Clinical and Genetic Spectra of Progressive Familial Intrahepatic Cholestasis With Normal <scp>GGT</scp> : 31 Pediatric Patients and 16 Novel Variants

Progressive familial intrahepatic cholestasis (PFIC) syndromes are rare autosomal recessive disorders. We present the first detailed phenotype-genotype of PFIC children with normal gamma-glutamyltransferase (GGT) [normal GGT/PFIC] in an African population. Thirty-one pediatric patients belonging to 28 unrelated Egyptian families with normal GGT/PFIC were reported. Clinical, biochemical, histopathological, and genetic data were systematically analyzed. Patients were 15 males/16 females (55 ± 52 months at diagnosis). Apart from cholestasis, clinical features included severe pruritus (visual analogue scale 7.5 ± 3.4), hepatomegaly (80.6%), sleep deprivation (41.9%), and splenomegaly (19.4%). 13/28 families had ABCB11 variants (PFIC2), 6/28 families had ATP8B1 (PFIC1) and TJP2 (PFIC4) variants each, 2/28 had MYO5B variants (PFIC10), and one family had USP53 variants (PFIC7). Twenty-five disease-causing variants were reported, including 16 novel variants. PFIC1 patients were more severely affected compared to other PFIC syndromes, as the incidence of growth retardation, sibling deaths, skin changes, and progression to biliary diversion were all significantly higher (p value 0.006, 0.012, 0.037, and 0.012, respectively). In contrast, none of the 13 PFIC2 children progressed to biliary diversion, and all four PFIC10 children had normal liver transaminases. Our study expands the global phenotypic and genotypic knowledge of normal GGT/PFIC and will facilitate better care for the syndrome in Egypt.