Bruton agammaglobulinemia

**Genetics/Pathophysiology:** X-linked recessive (Xq21.3-q22) mutation in BTK, a cytoplasmic non-receptor tyrosine kinase required for pre-B cell receptor signaling. Defective signaling causes maturation arrest at the pre-B cell stage in bone marrow (pro-B → pre-B → immature B). Heavy chain rearrangement occurs, but light chain rearrangement and progression do not. Result: markedly reduced or absent mature B cells in peripheral blood and all immunoglobulin isotypes. T-cell function is normal.

**Clinical presentation:** Males, typically presenting after ~6 months of age when maternal IgG wanes. Recurrent bacterial infections, especially sinopulmonary (otitis media, sinusitis, pneumonia) and GI, with encapsulated organisms (S. pneumoniae, H. influenzae type b, S. aureus, Pseudomonas). Also susceptible to enteroviruses (echovirus, poliovirus, with risk of chronic meningoencephalitis and vaccine-associated polio after live oral polio vaccine), and Giardia lamblia (chronic diarrhea). Fungal and most viral infections are generally spared because T-cell immunity is intact. Increased risk of autoimmune disease (e.g., arthritis) and, later, malignancy.

**Diagnosis/Findings:** - Flow cytometry: absent or very low CD19+/CD20+ B cells (<1%) - Markedly low IgG, IgA, IgM, and IgE - Absent or scant germinal centers; tiny or absent tonsils and lymph nodes; no plasma cells - Normal T-cell numbers and function (normal pro-B and pre-B cell counts in marrow) - Confirm with BTK gene sequencing or absent BTK protein expression

**Treatment:** Lifelong immunoglobulin replacement (IVIG or SCIG), prompt antibiotics for infections. Avoid live vaccines (especially oral polio). Prophylactic antibiotics may be used in selected patients.

**High-yield comparisons:** - Common variable immunodeficiency (CVID): Both sexes, later onset (age 20s–30s), normal or low B cell count, defective B-cell differentiation into plasma cells; increased risk of autoimmunity, lymphoma, and gastric cancer. - Selective IgA deficiency: Most common primary immunodeficiency. Often asymptomatic, with sinopulmonary and GI infections, anaphylaxis with blood products (anti-IgA antibodies), and celiac disease association. - Hyper-IgM syndrome (CD40L defect): X-linked, normal or high IgM with low IgG/IgA/IgE; B cells present. - SCID: Both B and T cells affected, presenting earlier with opportunistic infections and failure to thrive. - Transient hypogammaglobulinemia of infancy: Delayed onset of Ig production, with B cells present and spontaneous resolution.

**Mnemonic:** "Bruton = B-cell Tyrosine kinase; Boys; Bacterial infections after 6 months; no B cells; no tonsils."