NPHP3基因突变致婴幼儿期进展为终末期肾病的肾单位肾痨2例并文献复习

摘要

Objective To summarize and review the clinical data of two children with juvenile nephronophthisis so as to improve its knowledge.Methods Clinical data of two cases with juvenile nephronophthisis were summarized,including clinical manifestations,laboratory findings,renal pathological changes and imaging data.This study used next generation sequencing to screen 4 000 genes.Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing and segregation analysis was performed using parental DNA samples.Results Two cases were both male.The age of onset was 3 months and 17 months respectively.The symptoms of jaundice and liver dysfunction were the first symptoms,2 cases all progressed to ESRD,at the age of 11 and 35 months respectively.1 case of renal biopsy showed that renal tubulointerstitial inflammation,mild glomerular mesangial proliferation,segmental endothelial cell proliferation,in line with the renal tubules,the change of small lesion,no cyst;liver biopsy showed liver cell diffuse degeneration,interstitial fibrosis,regional bile duct hyperplasia,inflammatory cells infiltration.Family surveys did not identify members with similar diseases.In case 1,there were heterozygous missense mutations in the NPHP3 gene C.2369A＞G (p.L790P) and c.1358A＞G (p.L453P),and in 2 cases there were c.1174C＞T (p.R392X) nonsense mutations and IVS26-3A＞G shear mutations.Family mutation analysis revealed that the above mutations were derived from their parents,and they were complex heterozygous mutations.None of the above mutations was found in 100 normal controls.Both p.L453P and p.L790P missense mutations were predicted to be deleterious mutations by online software PolyPhen and SIFT,and IVS26-3A＞G shear mutations were also predicted to be deleterious mutations by the online software MaxEntScan.None of the above mutations had previously been reported.High throughput sequencing revealed no mutations causing other diseases.A review of the literature found that a total of 18 articles (Chinese 1 article) met the inclusion criteria,in these reported 1 504 cases of sporadic and familial NPNP patients by NPHP3 gene sequencing,NPHP3 gene were found in 79 cases with homozygous or compound heterozygous mutations.Of these 79 cases of patients with NPHP3 mutation,19 cases in the neonatal period had progressed to ESRD,and needed renal replacement therapy,were often associated with lung hypoplasia,pancreatic cyst,these patients showed less fetal amniotic fluid,bilateral renal enlargement by ultrasound and cystic change.They were usually diagnosed as autosomal recessive polycystic kidney disease.20 cases (including 2 cases of this study) progressed to ESRD before the age of 5,with abnormal liver function,anemia was the main manifestation,often accompanied by liver fibrosis and bile duct dysplasia.The other 42 cases progressed to ESRD after the age of 5 showed anemia,renal dysfunction,hypertension and renal phenotype.Conclusion NPHP caused by mutations in NPHP3 gene is not juvenile nephronophthisis in the traditional sense,because NPHP3 patients can progress to end-stage renal disease at any age.If infant and early child present with unknown jaundice and abnormal liver function,which rm ay be caused by mutations in NPHP3 gene.c.1358A＞G,C.2369A＞G and c.1174C＞T mutations are novel mutations in this study,they may further expand the NPHP3 gene mutation spectrum.%目的 总结2例在婴幼儿期进展为终末期肾病(ESRD)的NPHP3基因突变致肾单位肾痨(NPHP)患儿的临床特征及基因突变的特点.方法 收集患儿的一般情况、肾活检、影像学、实验室检查和基因测序结果,并行文献复习.结果 ①2例均为男性,发病年龄3和17个月,均以黄疸、肝功能异常为首发症状,2例进展至ESRD的年龄分别为11和35个月.例1肾活检病理肾小管间质炎,肾小球轻度病变,未见囊肿;肝脏活检肝细胞弥漫性变性,间质纤维组织增生.未发现家族中有类似疾病.②行高通量测序结果显示,例1存在NPHP3基因C.2369A＞G(p.L790P)、c.1358A＞G (p.L453P)杂合错义突变,例2存在c.1174C＞T(p.R392X)无义突变和IVS26-3A＞G剪切突变.2例均为复合杂合突变,均分别来自患儿父母.p.L453P和p.L790P错义突变及IVS26-3A＞G剪切突变经软件预测为有害突变.除IVS26-3A＞G外均为新发现的突变.③共检索到18篇文献1 504例NPHP患者行NPHP3测序,79例检测到NPHP3纯合突变或复合杂合突变.其中19例在新生儿期进展为ESRD,需要肾脏替代治疗,常伴有肺发育不良和胰腺囊肿,在胎儿期表现为羊水少,超声提示双肾增大,伴有囊性改变,常被诊断为常染色体隐性遗传多囊肾;余20例(含文2例)在5岁前进展为ESRD,以肝功能异常和贫血为主要表现,常伴肝脏纤维化和胆管发育异常;42例在5岁后进展为ESRD,以贫血、肾功能异常和高血压等肾脏表型为主.结论 NPHP3基因突变所致NPHP并非传统意义上的青年型NPHP,约半数在5岁前进展为ESRD,故婴幼儿期不明原因的黄疸和肝功能异常应警惕NPHP3基因突变可能.本研究发现的c.1358A＞G、C.2369A＞G和c.1174C＞T突变为新发现的NPHP3基因突变类型.