Monogenic Early-Onset Lymphoproliferation and Autoimmunity: The Natural History of STAT3 GOF Syndrome.
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Leiding, J. W. | Vogel, T. P. | Santarlas, V. G. J. | Mhaskar, R. | Smith, M. R. | Carisey, A. | Vargas-Hernandez, A. | Silva-Carmona, M. | Heeg, M. | Rensing-Ehl, A. | Neven, Bénédicte | Hadjadj, Jérôme | Hambleton, S. | Leahy, T. R. | van Hagen, M. | Cunningham-Rundles, C. | Dutmer, C. M. | Sharapova, S. O. | Taskinen, M. | Chua, I. | Hague, R. | Klemann, C. | Kostyuchenko, L. | Morio, T. | Thatayatikom, A. | Ozen, A. | Scherbina, A. | Bauer, C. S. | Flanagan, S. E. | Gambineri, E. | Giovannini-Chami, Lisa | Heimall, J. | Sullivan, K. E. | Allenspach, E. | Romberg, N. | Deane, S. G. | Prince, B. T. | Rose, M. | Bohnsack, J. | Mousallem, T. | Jesudas, R. | dos Santos Vilela, M. M. | O'Sullivan, M. | Schmid, J. P. | Průhová, Š. | Rees, M. | Su, H. | Bahna, S. | Baris, S. | Bartnikas, L. M. | Chang Berger, A. | Briggs, T. A. | Brothers, S. | Bundy, V. | Chan, A. Y. | Chandrakasan, S. | Christiansen, M. | Cole, T. | Cook, M. C. | Desai, M. M. | Fischer, U. | Fulcher, D. A. | Gallo, S. | Gauthier, A. | Gennery, A. R. | Marques, J. G. | Gottrand, Fréderic | Grimbacher, B. | Grunebaum, E. | Haapaniemi, E. | Hämäläinen, S. | Heiskanen, K. | Heiskanen-Kosma, T. | Hoffman, H. M. | Gonzalez-Granado, L. I. | Guerreiro, A. L. | Kainulainen, L. | Kumar, A. | Lawrence, M. G. | Levin, C. | Martelius, T. | Neth, O. | Olbrich, P. | Palma, A. | Patel, N. C. | Pozos, T. | Preece, K. | Lugo Reyes, S. O. | Russell, M. A. | Schejter, Y. | Seroogy, C. | Sinclair, J. | Skevofilax, E. | Suan, D. | Suegeorgz, D. | Szabolcs, P. | Velasco, H. | Warnatz, K. | Walkovich, K. | Worth, A. | Seppänen, M. R. J. | Torgerson, T. R. | Sogkas, G. | Ehl, S. | Tangye, S. G. | Cooper, M. A. | Milner, J. D. | Forbes Satter, L. R. | Aleshkevich, S. | Allende, L. M. | Atkinson, T. P. | Atschekzei, F. | Aydemir, S. | Aygunes, U. | Barlogis, V. | Baumann, U. | Belko, J. | Bezrodnik, L. | Biebl, A. | Broderick, L. | Bunin, N. J. | Caldirola, M. S. | Castelle, M. | Celmeli, F. | Charbonnier, L. M. | Chatila, T. A. | Chellapandian, D. | Cokugras, H. | Conlon, N. | Cox, F. | Crickx, E. | Dalgic, B. | Dalm, V. A. | Danielian, S. | Dominguez-Pinilla, N. | Dujovny, T. | Ebbo, M. | Eken, A. | Esty, B. | Fabre, A. | Fischer, A. | Hannibal, M. | Huppert, L. | Ikeda, M. D. | Jolles, S. | Jolly, K. W. | Jones, N. | Kakakukcu, M. | Kanariou, M. | Karakoc-Aydiner, E. | Karamantziani, T. | Kelaidi, C. | Keogan, M. | Kisaarslan, A. P. | Kiykim, A. | Klocperk, A. | Kotsonis, K. | Kuzmenko, N. | Leroy, S. | Lesmana, H. | Lianou, D. | Longhurst, H. | Lorenz, M. R. | Maffucci, P. | Manson, A. | Marchal, S. | Malphettes, M. | Marega, L. F. | Mauracher, A. A. | Meesilpavikai, K. | Miller, H. | Mombourquette, J. | Morgan, N. G. | Mukhina, A. | Nathalie, A. | Nelken, B. | Nolan, D. | Norlin, A. C. | Oleastro, M. | Ozcan, A. | Pasquet, M. | Pegler, J. R. | Picard, C. | Polychronopoulou, S. | Quartier, P. | Ramakers, J. | Randall, K. L. | Rao, V. K. | Remiker, A. | Resin, G. | Richmond, P. | Rieux-Laucat, F. | Rodina, Y. | Rohrlich, P. | Sachs, J. | Sakovich, I. | Santarlas, C. | Sari, S. | Sawicki, G. | Schauer, U. | Scheffler Mendoza, S. C. | Schvetz, O. | Schmidt, R. E. | Schwarz, K. | Sediva, A. | Sinclair, K. | Slatter, M. | Sleasman, J. | Stergiou, K. | Suratannon, N. | Tanita, K. | Thompson, G. | Travis, S. | Trojan, T. | Tsinti, M. | Unal, E. | Urdinez, L. | Vazquez-Gomez, F. | Villa, M. | Weinrich, M. | Weiss, M. J. | Wright, B. | Yilmaz, E. | Zachova, R. | Zhang, Y. | Quesada, J. F.
Edité par
CCSD ; Elsevier -
International audience.
BackgroundIn 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.ObjectiveThis pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.MethodsWe 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.ResultsOverall 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.
