title: De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly.
abstract: 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.
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhlen
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hönscheid
authors.affiliation: Pediatric Oncology-Hematology Clinic, Archbishop Makarios III Hospital, Nicosia, Cyprus.
authors.forename: Loizos
authors.initials: L
authors.lastname: Loizou
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Schafiq
authors.initials: S
authors.lastname: Nabhani
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Diagnostic and Interventional Radiology, Duesseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaper
authors.affiliation: Department of Pathology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Meinolf
authors.initials: M
authors.lastname: Siepermann
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schuster
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.affiliation: University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany. Electronic address: Arndt.Borkhardt@med.uni-duesseldorf.de.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
mesh_terms: D000293:Adolescent; D058543:Class Ia Phosphatidylinositol 3-Kinase; D003586:Cytomegalovirus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology; D006801:Humans; D008199:Lymphadenitis / Q000150:complications / Q000235:genetics / Q000276:immunology; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000235:genetics; D010256:Paranasal Sinuses / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000150:complications / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; C588001:PIK3R1 protein, human
keywords: Chronic CMV infection; Immunodeficiency; Lymphoproliferation; PIK3R1; TH17 cells