STAT3-gain of function mutation as a cause of severe bronchiectasis and multi-organ autoimmunity; A case report

Abstract

Background: Signal transducer and activator of transcription 3 (STAT3) is a member of a family of proteins involved in the regulation of inflammation, differentiation, proliferation and survival. Loss or gain-of-function mutations in STAT3 lead to infectious and autoimmune complications. Recently, STAT3 gain-of-function mutations have been associated with the development of a multi-organ autoimmune syndrome. Case presentation: Here, we describe a 38-year-old male who presented with severe diffuse bronchiectasis in addition to gastrointestinal, dermatological, and malignant manifestations. Following negative workup, whole exome sequencing, validated by Sanger sequencing, revealed a heterozygous missense mutation in the STAT3 gene, c.1261G>A (p.G421R). FACS analysis of peripheral T lymphocytes revealed low levels of CD4+CD25+FoxP3 and CD8+CD25+FoxP3 regulatory T cells (Tregs). Following treatment with two cycles of tocilizumab, an interleukin-6 receptor antibody, a significant increase in the level of Tregs was observed, accompanied by clinical improvement. Conclusion: This case sheds light on the emerging role of STAT3 gain of function mutation in the pathogenesis of autoimmune diseases and development of bronchiectasis, and further addresses the therapeutic role of IL-6 blocker treatment in this syndrome.