18q21杂合缺失致婴儿肝内胆汁淤积症伴智能发育落后1例病例报告

Heterozygous deletion in 18q21 causes infantile cholestasis and mental retardation: a case report

目的报告1例18q21杂合缺失致ATP8B1缺陷病(婴儿肝内胆汁淤积症)合并皮特-霍普金斯综合征(PHS)。方法总结患儿的临床特征、染色体芯片和基因检查结果。结果男,3个月2 d,因皮肤巩膜黄染2月余就诊。体重4 kg(<P3)。颜面、躯干和四肢皮肤轻中度黄染,巩膜中度黄染,手心和足心无黄染。血清总胆红素明显升高,以直接胆红素升高为主,ALT、AST、总胆汁酸(TBA)、甲胎蛋白(AFP)升高,谷氨酰转肽酶(GGT)和白蛋白(ALB)正常,提示为低GGT胆汁淤积症。染色体芯片分析发现,患儿18号染色体长臂(18q21.2-q21.33)缺失11.6 Mb,8号染色体短臂(8p23.2)缺失961 kb。18号染色体缺失区域包含ATP8B1及TCF4基因,可分别解释肝内胆汁淤积症和PHS表现。ATP8B1基因测序发现两个SNP,经Mutationtaster软件预测为非致病性。口服熊去氧胆酸及补充脂溶维生素,1岁龄黄疸消退,肝功能指标恢复正常。随访至2岁10个月,身高90 cm(P3~P10),体重12 kg(P3~P10),头围42.5 cm(<P3),呈特殊面容(嘴宽大,唇厚,鼻梁宽而高,鼻尖突出,下颌略微前突),有明显的智力发育落后,便秘严重。结论采用染色体芯片技术和基因测序确诊了1例婴儿期肝内胆汁淤积症合并PHS病例,提示原因不明的胆汁淤积,应重视分子学诊断,常规的基因外显子测序技术可能会漏诊一些染色体片段缺失的病例,应联合使用染色体芯片技术。

Objective To report one case of ATP8 B1 deficiency（ intrahepatic cholestasis in infants） combined with PittHopkins syndrome caused by heterozygous deletion at 18 q21. Methods To summarize the clinical characteristics of the infant and the results of chromosome microarray testing and genetic testing. Results A three-month-old boy was admitted to the hospital because of jaundice more than two months. Physical examination revealed the infant with weight of 4 kg（ P3）,mild-to-moderate jaundice of the skin and moderate jaundice of the sclera. Blood biochemical testing revealed the infant with increased total bilirubin and direct bilirubin,increased ALT,AST,TBA and AFP,and normal GGT and ALB,suggesting cholestasis with low GGT.Chromosome microarray testing revealed the infant had 11.6 Mb deletion in the long arm of chromosome 18（ 18 q21.2-q21.33） and8 p23.2 deletion in the short arm of chromosome 18（ 8 p23.2）. The deletion region of chromosome 18 contained ATP8 B1 and TCF4 genes,which were correlated with intrahepatic cholestasis and Pitt-Hopkins syndrome. Gene sequencing of ATP8 B1 revealed 2 SNP,which were predicted for non-pathogenic mutations by the Mutationtaster software. The boy was administrated oral ursodeoxycholic acid and fat-soluble vitamins. When the boy was 1 year old,his jaundice was resolved and his liver function also returned to normal range. The boy was followed up to 2 years and 10 months and with height of 90 cm（ P3 - P10）,weight of 12 kg（ P3- P10）,head circumference of 42.5 cm（ P3）. At that time,the boy showed a special face including big mouth,thick lips,wide and high nose,protruding nasal tip,slightly forward jaw and obvious mental retardation and severe constipation. Conclusion One children with intrahepatic cholestasis combined with Pitt-Hopkins syndrome is confirmed by chromosome microarray testing and gene sequencing,suggesting that molecular diagnosis should be paid attention to for unexplained cholestasis. Conventional gene exon sequencing may lead to the missed diagnosis of some cases with deletion of chromosome fragments. Therefore,chromosome microarray testing should be used in combination.