Marie-Louise Frémond1, Alice Hadchouel2, Laureline Berteloot3, Isabelle Melki4, Violaine Bresson5, Laura Barnabei6, Nadia Jeremiah7, Alexandre Belot8, Vincent Bondet9, Olivier Brocq10, Damien Chan11, Rawane Dagher12, Jean-Christophe Dubus13, Darragh Duffy9, Séverine Feuillet-Soummer14, Mathieu Fusaro15, Marco Gattorno16, Antonella Insalaco17, Eric Jeziorski18, Naoki Kitabayashi19, Mireia Lopez-Corbeto20, Françoise Mazingue21, Marie-Anne Morren22, Gillian I Rice23, Jacques G Rivière24, Luis Seabra19, Jérôme Sirvente25, Pere Soler-Palacin26, Nathalie Stremler-Le Bel13, Guillaume Thouvenin27, Caroline Thumerelle28, Eline Van Aerde29, Stefano Volpi16, Sophie Willcocks30, Carine Wouters31, Sylvain Breton3, Thierry Molina32, Brigitte Bader-Meunier33, Despina Moshous34, Alain Fischer35, Stéphane Blanche36, Frédéric Rieux-Laucat6, Yanick J Crow37, Bénédicte Neven38. 1. 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. 2. 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. 3. Pediatric Radiology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France. 4. 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. 5. Pediatric Emergency Department, Hôpital de la Timone, AP-HM, Centre Hospitalier Universitaire de Marseille, Marseille, France. 6. Université de Paris, Imagine Institute, Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, France. 7. Immunity and Cancer Department, Institut Curie, PSL Research University, Institut National de la Santé et de la Recherche Médicale U932, Paris, France. 8. 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. 9. Translational Immunology Lab, Institut Pasteur, Paris, France. 10. Rheumatology Department, Centre Hospitalier Princesse Grace, Monaco, Monaco. 11. Pediatric Allergy and Immunology Department, Women's and Children's Hospital, Adelaide, South Australia, Australia. 12. Department of Pediatrics, Notre Dame des Secours University Hospital, Jbeil, Lebanon. 13. Pediatric Pulmonology Department, Hôpital de la Timone, AP-HM, Centre Hospitalier Universitaire de Marseille, Marseille, France. 14. Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie-Lannelongue Hospital, Paris-Sud University, Le Plessis-Robinson, France. 15. 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. 16. Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Giannina Gaslini Institute, Genova, Italy. 17. Pediatric Rheumatology Unit, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy. 18. Pediatrics Department, Centre Hospitalier Universitaire de Montpellier, Montpellier, France. 19. Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Paris, France. 20. Pediatric Rheumatology Unit, Rheumatology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. 21. Pediatric Hematology Department, Centre Hospitalier Universitaire de Lille, Lille, France. 22. 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. 23. 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. 24. 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. 25. Internal Medicine Department, Hôpital Saint-Eloi, Centre Hospitalier Universitaire de Montpellier, Montpellier, France. 26. 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. 27. Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, AP-HP Sorbonne Université, Paris, France. 28. Pediatric Pneumology Department, Hôpital Jeanne de Flandre, CHRU Lille, Lille, France. 29. Dermatology Department, University Hospitals Leuven, Leuven, Belgium. 30. Pediatric Immunology and Allergy Service, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Queensland, Australia. 31. 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. 32. Université de Paris, Paris, France; Pathology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France. 33. 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. 34. 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. 35. 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. 36. Université de Paris, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP Centre Université de Paris, Paris, France. 37. 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. 38. 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.
Abstract
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.
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.
Keywords:
Interstitial lung disease; JAK inhibitors; Lymphopenia; Polyarthritis; STING1; Stimulator of interferon genes; Type I interferonopathy; Vasculopathy
Authors: Kevin MingJie Gao; Mona Motwani; Thomas Tedder; Ann Marshak-Rothstein; Katherine A Fitzgerald Journal: Proc Natl Acad Sci U S A Date: 2022-06-13 Impact factor: 12.779
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