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      Progressive Familial Intrahepatic Cholestasis Type 3 Homozygous Pathogenic Variant c.2906G>A in the ATP Binding Cassette Subfamily B Member 4 (ABCB4) Gene: A Case Report of an Unusual Presentation

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          Abstract

          Progressive familial intrahepatic cholestasis (PFIC) describes a heterogeneous group of autosomal-recessive childhood liver disorders in which cholestasis of hepatocellular origin frequently manifests during infancy or the first year of life and progresses to liver failure. We report a case of a five-year-old boy with homozygous pathogenic variant c.2906G>A in the ATP binding cassette subfamily B member 4 ( ABCB4) gene presented with hepatosplenomegaly and cytopenia without a history of jaundice or itching; he had a history of Epstein-Barr virus infection and family history of liver disease. The patient was started on ursodeoxycholic acid and fat-soluble vitamins and referred to a liver transplant center.

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          Progressive familial intrahepatic cholestasis

          Anne Davit-Spraul, Emmanuel Gonzales, Christiane Baussan … (2009)
          Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP). Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis can be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of hepatocellular carcinoma, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy or specific targeted pharmacotherapy may represent alternative treatments in the future.
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            Systematic review of progressive familial intrahepatic cholestasis

            Alastair Baker, Nanda Kerkar, Lora Todorova … (2018)
            Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is the first systematic review of the epidemiology, natural history and burden of PFIC.
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              A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3.

              Jean-Louis Delaunay, Anne-Marie Durand-Schneider, Claire Dossier … (2016)
              Progressive familial intrahepatic cholestasis type 3 is caused by biallelic variations of ABCB4, most often (≥70%) missense. In this study, we examined the effects of 12 missense variations identified in progressive familial intrahepatic cholestasis type 3 patients. We classified these variations on the basis of the defects thus identified and explored potential rescue of trafficking-defective mutants by pharmacological means. Variations were reproduced in the ABCB4 complementary DNA and the mutants, thus obtained, expressed in HepG2 and HEK293 cells. Three mutants were either fully (I541F and L556R) or largely (Q855L) retained in the endoplasmic reticulum, in an immature form. Rescue of the defect, i.e., increase in the mature form at the bile canaliculi, was obtained by cell treatments with cyclosporin A or C and, to a lesser extent, B, D, or H. Five mutations with little or no effect on ABCB4 expression at the bile canaliculi caused a decrease (F357L, T775M, and G954S) or almost absence (S346I and P726L) of phosphatidylcholine secretion. Two mutants (T424A and N510S) were normally processed and expressed at the bile canaliculi, but their stability was reduced. We found no defect of the T175A mutant or of R652G, previously described as a polymorphism. In patients, the most severe phenotypes appreciated by the duration of transplant-free survival were caused by ABCB4 variants that were markedly retained in the endoplasmic reticulum and expressed in a homozygous status.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cureus
                Journal ID (iso-abbrev): Cureus
                Journal ID (issn): 2168-8184
                Title: Cureus
                Publisher: Cureus (Palo Alto (CA) )
                ISSN (Electronic): 2168-8184
                Publication date (Electronic, pub): 12 December 2022
                Publication date (Electronic, collection): December 2022
                Volume: 14
                Issue: 12
                Electronic Location Identifier: e32455
                Affiliations
                [1 ] Pediatrics, Armed Forces Hospitals Southern Region (AFHSR), Khamis Mushait, SAU
                [2 ] Pathology, Armed Forces Hospitals Southern Region (AFHSR), Khamis Mushait, SAU
                [3 ] Pediatrics, Neleen University, Khartoum, SDN
                Author notes
                Article
                DOI: 10.7759/cureus.32455
                PMC ID: 9834668
                SO-VID: 6b7ac0ed-094f-4ba3-aba2-539fd63c4f48
                Copyright © Copyright © 2022, Alasmari et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date accepted : 12 December 2022
                Categories
                Subject: Genetics
                Subject: Pediatrics
                Subject: Gastroenterology

                Keywords: a new variant,a case report,epstein-barr virus infection,abcb4 gene,progressive familial intrahepatic cholestasis
                Data availability:
                Keywords: a new variant, a case report, epstein-barr virus infection, abcb4 gene, progressive familial intrahepatic cholestasis

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