Portal de Periódicos da CAPES

Artigo Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

2022; Elsevier BV; Volume: 151; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2022.09.002

1097-6825

Jennifer W. Leiding, Tiphanie P. Vogel, Valentine G.J. Santarlas, Rahul Mhaskar, M.R. Smith, Alexandre F. Carisey, Alexander Vargas‐Hernández, Manuel Silva‐Carmona, Maximilian Heeg, Anne Rensing‐Ehl, Bénédicte Neven, Jérôme Hadjadj, Sophie Hambleton, Timothy Ronan Leahy, Kornvalee Meesilpavikai, Charlotte Cunningham‐Rundles, Cullen M. Dutmer, Svetlana O. Sharapova, Mervi Taskinen, Ignatius Chua, Rosie Hague, Christian Klemann, Larysa Kostyuchenko, Tomohiro Morio, Akaluck Thatayatikom, Ahmet Özen, Anna Scherbina, Cindy S. Bauer, Sarah E. Flanagan, Eleonora Gambineri, Lisa Giovannini‐Chami, Jennifer Heimall, Kathleen E. Sullivan, Eric J. Allenspach, Neil Romberg, Sean G. Deane, Benjamin T. Prince, Melissa J. Rose, John F. Bohnsack, Talal Mousallem, Rohith Jesudas, Maria Marluce dos Santos Vilela, Michael O’Sullivan, Jana Pachlopnik Schmid, Štěpánka Průhová, Adam Klocperk, M. Rees, Helen C. Su, Sami L. Bahna, Safa Barış, Lisa M. Bartnikas, Amy Berger, Tracy A. Briggs, Shannon Brothers, Vanessa Bundy, Alice Chan, Shanmuganathan Chandrakasan, Mette Christiansen, Theresa Cole, Matthew Cook, Mukesh Desai, Ute Fischer, David A. Fulcher, Silvanna Gallo, A. Gauthier, Andrew R. Gennery, José Gonçalo Marques, F. Gottrand, Bodo Grimbacher, Eyal Grunebaum, Emma Haapaniemi, Sari Hämäläinen, Kaarina Heiskanen, Tarja Heiskanen‐Kosma, Hal M. Hoffman, Luis Ignacio González‐Granado, Anthony L. Guerrerio, Leena Kainulainen, Ashish Kumar, Monica G. Lawrence, Carina Levin, Timi Martelius, Olaf Neth, Peter Olbrich, Alejandro Palma, Niraj Patel, Tamara C. Pozos, Kahn Preece, Saúl Oswaldo Lugo Reyes, Mark A. Russell, Yael Dinur Schejter, Christine M. Seroogy, Jan Sinclair, Effie Skevofilax, Daniel Suan, Daniel Suez, Paul Szabolcs, Helena Velasco, Klaus Warnatz, Kelly Walkovich, Austen Worth, Mikko Seppänen, Troy R. Torgerson, Georgios Sogkas, Stephan Ehl, Stuart G. Tangye, Megan A. Cooper, Joshua D. Milner, Lisa Forbes Satter, Svetlana Aleshkevich, Luis M. Allende, T. Prescott Atkinson, Faranaz Atschekzei, Sezin Aydemir, Utku Aygüneş, Vincent Barlogis, Ulrich Baumann, John S. Belko, Liliana Bezrodnik, Ariane Biebl, Lori Broderick, Nancy Bunin, María Soledad Caldirola, Martin Castelle, Fatih Çelmeli, Louis‐Marie Charbonnier, Talal A. Chatila, Deepak Chellapandian, Haluk Çokuğraş, Niall Conlon, Fionnuala Cox, Étienne Crickx, Buket Dalgıç, Virgil ASH Dalm, Silvia Danielian, Nerea Domínguez‐Pinilla, Tal Dujovny, Mikaël Ebbo, Ahmet Eken, Brittany Esty, Alexandre Fabre, Alain Fischer, Mark C. Hannibal, Laura A. Huppert, Marc D. Ikeda, Stephen Jolles, Kent W. Jolly, Neil D. Jones, Maria Kanariou, Elif Karakoç-Aydıner, Theoni Karamantziani, Charikleia Kelaïdi, Mary T. Keogan, Ayşenur Paç Kısaarslan, Ayça Kıykım, Adam Klocperk, Kosmas Kotsonis, N. B. Kuzmenko, Sylvie Leroy, Dimitra Lianou, Hilary Longhurst, Myriam Ricarda Lorenz, Patrick Maffucci, Ania Manson, Sarah Marchal, Marion Malphettes, Lia Furlaneto Marega, Andrea Mauracher, Kornvalee Meesilpavikai, Holly Miller, Joy Mombourquette, Noel G. Morgan, Anna Mukhinа, Nathalie Aladjidi, Brigitte Nelken, David Nolan, Anna-Carin Norlin, Matías Oleastro, Alper Özcan, Marlène Pasquet, José Roberto Mendes Pegler, Capucine Pïcard, Sophia Polychronopoulou, Pierre Quartier, Juan Francisco Quesada‐Espinosa, Jan Ramakers, Katrina L. Randall, V. Koneti Rao, Allison Remiker, Geraldine Resin, Peter Richmond, Frédéric Rieux‐Laucat, Yulia Rodina, Pierre‐Simon Rohrlich, Johnathan Sachs, Inga Sakovich, Christopher Santarlas, Sinan Sarı, Gregory S. Sawicki, U. Schauer, Selma Scheffler‐Mendoza, Oksana Schvetz, Reinhold Schmidt, Klaus Schwarz, Anna Šedivá, Kyle Sinclair, Mary Slatter, John W. Sleasman, Katerina Stergiou, Narissara Suratannon, Kay Tanita, Grace Thompson, Stephen Travis, Timothy Trojan, Maria Tsinti, Ekrem Ünal, Luciano Urdinez, Felisa Vazquez-Gómez, Mariana Villa, Michael Weinrich, Mitchell J. Weiss, Benjamín Wright, Ebru Yılmaz, Radana Zachová, Yu Zhang,

Cytokine Signaling Pathways and Interactions

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. 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.