Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline, loss-of-function mutations in the transcription factor STAT3 cause immunodeficiency, while somatic, gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here we report thirteen individuals from ten families with lymphoproliferation and early-onset, solid organ autoimmunity associated with nine different germline, heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multi-organ autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 lead to clinical improvement in one patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly-described disorder. Some patients for this study were enrolled in a trial registered at ClinicalTrials.gov #NCT00001350.Copyright © 2014 American Society of Hematology.

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