常染色体显性小管间质肾病-肝细胞核因子1β的临床特点和基因诊断

Clinical features and genetic diagnosis of autosomal dominant tubulointerstitial kidney diseases(ADTKD)-hepatocyte nuclear factor 1β(HNF1β)

目的探讨常染色体显性小管间质肾病-肝细胞核因子1β(ADTKD-HNF1β)的临床特点和基因诊断。方法 2016年6月我院收治了1例肾衰竭、接受规律透析的男性患者(12岁),详细总结其临床资料,并利用二代测序技术对患者及其父母外周血进行基因检测。利用Sanger法对突变基因进行验证。结果患者既往"健康",无明确诱因出现终末期肾脏病(ESRD)。该患者的症状特点为,发育正常,无血尿,轻度蛋白尿,重度贫血,肝酶持续升高。尿蛋白电泳显示肾小管性蛋白尿为主(59.9%),尿糖阳性(血糖正常),尿β2微球蛋白、α1微球蛋白明显升高,显示明确的肾小管间质损伤。B超、CT检查显示双肾多发囊肿。共检测了163个肾病相关基因,发现患者HNF1β基因携带1个c.1413dupC(p.V472fsX78)杂合突变。患者父母均未检测到此突变。患者最终确诊为ADTKD-HNF1β。结论 HNF1β基因突变为诱发ADTKD的致病突变之一,可引起严重的肾小管间质损伤、多发肾囊肿和肝酶异常,导致ESRD,应引起足够警惕。本病例中该位点基因突变尚未见有文献报道。

Objective To study the clinical features and genetic diagnosis of autosomal dominant tubulointerstitial kidney diseases （ADTKD） - hepatocyte nuclear factor 1β （ HNF1 β ）. Methods In June, 2016, the hospital received a male child （12 years old） with renal failure and regular dialysis. Physicians collected the clinical and laboratory data in detail and performed gene detection with the second generation DNA sequencing technology. The genetic tests on the patient and his parents made use of their peripheral blood mononuclear cell genome DNA. The Sanger sequencing-based methods were used to search for gene mutations. Results The child was ＂well＂ before, and had end-stage renal failure （ESRD） without any obvious incentives. The child patient was with normal development, no hematuria, mild proteinuria, severe anemia, and elevated liver enzymes. The urine protein electrophoresis showed a lot of predominant renal tubular protein （59. 9% ）; the child also had renal glucosuria, and obvious urine increases of β-2 microglobulin and α-1 microglobulin, indicating substantial tubulointerstitial injury. The B-type ultrasonic and CT examinations showed multiple cysts in bilateral kidneys. The 163 genes which related to kidney diseases were checked. The gene sequencing results showed that the HNF1β had a hybrid mutation, c. 1413dupC （p. V472fsX78 ）. His parents didn＇t have the mutation. So the child patient was diagnosed as ADTKD-HNF1β. Conclusions Mutation of HNF1β gene is one of the causative mutations of ADTKD. ADTKD-HNF1β can lead to significant renal tubular interstitial lesions, renal multiple cysts, and ESRD, as well as elevated liver enzymes. This is a de novo gene mutation,which has not been reported elsewhere.