A 13-month-old boy is admitted to the hospital due to diarrhea and dehydration. Over the past week, the patient has developed severe, watery diarrhea and has had poor oral intake. Medical history includes multiple episodes of bronchiolitis and, at age 8 months, an intensive care unit admission due to pneumococcal pneumonia requiring a brief period of mechanical intubation and chest tube placement. The parents say that he has been growing poorly over the past 6 months despite feeding well and supplemention with high-calorie formulas. On examination, the patient appears lethargic with sunken eyes and poor skin turgor, as well as moderate tachycardia and tachypnea. As part of the laboratory evaluation, flow cytometry of in vitro-stimulated CD4⁺ T cells reveals a near absence of CD40 ligand. Which of the following additional findings is most likely associated with this patient's condition?

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11ec160b_37ac_1b3e_9249_016c5a95b2ba_MD0001_00 This patient has a severe diarrheal illness, failure to thrive, and a history of recurrent respiratory infections; findings concerning for a primary immunodeficiency. In this case, the absent CD40 ligand (CD40L) on flow cytometry is diagnostic for hyper-IgM syndrome. CD40L is normally present on activated CD4⁺ T cells and interacts primarily with CD40 on B cells in the secondary germinal centers of lymphoid tissues. This T-cell-dependent interaction is required to form B-cell germinal centers; without it, patients with hyper-IgM syndrome lack secondary germinal centers and often have small/nonpalpable lymph nodes. Because the interaction of CD40L with CD40 allows for B-cell activation and differentiation into immunoglobulin-producing plasma cells and memory B cells, lack of CD40L causes B cells to remain in their native IgM-producing state. Without opsonizing IgG antibody, patients with hyper-IgM syndrome are predisposed to recurrent sinopulmonary infections (eg, pneumonia, sinusitis) caused by encapsulated bacteria. In addition, lack of mucosal IgA increases the risk for gastrointestinal infections (eg, Giardia). Failure to thrive is also common because of increased metabolic demands from recurrent infections, as well as nutrient loss from chronic diarrhea. (Choice A) Absent thymic tissue, which can be seen in DiGeorge syndrome, results in absent T-cell production. T-cell deficiency presents with opportunistic infections and failure to thrive in infancy but would be associated with absence of CD4⁺ T cells themselves (not just CD40L). (Choice B) Giant granules within neutrophils is a pathognomonic finding for Chédiak-Higashi syndrome, a condition caused by impaired intracellular trafficking of vesicles (eg, lysosomes, melanosomes). In addition to pyogenic infections, patients typically have oculocutaneous albinism and neurologic dysfunction. (Choice C) Hypoplastic bone marrow is seen with aplastic anemia. Recurrent infections occur due to the absence of leukocyte production, but signs of anemia (eg, fatigue, pallor) and thrombocytopenia (eg, bleeding, bruising) are also typically present. (Choice E) Small-volume platelets are characteristic of Wiskott-Aldrich syndrome, in which a defect in the leukocyte cytoskeleton leads to recurrent infections. Educational objective: Hyper-IgM syndrome presents with recurrent sinopulmonary and gastrointestinal infections due to the absence of CD40 ligand on CD4⁺ T cells. Lack of interaction between CD40L and CD40 on B cells prevents the development of secondary germinal centers and impairs B-cell activation and immunoglobulin class switching.

A 13-Month-Old Boy Is Admitted to the Hospital Due to Diarrhea