以肝内胆汁淤积为主要表现的MYO5B基因缺陷1例并文献复习

Cholestasis caused by MYO5B mutation:a case report and literature review

目的总结以胆汁淤积为主要表现的MYO5B基因缺陷患儿的临床表现、生化特征和基因分析。方法报道2021年4月首都儿科研究所附属儿童医院消化内科收治的1例MYO5B基因缺陷致胆汁淤积症患儿的临床表现、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,女,2岁3个月,新生儿期出现胆汁淤积,持续至3个月龄消退,后于7~10个月龄再次出现黄疸反复,14~15个月黄疸持续1.5个月,口服熊去氧胆酸后黄疸消退。2岁3个月再次出现黄疸反复就诊。伴有轻微腹泻。检测发现MYO5B基因有2个杂合突变位点C.1364T>G;C.473C>A.其中C.1364T>G杂合突变位点来自患儿父亲,C.473C>A来自母亲,为复合杂合突变。予以静脉滴注丁二磺酸腺苷蛋氨酸,口服熊去氧胆酸(ursodeoxycholic acid,UDCA)、苯巴比妥及考来烯胺。随诊1个月,黄疸及瘙痒无明显好转。文献检索发现以胆汁淤积为主要表现的MYO5B基因突变37例。临床表现为间歇性或持续性黄疸、轻度或严重影响生活质量的瘙痒,17例患儿伴有轻度或重度腹泻。20例患儿出现肝大,5例脾大。7例患儿出现身材矮小,7例患儿出现体重增长缓慢。2例伴胆道闭锁,2例出现肝硬化、2例患儿出现败血症并死亡,2例小头畸形。化验肝功能表现为总胆红素、结合胆红素、碱性磷酸酶、胆汁酸不同程度升高。谷丙转氨酶、谷草转氨酶正常或轻度升高,谷氨酰转肽酶正常。37例行MYO5B基因检测:11例纯合突变,5例杂合突变,21例复合杂合突变。治疗主要包括药物治疗(UDCA、考来烯胺、利福平)、胆汁引流术、胆道分流术、肝移植术。37例患儿中5例失访,3例去世(1例因肝功能恶化去世,2例死于败血症)。病情完全缓解11例,症状好转及反复16例,药物治疗无效2例。结论对于黄疸及瘙痒反复发作,伴或不伴有腹泻的患儿,肝功能表现总胆红素、直接胆红素升高而谷氨酰转肽酶正常者,需考虑MYO5B基因突变引起的进行性家族性肝内胆汁淤积病6型(progressive familial intrahepatis cholestasis,PFIC6型)的可能,早期行基因分析可明确诊断,治疗上采用药物治疗(UDCA)联合外科手术(胆汁引流术)综合治疗。

Objective To study the clinical presentation,biochemical features and genetic analysis of an infant with cholestasis related to the MYO5B mutations.Method The clinical presentation,1aboratory investigations and management of a case with infantile cholestasis caused by MYO5B mutations were summarized and the relevant literature was reviewed.Result The patient was a 27 months old girl with cholestasis which developed in neonatal period and lasted 3 months.Jaundice was reappeared from 7 months to 10 months,and from 14 months to 15 months after birth.She was cured with ursodeoxycholic acid(UDCA)treatment.When she was 2 years and 3 months old,she developed cholestasis again with diarrhea and pruritus,ademetionine succinate was given intravenously,UDCA,phenobarbital and cholestyramine was given orally.After 1 month follow-up,jaundice and pruritus were not improved significantly.Literatures review identified 37 cholestatic cases related to MYO5B mutation diagnosed by gene analysis.All patients showed intermittent or persistent jaundice,mild or severe pruritus,and 17 patients with diarrhea.Hepatomegaly occurred in 20 patients and splenomegaly in 5 patients.7 patients had short stature,7 patients had slow weight gain.There were 2 cases with biliary atresia,2 cases with cirrhosis,2 cases with septicemia and death,2 cases with microcephaly.The liver function showed that total bilirubin,direct bilirubin,alkaline phosphatase and bile acid increased in varying degrees.Genetic analysis revealed 11 homozygous mutations,5 heterozygous mutations and 21 compound heterozygous heterozygous mutations.Treatment mainly included drug therapy(UDCA,cholestyramine,rifampicin),endoscopic nasobiliary drainage,biliary diversion and liver transplantation.Of the 37 patients,5 were lost to follow-up and 3 died(1 died of deterioration of liver function and 2 died of sepsis).There were 11 cases of complete remission,16 cases of improvement and recurrence of symptoms,and 2 cases of ineffective drug treatment.Conclusion The possibility of progressive familial intrahepatic cholestasis type 6(PFIC6)caused by mutation of MYO5B gene should be considered in patients with recurrent jaundice and pruritus,with or without diarrhea,elevated total/conjugated bilirubin,and normal glutamyltransferase,drug(UDCA)combined with surgery(bile drainage)was the most important treatment.