Novel genetic variants and atypical phenotypes in pediatric progressive familial intrahepatic cholestasis

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders characterized by impaired bile formation and secretion, frequently progressing to cirrhosis and end-stage liver disease. This study characterized the genotypic and phenotypic spectrum of PFIC in a pediatric cohort. METHODS: A retrospective cohort study with prospective enrollment of additional cases and longitudinal follow-up included 17 children with molecularly confirmed PFIC managed at Alexandria University Children's Hospital between 2017 and 2026. Clinical, biochemical, histopathological, genetic, therapeutic, and outcome data were reviewed. RESULTS: Three, ten, two, and two patients had PFIC types 1, 2, 3, and 8, respectively, with pathogenic variants in ATP8B1, ABCB11, ABCB4, and KIF12, including four novel variants. PFIC types 1 and 2 presented with early-onset low gamma-glutamyl transferase (GGT) cholestasis and severe pruritus; five patients underwent biliary diversion. PFIC type 2 showed more severe liver disease than PFIC type 1. PFIC types 3 and 8 presented later with atypical non-icteric presentations with hepatosplenomegaly and elevated GGT without classical histopathological cholestasis in three cases. Three patients underwent successful liver transplantation. CONCLUSION: PFIC exhibits marked phenotypic heterogeneity. Recognition of atypical and non-icteric presentations broadens its clinical spectrum and highlights the importance of comprehensive genetic testing for accurate diagnosis. IMPACT STATEMENT: The study identifies and characterizes novel variants in the ABCB11, ABCB4, and KIF12 genes within an Egyptian pediatric cohort, expanding the known mutational spectrum of the disease. The study reported unusual presentation for PFIC type 3 and 8 with rapid fibrotic progression even in the absence of clinical jaundice or histological evidence of bile plugs challenging the diagnostic reliance on overt cholestasis as the primary clinical marker for PFIC.