Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients
Marie-Louise Frémond
(1, 2)
,
Alice Hadchouel
(3, 4)
,
Laureline Berteloot
(5)
,
Isabelle Melki
(1, 2, 6)
,
Violaine Bresson
(7)
,
Laura Barnabei
(1)
,
Nadia Jeremiah
(8)
,
Alexandre Belot
(9, 10)
,
Vincent Bondet
(11, 12)
,
Olivier Brocq
(13)
,
Damien Chan
(14)
,
Rawane Dagher
(15)
,
Jean-Christophe Dubus
(16)
,
Darragh Duffy
(11, 12)
,
Séverine Feuillet-Soummer
(17)
,
Mathieu Fusaro
(1, 18)
,
Marco Gattorno
(19)
,
Antonella Insalaco
(20)
,
Eric Jeziorski
(21, 22)
,
Naoki Kitabayashi
(1)
,
Mireia Lopez-Corbeto
(23)
,
Françoise Mazingue
(24)
,
Marie-Anne Morren
(25, 26)
,
Gillian Rice
(27)
,
Jacques Rivière
(23, 28)
,
Luis Seabra
(1)
,
Jérôme Sirvente
(21)
,
Pere Soler-Palacin
(23, 28, 29)
,
Nathalie Stremler-Le Bel
(16)
,
Guillaume Thouvenin
(30)
,
Caroline Thumerelle
(24)
,
Eline van Aerde
(25)
,
Stefano Volpi
(19)
,
Sophie Willcocks
(31)
,
Carine Wouters
(2, 25, 32)
,
Sylvain Breton
(5)
,
Thierry Molina
(33)
,
Brigitte Bader-Meunier
(1, 2)
,
Despina Moshous
(1, 2)
,
Alain Fischer
(1, 2, 34)
,
Stéphane Blanche
(2)
,
Frédéric Rieux-Laucat
(1)
,
Yanick Crow
(1, 35)
,
Bénédicte Neven
(1, 2)
1
Imagine - U1163 -
Imagine - Institut des maladies génétiques (IHU)
2 Service d'immuno-hématologie pédiatrique [CHU Necker]
3 Service de Pneumologie Allergologie [CHU Necker]
4 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
5 Service de radiologie pédiatrique [CHU Necker]
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 Urgences pédiatriques [Hôpital de la Timone - APHM]
8 U932 - Immunité et cancer
9 HCL - Hospices Civils de Lyon
10 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases [CIRI]
11 IP - Institut Pasteur [Paris]
12 Immunologie Translationnelle - Translational Immunology lab
13 Hôpital Princesse Grace [Monaco]
14 Women’s and Children’s Hospital [Adelaide]
15 CHU Notre Dame des Secours [Jbeil]
16 Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM]
17 CCML - Centre Chirurgical Marie Lannelongue
18 Hôpital Necker - Enfants Malades [AP-HP]
19 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
20 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
21 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
22 PCCEI - Pathogenesis and Control of Chronic and Emerging Infections
23 Vall d'Hebron University Hospital [Barcelona]
24 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
25 University Hospitals Leuven [Leuven]
26 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
27 MAHSC - Manchester Academic Health Science Centre
28 VHIR - Vall d’Hebron Research Institute
29 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
30 CHU Trousseau [APHP]
31 QCH - Queensland Children's Hospital
32 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
33 Service de pathologie [CHU Necker]
34 CdF (institution) - Collège de France
35 IGMM - MRC Institute of Genetics and Molecular Medicine [Edinburgh]
2 Service d'immuno-hématologie pédiatrique [CHU Necker]
3 Service de Pneumologie Allergologie [CHU Necker]
4 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
5 Service de radiologie pédiatrique [CHU Necker]
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 Urgences pédiatriques [Hôpital de la Timone - APHM]
8 U932 - Immunité et cancer
9 HCL - Hospices Civils de Lyon
10 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases [CIRI]
11 IP - Institut Pasteur [Paris]
12 Immunologie Translationnelle - Translational Immunology lab
13 Hôpital Princesse Grace [Monaco]
14 Women’s and Children’s Hospital [Adelaide]
15 CHU Notre Dame des Secours [Jbeil]
16 Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM]
17 CCML - Centre Chirurgical Marie Lannelongue
18 Hôpital Necker - Enfants Malades [AP-HP]
19 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
20 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
21 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
22 PCCEI - Pathogenesis and Control of Chronic and Emerging Infections
23 Vall d'Hebron University Hospital [Barcelona]
24 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
25 University Hospitals Leuven [Leuven]
26 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
27 MAHSC - Manchester Academic Health Science Centre
28 VHIR - Vall d’Hebron Research Institute
29 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
30 CHU Trousseau [APHP]
31 QCH - Queensland Children's Hospital
32 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
33 Service de pathologie [CHU Necker]
34 CdF (institution) - Collège de France
35 IGMM - MRC Institute of Genetics and Molecular Medicine [Edinburgh]
Alice Hadchouel
- Fonction : Auteur
- PersonId : 762110
- ORCID : 0000-0001-7451-9890
Laureline Berteloot
- Fonction : Auteur
- PersonId : 786606
- ORCID : 0000-0001-9681-3142
Isabelle Melki
- Fonction : Auteur
- PersonId : 766552
- ORCID : 0000-0002-8057-333X
- IdRef : 158851897
Alexandre Belot
- Fonction : Auteur
- PersonId : 949521
- ORCID : 0000-0003-4902-5332
- IdRef : 115823824
Vincent Bondet
- Fonction : Auteur
- PersonId : 746608
- IdHAL : vincent-bondet
- ORCID : 0000-0002-6534-0984
Darragh Duffy
- Fonction : Auteur
- PersonId : 746816
- IdHAL : darragh-duffy
- ORCID : 0000-0002-8875-2308
- IdRef : 201316919
Mathieu Fusaro
- Fonction : Auteur
- PersonId : 800975
- ORCID : 0000-0002-5332-3626
Gillian Rice
- Fonction : Auteur
- PersonId : 767243
- ORCID : 0000-0002-4223-0571
Jacques Rivière
- Fonction : Auteur
- PersonId : 774331
- ORCID : 0000-0003-1055-2063
Luis Seabra
- Fonction : Auteur
- PersonId : 806099
- ORCID : 0000-0002-4678-3026
Guillaume Thouvenin
- Fonction : Auteur
- PersonId : 763642
- ORCID : 0000-0003-0528-5458
Stefano Volpi
- Fonction : Auteur
- PersonId : 791249
- ORCID : 0000-0002-7129-868X
Carine Wouters
- Fonction : Auteur
- PersonId : 764842
- ORCID : 0000-0002-6426-8845
Brigitte Bader-Meunier
- Fonction : Auteur
- PersonId : 764839
- ORCID : 0000-0001-8476-8196
- IdRef : 058551522
Despina Moshous
- Fonction : Auteur
- PersonId : 1187483
- IdHAL : despina-moshous
- ORCID : 0000-0001-6719-3693
Frédéric Rieux-Laucat
- Fonction : Auteur
- PersonId : 1062914
- IdHAL : frederic-rieux-laucat
- ORCID : 0000-0001-7858-7866
- IdRef : 086828509
Yanick Crow
- Fonction : Auteur
- PersonId : 11918
- IdHAL : yanick-crow
- ORCID : 0000-0001-7211-7564
- IdRef : 227205359
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.
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