Progressive Familial Intrahepatic Cholestasis: Detection of New Mutations and Unusual Modality of Transmission.
Paola Francalanci, Isabella Giovannoni, Filippo M Santorelli, Riccardo Mariani, Fabrizio Gennari, Giuliano Torre, Maja Di Rocco, Cinzia Castana, Lucia Zancan, Francesco Callea. Children's Hospital Bambino Gesu', Rome, Italy; Children's Hospital G. Gaslini, Genova, Italy; ISMET, Palermo, Italy; University of Padua, Italy
Background: Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three types of PFIC have been identified: PFIC 1 is caused by mutation in ATP8B1 gene encoding the FIC1 protein; PFIC 2 in ABCB11 encoding the bile salt export pump protein (BSEP) and PFIC 3 due to a defect in ABCB4 encoding the multi-drug resistant 3 protein (MDR3). Serum γ-glutamyltranspeptidase (γGT) activity is normal in PFIC 1 and 2, while is high in PFIC 3. Liver histology is not specific in each type of PFIC.
Design: We report on 13 children with intrahepatic cholestasis, in whom molecular analyses for PFIC were performed. Denaturing high-pressure liquid chromatography and direct gene sequencing for ATP9B1 and ABCB11 were carried out when γGT activity was normal, whereas the analysis of ABCB4 was done if high level of γGT was present. Genotypes were correlated with data on immunohistochemistry for BSEP and MDR3 deficiency.
Results: In our cohort, 3 cases were PFIC1, 8 showed BSEP deficiency and 2 cases had MDR3 deficiency. In 1 case of BSEP deficiency, we reported a homozygous c.2620C>T transition in exon 21, that was inherited through the rare phenomenon of paternal uniparental disomy (patUPD). In other 4 children, we identified some new mutations: c.1621A>C in 2 sisters, c.154C>T and c.1844A>G, (compound heterozygosity) in 1 child and c.2787_2788ins GAGAT (single heterozygous mutation) in the last one. Two cases of MDR3 deficiency were associated with a novel ABCB4 mutation (p.Arg595X), homozygous in one child and heterozygous in another patient where we also detected a new heterozygous c.937_992ins55/del6 mutation. On immunohistochemical analysis, all patients showed abnormal or absent BSEP or MDR3 staining. Five children underwent to liver transplant due to end-stage liver function.
Conclusions: PFIC are rare forms of cholestasis of hepatocellular origin. Diagnosis can be suspected on clinical manifestations and serology, but only full gene testing is able to offer a more accurate genetic counselling and recognition of rare phenomenon of padUPD.
Category: Liver & Pancreas
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 206, Wednesday Morning