A 12-year-old boy has had multiple recurrent infections for the past 10 years, including Pneumocystis jiroveci pneumonia, Streptococcus pneumoniae otitis media, and Pseudomonas aeruginosa urinary tract infection. On physical examination, he has a temperature of 38.5deg C and pharyngeal erythema with exudate. Laboratory studies show hemoglobin, 9.1 g/ dL; hematocrit, 27.6%; platelet count, 130,900/mm3; and WBC count, 3440/mm3 with 47% segmented neutrophils, 3% bands, 40% lymphocytes, and 10% monocytes. Serum immunoglobulin levels show very low IgG, very high IgM, and undetectable IgA. A peripheral blood smear shows nucleated RBCs. Which of the following immunologic defects is most likely to produce this disease?

These are features of the hyper-IgM syndrome, which results from lack of isotype switching from IgM to other immunoglobulins. Patients are particularly susceptible to Pneumocystis and to bacterial infections. The abnormal IgM antibodies in excess can attach to circulating cells and lead to cytopenias. An absence of adenosine deaminase characterizes a form of severe combined immunodeficiency. The deletion of chromosome 22q11 is a feature of the DiGeorge anomaly, which affects T cell differentiation and maturation. HIV infection can be accompanied by opportunistic infections, particularly Pneumocystis, but abnormal immunoglobulin production generally is not seen. A lack of just IgA production alone is seen with selective IgA deficiency. Mutations in the BTK gene account for Bruton agammaglobulinemia with reduction in levels of all immunoglobulins.