Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.
STAT3
autoimmunity
cytopenia
gain of function
immune dysregulation
immunodeficiency
lymphoproliferation
precision medicine
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:
04 2023
04 2023
Historique:
received:
03
11
2021
revised:
29
08
2022
accepted:
01
09
2022
pmc-release:
01
04
2024
medline:
11
4
2023
pubmed:
14
10
2022
entrez:
13
10
2022
Statut:
ppublish
Résumé
In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
Sections du résumé
BACKGROUND
In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity.
OBJECTIVE
This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.
METHODS
We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3.
RESULTS
Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate.
CONCLUSION
STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
Identifiants
pubmed: 36228738
pii: S0091-6749(22)01182-4
doi: 10.1016/j.jaci.2022.09.002
pmc: PMC10081938
mid: NIHMS1843105
pii:
doi:
Substances chimiques
STAT3 protein, human
0
STAT3 Transcription Factor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1081-1095Subventions
Organisme : Wellcome Trust
ID : 207556/Z/17/Z
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI128976
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AI001059
Pays : United States
Investigateurs
Svetlana Aleshkevich
(S)
Luis M Allende
(LM)
T Prescott Atkinson
(TP)
Faranaz Atschekzei
(F)
Sezin Aydemir
(S)
Utku Aygunes
(U)
Vincent Barlogis
(V)
Ulrich Baumann
(U)
John Belko
(J)
Liliana Bezrodnik
(L)
Ariane Biebl
(A)
Lori Broderick
(L)
Nancy J Bunin
(NJ)
Maria Soledad Caldirola
(MS)
Martin Castelle
(M)
Fatih Celmeli
(F)
Louis-Marie Charbonnier
(LM)
Talal A Chatila
(TA)
Deepak Chellapandian
(D)
Haluk Cokugras
(H)
Niall Conlon
(N)
Fionnuala Cox
(F)
Etienne Crickx
(E)
Buket Dalgic
(B)
Virgil Ash Dalm
(V)
Silvia Danielian
(S)
Nerea Dominguez-Pinilla
(N)
Tal Dujovny
(T)
Mikael Ebbo
(M)
Ahmet Eken
(A)
Brittany Esty
(B)
Alexandre Fabre
(A)
Alain Fischer
(A)
Mark Hannibal
(M)
Laura Huppert
(L)
Marc D Ikeda
(MD)
Stephen Jolles
(S)
Kent W Jolly
(KW)
Neil Jones
(N)
Maria Kanariou
(M)
Elif Karakoc-Aydiner
(E)
Theoni Karamantziani
(T)
Charikleia Kelaidi
(C)
Mary Keogan
(M)
Ayşenur Pac Kisaarslan
(A)
Ayca Kiykim
(A)
Adam Klocperk
(A)
Kosmas Kotsonis
(K)
Natalia Kuzmenko
(N)
Sylvie Leroy
(S)
Dimitra Lianou
(D)
Hilary Longhurst
(H)
Myriam Ricarda Lorenz
(MR)
Patrick Maffucci
(P)
Ania Manson
(A)
Sarah Marchal
(S)
Marion Malphettes
(M)
Lia Furlaneto Marega
(LF)
Andrea A Mauracher
(AA)
Kornvalee Meesilpavikai
(K)
Holly Miller
(H)
Joy Mombourquette
(J)
Noel G Morgan
(NG)
Anna Mukhina
(A)
Aladjidi Nathalie
(A)
Brigitte Nelken
(B)
David Nolan
(D)
Anna-Carin Norlin
(AC)
Matias Oleastro
(M)
Alper Ozcan
(A)
Marlene Pasquet
(M)
José Roberto Pegler
(JR)
Capucine Picard
(C)
Sophia Polychronopoulou
(S)
Pierre Quartier
(P)
Juan Francisco Quesada
(JF)
Jan Ramakers
(J)
Katrina L Randall
(KL)
V Koneti Rao
(VK)
Allison Remiker
(A)
Geraldine Resin
(G)
Peter Richmond
(P)
Frederic Rieux-Laucat
(F)
Yulia Rodina
(Y)
Pierre Rohrlich
(P)
Johnathan Sachs
(J)
Inga Sakovich
(I)
Christopher Santarlas
(C)
Sinan Sari
(S)
Gregory Sawicki
(G)
Uwe Schauer
(U)
Selma C Scheffler Mendoza
(SC)
Oksana Schvetz
(O)
Reinhold Ernst Schmidt
(RE)
Klaus Schwarz
(K)
Anna Sediva
(A)
Kyle Sinclair
(K)
Mary Slatter
(M)
John Sleasman
(J)
Katerina Stergiou
(K)
Narissara Suratannon
(N)
Kay Tanita
(K)
Grace Thompson
(G)
Stephen Travis
(S)
Timothy Trojan
(T)
Maria Tsinti
(M)
Ekrem Unal
(E)
Luciano Urdinez
(L)
Felisa Vazquez-Gomez
(F)
Mariana Villa
(M)
Michael Weinrich
(M)
Mitchell J Weiss
(MJ)
Benjamin Wright
(B)
Ebru Yilmaz
(E)
Radana Zachova
(R)
Yu Zhang
(Y)
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.
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