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1例Dubin-Johnson综合征婴儿的临床特征及ABCC2基因型研究

2020-01-20 孟璐璐 邱建武 林伟霞 中国当代儿科杂志

Dubin-Johnson综合征婴儿
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患儿，男，9.5个月，因发现肝功能异常9个月入院。因早产生后在当地人民医院住院治疗，入院第5天出现皮肤巩膜黄染，经蓝光照射等治疗后黄疸减轻，住院10d好转出院。生后25d时因黄疸加重入当地儿童医院就诊，肝功能检查提示总胆红素（Tbil）、结合胆红素（Dbil）、非结合胆红素（Ibil）、总胆汁酸（TBA）均显著升高（表1）。肝炎病毒及TORCH检查均阴性，葡萄糖-6磷酸脱氢酶（G6PD）活性正常，

患儿，男，9.5个月，因发现肝功能异常9个月入院。因早产生后在当地人民医院住院治疗，入院第5天出现皮肤巩膜黄染，经蓝光照射等治疗后黄疸减轻，住院10d好转出院。生后25d时因黄疸加重入当地儿童医院就诊，肝功能检查提示总胆红素（Tbil）、结合胆红素（Dbil）、非结合胆红素（Ibil）、总胆汁酸（TBA）均显著升高（表1）。肝炎病毒及TORCH检查均阴性，葡萄糖-6磷酸脱氢酶（G6PD）活性正常，溶血筛查阴性，甲状腺功能检测未见异常，血尿遗传代谢病筛查未发现特定遗传代谢病依据。患儿诊断为婴儿胆汁淤积性肝病，予光疗退黄、护肝、利胆等处理9d，皮肤、巩膜黄染减轻出院，但之后门诊随访直接胆红素、胆汁酸增高一直未恢复正常。患儿3.7月龄时转入某大学附属儿童医院进行诊治，当时体格检查发现面色暗黄，心前区可闻及2/6级收缩期杂音。肝右肋下3cm可触及，剑突下1cm可触及，质软，脾左肋下1.5cm可触及，质软。生化检查发现Tbil、Dbil和TBA升高，丙氨酸氨基转移酶（ALT）和门冬氨酸氨基转移酶（AST）正常，γ-谷氨酰转肽酶（GGT）略高（表1）。诊断为黄疸原因待查：（1）感染因素？（2）遗传代谢病？（3）胆道畸形？予保肝、利胆、支持治疗11d，患儿好转出院。出院后继续金双岐、熊去氧胆酸、阿托莫兰等口服治疗，但肝功能持续异常，为明确诊断来我院就诊。患儿自起病以来，精神、食纳一般，睡眠可，混合喂养，大小便正常。


患儿系第1胎第1产，出生胎龄35+4周，因“胎膜早破、脐带扭转、胎盘早剥”剖宫产出生，Apgar评分1min9分、5min10分、10min10分，出生体重2200g（<-3SD），身长49cm（正常）。父母体健，非近亲结婚。否认家族史及传染病史。

入院体格检查：体重8000g,身长57.0cm，头围45.0cm。神志清楚，反应可。皮肤、巩膜轻度黄染。头颅无畸形，萌牙2颗。双肺呼吸音清，律齐，心音有力，各瓣膜听诊区未闻及病理性杂音。腹不胀，肝右肋下3cm可及，质中，脾不大，肠鸣音正常。四肢肌张力正常，活动自如，神经系统体查无异常。

辅助检查：血常规检查正常，但生化检查示Tbil和Dbil升高（表1）。



遗传学分析结果 

代谢性肝病组套二代测序检测结果显示：患儿 ABCC2 基因存在 2 个变异，其中 c.3988-2A>T 为第 28 内含子的5' 端经典剪接位点变异，c.3825C>G(p. Y1275X) 为外显子 27 的无义变异（图 1）。经过 Sanger 测序验证证实，患儿为上述变异的复合杂合 子，而其母亲和父亲分别为相应变异携带者（图2）。





变 异 c.3825C>G(p.Y1275X) 在 HGMD（http:// www.hgmd.cf.ac.uk/ac/index.php）专业版数据库已 报道与DJS相关[2]。在***基因组计划（http:// browser.1000genomes.org）、EAC 数 据 库（Exome Aggregation Consortium, http://exac.broadinstitute. org/）中均未检索到变异 c.3988-2A>T 的记录，查 阅中国知网、万方、维普、美国 PubMed 等国内外 文献数据库，均未见该变异的正式文献报道。HSF 预测结果提示，c.3988-2A>T 变异影响受体剪接位 点，可能通过影响mRNA剪接阻碍MRP2蛋白的 正常合成。

治疗与结局 

根据患儿的临床特点和实验室检查，诊断考虑遗传性胆汁淤积症，经二代测序及Sanger测序验证，最终确诊为ABCC2基因变异导致的DJS。给予患儿熊去氧胆酸和苯巴比妥口服治疗，10月龄门诊随访时黄疸消退，生化复查 Tbil和Dbil改 善，TBA 正常（表 1）。目前临床随访中，远期预 后有待观察。 

原始出处：

孟璐璐,邱建武,林伟霞,宋元宗.1例Dubin-Johnson综合征婴儿的临床特征及ABCC2基因型研究[J].中国当代儿科杂志,2019,21(01):64-70.

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