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.
Bibliographical noteFunding Information:
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 BMBF GAIN 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 Fook Foundation.
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