Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
APDS
CTLA4
ESID
IEI
NFKB1
PI3K
PIK3CD
PIK3R1
STAT3
immunodeficiency
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
08
04
2023
revised:
30
05
2023
accepted:
08
06
2023
medline:
9
10
2023
pubmed:
1
7
2023
entrez:
30
6
2023
Statut:
ppublish
Résumé
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. 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. Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37390899
pii: S0091-6749(23)00812-6
doi: 10.1016/j.jaci.2023.06.015
pii:
doi:
Substances chimiques
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
CTLA-4 Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
984-996.e10Subventions
Organisme : Medical Research Council
ID : MR/M012328/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206618/Z/17/Z
Pays : United Kingdom
Investigateurs
Markus G Seidel
(MG)
Mikko R J Seppänen
(MRJ)
Andrew Gennery
(A)
Maria G Kanariou
(MG)
Sofia Tantou
(S)
Sofia Grigoriadou
(S)
Gabriella Cericola
(G)
Leif G Hanitsch
(LG)
Carmen Scheibenbogen
(C)
Eva O Hlaváčková
(EO)
Gergely Krivan
(G)
Frances K McGuire
(FK)
Timothy Ronan Leahy
(TR)
John David M Edgar
(JDM)
Shahrzad Bakhtiar
(S)
Peter Bader
(P)
Geraldine Blanchard Rohner
(GB)
Filomeen Haerynck
(F)
Karlien Claes
(K)
Kai Lehmberg
(K)
Ingo Müller
(I)
Susan Farmand
(S)
Maria Fasshauer
(M)
Dagmar Graf
(D)
Joao Farela Neves
(JF)
Larysa Kostyuchenko
(L)
Luis Ignacio Gonzalez-Granado
(LI)
Miloš Jeseňák
(M)
Maria Carrabba
(M)
Giovanna Fabio
(G)
Claudio Pignata
(C)
Giuliana Giardino
(G)
Ilknur Kökçü Karadağ
(IK)
Alişan Yıldıran
(A)
Gonca Hancioglu
(G)
Pavlína Králíčková
(P)
Sandra Steinmann
(S)
Barbara Maria Pietrucha
(BM)
Michael Gernert
(M)
Maarja Soomann
(M)
Torsten Witte
(T)
Adam Markocsy
(A)
Beata Wolska-Kusnierz
(B)
Philippe Randrianomenjanahary
(P)
Jérémie Rouger
(J)
Stavroula Kostaridou
(S)
Dariia V Zabara
(DV)
Yulia A Rodina
(YA)
Oksana A Shvets
(OA)
Informations de copyright
Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.