Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
Abstract
Background: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). Objective: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
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BibTeX
@article{coulter2026clinical,
title = {{Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study}},
author = {Tanya I Coulter and Anita Chandra and Chris M Bacon and Judith Babar and James Curtis and Nick Screaton and John R Goodlad and George Farmer and Cathal Laurence Steele and Timothy Ronan Leahy and Rainer Doffinger and Helen Baxendale and Jolanta Bernatoniene and J David M Edgar and Hilary J Longhurst and Stephan Ehl and Carsten Speckmann and Bodo Grimbacher and Anna Sediva and Tomas Milota and Saul N Faust and Anthony P Williams and Grant Hayman and Zeynep Yesim Kucuk and Rosie Hague and Paul French and Richard Brooker and Peter Forsyth and Richard Herriot and Caterina Cancrini and Paolo Palma and Paola Ariganello and Niall Conlon and Conleth Feighery and Patrick J Gavin and Alison Jones and Kohsuke Imai and Mohammad a A Ibrahim and Gašper Markelj and Mario Abinun and Frédéric Rieux-Laucat and Sylvain Latour and Isabelle Pellier and Alain Fischer and Fabien Touzot and Jean-Laurent Casanova and Anne Durandy and Siobhan O Burns and Sinisa Savic and D.S. Kumararatne and Despina Moshous and Sven Kracker and Bart Vanhaesebroeck and Klaus Okkenhaug and Capucine Picard and Sergey Nejentsev and Alison M Condliffe and Andrew James Cant},
journal = {Journal of Allergy and Clinical Immunology},
year = {2026},
month = sep,
doi = {10.1016/j.jaci.2016.06.021},
url = {https://nantes-universite.hal.science/hal-05742623v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
AU - Tanya I Coulter
AU - Anita Chandra
AU - Chris M Bacon
AU - Judith Babar
AU - James Curtis
AU - Nick Screaton
AU - John R Goodlad
AU - George Farmer
AU - Cathal Laurence Steele
AU - Timothy Ronan Leahy
AU - Rainer Doffinger
AU - Helen Baxendale
AU - Jolanta Bernatoniene
AU - J David M Edgar
AU - Hilary J Longhurst
AU - Stephan Ehl
AU - Carsten Speckmann
AU - Bodo Grimbacher
AU - Anna Sediva
AU - Tomas Milota
AU - Saul N Faust
AU - Anthony P Williams
AU - Grant Hayman
AU - Zeynep Yesim Kucuk
AU - Rosie Hague
AU - Paul French
AU - Richard Brooker
AU - Peter Forsyth
AU - Richard Herriot
AU - Caterina Cancrini
AU - Paolo Palma
AU - Paola Ariganello
AU - Niall Conlon
AU - Conleth Feighery
AU - Patrick J Gavin
AU - Alison Jones
AU - Kohsuke Imai
AU - Mohammad a A Ibrahim
AU - Gašper Markelj
AU - Mario Abinun
AU - Frédéric Rieux-Laucat
AU - Sylvain Latour
AU - Isabelle Pellier
AU - Alain Fischer
AU - Fabien Touzot
AU - Jean-Laurent Casanova
AU - Anne Durandy
AU - Siobhan O Burns
AU - Sinisa Savic
AU - D.S. Kumararatne
AU - Despina Moshous
AU - Sven Kracker
AU - Bart Vanhaesebroeck
AU - Klaus Okkenhaug
AU - Capucine Picard
AU - Sergey Nejentsev
AU - Alison M Condliffe
AU - Andrew James Cant
PY - 2026
DA - 2026/09/08
JO - Journal of Allergy and Clinical Immunology
DO - 10.1016/j.jaci.2016.06.021
UR - https://nantes-universite.hal.science/hal-05742623v1
AB - Background: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). Objective: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
SN - 0091-6749
ER -