Dent病1型5例病例系列报告并文献复习

目的 报告5例Dent病1型患儿的临床资料，提高对其认识。 方法 分析5例Dent病1型患儿病史、实验室检查，对先证者进行Dent病相关基因CLCN5、OCRL外显子及附近调控区域的直接测序，验证先证者父母有无相应位点突变，系统复习国内外文献报告的Dent病1型，归纳临床表型与突变类型。 结果 5例患儿实验室检查发现24 h尿蛋白定量33.0~68.9 mg·kg-1，尿α1微球蛋白、尿白蛋白和尿免疫球蛋白均明显升高，均伴有高钙尿症，其中镜下血尿1例、肾钙质沉着2例，行CLCN5、OCRL基因测序各发现了1个CLCN5突变，分别为R637X、Y479X、G530V、W103fsX104和R707X，其中Y479X、G530V和W103fsX104为新发现的突变位点。系统文献检索260篇Dent病相关文献，逐篇筛选，共有72篇Dent病1型病例报告和病例系列报告进入本文分析，均为病例报道或病例系列报道，欧美人群422例，亚洲人群176例。欧美与亚洲国家Dent病1型临床表型低分子量蛋白尿表现一致，差异无统计学意义，高钙尿症、肾钙质沉着、肾积石、佝偻病和肾功能异常差异均有统计学意义，不同的临床表型没有突出显现突变类型（错义、无义、移码、剪切和缺失突变）的优势。 结论 临床提示Dent病1型可能的患儿可通过基因检测以明确诊断，避免不必要的免疫抑制剂治疗。CLCN5突变具有高度异质性，临床表型与CLCN5突变类型没有显现较好的关联性。

Five case series of Dent-1 disease and literature review

Objective To summarize the clinical data of five cases of Dent-1 disease so as to improve our understanding of the disease. Methods Clinical data of five cases with Dent-1 disease were summarized, including clinical manifestations, laboratory findings and renal pathological changes. Mutation analysis on CLCN5 and OCRL genes was performed by direct sequencing in these families. Related literatures of Dent-1 disease were reviewed and the phenotypes and genotypes were summarized. Results Laboratory findings of five patients showed 24-hr urine protein ranged from 33.0 to 68.9 mg·kg-1, and high levels of urinary α1-microglobulin, albuminuria, immunoglobulin G and hypercalciuria, and one patient with microscopic haematuria and other two patients with nephrocalcinosis. Five CLCN5 mutations were detected, including R637X, Y479X, G530V, W103fsX104 and R707X, respectively. Y479X, G530V and W103fsX104 were novel mutations. Among 260 articles related to Dent's disease, we found 72 case reports or case series of Dent-1 disease including 598 patients, 422 from Europe and America and 176 from Asia. Except low-molecular-weight proteinuria, the incidence between Europe and America cases and Asia cases of hypercalciuria, nephrocalcinosis, rickets and renal insufficiency were statistically significantly different. No significant correlations between phenotypes and genotypes in all cases were found, including nonsense mutations, missense mutations and frameshift mutations. Conclusion Clinical diagnosis of Dent-1 disease should be confirmed by CLCN5 mutation test to avoid unnecessary immunosuppressants therapy. CLCN5 mutations show high heterogenetic, and the relationships between the phenotypes and genotypes of Dent-1 disease are not found yet.