儿童1型Dent病1例并文献复习

One case of child with Dent-1 disease and literatures review

目的探讨儿童1型Dent病的临床特征,并进行文献复习,提高临床对该病的认识。方法选取2015年11月26日,经临床表现和基因检测于广州市妇女儿童医疗中心确诊的1例1型Dent病男性患儿为研究对象。采用回顾性分析方法,收集该例患儿的临床资料,对其临床特征和诊治经过进行总结。设定文献检索策略为:分别以"Dent病""Dent disease"为中、英文主题词,以"Dent′s disease"为关键词,在PubMed数据库,深圳市迈特思创科技有限公司外文医学信息资源检索平台,以及万方和中国知网数据库,进行1型Dent病相关文献检索,检索时间设定为1997年10月至2017年12月。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》的要求。结果对该例1型Dent病男性患儿的研究结果显示:(1)体检时,尿常规检查发现蛋白尿。(2)尿蛋白定量达到肾病综合征诊断标准,无明显水肿、高胆固醇血症及低蛋白血症。尿液肾功能检查结果显示,α1-、β2-微球蛋白(MG),尿视黄醇结合蛋白(URBP)明显升高(超过正常参考值上限5倍)。尿蛋白电泳检测结果显示,以尿液中低分子质量蛋白(LMWP)为主。根据肾穿刺活检结果,临床对该例患儿误诊为轻度系膜增生性肾小球肾炎,予以激素和免疫抑制剂治疗无效。患儿存在高钙尿症,肾功能正常,泌尿系统超声检查结果未见异常。(3)存在CLCN5基因c.2119C>T(半合子突变),其母亲、妹妹该位点均无突变。临床对该例患儿采用低草酸盐、低钠、低钙饮食摄入,大量饮水,以及口服氢氯噻嗪1~2mg/(kg·d)治疗3个月,其尿钙/肌酐降低至正常水平,停用氢氯噻嗪1个月后,尿钙/肌酐升高。采用福辛普利0.2~0.3mg/(kg·d)治疗9个月后,其尿蛋白定量无明显降低。结论对于以尿LMWP为主要临床表现,尿蛋白定量达到肾病综合征诊断标准的患者,临床应进一步进行基因检测,以确诊1型Dent病,可避免不必要的有创性肾穿刺活检及激素、免疫抑制剂治疗。氢氯噻嗪可降低1型Dent病患者尿高钙含量,但是停药后反复,临床需制定规范化的1型Dent病治疗指南。

Objective To explore the clinical characteristics of children with Dent-1 disease and review the related literatures to improve the clinicians′recognition of this disease.Methods One boy with Dent-1 disease who was diagnosed by clinical manifestations and gene test at the Guangzhou Women and Children′s Medical Center on November 26,2015 was selected as the research subject.The clinical data of the patient was collected so as to summarize its clinical characteristics and the process of diagnosis and treatment by retrospectively analysis method.The western literatures related with Dent-1 disease were reviewed from PubMed database and Foreign Medicine Information Resource Retrieval Platform of Shenzhen Maitre Technology Co.Ltd.by the search strategy with ＂ Dent disease＂ as the subject heading and ＂ Dent′s disease＂ as the key word.Chinese literatures related with Dent-1 disease were reviewed from Wanfang Data Knowledge Service Platform and China National Knowledge Infrastructure by the search strategy with ＂ Dent disease＂ as the key word.All literatures were reviewed from October 1997 to December 2017.This study met the requirements of the World Medical Association Declaration of Helsinki revised in 2013.Results The results of the study on the male patients with Dent-1 disease showed as follows.（1）Proteinuria was found by urine routine during physical examination.（2）The proteinuria was as high as the diagnostic criteria for nephrotic syndrome without obvious edema,high serum cholesterol and hypoproteinemia.The urinary renal tubular test showed that the level of urine low-molecular-weight protein（LMWP）including urineα1-microglobulin（MG）,urineβ2-MG,and urine retinol-binding protein（URBP）were obviously increased（more than five times higher than the upper limit of normal reference level）and the urinary protein electrophoresis pointed to LMWP.According to the results of renal biopsy,the patient was misdiagnosed as mild mesangial proliferative glomerulonephritis,and received ineffective treatment of hormones and immunosuppressants.The patient had hypercalciuria,and his urinary system ultrasound and renal functions were normal.（3）Genetic test results showed that a c.2119 C〉T hemizygote mutation in CLCN5 gene was found in the patient,but this mutation was not found in his mother or sister.He was treated with low oxalate,low sodium,low calcium diet,and drinking lots of water.Besides,the ratio of urinary calcium and urinary creatinine decreased to normal by the treatment of hydrochlorothiazide 1-2 mg/（kg·d）for three months,however it increased after drug withdrawal for one month.The amount of urine protein quantification did not decrease obviously after fosinopril0.2-0.3 mg/（kg·d）treatment for nine months.Conclusions For patients with LWMP urine as the main clinical manifestation and proteinuria which is as high as the diagnostic criteria for nephrotic syndrome,genetic testing should be conducted to confirm whether it is Dent-1 disease or not,avoiding unnecessary invasive and hemorrhagic renal biopsy and a trial of steroid and immunosuppressive treatment.Hypercalcinuria can be controlled by hydrochlorothiazide treatment,and it is necessary to develop a standardized clinical guideline for Dent-1 disease treatment.