Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Albert-Ludwigs-Universität Freiburg
  • University of Brescia
  • Johns Hopkins University
  • Regional Centre for Prevention of Healthcare Associated Infections
  • Karolinska Institutet
  • Tehran University of Medical Sciences
  • Université de Lille
  • Fondazione Telethon
  • Vita-Salute San Raffaele University
  • Hopital Robert-Debre AP-HP
  • Marmara University
  • Vall d'Hebron Research Institute (VHIR)
  • Aix-Marseille Université
  • Medizinische Hochschule Hannover (MHH)
  • Karlsuniversität Prag
  • Children's Memorial Health Institute
  • Université de Caen
  • Université Paris Cité
  • KU Leuven
  • Barts Health NHS Trust
  • University College London
  • Institute of Immunity and Transplantation
  • Royal Free London NHS Foundation Trust
  • University of Rome Tor Vergata
  • IRCCS Ospedale pediatrico Bambino Gesù - Roma
  • CHU de Saint-Étienne
  • Assistance publique – Hôpitaux de Paris
  • Ospedale Policlinico
  • Comenius University
  • Belfast Health and Social Care Trust
  • CHU de Nancy
  • Université de Lorraine
  • University of Gothenburg
  • University Clinical Centre of the Republic of Srpska
  • University Hospital Southampton NHS Foundation Trust
  • Queen Silvia Children's Hospital
  • Autonomous University of Barcelona
  • Université d'Angers
  • Universitätsklinikum Düsseldorf
  • Central Hospital of Southern Pest
  • Ludwig-Maximilians-Universität München (LMU)
  • International European University
  • Cardiff & Vale University Health Board
  • Isil Berat Barlan Center for Translational Medicine


Background: Activated phosphoinositide-3-kinase 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: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS 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 CTLA4 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. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs 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.


Seiten (von - bis)984-996.e10
FachzeitschriftJournal of allergy and clinical immunology
PublikationsstatusVeröffentlicht - Okt. 2023

Externe IDs

PubMed 37390899
ORCID /0009-0003-6519-0482/work/146644415
ORCID /0000-0001-6313-4434/work/147143698



  • APDS, CTLA4, ESID, IEI, immunodeficiency, NFKB1, PI3K, PIK3CD, PIK3R1, STAT3, Humans, Class I Phosphatidylinositol 3-Kinases, Primary Immunodeficiency Diseases/genetics, CTLA-4 Antigen/genetics, Registries, Mutation, Phosphatidylinositol 3-Kinases/genetics, Phosphatidylinositol 3-Kinase/genetics