[Clinical analysis of seven cases with primary hyperoxaluria type 1 in children].

Objective: To investigate the clinical, imaging and molecular characteristics of primary hyperoxaluria type 1 (PH1) in children and to sum up existing evidence for further understanding the phenotype-genotype correlation of infantile PH1. Methods: This retrospective analysis was based on the medical records of children with PH1 diagnosed by gene test in the Department of Nephrology, Guangzhou Women and Children's Medical Center from June 2016 to May 2019. Targeted exome sequencing was performed on tubular disease-related genes of the probands and Sanger sequencing was conducted to validate suspected pathogenic variants of family members. Logistic regression analysis of NC and CCr was adopted to show the relation between NC and renal function. The literature review was conducted, and the clinical, imaging and molecular biogenetic characteristics of the disease were analyzed and summarized. Results: A total of 7 children from 6 families were enrolled. The median age of onset was 5 months. The median age of diagnosis was 8 months. Five cases had progressed to end-stage renal disease (ESRD), one case had chronic kidney disease (CKD) stage 1, and the other one had CKD stage 2. Four cases died, one case maintained on hemodialysis, and the other two non-dialysis cases were followed up. Among the 7 cases, 4 patients had infantile PH1, 1 patient had child and adolescent type, 1 patient had family type and the other one had unknown classification. There were two siblings (the younger brother had uremia and the sister had normal renal function) who had the delayed diagnosis for 5 and 3 years respectively. All patients in this cohort had proteinuria and microscopic hematuria, but no patients had gross hematuria. Three cases had hypercalciuria. Comprehensive diagnostic imaging evaluation include CT scan, MR scan, radiography and ultrasound led to the diagnosis of nephrocalcinosis (NC) in 5 cases, including 4 cases of simple NL and 1 case of NC with nephrolithiasis (NL), 1 case of multiple NL and 1 case of microcrystal deposition in renal medulla. However, only one case of NC was identified by ultrasound, the other 4 cases of NC were identified by radiograph examination. In the logistic regression analysis involving NC and creatinine clearnce rate (CCr), the results showed that NC was an independent risk factor for renal dysfunction (OR 2.5, 95%CI 0.7-1.2, P<0.05). All the 7 cases had AGXT gene variant, including homozygous variant in 4 cases and compound heterozygous variant in 3 cases. A total of 9 variant genotypes were found, and exon 6 variants were found in 4 children. Among them, there were 3 cases with c.679_680delAA. To our knowledge, both c.679_680delAA and c.190A>T in the cohort have not been reported previously. Conclusions: Infantile PH1 is the most common type of PH1 in children, which progresses rapidly or even begins with renal failure, with poor prognosis. It is also highly heterogeneous in phenotype and genotype. NC is an independent risk factor leading to renal failure. Radiograph examination showed high specificity for the diagnosis of NC. At present, the misdiagnosis and delayed diagnosis of PH1 are still common in China. It is of great significance to carry out quantitative determination of uric oxalate in order to reduce the misdiagnosis rate and enhance follow-up technologies for evaluating the therapeutic effect.目的： 探讨1型原发性高草酸尿症（PH1）患儿的临床、影像、分子生物学特征，及临床表型与基因型的相关性。 方法： 回顾性分析2016年6月至2019年5月广州市妇女儿童医疗中心肾内科住院经基因检测确诊为PH1的7例患儿（男4例、女3例）病例资料，分子生物遗传学检测方法采用对先证者进行肾小管疾病相关靶向基因外显子测序并采用Sanger测序法对家系进行验证，采用非条件Logistic回归分析统计肾钙质沉着与肾功能的关系。 结果： 共纳入来自6个家庭的7例患儿，发病中位年龄5月龄，确诊中位年龄8月龄，5例已进展至终末期肾病、1例为慢性肾脏病2期、1例为慢性肾脏病1期。死亡4例、维持性透析1例、非透析随访患儿2例。婴儿型PH1患儿4例，儿童及青少年型1例，家族型1例，分类不明1例。2例为胞生姐弟，其中弟弟为先证者，因尿毒症而被确诊，姐姐继而因家系验证被确诊，为轻度肾功能不全，两人均有延迟诊断，弟弟延迟5年、姐姐延迟3年。7例患儿均有不同程度的尿蛋白升高（随机尿蛋白与尿肌酐比值的平均值为1.1）及镜下血尿、无肉眼血尿，3例患儿出现高钙尿症。综合CT、磁共振成像、X线片及超声等多种影像学检查，确诊4例单纯肾钙质沉着症、1例肾钙质沉着症伴肾石症、1例单纯多发肾结石及1例肾髓质小结晶，但其中超声检查能明确肾钙质沉着症的只有1例，其余4例由CT等放射性影像检查确诊，而且肾钙质沉着是肾功能不全的独立危险因素（OR 2.5，95%CI 0.7~1.2，P<0.05）。基因检测7例均为AGXT基因变异，其中纯合变异4例、复合杂合变异3例。共发现9个变异基因型，有4个基因型出现在6号外显子变异，其中c.679_680del缺失变异3例（2例为胞生姐弟），c.679_680+2del缺失1例。 结论： PH1患儿以婴儿型为多见，病情进展迅速甚至以肾功能不全起病预后极差，是临床表型与基因型高度异质性疾病；肾钙质沉着是导致肾功能衰竭的一个独立危险因素，放射性影像检查对于肾钙质沉着症的诊断具有较高特异性；国内儿科领域PH1的漏诊及延迟诊断仍较突出，普遍开展尿草酸定量测定对降低漏诊率及追踪评估疗效具有重要意义。.