目的 总结DCDC2基因变异引起的新生儿硬化性胆管炎(NSC)的临床及遗传学特点.方法 采用全外显子组测序技术,复旦大学附属儿科医院在2017年5月明确诊断了来自同一家系的2例DCDC2缺陷致NSC患儿,对其临床特征和基因结果进行总结,并以“DCDC2”和“新生儿硬化性胆管炎”为关键词,检索建库至2018年4月中文数据库及PUBMED数据库进行文献复习.结果 例1男,3岁2月龄,发现胆汁淤积3年余,血清γ-谷氨酰转肽酶(161~1 092 U/L)和总胆固醇(5.4~7.7 mmol/L)升高,磁共振胰胆管造影示肝内胆管多发扩张和双肾积水.例2男,9岁9月龄,是例1的同胞兄长.发现胆汁淤积9年余,CT血管造影示脑积水和左侧颈内动脉交通段动脉瘤并有血管畸形.例1通过全外显子组测序发现DCDC2基因(NM_001195610) c.529dupA纯合移码变异.通过Sanger测序发现例2在该位点为纯合变异,父母均为杂合变异.共检索到英文文献2篇,中文文献0篇,11例DCDC2基因变异致NSC患儿.包括本研究2例共计13例患儿均在生后6个月之内发病,最常见的临床表现有高水平γ-谷氨酰转肽酶的胆汁淤积伴陶土样便,进展至门静脉高压;其次是肾脏和神经系统表型;仅有1例患儿有高胆固醇血症;影像学特征为肝内和(或)肝外胆管多灶性狭窄或扩张;肝脏病理表现为胆管板形成障碍、小叶间胆管缺乏、纤维化以及肝硬化等;13例患儿中有10例需要肝移植治疗.13例患儿中共检测到7种DCDC2基因变异.结论 DCDC2基因变异致NSC临床特征为:婴儿期出现高水平γ-谷氨酰转肽酶的胆汁淤积伴陶土样便,常在儿童期进展为肝硬化;胆道造影或磁共振胰胆管造影显示肝内和(或)肝外胆管多灶性狭窄;常伴有肾脏和神经系统表型.确诊依靠DCDC2基因检测.
Objective To summarize and review the clinical and genetic features of neonatal sclerosing cholangitis (NSC) caused by DCDC2 variations.Methods Whole exome sequencing was performed to identify DCDC2 variants in two Chinese siblings with NSC who were diagnosed in Children's Hospital of Fudan University in May 2017.Clinical,laboratory and genetic data of the two cases were summarized.Key words of "DCDC2" "neonatal sclerosing cholangitis" were searched in Chinese databases and PubMed for articles published until April 2018,and all the relevant literature were reviewed.Results Patient 1 was a 3-year-and-2-month-old boy.He was admitted to our hospital due to cholestasis for 3 years.Laboratory findings showed elevated levels of gamma-glutamyl transpeptidase (161-1 092 U/L) and total cholesterol (5.4-7.7 mmol/L).Magnetic resonance cholangiopancreatography showed multiple dilations of intrahepatic bile ducts and bilateral hydronephrosis.Patient 2,the older brother of patient 1,was a 9-year-and-9-month-old boy.He was admitted to our hospital due to "cholestasis for 9 years".CT angiography showed hydrocephalus and left internal carotid artery aneurysms with vascular malformations.A homozygous variant c.529dupA (NM_001195610) in DCDC2 gene was identified in patient 1 by whole exome sequencing.Patient 2 was a homozygote and his parents were heterozygotes with the variation.There has been 2 relevant articles published (Chinese 0,English 2),which reported 11 cases of DCDC2-related NSC in total.All the 13 patients,including the 2 cases reported here,had an onset of symptoms at 0 to 6 months of age.The most common clinical manifestation was cholestasis with high gamma-glutamyl transpeptidase levels,acholic stool,and progression to portal hypertension.Renal and neurological abnormalities were also frequently present.Hypercholesterolemia was observed in one case.Radiological findings revealed the characteristic strictures and dilatations of the intrahepatic and (or) extrahepatic biliary tree.Liver histological examination showed peripheral ductopenia,ductal plate malformation,fibrosis,and cirrhosis.Among the 13 patients,10 patients required liver transplantation.A total of 7 types of DCDC2 variants were detected in 13 patients.Conclusions DCDC2-related NSC is characterized by the onset of cholestasis with high gamma-glutamyl transpeptidase level and acholic stool in early infancy,which was likely to progress to cirrhosis in early childhood.Renal and neurological abnormalities are also frequently present.Cholangiography or magnetic resonance cholangiopancreatography show strictures and dilatations of the intrahepatic or (and) extrahepatic biliary tree.Identification of pathogenic DCDC2 variants would aid the diagnosis of NSC.