Expanding the Clinical and Molecular Spectrum of Progressive Familial Intrahepatic Cholestasis Associated With Biallelic Variants in LSR

Progressive familial intrahepatic cholestasis (PFIC) comprises autosomal recessive disorders causing early‐onset cholestasis that may progress to cirrhosis and liver failure. Although more than 13 genes are associated with PFIC, some patients remain genetically undiagnosed. LSR , encoding lipolysis‐stimulated lipoprotein receptor, has recently emerged as a candidate gene. LSR contributes to tricellular tight‐junction integrity and epithelial barrier function. We report four additional patients from three unrelated families with biallelic LSR variants, expanding the reported clinical and molecular spectrum. Features included intractable pruritus, cholestasis with normal or mildly elevated gamma‐glutamyl transferase (GGT), progressive hepatic dysfunction and variable extrahepatic findings, including growth failure, neurodevelopmental delay, seizures and microcephaly. Two patients died from end‐stage liver disease. Review of published cases suggests a predominantly progressive cholestatic phenotype with variable syndromic features. These findings support consideration of LSR variants in unresolved PFIC and the value of comprehensive genomic testing.