title: Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility.
abstract: Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients' elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies.
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Crank
authors.forename: J K
authors.initials: JK
authors.lastname: Grossman
authors.forename: S
authors.initials: S
authors.lastname: Moir
authors.forename: S
authors.initials: S
authors.lastname: Pittaluga
authors.forename: C M
authors.initials: CM
authors.lastname: Buckner
authors.forename: L
authors.initials: L
authors.lastname: Kardava
authors.forename: A
authors.initials: A
authors.lastname: Agharahimi
authors.forename: H
authors.initials: H
authors.lastname: Meuwissen
authors.forename: J
authors.initials: J
authors.lastname: Stoddard
authors.forename: J
authors.initials: J
authors.lastname: Niemela
authors.forename: H
authors.initials: H
authors.lastname: Kuehn
authors.forename: S D
authors.initials: SD
authors.lastname: Rosenzweig
mesh_terms: D000328:Adult; D001706:Biopsy; D002648:Child; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000209:etiology*; D010375:Pedigree; D055815:Young Adult
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human