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In addition to infectious complications, the 14-year-old patient experienced lymphoproliferation in the form of splenomegaly, lymphadenopathy, and thymic hyperplasia; trilineage cytopenia; multiple forms of autoimmunity; and interstitial lung disease. Decision to initiate treatment with leniolisib was based on multiorgan-disease progression, lack of therapeutic alternatives, molecular evidence, overlap with APDS manifestations, and mammalian target of rapamycin hyperactivity. We observed improvement in lymphoproliferation, cytopenias, hepatic cytolysis, skin manifestations, pulmonary function, favorable changes in immunophenotypes, and no known drug-related adverse events. This experience supports expanding Leniolisib\u2019s potential indications to appropriately selected patients and conditions. Broader repurposing strategies for targeted therapies in diseases involving dysregulated PI3K signaling should be systematically evaluated in clinical trials.<\/jats:p>","DOI":"10.70962\/jhi.20250203","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T07:21:46Z","timestamp":1771572106000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Expanding the scope of PI3K-\u03b4 inhibition: Leniolisib treatment in PRKCD deficiency"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6902-544X","authenticated-orcid":true,"given":"Lorenzo","family":"Lodi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01n2xwm51","id-type":"ROR","asserted-by":"publisher"}],"name":"Pediatric Immunology Unit, Meyer Children\u2019s Hospital IRCCS 1 , 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