Clinical Scenario:
An 18-month-old boy is evaluated for recurrent episodes of otitis media and two episodes of bacterial pneumonia since 9 months of age. He had been relatively well during the first several months of life. On examination, the tonsils are very small and cervical lymph nodes are barely palpable. His growth is appropriate for age.
Laboratory investigations show:
- IgG: 120 mg/dL
- IgA: <7 mg/dL
- IgM: 12 mg/dL
- CD19+ B lymphocytes: 0.3% of peripheral lymphocytes
- CD3+ T lymphocytes: normal
- CD16/56+ NK cells: normal
His maternal uncle reportedly had recurrent severe infections during childhood.
Which of the following is the most likely diagnosis?
A. Common variable immunodeficiency
B. Hyper-IgM syndrome
C. Selective IgA deficiency
D. Severe combined immunodeficiency
E. X-linked agammaglobulinemia
Correct answer & Explanation:
Correct answer: E. X-linked agammaglobulinemia
Explanation
X-linked agammaglobulinemia (XLA; Bruton disease) results from pathogenic variants in the BTK gene, which is required for normal B-cell maturation. The characteristic laboratory finding is profoundly reduced or absent circulating B cells, together with markedly reduced concentrations of all major immunoglobulin classes.
Affected boys are often relatively well during the first few months of life because of transplacentally acquired maternal IgG. Recurrent bacterial infections typically become apparent after maternal IgG levels decline, commonly during the first 1–2 years of life. Otitis media, sinusitis and pneumonia are frequent presentations. Small or absent tonsils and lymph nodes reflect the severe reduction in mature B cells.
The combination of:
- Recurrent bacterial sinopulmonary infections
- Markedly reduced IgG, IgA and IgM
- CD19+ B cells <1%
- Preserved T-cell and NK-cell populations
- X-linked family history
is highly characteristic of XLA.
Why the other options are less likely
- A. Common variable immunodeficiency: CVID causes hypogammaglobulinemia and impaired antibody responses, but circulating B cells are generally present. The profound reduction in B cells in this child strongly favors XLA.
- B. Hyper-IgM syndrome: Patients with CD40L deficiency usually have normal or increased B-cell numbers and characteristically have disproportionately low IgG with normal or elevated IgM.
- C. Selective IgA deficiency: By definition, IgA is selectively reduced while IgG and IgM are generally preserved.
- D. Severe combined immunodeficiency: SCID is characterized by significant T-cell dysfunction or deficiency, often with severe infections beginning much earlier in infancy. This child’s T-cell population is preserved.
Exam Pearl
Recurrent bacterial infections + very small tonsils/lymph nodes + panhypogammaglobulinemia + almost absent CD19+ B cells = think XLA.
The diagnostic gene is BTK (Bruton tyrosine kinase) on Xq22.1. Molecular identification of a pathogenic BTK variant establishes the diagnosis in a male with the characteristic phenotype.
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References
- Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Updated June 27, 2024.
- Kliegman RM, St Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, editors. Nelson Textbook of Pediatrics. 22nd ed. Philadelphia: Elsevier; 2025.
