Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review

J Allergy Clin Immunol Pract. 2019 Jul-Aug;7(6):1958-1969.e9. doi: 10.1016/j.jaip.2019.02.018. Epub 2019 Feb 27.


Background: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled.

Objective: We have conducted a systematic review of published STAT3 GOF cases to describe clinical, diagnostic, and therapeutic aspects of the disease.

Methods: A systematic review including articles published before October 10, 2018, in PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed. We described cases of patients with STAT3 GOF germline mutations with genetic analysis and a concordant phenotype if functional analyses were not performed for the mutation.

Results: The search identified 18 publications describing 42 unique patients. Twenty-eight different mutations were described. Onset of disease was very early with an average age of 3 (0.5-5) years. The most frequent manifestations were autoimmune cytopenias (28 of 42), lymphoproliferation (27 of 42), enteropathy (24 of 42), interstitial lung disease (15 of 42), thyroiditis (13 of 42), diabetes (10 of 42), and postnatal growth failure (15 of 21). Immunodeficiency was not always a predominant feature. Most patients required significant immunosuppressive therapy. Five patients received hematopoietic stem cell transplantation, and 4 died from complications. Improvement of symptoms was observed for 8 of 9 patients who received targeted biotherapies.

Conclusions: STAT3 GOF syndrome is a new clinical entity to consider when confronted with a patient with early-onset polyautoimmunity, lymphoproliferation, and growth failure. At this time, precise therapeutic guidelines are lacking, but use of anti-IL-6 receptor and JAK inhibitor biologics is an attractive possibility.

Keywords: Autoimmunity; Celiac disease; Child; Early-onset diabetes; Evans syndrome; GOF; Interstitial lung disease; Lymphoproliferative disease; Short stature.

Publication types

  • Systematic Review

MeSH terms

  • Endocrine System Diseases / genetics
  • Gain of Function Mutation
  • Gastrointestinal Diseases / genetics
  • Germ-Line Mutation
  • Hematologic Diseases / genetics
  • Humans
  • Immune System Diseases / genetics
  • Lung Diseases / genetics
  • STAT3 Transcription Factor / genetics*


  • STAT3 Transcription Factor
  • STAT3 protein, human