Tawfik Khoury1, Vered Molho-Pessach2, Yuval Ramot2, Abu Rmeileh Ayman3, Orly Elpeleg4, Neville Berkman5, Abraham Zlotogorski2, Yaron Ilan3. 1. Gastroenterology and Liver Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: tawfikkhoury1@hotmail.com. 2. Department of Dermatology and the Center for Genetic Diseases of the Skin and Hair, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 3. Gastroenterology and Liver Unit, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 4. Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 5. Department of Pulmonology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Abstract
PURPOSE: Signal transducer and activator of transcription 3 is a member of a family of proteins involved in the regulation of inflammation, differentiation, proliferation, and survival of cells. Here we describe a 38-year-old male who has experienced gastrointestinal, dermatologic, pulmonary, and malignant manifestations. METHODS: Whole-exome sequencing, validated by Sanger sequencing, was performed after extensive investigations. FINDINGS: Whole-exome sequencing revealed a heterozygous missense mutation in the signal transducer and activator of transcription 3 gene, c.1261G>A (p.G421R). Fluorescence-activated cell sorting analysis of peripheral T lymphocytes revealed low levels of CD4+CD25+FoxP3 and CD8+CD25+FoxP3 regulatory T cells. After treatment with 2 cycles of tocilizumab, an interleukin-6 receptor antibody, a significant increase in the level of regulatory T cells was observed, accompanied by clinical improvement. IMPLICATIONS: This case sheds light on the emerging role of signal transducer and activator of transcription 3 gain-of-function mutation in the pathogenesis of autoimmune diseases, and further addresses the therapeutic role of interleukin-6 blocker treatment in this syndrome.
PURPOSE:Signal transducer and activator of transcription 3 is a member of a family of proteins involved in the regulation of inflammation, differentiation, proliferation, and survival of cells. Here we describe a 38-year-old male who has experienced gastrointestinal, dermatologic, pulmonary, and malignant manifestations. METHODS: Whole-exome sequencing, validated by Sanger sequencing, was performed after extensive investigations. FINDINGS: Whole-exome sequencing revealed a heterozygous missense mutation in the signal transducer and activator of transcription 3 gene, c.1261G>A (p.G421R). Fluorescence-activated cell sorting analysis of peripheral T lymphocytes revealed low levels of CD4+CD25+FoxP3 and CD8+CD25+FoxP3 regulatory T cells. After treatment with 2 cycles of tocilizumab, an interleukin-6 receptor antibody, a significant increase in the level of regulatory T cells was observed, accompanied by clinical improvement. IMPLICATIONS: This case sheds light on the emerging role of signal transducer and activator of transcription 3 gain-of-function mutation in the pathogenesis of autoimmune diseases, and further addresses the therapeutic role of interleukin-6 blocker treatment in this syndrome.