Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome - 05/04/23

Doi : 10.1016/j.jaci.2022.09.002

Jennifer W. Leiding, MD ^a,^b,^⁎ , Tiphanie P. Vogel, MD, PhD ^c, Valentine G.J. Santarlas, BS, BA ^d, Rahul Mhaskar, MPH, PhD ^e, Madison R. Smith, BS ^c, Alexandre Carisey, PhD ^f, Alexander Vargas-Hernández, PhD ^c, Manuel Silva-Carmona, MD ^g, Maximilian Heeg, MD ^h, Anne Rensing-Ehl, MD ^h, Bénédicte Neven, MD ⁱ, Jérôme Hadjadj, PhD ⁱ, Sophie Hambleton, PhD ^j, Timothy Ronan Leahy, MD ^k, Kornvalee Meesilpavikai, MD, PhD ^l,^m, Charlotte Cunningham-Rundles, MD ⁿ, Cullen M. Dutmer, MD ^o, Svetlana O. Sharapova, PhD ^p, Mervi Taskinen, MD, PhD ^q, Ignatius Chua, PhD ^r,^s, Rosie Hague, MD ^t, Christian Klemann, MD ^u, Larysa Kostyuchenko, MD, PhD ^v, Tomohiro Morio, MD, PhD ^w, Akaluck Thatayatikom, MD ^x, Ahmet Ozen, MD ^y, Anna Scherbina, MD ^z, Cindy S. Bauer, MD ^aa, Sarah E. Flanagan, PhD ^ab, Eleonora Gambineri, MD ^ac, Lisa Giovannini-Chami, MD, PhD ^ad, Jennifer Heimall, MD ^ae, Kathleen E. Sullivan, MD, PhD ^ae, Eric Allenspach, MD, PhD ^af,^ag, Neil Romberg, MD ^ae, Sean G. Deane, MD ^ah, Benjamin T. Prince, MD ^ai,^aj, Melissa J. Rose, DO ^aj,^ak, John Bohnsack, MD ^al, Talal Mousallem, MD ^am, Rohith Jesudas, MD ^an, Maria Marluce Dos Santos Vilela, MD ^ao, Michael O’Sullivan, MD ^s,^ap, Jana Pachlopnik Schmid, MD, PhD ^aq, Štěpánka Průhová, PhD ^ar, Adam Klocperk, PhD ^cx, Matthew Rees, MD ^an, Helen Su, MD, PhD ^as, Sami Bahna, MD ^at, Safa Baris, MD ^y, Lisa M. Bartnikas, MD ^au, Amy Chang Berger, MD ^av, Tracy A. Briggs, MD, PhD ^aw,^ax, Shannon Brothers, MD ^s,^ay, Vanessa Bundy, MD, PhD ^az, Alice Y. Chan, MD ^ba, Shanmuganathan Chandrakasan, MD ^bb, Mette Christiansen, PhD ^bc, Theresa Cole, BM, PhD ^bd, Matthew C. Cook, MB, BS, PhD ^be, Mukesh M. Desai, MD ^bf, Ute Fischer, PhD ^bg, David A. Fulcher, PhD ^be, Silvanna Gallo, MD ^bh, Amelie Gauthier, MD ^bi, Andrew R. Gennery, MD ^j, José Gonçalo Marques, MD ^bj, Frédéric Gottrand, MD ^bk, Bodo Grimbacher, MD ^h, Eyal Grunebaum, MD ^bl, Emma Haapaniemi, MD, PhD ^bm,^bn, Sari Hämäläinen, MD, PhD ^bo, Kaarina Heiskanen, MD, PhD ^q, Tarja Heiskanen-Kosma, MD, PhD ^bp, Hal M. Hoffman, MD ^bq,^br, Luis Ignacio Gonzalez-Granado, MD ^bs, Anthony L. Guerrerio, MD, PhD ^bt, Leena Kainulainen, MD ^bu, Ashish Kumar, MD, PhD ^bv, Monica G. Lawrence, MD ^bw, Carina Levin, MD, PhD ^bx, Timi Martelius, MD, PhD ^by, Olaf Neth, MD, PhD ^bz, Peter Olbrich, MD, PhD ^bz, Alejandro Palma, MD ^ca, Niraj C. Patel, MD ^cb, Tamara Pozos, MD, PhD ^cc, Kahn Preece, MD ^s,^cd, Saúl Oswaldo Lugo Reyes, MD ^ce, Mark A. Russell, PhD ^cf, Yael Schejter, MD ^cg, Christine Seroogy, MD ^ch, Jan Sinclair, MD ^s,^ci, Effie Skevofilax, MD ^cj, Daniel Suan, MBBS, PhD ^s,^ck,^cl, Daniel Suez, MD ^cm, Paul Szabolcs, MD ^cn, Helena Velasco, MD ^co, Klaus Warnatz, MD ^h, Kelly Walkovich, MD ^cp, Austen Worth, MD ^cq, and
STAT3 GOF Working Group members^{^∗}
STAT3 GOF Working Group members are listed in the acknowledgments at the end of the article.
Svetlana Aleshkevich, MD, Luis M. Allende, PhD, T. Prescott Atkinson, MD, PhD, Faranaz Atschekzei, MD, PhD, Sezin Aydemir, MD, Utku Aygunes, MD, Vincent Barlogis, MD, PhD, Ulrich Baumann, PhD, John Belko, MD, Liliana Bezrodnik, MD, Ariane Biebl, MD, Lori Broderick, MD, PhD, Nancy J. Bunin, MD, Maria Soledad Caldirola, PhD, Martin Castelle, MD, Fatih Celmeli, MD, Louis-Marie Charbonnier, PhD, Talal A. Chatila, MD MSc, Deepak Chellapandian, MD, Haluk Cokugras, MD, Niall Conlon, PhD, Fionnuala Cox, PhD, Etienne Crickx, MD, PhD, Buket Dalgic, MD, Virgil ASH Dalm, MD, PhD, Silvia Danielian, PhD, Nerea Dominguez-Pinilla, MD, Tal Dujovny, MD, Mikael Ebbo, MD, PhD, Ahmet Eken, MD, Brittany Esty, MD, Alexandre Fabre, MD, PhD, Alain Fischer, MD, PhD, Mark Hannibal, MD, PhD, Laura Huppert, MD, Marc D. Ikeda, MD, Stephen Jolles, MD, Kent W. Jolly, MD, Neil Jones, MD, Maria Kanariou, MD, Elif Karakoc-Aydiner, MD, Theoni Karamantziani, MD, Charikleia Kelaidi, MD, Mary Keogan, MD, Ayşenur Pac Kisaarslan, MD, Ayca Kiykim, MD, Adam Klocperk, PhD, Kosmas Kotsonis, MD, Natalia Kuzmenko, MD, Sylvie Leroy, MD, Dimitra Lianou, MD, Hilary Longhurst, PhD, Myriam Ricarda Lorenz, PhD, Patrick Maffucci, MD, PhD, Ania Manson, PhD, Sarah Marchal, MD, Marion Malphettes, MD, Lia Furlaneto Marega, PhD, Andrea A. Mauracher, MD, PhD, Kornvalee Meesilpavikai, MD, PhD, Holly Miller, DO, Joy Mombourquette, MD, Noel G. Morgan, PhD, Anna Mukhina, MD, Aladjidi Nathalie, MD, Brigitte Nelken, MD, David Nolan, MD, Anna-Carin Norlin, MD, PhD, Matias Oleastro, MD, Alper Ozcan, MD, Marlene Pasquet, MD, PhD, José Roberto Pegler, MD, Capucine Picard, MD, PhD, Sophia Polychronopoulou, MD, PhD, Pierre Quartier, MD, Juan Francisco Quesada, MD, Jan Ramakers, MD, Katrina L. Randall, MBBS, PhD, V. Koneti Rao, MD, Allison Remiker, MD, Geraldine Resin, MD, Peter Richmond, MD, Frederic Rieux-Laucat, PhD, Yulia Rodina, MD, Pierre Rohrlich, MD, PhD, Johnathan Sachs, MD, Inga Sakovich, PhD, Christopher Santarlas, BS, Sinan Sari, MD, Gregory Sawicki, MD, Uwe Schauer, MD, Selma C. Scheffler Mendoza, MD, MS, Oksana Schvetz, MD, Reinhold Ernst Schmidt, MD, Klaus Schwarz, MD, Anna Sediva, MD, PhD, Kyle Sinclair, MD, Mary Slatter, MD, John Sleasman, MD, Katerina Stergiou, MD, Narissara Suratannon, MD, Kay Tanita, MD, PhD, Grace Thompson, MD, Stephen Travis, MD, Timothy Trojan, MD, Maria Tsinti, MD, PhD, Ekrem Unal, MD, Luciano Urdinez, MD, Felisa Vazquez-Gomez, MD, Mariana Villa, MD, Michael Weinrich, MD, Mitchell J. Weiss, MD, PhD, Benjamin Wright, MD, Ebru Yilmaz, MD, Radana Zachova, MD, Yu Zhang, PhD

Mikko R.J. Seppänen, MD, PhD ^cr, Troy R. Torgerson, MD, PhD ^cs, Georgios Sogkas, MD, PhD ^ct, Stephan Ehl, MD ^h, Stuart G. Tangye, PhD ^s,^ck,^cu, Megan A. Cooper, MD, PhD ^cv, Joshua D. Milner, MD ^cw, Lisa R. Forbes Satter, MD ^c,^⁎
^a Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore
^b Johns Hopkins All Children’s Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital, St Petersburg
^c Department of Pediatrics, Baylor College of Medicine and William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston
^d Lake Erie College of Osteopathic Medicine, Erie
^e Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa
^f Department of Cell and Molecular Biology, St Jude Children’s Research Hospital, Memphis
^g Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston
^h Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg
ⁱ Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163-Institut Imagine, Paris
^j Newcastle University Translational and Clinical Research Institute, Newcastle (United Kingdom)
^k Children’s Health Ireland at Crumlin, Dublin
^l Department of Internal Medicine, Division of Clinical Immunology and Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
^m Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
ⁿ Department of Medicine, Mount Sinai School of Medicine, New York
^o Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora
^p Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk
^q New Children’s Hospital, Pediatric Research Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Turku and Kuopio, Finland
^r Department of Rheumatology, Immunology and Allergy, Christchurch Hospital, Christchurch
^s Clinical Immunogenomics Research Consortium of Australasia (CIRCA)
^t Royal Hospital for Children, Glasgow
^u Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover
^v Center of Pediatric Immunology, Western Ukrainian Specialized Children’s Medical Centre, Lviv
^w Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo
^x Division of Pediatric Allergy/Immunology/Rheumatology, Shands Children’s Hospital, University of Florida, Gainesville
^y School of Medicine, Pediatric Allergy and Immunology, Marmara University, Istanbul
^z Dmitry Rogachev National Medical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow
^aa Division of Allergy and Immunology, Phoenix Children’s Hospital, Phoenix
^ab Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter
^ac Department of NEUROFARBA, Section of Children’s Health, University of Florence, Anna Meyer Children’s Hospital, Florence
^ad Pediatric Pulmonology Department, Hôpitaux pédiatriques de Nice CHU-Lenval, Nice
^ae Perelman School of Medicine at University of Pennsylvania, Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia
^af Pediatric Immunology/Rheumatology, University of Washington, Seattle
^ag Seattle Children’s Hospital, Seattle
^ah Department of Allergy, The Permanente Medical Group, Sacramento, and the Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, School of Medicine, Sacramento
^ai Nationwide Children’s Hospital Department of Allergy and Immunology, Columbus
^aj College of Medicine, The Ohio State University, Columbus
^ak Division of Pediatric Hematology-Oncology, Nationwide Children’s Hospital, Columbus
^al Department of Pediatrics, University of Utah, Salt Lake City
^am Duke Department of Pediatric Allergy and Immunology, Durham
^an Department of Hematology, St Jude Children’s Research Hospital, Memphis
^ao Pediatric Allergy and Immunology/Center of Investigation in Pediatrics, Faculty of Medical Sciences, State University of Campinas—Unicamp, São Paulo
^ap Immunology Department, Perth Children’s Hospital, Nedlands
^aq Division of Immunology, University Children’s Hospital Zurich, Children’s Research Center (CRC), Zurich
^ar Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague
^as Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda
^at Allergy and Immunology Section, Louisiana State University Health Sciences Center, Shreveport
^au Division of Immunology, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston
^av Division of Hospital Medicine, Department of Medicine, University of California, San Francisco
^aw Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester
^ax NW Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester
^ay Starship Children’s Hospital, Auckland
^az Allergy and Immunology, University of California, Los Angeles
^ba Department of Medicine, University of California, San Francisco
^bb Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta
^bc Department of Clinical Immunology, AUH, Aarhus
^bd Department of Allergy and Immunology, The Royal Children’s Hospital, Melbourne
^be Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra
^bf Bai Jerbai Wadia Children Hospital, Mumbai, Parel
^bg Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf
^bh Department of Pediatrics, Immunology and Rheumatology Section, Puerto Montt Hospital, Puerto Montt
^bi Department of Allergy and Immunology, CHU de Québec-CHUL, Laval University Hospital Center, Laval University, Quebec City
^bj Infectious Diseases and Immunodeficiencies Unit, Department of Pediatrics, Hospital de Santa Maria-CHULN and Faculdade de Medicina, Universidade de Lisboa, Lisbon
^bk University Lille, Inserm, CHU Lille, U1286-INFINITE—Institute for Translational Research in Inflammation, Lille
^bl Division of Immunology and Allergy, and the Department of Pediatrics, Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto
^bm Centre for Molecular Medicine Norway, Oslo
^bn Department of Pediatric Research, Oslo
^bo Department of Medicine, Kuopio University Hospital, Kuopio
^bp Department of Pediatrics, Rare Diseases Unit, Kuopio University Hospital, Kuopio
^bq Department of Pediatrics, University of California San Diego, La Jolla
^br Rady Children’s Hospital San Diego, Division of Pediatric Allergy, Immunology, and Rheumatology, San Diego
^bs Pediatrics Department, University Hospital 12 de Octubre, Research Institute Hospital, School of Medicine Complutense University, Madrid
^bt Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore
^bu Department of Pediatrics and Medicine, Turku University Hospital, University of Turku, Turku, Finland
^bv Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati
^bw University of Virginia Health, Charlottesville
^bx Pediatric Hematology Unit, Emek Medical Centre, Afula, and the Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa
^by Adult Immunodeficiency Unit, Inflammation Center, Helsinki University Hospital and University of Helsinki, Helsinki
^bz Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
^ca Servicio de Immunología y Reumatología, Hospital Nacional de Pediatría Prof Dr Juan P. Garrahan, Buenos Aires
^cb Division of Allergy and Immunology, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta
^cc Department of Clinical Immunology, Children’s Minnesota, Minneapolis
^cd Department of Paediatric Immunology, John Hunter Children’s Hospital, Newcastle (Australia)
^ce Immunodeficiencies Research Unit, National Institute of Pediatrics, Coyoacan, Mexico City
^cf University of Exeter Medical School, Exeter
^cg Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Ein-Kerem Medical Center and Faculty of Medicine, Hebrew University, Jerusalem
^ch Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison
^ci Starship Children’s Hospital, Auckland
^cj Department of Pediatric Hematology-Oncology (TAO) and First Department of Pediatrics, Aghia Sophia Children’s Hospital, Athens
^ck Garvan Institute of Medical Research, Darlinghurst
^cl Westmead Clinical School, University of Sydney, Westmead
^cm Allergy, Asthma & Immunology Clinic, PA, Irving
^cn University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Pittsburgh
^co Division of Allergy and Clinical Immunology, Moinhos de Vento Hospital, Porto Alegre
^cp Department of Pediatrics, C. S. Mott Children’s Hospital, Michigan Medicine, Ann Arbor
^cq Great Ormond Street Hospital for Children, London
^cr Rare Disease Center, Children’s Hospital, and Adult Primary Immunodeficiency Outpatient Clinic, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki
^cs Allen Institute, Seattle
^ct Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hanover
^cu St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney
^cv Department of Pediatrics, Division of Rheumatology and Immunology, Washington University School of Medicine, St Louis
^cw Department of Pediatrics, Division of Allergy and Immunology, Columbia University, New York Presbyterian Hospital, New York
^cx Department of Immunology, Second Faculty of Medicine and University Hospital Motol, Charles University in Prague, Prague

^∗Corresponding author: Lisa R. Forbes Satter, MD, Baylor College of Medicine, Texas Children’s Hospital Center for Human Immunobiology, 1102 Bates Ave, Ste 330, Houston, TX 77030.Baylor College of MedicineTexas Children’s Hospital Center for Human Immunobiology1102 Bates AveSte 330HoustonTX77030^∗∗Jennifer W. Leiding, MD, Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 Fifth Street South, Suite 3200, St. Petersburg, FL 33701.Division of Allergy and ImmunologyDepartment of PediatricsJohns Hopkins University School of Medicine

Abstract

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.

Le texte complet de cet article est disponible en PDF.

Key words : STAT3, gain of function, lymphoproliferation, cytopenia, autoimmunity, immune dysregulation, immunodeficiency, precision medicine

Abbreviations used : AD-HIES, CI, DN, DNT, GOF, HCT, ILD, JAK, Jakinib, LGL, OS, PD-1, PD-L1, STAT

Plan

Clinical manifestations

Immunologic abnormalities

Infections

Treatment

Domain–phenotype correlations

Survival

Discussion

Supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. S.B. was supported by the Scientific and Technological Research Council of Turkey (318S202). S.E. is supported by the German Research Foundation (DFG) under Germany’s excellence strategy (CIBBS-EXC-2189-Project ID 390939984) and the BMBFGAIN consortium (01GM1910A). L.R.F.S. is supported by the Jeffrey Modell Foundation and Baylor College of Medicine Chao Physician Scientist Award. G.S. was supported by the Germany’s Excellence Strategy–EXC 2155 “RESIST” (39087428) and the BMBF German Auto-Immunity Network (GAIN) (01GM1910E). T.P.V. was supported by the Arthritis National Research Foundation. B.G. is supported by the Deutsche Forschungsgemeinschaft (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST-EXC 2155-Project ID 390874280; and CIBSS-EXC-2189-Project ID 390939984), and the BMBF (GAIN) 01GM1910A. S.G.T. was supported by a Principal Research Fellowship (1042925) and Leadership 3 Investigator grant (1176665) from the National Health and Medical Research Council of Australia and CIRCA Investigators I.C., M.O’S., S.B., J.S., K.P., D.S., and S.G.T. are funded by grants awarded by the Jeffrey Modell Foundation and the Jon Brown Cook Foundation.

Disclosure of potential conflict of interest: A. Kumar reports speakers’ bureau for SOBI; L. Forbes Satter reports consultancy for Enzyvant, Grifols, CSL Behring, Takeda, and ADMA; J. W. Leiding is a full-time employee and shareholder of Bluebirdbio and speaker and consultant for Sobi and Horizon Therapeutics; and T. Vogel has consulted for SOBI, Novartis, Pfizer, and Moderna. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 151 - N° 4

P. 1081-1095 - avril 2023 Retour au numéro

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Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome - 05/04/23

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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