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Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome
Journal of allergy and clinical immunology, 2023-04, Vol.151 (4), p.1081-1095
2023

Details

Autor(en) / Beteiligte
Titel
Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome
Ist Teil von
  • Journal of allergy and clinical immunology, 2023-04, Vol.151 (4), p.1081-1095
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2023
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 0091-6749
eISSN: 1097-6825
DOI: 10.1016/j.jaci.2022.09.002
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10081938
Format
–
Schlagworte
autoimmunity, Autoimmunity - genetics, Cell Proliferation, Child, Cohort Studies, cytopenia, gain of function, Gain of Function Mutation, Humans, immune dysregulation, Immune System Diseases, immunodeficiency, Immunologic Deficiency Syndromes - genetics, Lymphocytes, lymphoproliferation, Mutation, precision medicine, STAT3, STAT3 Transcription Factor - genetics

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