ALLERGIC AND IMMUNOLOGIC CONDITIONS

X-linked Agammaglobulinemia (XLA, Bruton Agammaglobulinemia)

Classification: Primary humoral immunodeficiency caused by BTK dysfunction and arrest of B-cell maturation (Kishiyama et al., 2019).

Key diagnostic discriminator: Male infant develops recurrent encapsulated bacterial infection after maternal IgG wanes. Mature B cells are nearly absent and all immunoglobulin classes are markedly reduced (Kishiyama et al., 2019).

Clinical priority: Chronic cough, recurrent pneumonia, or reduced exercise tolerance may indicate bronchiectasis (Kishiyama et al., 2019).

Etiology and risk factors

  • Pathogenic variants in BTK on the X chromosome cause disease in affected males. Family history may show maternal-line male deaths or infection, but new variants occur (Kishiyama et al., 2019).
  • Symptoms generally emerge after about 6 months when passively acquired maternal IgG declines (Kishiyama et al., 2019).

Pathophysiology

  • BTK signaling is required for pre-B cells to mature. Arrest at the pre-B stage leaves very few circulating mature B lymphocytes, plasma cells, germinal centers, and antibodies (Kishiyama et al., 2019).
  • Loss of antibody-mediated neutralization and opsonization causes susceptibility to encapsulated pyogenic bacteria, Giardia, and enteroviruses. T-cell function is generally preserved (Kishiyama et al., 2019).

Clinical manifestations

  • Recurrent otitis, sinusitis, pneumonia, bacteremia, meningitis, chronic diarrhea, Giardia infection, or enteroviral disease after infancy (Kishiyama et al., 2019).
  • Tonsils, adenoids, and peripheral lymph nodes may be very small or absent because mature B-cell tissue is lacking (Kishiyama et al., 2019).

Findings that argue against or redirect

  • Normal mature B-cell numbers and normal immunoglobulins argue strongly against classic XLA (Kishiyama et al., 2019).
  • Onset in either sex with B cells present and later low IgG/poor vaccine response favors CVID. Opportunistic fungal/viral infection and severe T-cell deficiency favor SCID (Kishiyama et al., 2019).
  • Maternal IgG can obscure the phenotype in early infancy (Kishiyama et al., 2019).

Diagnostic evaluation

  • Obtain quantitative IgG, IgA, and IgM and flow cytometry for circulating B cells, with T-cell assessment to distinguish an isolated humoral defect from combined immunodeficiency (Kishiyama et al., 2019).
  • Confirm the diagnosis with BTK genetic testing in the compatible clinical and immunologic phenotype. Evaluate chronic lung and sinus injury and offer family testing and genetic counseling (Kishiyama et al., 2019).

Expected diagnostic and laboratory findings

  • The characteristic pattern is profound reduction of all immunoglobulin classes with nearly absent mature circulating B cells and preserved T-cell number and function (Kishiyama et al., 2019).
  • A pathogenic BTK variant confirms the molecular diagnosis in the appropriate phenotype (Kishiyama et al., 2019).
  • Specific antibody responses are poor or absent. Neutropenia may accompany severe infection but is not the defining defect (Kishiyama et al., 2019).

Differential diagnosis

  • CVID: B cells usually present, later onset, both sexes, variable autoimmunity/lymphoproliferation (Kishiyama et al., 2019).
  • Transient hypogammaglobulinemia of infancy: B cells present and immunoglobulin production recovers over time (Kishiyama et al., 2019).
  • Secondary hypogammaglobulinemia: protein loss, medication, hematologic malignancy, nephrotic syndrome, or other cause identified (Kishiyama et al., 2019).
  • SCID: low/dysfunctional T cells and opportunistic infection distinguish it from isolated humoral failure (Kishiyama et al., 2019).

Treatment and management

  • Lifelong intravenous or subcutaneous immunoglobulin replacement is the mainstay. Treat bacterial infection promptly and consider antimicrobial prophylaxis for recurrent breakthrough infection (Kishiyama et al., 2019; Norris, 2020).
  • Monitor for chronic sinus and lung injury, bronchiectasis, chronic diarrhea, and enteroviral disease through immunology-directed care (Kishiyama et al., 2019; Norris, 2020).

Additional complications and red flags

  • Neurologic symptoms raise concern for enteroviral meningoencephalitis and require urgent evaluation (Kishiyama et al., 2019).

Content last reviewed:

References

Kishiyama, J. L., Chang, J. J., & Donovan, S. M. (2019). Disorders of the immune system. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.