表现为婴儿胆汁淤积的CFTR基因缺陷致囊性纤维化病一例并文献复习

Infantile cholestasis caused by CFTR mutation： case report and literature review

目的 总结表现为婴儿胆汁淤积的CFTR基因缺陷致囊性纤维化病的临床表现,生化特征和基因分析.方法 报道2014年上海复旦大学附属金山医院儿科收治的1例CFTR基因缺陷致胆汁淤积症婴儿的临床表现,生化特征,基因分析结果及治疗和转归,并结合文献分析.结果 患儿男,5月龄余,新生儿期出现胆汁淤积,胎粪排出延迟,因陶土样大便于2月龄行腹腔镜探查胆道造影排除胆道闭锁,口服熊去氧胆酸（UDCA）,考来烯胺和苯巴比妥片.检测发现CFTR基因第3,6,21外显子分别存在3个杂合突变位点c.214G＞ G/A,p.A72T;c.650A＞ A/G,p.E217G和c.3406G＞ G/A,p.A1136T,其中c.650A＞ A/G和c.3406G＞ G/A两个杂合突变位点来自患儿父亲,c.214G＞ G/A来自母亲,为复合杂合突变.11月龄肝功能恢复正常,继续服用UDCA,随诊至1岁9月龄,生长发育正常除脾稍大外无其他症状和体征.文献检索发现以婴儿胆汁淤积症起病的囊性纤维化（CF）25例,经汗液试验或基因分析诊断.临床表现有胎粪排出延迟5例,胎粪性肠梗阻6例,其他胃肠道症状（腹泻,呕吐等）2例,呼吸道症状12例,生长发育迟缓6例.生化特征主要表现胆红素、谷氨酸转氨酶、天冬氨酸转氨酶、γ-谷氨酰转移酶及碱性磷酸酶升高.基因检测发现8例delF508纯合突变,4例delF508杂合突变,1例c.263T＞ G/c.2089-2090insA复合杂合突变.黄疸消退20例,10例患儿接受UDCA 15 ～20 mg/（kg＆#183;d）治疗.死亡的5例均未接受UDCA治疗,其中2例分别因肺炎链球菌脑膜炎,肝衰竭死亡,黄疸持续至死亡;另外2例死于呼吸衰竭;1例死于心肺衰竭.结论 对于合并有胎粪性肠梗阻和（或）胎粪排出延迟的胆汁淤积患儿,肝功能表现直接胆红素、转氨酶、γ-谷氨酰转移酶升高,需考虑囊性纤维化可能,早期行基因分析可明确诊断,UDCA治疗可能对改善疾病预后有益.

Objective To study the clinical presentation,biochemical features and genetic analysis of an infant with cholestasis related to the CFTR mutations.Method The clinical presentation,laboratory investigations and management of a case with infantile cholestasis caused by CFTR mutations were summarized and the relevant literature was reviewed.Result （1） The patient was a 5 months old boy with cholestasis which developed in neonatal period with delayed meconium exclusion.The laparoscopic exploration was performed to exclude biliary atresia because of acholic stool when he was two months old.Ursodeoxycholic acid （UDCA）,cholestyramine and phenobarbital treatment was applied.The genetic analysis showed compound heterozygous mutations in CFTR.The liver function normalized when he was 11 months old.When he was 21 months old,he had normal appearance except mild splenomegaly.（2） Literatures review identified 25 infantile cholestatic cases related to cystic fibrosis （CF） diagnosed by sweat test or gene analysis.Delayed meconium passage was found in five,meconium ileus in six cases.The liver function tests characterized by the direct hyperbilirubinemia with elevated transaminase,glutamyltranspeptidase and alkaline phosphatase levels.Genetic analysis revealed eight homozygotes of delF508,four heterozygotes of delF508 and one compound heterozygotes of c.263T 〉 G/ c.2089-2090ins in CFTR.Jaundice resolved in 20 patients,ten of them were prescribed oral ursodesoxycholic acid （15-20 mg/（kg＆#183; d））.Five patients died,none of them received oral UDCA.Two of them had persisted cholestatic until death.Among the other three dead,two died from respiratory failure and one from cardiopulmonary failure.Conclusion Cystic fibrosis should be considered in cholestatic infants with meconium ileus or delayed meconium passage.Genetic analysis could confirm the diagnosis.UDCA may be beneficial to improve the liver function.