Extending the clinical and immunological phenotype of human interleukin-21 receptor deficiency.

Combined immune deficiencies (CID) are defined by severely impaired adaptive immunity leading to increased susceptibility to opportunistic infections, immune dysregulation and malignancies. CID of moderate severity may not lead to death in infancy but still carry a high burden of morbidity and mortality during childhood. Here we report a deleterious homozygous mutation in the Interleukin-21 receptor (IL-21R) in a Palestinian girl of consanguineous descent presenting with hypogammaglobulinemia and Pneumocystis jirovecii pneumonia corroborating the previously reported profound CID in IL-21R deficiency. The early development of the 8-year old index patient was unremarkable but at 2-years old she presented with recurrent otitis media. At 5-years old she was admitted with severe interstitial pneumonia that rapidly progressed to acute respiratory distress syndrome requiring prolonged mechanical ventilation. All cultures were sterile. Laboratory investigations revealed reduced IgG and IgA, while IgM was increased. Other routine laboratory parameters [T-, B-, NKand naïve CD4 T-cell numbers, proliferative response to mitogens phytohemagglutinin (PHA), Concanavalin A (ConA) and pokeweed mitogen (PWM), T-cell receptor Vβ repertoire and T-cell receptor excision circle (TREC) numbers] were normal. Due to persistent panhypogammaglobulinemia she was treated with monthly immunoglobulin infusions. At 6-years old she presented with significant respiratory distress and hypoxia due to Pneumocystis jirovecii infection, indicating a severe T-cell dysfunction. Trimethoprim-sulfamethoxazole and steroids were administered and the patient recovered; however, chest computed tomography (CT) disclosed bronchiectasis at the bases of both lungs. Her liver presented normal in ultrasound and by laboratory evaluation, rendering liver disease in the previously reported patients most likely a sequela of cryptosporidial infection and not of the IL-21R deficiency itself, resembling the experience in CD40 ligand (CD40L) deficiency. Thus, like the other IL-21R-deficient patients, our patient presented during later childhood with recurrent respiratory tract infections, bronchiectasis and Pneumocystis jirovecii pneumonia, but without liver disease or gastrointestinal manifestations, which had been observed in the first patient with IL-21 deficiency. The homozygous mutation chr16:27455957 G>A, p. Arg201Gln in the IL21R gene had been discovered by