TY - JOUR
T1 - Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome
T2 - A large patient cohort study
AU - Coulter, Tanya I.
AU - Chandra, Anita
AU - Bacon, Chris M.
AU - Babar, Judith
AU - Curtis, James
AU - Screaton, Nick
AU - Goodlad, John R.
AU - Farmer, George
AU - Steele, Cathal Laurence
AU - Leahy, Timothy Ronan
AU - Doffinger, Rainer
AU - Baxendale, Helen
AU - Bernatoniene, Jolanta
AU - Edgar, J. David M.
AU - Longhurst, Hilary J.
AU - Ehl, Stephan
AU - Speckmann, Carsten
AU - Grimbacher, Bodo
AU - Sediva, Anna
AU - Milota, Tomas
AU - Faust, Saul N.
AU - Williams, Anthony P.
AU - Hayman, Grant
AU - Kucuk, Zeynep Yesim
AU - Hague, Rosie
AU - French, Paul
AU - Brooker, Richard
AU - Forsyth, Peter
AU - Herriot, Richard
AU - Cancrini, Caterina
AU - Palma, Paolo
AU - Ariganello, Paola
AU - Conlon, Niall
AU - Feighery, Conleth
AU - Gavin, Patrick J.
AU - Jones, Alison
AU - Imai, Kohsuke
AU - Ibrahim, Mohammad A.A.
AU - Markelj, Gašper
AU - Abinun, Mario
AU - Rieux-Laucat, Frédéric
AU - Latour, Sylvain
AU - Pellier, Isabelle
AU - Fischer, Alain
AU - Touzot, Fabien
AU - Casanova, Jean Laurent
AU - Durandy, Anne
AU - Burns, Siobhan O.
AU - Savic, Sinisa
AU - Kumararatne, D. S.
N1 - Publisher Copyright:
© 2016 The Authors
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
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.
KW - Activated phosphoinositide 3-kinase δ syndrome
KW - bronchiectasis
KW - hematopoietic stem cell transplantation
KW - immunodeficiency
KW - p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency
KW - phosphoinositide 3-kinase inhibitor
KW - phosphoinositide 3-kinase δ
KW - PIK3CD gene
UR - http://www.scopus.com/inward/record.url?scp=84996528817&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2016.06.021
DO - 10.1016/j.jaci.2016.06.021
M3 - Article
C2 - 27555459
AN - SCOPUS:84996528817
SN - 0091-6749
VL - 139
SP - 597-606.e4
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -