Reduction in mucosal phosphorylated STAT3 under therapy with JAK inhibitor in STAT3 gain of function mutation - a case study.

Germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 (STAT3) cause early-onset autoimmunity, lymphoproliferation, and immune dysregulation. Enteropathy is frequent, but longitudinal histopathological data remain limited. We report the clinical course and histological evolution of autoimmune enteropathy in an infant with a previously described STAT3 GOF mutation (c.2144C > T, p.Pro715Leu). Over 29 months, four endoscopies with duodenal biopsies conducted during different treatments revealed progressive villous atrophy and persistent inflammation despite clinical remission under Janus kinase (JAK) inhibitor therapy. Immunohistochemical staining showed consistent STAT3 expression, whereas phosphorylated STAT3 (pSTAT3) markedly decreased in epithelial and lamina propria lymphocytes under JAK inhibition. Additionally, initially altered goblet cell morphology normalized. This case demonstrates that JAK inhibitor therapy can induce clinical remission and reduce tissue pSTAT3 despite ongoing histological inflammation, supporting its role as targeted treatment in STAT3 GOF syndrome. The potential relevance of goblet cell restoration in STAT3 GOF-associated enteropathy is highlighted.