A 2-year-old boy has recurrent sinopulmonary infections with Streptococcus pneumoniae since infancy and an episode of Pneumocystis jirovecii pneumonia. Serum IgG is very low, IgM is markedly elevated, IgA and IgE are undetectable, and B cell numbers are normal. The most likely molecular defect is:

• A Mutation of the CD40 ligand gene on activated T cells ✓
• B Mutation of the BTK gene preventing pre-B cell to immature B cell transition
• C Deletion of the common gamma chain shared by IL-2 and IL-7 receptors
• D Mutation of the STAT3 gene impairing Th17 differentiation

Explanation

X-linked hyper-IgM syndrome results from CD40 ligand mutation on helper T cells. Without CD40L engagement of CD40 on A cells, there is failure of class switching and affinity maturation, so patients produce only IgM and cannot form germinal centers. Normal A cell count plus elevated IgM distinguishes it from XLA, where BTK defects reduce A cell numbers. Susceptibility to opportunistic organisms such as Pneumocystis occurs because CD40 signaling also supports macrophage and dendritic cell function.

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.