Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

Adolescent Adult Child Humans Infant Inflammation Lung Diseases, Interstitial Membrane Proteins / genetics Mutation Vascular Diseases
Interstitial lung disease JAK inhibitors Lymphopenia Polyarthritis STING1 Stimulator of interferon genes Type I interferonopathy Vasculopathy

Journal

The journal of allergy and clinical immunology. In practice
ISSN: 2213-2201
Titre abrégé: J Allergy Clin Immunol Pract
Pays: United States
ID NLM: 101597220

Informations de publication

Date de publication:
02 2021
Historique:
received: 29 07 2020
revised: 30 10 2020
accepted: 03 11 2020
pubmed: 21 11 2020
medline: 22 5 2021
entrez: 20 11 2020
Statut: ppublish

Résumé

Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD). To describe a cohort of patients with SAVI. Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out. Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good. The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.

Sections du résumé

BACKGROUND
Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).
OBJECTIVE
To describe a cohort of patients with SAVI.
METHODS
Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.
RESULTS
Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.
CONCLUSION
The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.

Identifiants

DOI: 10.1016/j.jaip.2020.11.007 PMID: 33217613
pubmed: 33217613
pii: S2213-2198(20)31226-5
doi: 10.1016/j.jaip.2020.11.007
pii:
doi:

Substances chimiques

Membrane Proteins 0
STING1 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

803-818.e11

Informations de copyright

Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Auteurs

Marie-Louise Frémond (ML)

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France.

Alice Hadchouel (A)

Université de Paris, Paris, France; Pediatric Pulmonology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; INEM, INSERM U1151, Paris, France.

Laureline Berteloot (L)

Pediatric Radiology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France.

Isabelle Melki (I)

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; General Pediatrics-Infectious Diseases and Internal Medicine Department, Hôpital Robert Debré, AP-HP Nord-Université de Paris, Paris, France.

Violaine Bresson (V)

Pediatric Emergency Department, Hôpital de la Timone, AP-HM, Centre Hospitalier Universitaire de Marseille, Marseille, France.

Laura Barnabei (L)

Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, France.

Nadia Jeremiah (N)

Immunity and Cancer Department, Institut Curie, PSL Research University, Institut National de la Santé et de la Recherche Médicale U932, Paris, France.

Alexandre Belot (A)

Pediatric Rheumatology, Nephrology and Dermatology Department, Hospices Civils de Lyon, Lyon, France; CIRI, Centre International de Recherche en Infectiologie, INSERM, U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, Lyon, France.

Vincent Bondet (V)

Translational Immunology Lab, Institut Pasteur, Paris, France.

Olivier Brocq (O)

Rheumatology Department, Centre Hospitalier Princesse Grace, Monaco, Monaco.

Damien Chan (D)

Pediatric Allergy and Immunology Department, Women's and Children's Hospital, Adelaide, South Australia, Australia.

Rawane Dagher (R)

Department of Pediatrics, Notre Dame des Secours University Hospital, Jbeil, Lebanon.

Jean-Christophe Dubus (JC)

Pediatric Pulmonology Department, Hôpital de la Timone, AP-HM, Centre Hospitalier Universitaire de Marseille, Marseille, France.

Darragh Duffy (D)

Translational Immunology Lab, Institut Pasteur, Paris, France.

Séverine Feuillet-Soummer (S)

Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie-Lannelongue Hospital, Paris-Sud University, Le Plessis-Robinson, France.

Mathieu Fusaro (M)

Study Center for Primary Immunodeficiencies, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Université de Paris, Imagine Institute, Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Paris, France.

Marco Gattorno (M)

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Giannina Gaslini Institute, Genova, Italy.

Antonella Insalaco (A)

Pediatric Rheumatology Unit, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Eric Jeziorski (E)

Pediatrics Department, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.

Naoki Kitabayashi (N)

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.

Mireia Lopez-Corbeto (M)

Pediatric Rheumatology Unit, Rheumatology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.

Françoise Mazingue (F)

Pediatric Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France.

Marie-Anne Morren (MA)

Dermatology Department, University Hospitals Leuven, Leuven, Belgium; Department of Pediatrics and Dermatol-Venereology, University Hospital Lausanne and University of Lausanne Pediatric Dermatology Unit, Lausanne, Switzerland.

Gillian I Rice (GI)

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

Jacques G Rivière (JG)

Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain.

Luis Seabra (L)

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.

Jérôme Sirvente (J)

Internal Medicine Department, Hôpital Saint-Eloi, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.

Pere Soler-Palacin (P)

Infection in Immunocompromised Pediatric Patients Research Group, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.

Nathalie Stremler-Le Bel (N)

Pediatric Pulmonology Department, Hôpital de la Timone, AP-HM, Centre Hospitalier Universitaire de Marseille, Marseille, France.

Guillaume Thouvenin (G)

Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, AP-HP Sorbonne Université, Paris, France.

Caroline Thumerelle (C)

Pediatric Pneumology Department, Hôpital Jeanne de Flandre, CHRU Lille, Lille, France.

Eline Van Aerde (E)

Dermatology Department, University Hospitals Leuven, Leuven, Belgium.

Stefano Volpi (S)

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Giannina Gaslini Institute, Genova, Italy.

Sophie Willcocks (S)

Pediatric Immunology and Allergy Service, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Queensland, Australia.

Carine Wouters (C)

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Pediatrics Department, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology-Childhood Immunology University of Leuven, Leuven, Belgium.

Sylvain Breton (S)

Pediatric Radiology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France.

Thierry Molina (T)

Université de Paris, Paris, France; Pathology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France.

Brigitte Bader-Meunier (B)

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, France.

Despina Moshous (D)

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Paris, France.

Alain Fischer (A)

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Université de Paris, Imagine Institute, INSERM UMR 1163, Paris, France; Collège de France, Paris, France.

Stéphane Blanche (S)

Université de Paris, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France.

Frédéric Rieux-Laucat (F)

Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, France.

Yanick J Crow (YJ)

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: yanickcrow@mac.com.

Bénédicte Neven (B)

Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France; Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, France. Electronic address: benedicte.neven@aphp.fr.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Maladies pulmonaires › Pneumopathies interstitielles › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Overview of STING-Associated Vasculopathy with...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Overview of STING-Associated Vasculopathy with...