1. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: A cohort study
- Author
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Elkaim, Elodie, Neven, Benedicte, Bruneau, Julie, Mitsui-Sekinaka, Kanako, Stanislas, Aurelie, Heurtier, Lucie, Lucas, Carrie L., Matthews, Helen, Deau, Marie-Celine, Sharapova, Svetlana, Curtis, James, Reichenbach, Janine, Glastre, Catherine, Parry, David A., Arumugakani, Gururaj, McDermott, Elizabeth, Yamashita, Motoi, Moshous, Despina, Lamrini, Hicham, Otremba, Burkhard, Gennery, Andrew, Coulter, Tanya, Quinti, Isabella, Stephan, Jean-Louis, Lougaris, Vassilios, Brodszki, Nicholas, Barlogis, Vincent, Asano, Takaki, Galicier, Lionel, Boutboul, David, Nonoyama, Shigeaki, Cant, Andrew, Imai, Kohsuke, Picard, Capucine, Nejentsev, Sergey, Molina, Thierry Jo, Lenardo, Michael, Savic, Sinisa, Cavazzana, Marina, Fischer, Alain, Durandy, Anne, Kracker, Sven, Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Çocuk İmmünoloji Bilim Dalı., Kılıç, Sara Şebnem, and AAH-1658-2021
- Subjects
Male ,Kinase ,Lymphoid hyperplasia ,And immunodeficiency ,Lymphadenopathy ,Genomic DNA ,Autoimmunity ,Azithromycin ,Immunoglobulin blood level ,Azathioprine ,T-lymphocyte subsets ,CD8+ T lymphocyte ,Child ,Phosphatidylinositol 3 kinase inhibitor ,Primary immunodeficiency ,T lymphocyte subpopulation ,CD8 antigen ,Immunologic deficiency syndromes ,Amino acid ,Phosphatidylinositol 3 kinase gamma ,Bronchiectasis ,Adenopathy ,Cohort studies ,P110 delta ,Cohort analysis ,CD4 antigen ,Rituximab ,Human ,Activated PI3K-delta Syndrome ,Hyper Igm Syndrome ,Immune Deficiency ,Genotype ,Treosulfan ,P85 alpha ,Cells ,Clinical article ,Immunology ,Autosomal dominant inheritance ,Article ,Disease association ,Donor site ,Genetics ,Immunodeficiency ,Humans ,Antibody deficiency ,Autoimmune hemolytic anemia ,Steroid ,Alleles ,RNA splice sites ,Infant ,Upper respiratory tract infection ,Pneumonia ,Growth retardation ,Gene frequency ,Cotrimoxazole ,B cell lymphoma ,Methotrexate ,Mutation ,Cytopenia ,Splenomegaly ,Allergy ,Biopsy ,Immune deficiency ,Phosphoinositide 3-kinase ,Fludarabine ,Pre B lymphocyte ,Lymphocyte proliferation ,Activated phosphoinositide 3 kinase gamma syndrome 2 ,Class I phosphatidylinositol 3-kinases ,Human immunodeficiency ,P110 delta-activating mutations causing senescent T cells ,Middle aged ,Memory T lymphocyte ,Alemtuzumab ,Priority journal ,Allele ,Mycophenolate mofetil ,Gastrointestinal disease ,Phenotype ,Activated phosphoinositide 3-kinase delta syndrome ,CD8-positive T-lymphocytes ,Female ,Nucleotide ,Mutations ,Adult ,Adolescent ,Child, preschool ,Developmental disorder ,Exon ,Histopathology ,Phenotypic variation ,Immunoglobulin ,Rapamycin ,Gene mutation ,Human tissue ,Mortality ,Chronic diarrhea ,RNA splice site ,Phosphatidylinositol 4,5 bisphosphate 3 kinase ,Lymphocytopenia ,Infectious complication ,Infliximab ,Immunoglobulin A ,Immune dysregulation ,Young adult ,Malignant neoplastic disease ,Metabolism ,Immunoglobulin M ,Clinical feature ,Preschool child ,Hyper-IgM ,Immunoglobulin G ,Genetic association ,Controlled study - Abstract
Background: 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. European Union's 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE) - 249816 French National Research Agency (ANR) - ANR-10-IAHU-01 Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH) French National Research Agency (ANR)-European Commission - ANR-15-CE15-0020 Gebert Ruf Stiftung program "Rare Diseases-New Approaches'' - GRS-046/10 European Commission - CELL-PID HEALTH-261387 Zurich Centre for Integrative Human Physiology (ZIHP) Gottfried und Julia Bangerter-Rhyner-Stiftung Rossi Stiftung European Research Council (ERC)-European Commission - 260477 European Commission - 261441 National Institute for Health Research (NIHR) Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)-Japan Society for the Promotion of Science Ministry of Health, Labour and Welfare, Japan Ministry of Defense Japan Agency for Medical Research and Development (AMED) National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Unit (and Leeds Teaching Hospitals Charitable Foundation) National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland United States Department of Health & Human Services/National Institutes of Health (NIH) - USA/NIH National Institute of Allergy & Infectious Diseases (NIAID) Postdoctoral Research Associate (PRAT) Fellowship, National Institute of General Medical Sciences(NIGMS)/NIH EU-FP7 NET4CGD UK Research & Innovation (UKRI)/Medical Research Council UK (MRC)/European Commission - MR/M012328 - MR/M012328/2 UK Research & Innovation (UKRI)/Medical Research Council UK (MRC) - MR/M012328/2 - MR/M012328/1 Institut National de la Sante et de la Recherche Medicale (Inserm) Fondation pour la Recherche Medicale - ING20130526624 la Ligue Contre le Cancer (Comite de Paris)
- Published
- 2016