Abstract：Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder resulting from biallelic mutations of ABCC2 gene, with long-term or intermittent conjugated hyperbilirubinemia being the main clinical manifestation. This paper aims to report the clinical features and ABCC2 genotypes of an infant with DJS. A 9.5-month-old male infant was referred to the hospital due to abnormal liver function discovered over 9 months. The major clinical presentation was prolonged jaundice since neonatal period. A series of biochemistry analysis revealed markedly elevated total bilirubin, conjugated bilirubin and total bile acids. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. Physical examination revealed jaundiced skin and sclera, and a palpable liver 3 cm below the right subcostal margin with medium texture. The spleen was not enlarged. Genetic analysis revealed a splice-site variant c.3988-2A > T and a nonsense variant c.3825C > G (p.Y1275X) in the ABCC2 gene of the infant, which were inherited from his mother and father respectively. The former had not been previously reported. Then ursodeoxycholic acid and phenobarbital were given orally. Half a month later, as a result, his jaundice disappeared and the biochemistry indices improved. However, the long-term outcome needs to be observed. Literature review revealed that neonates/infants with DJS presented with cholestatic jaundice soon after birth as the major clinical feature, and the ABCC2 variants exhibited marked heterogeneity.
MENG Lu-Lu,QIU Jian-Wu,LIN Wei-Xia et al. Clinical features and ABCC2 genotypic analysis of an infant with Dubin-Johnson syndrome[J]. CJCP, 2019, 21(1): 64-70.
Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases[J]. Medicine (Baltimore), 1954, 33(3):155-197.
[2]
Lee JH, Chen HL, Chen HL, et al. Neonatal Dubin-Johnson syndrome:long-term follow-up and MRP2 mutations study[J]. Pediatr Res, 2006, 59(4 Part 1):584-589.
[3]
Kartenbeck J, Leuschner U, Mayer R, et al. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome[J]. Hepatology, 1996, 23(5):1061-1066.
[4]
König J, Nies AT, Cui Y, et al. Conjugate export pumps of the multidrug resistance protein (MRP) family:localization, substrate specificity, and MRP2-mediated drug resistance[J]. Biochim Biophys Acta, 1999, 1461(2):377-394.
[5]
Trauner M, Boyer JL. Bile salt transporters:molecular characterization, function, and regulation[J]. Physiol Rev, 2003, 83(2):633-671.
[6]
Mottino AD, Cao J, Veggi LM, et al. Altered localization and activity of canalicular Mrp2 in estradiol-17beta-D-glucuronideinduced cholestasis[J]. Hepatology, 2002, 35(6):1409-1419.
[7]
Keitel V, Kartenbeck J, Nies AT, et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in DubinJohnson syndrome[J]. Hepatology, 2000, 32(6):1317-1328.
[8]
Mor-Cohen R, Zivelin A, Rosenberg N, et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome[J]. J Biol Chem, 2001, 276(40):36923-36930.
[9]
Hashimoto K, Uchiumi T, Konno T, et al. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome[J]. Hepatology, 2002, 36(5):1236-1245.
[10]
Keitel V, Nies AT, Brom M, et al. A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2(ABCC2)[J]. Am J Physiol Gastrointest Liver Physiol, 2003, 284(1):G165-G174.
[11]
Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome[J]. Hepatology, 1997, 25(6):1539-1542.
[12]
Togawa T, Mizuochi T, Sugiura T, et al. Clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome:a multicenter study in Japan[J]. J Pediatr, 2018, 196:161-167.
[13]
Pacifico L, Carducci C, Poggiogalle E, et al. Mutational analysis of ABCC2 gene in two siblings with neonatal-onset Dubin Johnson syndrome[J]. Clin Genet, 2010, 78(6):598-600.
[14]
Okada H, Kusaka T, Fuke N, et al. Neonatal Dubin-Johnson syndrome:novel compound heterozygous mutation in the ABCC2 gene[J]. Pediatr Int, 2014, 56(5):e62-e64.
[15]
Wada M, Toh S, Taniguchi K, et al. Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia Ⅱ/DubinJohnson syndrome[J]. Hum Mol Genet, 1998, 7(2):203-207.
[16]
Tsujii H, König J, Rost D, et al. Exon-intron organization of the human multidrug-resistance protein 2(MRP2) gene mutated in Dubin-Johnson syndrome[J]. Gastroenterology, 1999, 117(3):653-660.
[17]
Toh S, Wada M, Uchiumi T, et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome[J]. Am J Hum Genet, 1999, 64(3):739-746.
Kimura A, Yuge K, Kosai KI, et al. Neonatal cholestasis in two siblings:a variant of Dubin-Johnson syndrome?[J]. J Paediatr Child Health, 1995, 31(6):557-560.
[23]
Memon N, Weinberger BI, Hegyi T, et al. Inherited disorders of bilirubin clearance[J]. Pediatr Res, 2016, 79(3):378-386.
[24]
Tsai WH, Teng RJ, Chu JS, et al. Neonatal Dubin-Johnson syndrome[J]. J Pediatr Gastroenterol Nutr, 1994, 18(2):253-254.
[25]
Kimura A, Ushijima K, Kage M, et al. Neonatal Dubin-Johnson syndrome with severe cholestasis:effective phenobarbital therapy[J]. Acta Paediatr Scand, 1991, 80(3):381-385.
[26]
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
Regev RH, Stolar O, Raz A, et al. Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid[J]. J Perinat Med, 2002, 30(2):185-187.
[29]
Bremmelgaard A, Sjövall J. Hydroxylation of cholic, chenodeoxycholic, and deoxycholic acids in patients with intrahepatic cholestasis[J]. J Lipid Res, 1980, 21(8):1072-1081.
[30]
Back P. Phenobarbital-induced alterations of bile acid metabolism in cases of intrahepatic cholestasis[J]. Klin Wochenschr, 1982, 60(11):541-549.
[31]
Balistreri WF. Bile acid therapy in pediatric hepatobiliary disease:the role of ursodeoxycholic acid[J]. J Pediatr Gastroenterol Nutr, 1997, 24(5):573-589.
[32]
Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis[J]. J Hepatol, 2009, 51(3):565-580.
[33]
Fickert P, Zollner G, Fuchsbichler A, et al. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver[J]. Gastroenterology, 2001, 121(1):170-183.
