Brief CommunicationDe novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly

•PIK3R1 gain-of-function leads to sinopulmonary infections, chronic CMV −/EBV-infections, lymphoproliferation, and hypogammaglobulinemia.•A severe developmental defect of Th17 cells contributes to the disturbed immune function with immunodeficiency and autoimmunity.•Given the hyperactive PI3K signaling, PI3K targeted therapy, e.g. with mTOR inhibitors or PI3Kδ inhibitors, may represent a potentially effective treatment.•PIK3R1 gain-of-function mutations can successfully be treated with haploidentical hematopoietic stem cell transplantation with low toxicity.

PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV −/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G > C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients.