Abstract
BackgroundActivated 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).ObjectiveWe sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.MethodsWe applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.ResultsRecurrent 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.ConclusionAPDS 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.
Highlights
Activated phosphoinositide 3-kinase d 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 d (PI3Kd)
Neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kd in the central nervous system; consistent with this, PI3Kd is broadly expressed in the developing murine central nervous system
Activated phosphoinositide 3-kinase d syndrome (APDS) is an autosomal dominant primary immunodeficiency caused by gain
Summary
From athe Department of Immunology, School of Medicine, Trinity College, Dublin, and St James’s Hospital, Dublin; bthe Department of Paediatric Immunology and Infectious Diseases, Our Lady’s Children’s Hospital Crumlin, Dublin; cthe Department of Clinical Biochemistry and Immunology, Addenbrooke’s Hospital, Cambridge; dLymphocyte Signalling & Development, Babraham Institute, Cambridge; ethe Department of Medicine, University of Cambridge; fthe Northern Institute for Cancer Research, Newcastle University; gthe Department of Radiology, Cambridge University Hospitals NHS Foundation Trust; hRaigmore Hospital, Inverness; ithe Regional Immunology Service, The Royal Hospitals, Belfast; jthe National Institute for Health Research, Cambridge Biomedical Research Centre; kthe Department of Infectious Disease and Immunology, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Hospital for Children; lBarts Health NHS Trust, London; mthe Center for Chronic Immunodeficiency, University Hospital Freiburg; nthe Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg; othe Institute of Immunology, University Hospital Motol, Prague; pthe Faculty of Medicine and Institute of Life Sciences, University of Southampton; qNIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust; rthe Department of Immunology, Epsom & St Helier University Hospitals NHS Trust, Surrey; sthe Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center; tRoyal Aberdeen Childrens’ Hospital; uthe Department of Pediatrics, Ospedale Pediatrico Bambino Gesu and University of Rome ‘‘Tor Vergata,’’ Rome; vthe Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London; wKing’s College London, King’s.
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