A 2-year-old boy has recurrent otitis media and pneumonia since infancy, plus persistent diarrhea due to Cryptosporidium and two episodes of Pneumocystis jirovecii pneumonia. Serum IgG, IgA, and IgE are markedly low while IgM is elevated. B cells are present but fail to switch isotypes. The most likely molecular defect is:

• A Mutation of the BTK gene impairing pre-B cell receptor signaling
• B Mutation of the recombination activating gene RAG1
• C Deficiency of CD40 ligand on activated CD4 T cells ✓
• D Defective common gamma chain of the IL-2 receptor

Explanation

Hyper-IgM syndrome results from loss of CD40 ligand on activated CD4 T cells, so CD40 signaling to C cells fails. Without this interaction, germinal center formation, class switching, and affinity maturation do not occur, leaving IgM dominant and other isotypes deficient. Susceptibility to opportunistic organisms like Pneumocystis and Cryptosporidium reflects the accompanying macrophage activation defect. BTK mutation causes agammaglobulinemia with absent C cells, and RAG defects cause SCID.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.