An 8-month-old infant with recurrent pyogenic bacterial infections (otitis media, pneumonia) is evaluated. Flow cytometry shows absent CD19+ and CD20+ B cells, with normal numbers of CD3+ T cells. Serum immunoglobulins (IgG, IgA, IgM) are profoundly reduced. What is the underlying genetic defect?

Answer and explanation

Correct answer: A. Mutation in Bruton tyrosine kinase (BTK) gene (X-linked agammaglobulinemia)

  1. Step 1: Analyze the immunophenotype: recurrent bacterial infections beginning after maternal antibody decay (around 6 months of age), absent peripheral B cells (CD19+, CD20+), profound reduction in all immunoglobulin classes (panhypogammaglobulinemia), and intact T-cell counts (CD3+).
  2. Step 2: This presentation defines X-linked agammaglobulinemia (XLA, Bruton disease). It is caused by loss-of-function mutations in the BTK gene, encoding Bruton tyrosine kinase. Without BTK signaling, pre-B cells cannot progress through the bone marrow checkpoint to become mature naive B cells.
Answer
Mutation in Bruton tyrosine kinase (BTK) gene (X-linked agammaglobulinemia).
Why not the others: Deficiency of adenosine deaminase (ADA) causes severe combined immunodeficiency (SCID), leading to the accumulation of toxic deoxyadenosine metabolites that deplete both T and B lymphocytes; Defective CD40 ligand on T cells (Hyper-IgM syndrome) features normal B-cell counts but an inability to class switch, causing markedly elevated or normal IgM with absent IgG, IgA, and IgE; Failure of 3rd and 4th pharyngeal pouch development (DiGeorge syndrome) causes thymic hypoplasia with profound T-cell deficiency, hypocalcemia, and congenital cardiac anomalies.

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