Hepatic Manifestations of STAT1 Gain-of-Function Variants.

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity characterized by immune dysregulation and multisystem involvement, whose hepatic manifestations can mimic autoimmune, cholestatic, or microvascular liver disease. Among these, heterozygous signal transducer and activator of transcription 1 gain-of-function pathogenic variants are predominantly associated with autoimmune hepatitis-like liver injury whereas vascular and portal hypertensive phenotypes are rarely reported and likely underrecognized. We describe a young adult with recurrent infections and progressive liver disease who ultimately received the diagnosis of a signal transducer and activator of transcription 1 gain-of-function mutation. The case illustrates the spectrum of hepato-gastrointestinal involvement in PIRDs, emphasizing diagnostic considerations, imaging and histopathologic features, and management strategies including conventional immunosuppression, targeted Janus kinase inhibition, and hematopoietic stem cell transplantation. We also outline infectious complications of Janus kinase inhibition, including progressive multifocal leukoencephalopathy.