ZNFX1 Deficiency: An Interferonopathy Mimicking Wilson Disease with Hepatic and Neurologic Manifestations

ZNFX1 deficiency is a recently recognized type I interferonopathy with heterogeneous systemic manifestations. We report a 15-year-old boy presenting with chronic liver disease, hepatic fibrosis, gait disturbance, and persistent proteinuria. Neuroimaging demonstrated bilateral globus pallidus signal changes and diffuse cerebral calcifications, raising suspicion for a metabolic disorder, particularly Wilson disease. However, copper metabolism studies and hepatic copper quantification were normal, and ATP7B sequencing was negative. Liver biopsy showed portal-to-portal bridging fibrosis without steatosis or copper accumulation. Whole-exome sequencing identified a novel homozygous ZNFX1 c.5733del variant, establishing the diagnosis. Over eight years of follow-up, hepatic disease remained stable without progression or hyperinflammatory episodes. This case expands the phenotypic spectrum of ZNFX1 deficiency, emphasizing that interferonopathies may mimic Wilson disease through hepatic and neurologic involvement. Recognition of this overlap is essential for accurate diagnosis, appropriate genetic testing, and long-term surveillance.

Keywords: genetic hepatopathy, hepato-neurologic phenotype, liver disease.