{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T04:48:28Z","timestamp":1774673308837,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ft\u0131rma Kurumu","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Allergy Immunology"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Phosphoinositide 3 kinases (PI3K) are lipid kinases expressed in lymphocytes\/myeloid cells. PI3K\/AKT\/mTOR signaling defects present with recurrent infections, autoimmunity, lymphoproliferation, and agammaglobulinemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To characterize the PI3K\/AKT\/mTOR pathway defects and perform pathway analyses to assess novel variant pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We included 12 patients (heterozygous <jats:italic>PIK3CD<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20099) and <jats:italic>PIK3R1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20091) (activated PI3K delta syndrome (APDS) with gain\u2010of\u2010function mutations) and homozygous <jats:italic>PIK3R1<\/jats:italic> variant (<jats:italic>n<\/jats:italic>\u2009=\u20092)), performed clinical\/laboratory\/genetic evaluation, and flow cytometric PI3K\/AKT\/mTOR pathway analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Median age at onset of complaints was 17.5\u2009months (3\u2009months to 12\u2009years) and at diagnosis was 15.7\u2009years (2.5\u201337) in APDS. Median diagnostic delay was 12.9\u2009years (1.6\u201327). Recurrent respiratory tract infections (90%), lymphoproliferation (70%), autoimmune\/inflammatory findings (60%), and allergy (40%) were common in APDS. Recurrent viral infections were present in 4\/10 and malignancy (non\u2010Hodgkin lymphoma and testicular yolk sac tumor) was present in 2\/10 in APDS. Low CD4+ T cells(5\/8) with increased CD4+ effector memory (8\/8) and CD4+ TEMRA cells (6\/8) were present in the given number of APDS patients. We diagnosed tubulointerstitial nephritis, Langerhans cell histiocytosis, and late\u2010onset congenital adrenal hyperplasia in APDS. Allergic findings, lymphoproliferation\/malignancy, and high IgM were present in the APDS but not in PIK3R1 deficiency. Low IgM\/IgG\/CD19<jats:sup>+<\/jats:sup> B cell counts were characteristic in patients with <jats:italic>PIK3R1<\/jats:italic> homozygous loss\u2010of function mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous <jats:italic>PIK3R1<\/jats:italic> defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/pai14245-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1111\/pai.14245","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T15:42:30Z","timestamp":1727106150000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A single center experience on <scp>PI3K<\/scp>\/<scp>AKT<\/scp>\/<scp>MTOR<\/scp> signaling defects: Towards pathogenicity assessment for four novel defects"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-8494","authenticated-orcid":false,"given":"Hacer Neslihan","family":"Bildik","sequence":"first","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0562-9863","authenticated-orcid":false,"given":"Saliha","family":"Esenboga","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1101-1779","authenticated-orcid":false,"given":"Sevil Oskay","family":"Halacl\u0131","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8383-6350","authenticated-orcid":false,"given":"Bet\u00fcl","family":"Karaatmaca","sequence":"additional","affiliation":[{"name":"Pediatric Allergy and Immunology Ankara Bilkent City Hospital  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2329-7543","authenticated-orcid":false,"given":"Elif Soyak","family":"Aytekin","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0621-4312","authenticated-orcid":false,"given":"Nadira","family":"Nabiyeva","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1544-3408","authenticated-orcid":false,"given":"Ay\u015fegul","family":"Akarsu","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7841-4690","authenticated-orcid":false,"given":"Melike","family":"Ocak","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9398-8465","authenticated-orcid":false,"given":"Baran","family":"Erman","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Can Sucak Research Laboratory for Translational Immunology Hacettepe University  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6972-1349","authenticated-orcid":false,"given":"Cagman","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3340-571X","authenticated-orcid":false,"given":"Tugba","family":"Arikoglu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Allergy and Immunology Mersin University Faculty of Medicine  Mersin Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5278-7456","authenticated-orcid":false,"given":"Ismail","family":"Yaz","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9053-2785","authenticated-orcid":false,"given":"Begum","family":"Cicek","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7257-4554","authenticated-orcid":false,"given":"Ilhan","family":"Tezcan","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2213-4627","authenticated-orcid":false,"given":"Deniz","family":"Cagdas","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Immunology Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Ihsan Dogramaci Childrens' Hospital Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1704560"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095946"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.93"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2014.12.006"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1243292"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2771"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112533"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141759"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12706"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.03.022"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.06.021"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1056"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02043"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00966"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00782"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2019.09.015"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-017-0462-y"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2021.07.044"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-019-08738-9"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01218-4"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/08820139.2020.1863982"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9103335"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01455-10"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00237"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2015.02.040"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.08.015"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2016.01.016"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-014-0012-9"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000256"},{"key":"e_1_2_14_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-019-00677-6"},{"key":"e_1_2_14_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.03.017"},{"key":"e_1_2_14_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.09.009"},{"key":"e_1_2_14_34_1","doi-asserted-by":"publisher","DOI":"10.1177\/03000605211013222"},{"key":"e_1_2_14_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00749-y"},{"key":"e_1_2_14_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-08-801191"},{"key":"e_1_2_14_37_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022018546"},{"key":"e_1_2_14_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2023.102201"},{"key":"e_1_2_14_39_1","unstructured":"https:\/\/www.ucb.com\/clinical\u2010studies\/Clinical\u2010studies\u2010index\/Seletalisib\u2010UCB5857UAO."},{"key":"e_1_2_14_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2021.05.032"}],"container-title":["Pediatric Allergy and Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pai.14245","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T11:51:33Z","timestamp":1735213893000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/pai.14245"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9]]},"references-count":39,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1111\/pai.14245"],"URL":"https:\/\/doi.org\/10.1111\/pai.14245","archive":["Portico"],"relation":{},"ISSN":["0905-6157","1399-3038"],"issn-type":[{"value":"0905-6157","type":"print"},{"value":"1399-3038","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9]]},"assertion":[{"value":"2024-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14245"}}