X-linked (Bruton) agammaglobulinemia
X-linked agammaglobulinemia is a BTK gene defect that arrests B-cell maturation, producing absent peripheral B cells and panhypogammaglobulinemia in boys with recurrent sinopulmonary infection after 6 months of age. Diagnosis rests on quantitative immunoglobulins, B-cell flow cytometry, and BTK sequencing; treatment is lifelong immunoglobulin replacement plus prompt antibiotics and avoidance of live vaccines.
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What this article covers
- Overview
Prototypical B-cell primary immunodeficiency: X-linked (Bruton) agammaglobulinemia (XLA) results from a defect in Bruton tyrosine kinase (BTK), an enzyme required for pre-B-cell receptor signaling…
- Epidemiology
Rare but the classic X-linked B-cell defect: one of the more commonly recognized primary antibody deficiencies in pediatric practice, though individually rare.
- Risk factors
Male sex with X-linked recessive inheritance: a hemizygous BTK mutation on Xq22 is necessary and sufficient for disease; heterozygous female carriers are unaffected.
- Pathophysiology
BTK mutation blocks pre-B-cell receptor signaling: BTK is required for the pre-B-cell receptor to transmit the signal that drives progression from the pro-B to the pre-B stage of development in the bone marrow.
- Clinical features
Recurrent and chronic sinopulmonary bacterial infections beginning after 6 months of age: otitis media, sinusitis, and Pneumonia caused by encapsulated organisms (Streptococcus pneumoniae…
- Differential diagnosis
Common variable immunodeficiency (CVID): also causes low immunoglobulins and recurrent sinopulmonary infection, but B cells and lymphoid tissue are present, onset is later (15-35 years), either sex…
- Diagnosis
Confirmed by absent peripheral B cells with panhypogammaglobulinemia, established definitively by BTK gene testing: the diagnosis is made when quantitative immunoglobulins of all classes are low…
- Management
First, start lifelong immunoglobulin replacement therapy: IVIG 400-600 mg/kg IV every 3 to 4 weeks (or a weekly subcutaneous immunoglobulin equivalent), titrated to the trough IgG level and clinical infection control; continue indefinitely.
- Complications
Invasive, life-threatening bacterial infection: bacteremia, sepsis, or meningitis from encapsulated or gram-negative organisms (S.
- Prognosis
Good with adherence to lifelong immunoglobulin replacement and prompt antibiotic treatment of infections: regular IVIG or SCIG dosing every 3 to 4 weeks (or weekly) restores passive humoral…
- Prevention
No newborn screen exists for XLA: unlike the T-cell receptor excision circle (TREC) assay used to screen for SCID, XLA is not detected on standard newborn screening, so recognition depends on…
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