atypical XLA with some B cells
Late-onset XLA
XLA with autoimmunity
Leaky mutations
Female XLA (X-inactivation).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
X-Linked Agammaglobulinemia
Classification
Classification: Primary antibody deficiency with B cell developmental arrest
Bone Marrow Cellularity
Cellularity: [X]% for age (normal), with absent mature B cells
Lineage Assessment
B cell lineage: absent mature B cells (CD19-, CD20-). T cells: normal. Other lineages: normal
Morphological Features
Shows selective absence of mature B cells with normal other hematopoietic lineages
Special Studies
Flow cytometry: absent CD19+/CD20+ B cells
BTK protein: [absent/reduced]
Genetic testing: recommend BTK gene analysis
Clinical Correlation
Findings consistent with X-linked agammaglobulinemia. Recommend genetic counseling
Final Diagnosis
Bone marrow showing B cell developmental arrest consistent with X-linked agammaglobulinemia