Maccari, M.E. orcid.org/0000-0001-6488-7622, Wolkewitz, M., Schwab, C. et al. (125 more authors) (2023) Activated Phosphoinositide 3-Kinase δ Syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity. Journal of Allergy and Clinical Immunology, 152 (4). 984-996.E10. ISSN 0091-6749
Abstract
Background Activated phosphoinositide-3-kinase (PI3K) δ Syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.
Objectives Report the extended spectrum of disease manifestations in APDS1 versus APDS2, compare these to CTLA-4 deficiency, NFκB1 deficiency, and STAT3 gain-of-function (GOF) disease; identify predictors of severity in APDS.
Methods Data collection with the European Society for Immunodeficiencies (ESID)-APDS registry. Comparison with published cohorts of the other IEIs.
Results The analysis of 170 APDS patients outlines high penetrance and early-onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA-4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS.
Conclusion APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEI is substantial. Some specific features distinguish APDS1 from APDS2. Early-onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Keywords: | APDS; PIK3CD; PIK3R1; PI3K; STAT3; CTLA-4; NFκB1; IEI; ESID; immunodeficiency |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Inflammatory Arthritis (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 14 Jul 2023 09:41 |
Last Modified: | 30 Nov 2023 16:18 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jaci.2023.06.015 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:201543 |