1例Dubin-Johnson综合征婴儿的临床特征及ABCC2基因型研究
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摘要
Dubin-Johnson综合征(DJS)是ABCC2基因变异引起的常染色体隐性遗传病,以长期或间歇性结合胆红素升高为主要临床表现。该文报道1例DJS患儿的临床特征和ABCC2变异特点。患儿为9.5月龄男婴,因发现肝功能异常9个月就诊,主要临床表现为新生儿期起病的黄疸,多次血生化检查均显示血清总胆红素、结合胆红素、总胆汁酸明显升高,先后在多家医院诊治,病因不明,疗效不佳。体格检查:皮肤巩膜黄染,肝右肋下3 cm可及,质中,脾不大。遗传学分析显示患儿ABCC2基因存在c.3988-2A>T和c.3825C>G(p.Y1275X)两个致病性变异,分别来源于母亲和父亲,其中c.3988-2A>T为未报道的新剪接位点变异,从而确诊为DJS。给予熊去氧胆酸和苯巴比妥口服治疗半月,黄疸消退,生化指标改善,但远期预后有待随访观察。文献复习发现,DJS新生儿/婴儿患者主要临床表现为生后不久出现的胆汁淤积性黄疸,其ABCC2基因变异存在明显异质性。
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.
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.
引文
[1]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]K?nig 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,K?nig 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.
[18]郭长吉,林三仁,李益农,等.腹腔镜和肝活检对DubinJohnson综合征诊断的价值[J].北京大学学报(医学版),2000,32(2):128-130.
[19]张义红,刘俊英,曾广仙,等.Dubin-Johnson综合征一例[J].中华医学遗传学杂志,2003,20(5):446.
[20]林伟霞,郑琪琪,郭丽,等.首例非白人婴儿肝衰竭综合征1型患儿临床特点和分子诊断研究[J].中国当代儿科杂志,2017,19(8):913-920.
[21]程映,梁红,蔡娜莉,等.微绒毛包涵体病一家系临床特点和MYO5B基因突变分析[J].中国当代儿科杂志,2017,19(9):968-974.
[22]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.
[27]余思邈,朱云,高含佳,等.Dubin-Johnson综合征临床及病理特征[J].肝脏,2017,22(5):404-405.
[28]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,Sj?vall 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.
[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]K?nig 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,K?nig 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.
[18]郭长吉,林三仁,李益农,等.腹腔镜和肝活检对DubinJohnson综合征诊断的价值[J].北京大学学报(医学版),2000,32(2):128-130.
[19]张义红,刘俊英,曾广仙,等.Dubin-Johnson综合征一例[J].中华医学遗传学杂志,2003,20(5):446.
[20]林伟霞,郑琪琪,郭丽,等.首例非白人婴儿肝衰竭综合征1型患儿临床特点和分子诊断研究[J].中国当代儿科杂志,2017,19(8):913-920.
[21]程映,梁红,蔡娜莉,等.微绒毛包涵体病一家系临床特点和MYO5B基因突变分析[J].中国当代儿科杂志,2017,19(9):968-974.
[22]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.
[27]余思邈,朱云,高含佳,等.Dubin-Johnson综合征临床及病理特征[J].肝脏,2017,22(5):404-405.
[28]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,Sj?vall 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.
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