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中国循证儿科杂志

中国循证儿科杂志 ›› 2022, Vol. 17 ›› Issue (3): 230-234.DOI: 10.3969/j.issn.1673-5501.2022.03.011

• 论著 • 上一篇    下一篇

原发性高草酸尿症3型8例病例系列报告并文献复习

计晓露1a,2，刘娇娇1a,2，王春燕1a，陈径1a，方晓燕1a，沈茜1a，王翔1b，徐虹1a

 

    

  1. 1 复旦大学附属儿科医院上海，201102，a 肾内科，b 泌尿外科；2 共同第一作者
  • 收稿日期:2021-12-13 修回日期:2021-12-31 出版日期:2022-06-25 发布日期:2022-06-25
  • 通讯作者: 徐虹，email：hxu@shmu.edu.cn; 王翔，email：13501838663@163.com；沈茜，email：shenqian@shmu.edu.cn

Primary hyperoxaluria type 3 in 8 children: A case series report and literature review

JI Xiaolu1a,2, LIU Jiaojiao1a,2, WANG Chunyan1a, CHEN Jing1a, FANG Xiaoyan1a, SHEN Qian1a, WANG Xiang1b, XU Hong1a   

  1. 1 Children's  Hospital of Fudan University,  Shanghai 201102, China，a Department of Nephrology, b Department of Urology;  2 Co-first author
  • Received:2021-12-13 Revised:2021-12-31 Online:2022-06-25 Published:2022-06-25
  • Contact: XU Hong, email: hxu@shmu.edu.cn; WANG Xiang, email:13501838663@163.com; SHEN Qian, email: shenqian@shmu.edu.cn

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摘要： 背景：原发性高草酸尿症（PH）是一种罕见的由于先天性肝内乙醛酸代谢异常导致的遗传性肾结石/肾钙质沉着症，既往多关注1型和2型PH，PH3的致病基因HOGA1发现较晚，报告不多。 目的：总结PH3临床表型，探讨不同种族人群的PH3热点变异。 设计：病例系列报告。 方法：纳入2015年1月至2021年12月复旦大学附属儿科医院经HOGA1基因变异确诊为PH3的连续病例。从住院病史中采集临床和生物学检测信息，在PubMed、Embase、万方数据库和中国知网数据库中检索PH3病例的中、英文文献，采集病例来源（国家）、例数、性别、起病年龄、诊断年龄、起病临床表现（尿石症、肾钙质沉着症、高钙尿症、高草酸尿症）、随访时间、肾功能（慢性肾脏病2期、3期、4~5期）、随访年龄、尿路结石转归 (活动性结石、无症状结石或结石消失)、HOGA1基因变异位点。 主要结局指标：临床表型和不同种族人群的热点变异。 结果：纳入8例PH3患儿，男7例，女1例；起病年龄中位数10月龄，诊断年龄中位数16月龄。3例以肉眼血尿起病，5例以泌尿道感染起病。影像学均提示肾结石，均无肾钙质沉着表现。3例检测了24 h尿草酸，1例提示高草酸尿症；6例检测了尿钙，5例提示高钙尿症。1例失访，7例随访中位时间25个月，肾小球滤过率均维持稳定，3例肾结石消失。8例均检出HOGA1基因变异（共10个变异位点），其中复合杂合变异5例，纯合变异3例，经ACMG分级判定6个位点为可能致病变异，4个位点为致病变异。中英文数据库共检索到82篇文献，筛选后23篇文献中321例PH3患者进入本文分析，中国36例（包括本文8例），欧美293例。中国和欧美PH3患者：起病表现为尿石症的比例分别为83%(30/36)和85%(195/230)，肾钙质沉着症分别为3%(1/29)和8%(20/261)，高草酸尿症分别为90%(26/29)和96%(66/69)，差异均无统计学意义；高钙尿症分别为44%(11/25)和23%（34/150)，差异有统计学意义；末次随访时肾功能：中国1例PH3患者25岁时进展至终末期肾病，欧美2例PH3患者分别在8岁和33岁进展至终末期肾病；活动性结石：中国和欧美PH3患者分别为13%(3/23)和37%(22/59)，差异有统计学意义。中国PH3患者热点变异为c.834G>A (splice site)、c.834_c.834+1GG>TT (splice site)和c.769T＞G (p.C257G)，分别占28%(20/72)、21%(15/72)和11%(8/72)；欧美PH3患者热点变异为c.700+5G>T (splice site)和c.944_946delAGG(p.E315del)，分别占40%(236/586)和12%(73/586)。 结论：PH3起病年龄和诊断年龄较早，整体预后较PH1和PH2良好，中国与欧美PH3患者HOGA1基因突变可能存在不同的热点变异位点。

关键词: 原发性高草酸尿症, 肾结石, HOGA1基因

Abstract: Background：The primary hyperoxalurias (PHs) is a rare hereditary nephrolithiasis and nephrocalcinosis caused by different gene mutations of enzymes that control the glyoxylate metabolism. PH1 and PH2 have already been paid more attention, while PH3 is the most recently identified type and there are only a few PH3 cases reported to date. Objective：To summarize the clinical phenotypes of PH3 patients and to explore the putative mutation hotspot regions in different ethnic groups. Design：Case series report. Methods：From January 2015 to December 2021, the PH3 patients diagnosed by genetic testing in Children's Hospital of Fudan University were enrolled. Clinical and molecular biological data were collected from inpatient medical history. The Chinese and English literature of PH3 cases was searched in PubMed, Embase, Wanfang database and CNKI database to collect case source (country), gender, number of cases, onset age, diagnosis age, clinical manifestations (urolithiasis, nephrocalcinosis, hypercalciuria, hyperoxaluria), followup time, kidney function (chronic kidney disease stage 2, chronic kidney disease stage 3, chronic kidney disease stage 45), followup, outcome of urinary tract stones (active stones, asymptomatic stones or disappearance of stones), and HOGA1 gene mutation type. Main outcome measures：Clinical phenotypes and hotspot variation in different ethnic groups. Results：Eight PH3 patients were enrolled (7 boys, 1 girl). The median age of onset was 10 months, and the median diagnosis age was 16 months. Initial symptoms showed urinary tract infection in 5 patients and gross hematuria in 3 patients. Imaging evaluation identified the diagnosis of nephrolithiasis in 8 cases, and none of them showed nephrocalcinosis. Three patients were tested for urinary excretion of oxalate, and 1 showed hyperoxaluria. Six patients conducted urinary calcium test and 5 of them showed hypercalciuria. One patient was loss to follow up and the other 7 cases were followed up for a median of 25 months. The glomerular filtration rate remained stable. Furthermore, 3 cases showed kidney stones disappearing during the followup. All the 8 cases had HOGA1 gene variant, including compound heterozygous variants in 5 cases and homozygous variants in the other 3 cases. According to ACMG classification, 6 variants were identified as likely pathogenic variants and the other 4 were identified as pathogenic variants. Among 82 articles related to PH3, 23 were case reports or case series reports which included 321 cases of PH3. Among these cases, 36 patients from China and 293 patients form Europe and America. The percentage of nephrolithiasis in Chinese group and EuropeanAmerican group were 83 percent(30/36) and 85 percent(195/230) respectively. The percentage of nephrocalcinosis in these two groups were 3 percent (1/29) and 8 percent (20/261). There was no difference in hyperoxaluria between the two groups ［90 percent (26/29) vs 96percent (66/69)］. There was significant difference in hypercalciuria between the two groups ［44 percent (11/25) vs 23 percent (34/150)］. In Chinese group, one patient progressed to endstage renal disease when he was 25 years old. In EuropeAmerica group, there were 2 patients progressed to endstage renal disease at the age of 8 and 33 respectively. The percentage of active stone in these two groups were 13 percent (3/23) and 37 percent (22/59), and the difference was significant. The hotspot variants of the Chinese group were c.834G>A (splice site), c.834_c.834+1GG>TT (splice site) and c.769T＞G (p.C257G), accounting for 28 percent(20/72), 21percent(15/72) and 11 percent(8/72), respectively. The hotspot variants of the EuropeanAmerican populations were c.700+5G>T (splice site) and c.944_946delAGG (p. E315del), accounting for 40 percent(236/586) and 12 percent(73/586), respectively. Conclusion：The age of onset and diagnosis of PH3 is quite earlier, and the overall prognosis is better than that of PH1 and PH2. Chinese and EuropeanAmerican PH3 patients may have different hotspot variants for HOGA1 gene.

Key words: Primary hyperoxaluria type 3, Nephrolithiasis, HOGA1 gene