ORIGINAL RESEARCH article
Front. Immunol.
Sec. Primary Immunodeficiencies
This article is part of the Research TopicEnhancing Early Detection of Primary Immunodeficiencies (PIDs)View all 12 articles
Activated PI3Kδ Syndrome in Inborn Errors of Immunity: Diagnostic Strategies and Clinical Challenges
Provisionally accepted
Selcen Bozkurt1
Necmiye Ozturk Ozturk1Melek Yorgun Altunbas1
Salim Can1Razin Amirov1Ramin Mahmudov1Burkay Cagan Colak1
Esra Karabiber2Manuela Baronio3
Vassilios Lougaris3
Giulio Tessarin3
Sevgi Bilgic Eltan1
Ahmet Ozen1
Safa Baris1
Elif Karakoc Aydiner1*- 1Marmara University, Faculty of Medicine, Department of Pediatrics, Division of Allergy and Immunology, İstanbul, Türkiye
- 2Marmara University, Faculty of Medicine, Department of Chest Diseases, Division of Adult Allergy and Immunology, Istanbul, Türkiye
- 3Pediatrics Clinic and Institute for Molecular Medicine "A. Nocivelli”, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili di Brescia, Brescia, Italy
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Abstract Introduction: This study aims to present in a large real-world cohort a diagnostic algorithm developed to facilitate the early recognition of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), a rare disease with targeted treatment options, and to provide clinicians with a practical roadmap for navigating diagnostic challenges. Methods: The study was conducted as a retroactive cross-sectional observational study. We reviewed the medical records of 6,458 pediatric and adult patients who were referred to our clinic between 2018 and 2025. A medical algorithm was generated based on major clinical and laboratory features of APDS. Next-generation sequencing analyses were performed on patients who were appropriate for further evaluation. Variant analysis using in silico predictors and S6 phosphorylation analysis in patients carrying previously undescribed variants were conducted accordingly. Results: In this cohort of 6,458 patients, the diagnostic algorithm identified 1,138 who met at least one major clinical or laboratory criterion. After excluding 7 with a prior APDS diagnosis and 573 with other inborn errors of immunity, genetic analysis was performed in 20 consenting patients under clinical follow-up (11 [55%] female, 9 [45%] male; median age 15 years; IQR 7.5–24). APDS type 2 was confirmed in 1 patient; five others harbored novel variants of uncertain significance. Conclusion: Delayed diagnosis and treatment of APDS may result in life-threatening complications and irreversible end-organ damage. Given its heterogeneous, overlapping phenotype, timely referral for genetic testing is essential.
Keywords: activated phosphoinositide 3-kinase delta syndrome, APDs, diagnostic strategies, inborn errors of immunity, PIK3CD, PIK3R1
Received: 29 Oct 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 Bozkurt, Ozturk, Altunbas, Can, Amirov, Mahmudov, Colak, Karabiber, Baronio, Lougaris, Tessarin, Bilgic Eltan, Ozen, Baris and Karakoc Aydiner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Elif Karakoc Aydiner
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