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