Elkaim, ElodieNeven, BenedicteBruneau, JulieMitsui-Sekinaka, KanakoStanislas, AurelieHeurtier, LucieLucas, Carrie L.Matthews, HelenDeau, Marie-CelineSharapova, SvetlanaCurtis, JamesReichenbach, JanineGlastre, CatherineParry, David A.Arumugakani, GururajMcDermott, ElizabethYamashita, MotoiMoshous, DespinaLamrini, HichamOtremba, BurkhardGennery, AndrewCoulter, TanyaQuinti, IsabellaStephan, Jean-LouisLougaris, VassiliosBrodszki, NicholasBarlogis, VincentAsano, TakakiGalicier, LionelBoutboul, DavidNonoyama, ShigeakiCant, AndrewImai, KohsukePicard, CapucineNejentsev, SergeyMolina, Thierry JoLenardo, MichaelSavic, SinisaCavazzana, MarinaFischer, AlainDurandy, AnneKracker, Sven2022-10-282022-10-282016-07Elkaim, E. vd. (2016). "Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: A cohort study". Journal of Allergy and Clinical Immunology, 138(1), 210-218.0091-67491097-6825https://doi.org/10.1016/j.jaci.2016.03.022https://www.sciencedirect.com/science/article/pii/S0091674916300975http://hdl.handle.net/11452/29255Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) 2 (p110 delta-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85 alpha, p55 alpha, and p50 alpha) of class IA phosphoinositide 3-kinases. Objectives: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. Conclusion: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase delta inhibitors are possible treatment options.eninfo:eu-repo/semantics/openAccessAllergyImmunologyPrimary immunodeficiencyPhosphoinositide 3-kinaseActivated phosphoinositide 3-kinase delta syndromeP110 delta-activating mutations causing senescent T cellsLymphadenopathyAnd immunodeficiencyHyper-IgMAdenopathyImmunodeficiencyAntibody deficiencyP85 alphaP110 deltaHuman immunodeficiencyMutationsKinaseCellsAdolescentAdultAllelesBiopsyCD8-positive T-lymphocytesChildChild, preschoolClass I phosphatidylinositol 3-kinasesCohort studiesFemaleGene frequencyGenotypeHumansImmunologic deficiency syndromesMaleMiddle agedMutationPhenotypeRNA splice sitesT-lymphocyte subsetsYoung adultArticle0003796591000232-s2.0-84969583249210218138127221134AllergyImmunologyActivated PI3K-delta Syndrome; Hyper Igm Syndrome; Immune DeficiencyAlemtuzumabAmino acidAzathioprineAzithromycinCD4 antigenCD8 antigenCotrimoxazoleFludarabineGenomic DNAImmunoglobulinImmunoglobulin AImmunoglobulin GImmunoglobulin MInfliximabMethotrexateMycophenolate mofetilNucleotidePhosphatidylinositol 3 kinase gammaPhosphatidylinositol 3 kinase inhibitorRapamycinRituximabSteroidTreosulfanPhosphatidylinositol 4,5 bisphosphate 3 kinaseRNA splice siteActivated phosphoinositide 3 kinase gamma syndrome 2AdolescentAdultArticleAutoimmune hemolytic anemiaAutoimmunityAutosomal dominant inheritanceB cell lymphomaBronchiectasisChildChronic diarrheaClinical articleClinical featureCohort analysisControlled studyCytopeniaDevelopmental disorderDisease associationDonor siteExonFemaleGastrointestinal diseaseGene mutationGenetic associationGrowth retardationHistopathologyHumanHuman tissueImmune deficiencyImmune dysregulationImmunoglobulin blood levelInfantInfectious complicationLymphadenopathyLymphocyte proliferationLymphocytopeniaLymphoid hyperplasiaMaleMalignant neoplastic diseaseMemory T lymphocytePhenotypic variationPneumoniaPre B lymphocytePriority journalSplenomegalyUpper respiratory tract infectionAlleleBiopsyCD8+ T lymphocyteGene frequencyGeneticsGenotypeImmunologic deficiency syndromesImmunologyMetabolismMiddle agedMortalityMutationPhenotypePreschool childRNA splice siteT lymphocyte subpopulationYoung adult