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Activated Phosphoinositide 3-Kinase δ Syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Maccari, Maria Elena; Wolkewitz, Martin; Schwab, Charlotte; Lorenzini, Tiziana; Leiding, Jennifer W; Aladjdi, Nathalie; Abolhassani, Hassan; ... European Society for Immunodeficiencies Registry Working, Party; + view all (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 10.1016/j.jaci.2023.06.015. (In press).

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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.

Type: Article
Title: Activated Phosphoinositide 3-Kinase δ Syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity
Location: United States
DOI: 10.1016/j.jaci.2023.06.015
Publisher version: https://doi.org/10.1016/j.jaci.2023.06.015
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: APDS, CTLA-4, ESID, IEI, NFκB1, PI3K, PIK3CD, PIK3R1, STAT3, immunodeficiency
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10174724
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