Citrin蛋白缺乏所致新生儿肝内胆汁淤积症患儿临床特征及基因分析

目的：分析citrin蛋白缺乏所致新生儿肝内胆汁淤积症（NICCD）患儿的临床特征及基因突变特点。方法：回顾性分析2012年9月至2017年12月于重庆医科大学附属儿童医院就诊的30例NICCD患儿和同期诊治的30例特发性新生儿胆汁淤积症（INC）患儿的临床表现、生化指标和目标基因捕获结合高通量测序和桑格-库森法验证结果。结果：NICCD与INC临床表现相似，但圆胖脸和陶土便在NICCD患儿中更为常见（均P<0.01）。NICCD组血糖、前白蛋白、白蛋白、总蛋白、纤维蛋白原、转氨酶水平较INC组低（P<0.05或P<0.01），而间接胆红素、总胆汁酸、碱性磷酸酶、乳酸脱氢酶、血氨、甲胎蛋白、凝血功能标志物较INC组均升高（P<0.05或P<0.01）；INC组血氨基酸水平多在正常值范围内，而NICCD组血瓜氨酸、甲硫氨酸、酪氨酸、精氨酸及苏氨酸水平均升高（均P<0.01）；INC组尿有机酸轻度升高或正常，而NICCD组尿4-羟基苯乳酸、4-羟基苯丙酮酸及苯乳酸浓度显著升高（均P<0.01）。NICCD组均存在SLC25A13突变，其中8例为纯合突变，9例为复合杂合突变，13例为单位点突变，以c.851_854del（53.19%）最常见，同时发现2个新的致病性突变c.1196T>A和c.919G>T。结论：对于新生儿肝内胆汁淤积症并伴有圆胖脸、陶土便的患儿应警惕NICCD，血氨、甲胎蛋白、瓜氨酸以及尿4-羟基苯乳酸、4-羟基苯丙酮酸、苯乳酸水平升高可为临床诊断提供重要依据，目标基因捕获结合高通量测序对其诊断及鉴别诊断具有重要价值。

Clinical characteristics and genetic analysis of neonatal intrahepatic cholestasis caused by citrin deficiency in comparison with idiopathic neonatal cholestasis

Objective:To compare the clinical and genetic characteristics of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and idiopathic neonatal cholestasis (INC). Methods: The clinical data of 30 patients with NICCD and 30 patients with INC admitted in Children’s Hospital of Chongqing Medical University during September 2012 and December 2017 were retrospectively analyzed. The clinical manifestations, biochemical indicators and genetic characteristics were compared between two groups. Results:Patients in both groups presented similar clinical manifestations, however the chubby face and clay-colored stool were more common in NICCD patients (both P<0.01). Comparing with INC group, NICCD group showed significantly decreased blood levels of glucose, prealbumin, albumin, total protein, fibrinogen, and aminotransferases (P<0.05 orP<0.01), while significantly increased blood levels of indirect bilirubin, total bile acid, alkaline phosphatase, lactic dehydrogenase, ammonium, alpha fetoprotein, and markers of coagulation function (P<0.05 orP<0.01). In addition, NICCD patients showed remarkably increased blood levels of citrulline, methionine, tyrosine, arginine, and threonine; as well as significantly increased urine levels of 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvic acid and phenyllactic acid, while those indicators in INC patients were normal (allP<0.01). All the patients with NICCD hadSLC25A13 mutation including 8 homozygotes, 9 compound heterozygotes, and 13 single heterozygotes. Among all mutations, c.851_854del was most common (53.19%), c.1196T>A and c.919G>T were two novel mutations.Conclusions:The manifestations of chubby face and clay-colored stool may provide clue for early diagnosis of NICCD along with the elevated biochemical parameters, such as ammonium, alpha-fetal protein, citrulline in blood and 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvic acid, phenyllactic acid in urine. Target gene trapping and high-throughput sequencing have the key values in diagnosis and differential diagnosis of NICCD.