Abstract: To investigate the clinical charateristics and treatment outcome of children with primary distal tubular acidosis （dRTA），analyze the difference among children with different gene phenotypes，and to improve the understanding of primary dRTA in children. Methods    From April 2011 to November 2022，19 patients diagnosed with primary dRTA were included. Clinical and laboratory characteristics were summarized and compared among genotype. Outcome factors were also analyzed. Results    There were 19 patients （8 males and 11 females）. The age of onset ranged from 10 days to 4 years. The last follow-up age was 8 months to 17 years and one month. Growth retardation was the most common clinical symptom. Height or weight below - 2SD accounted for 78.94%. All patients had hypokalemia，hyperchloremic metabolic acidosis，alkaline urine，increased urine calcium and renal medullary calcinosis. Twenty mutations of SCL4A1，ATP6V0A4 and ATP6V1B1 gene were found in the 19 patients，and 9 of them were novel mutations. The proportion of patients with SLC4A1 recessive inheritance and SLC4A1 dominant inheritance，ATP6V0A4 and ATP6VB1 inheritance was 31.58%，15.79%，36.84% and 15.79%，respectively. The onset age of patients with SLC4A1 mutations was significantly higher than patients with ATP6V0A4 and ATP6VB1 mutations （P<0.001）. Bicarbonate level of SLC4A1 recessive inherited patients was significantly lower than others （P=0.01）. Combination rate of bone abnormalities：in SLC4A1 dominant inherited patients it was 66.67%，in SLC4A1 recessive inherited patients it was 100%，in ATP6V1B1 group in was 33.33%，and in ATP6V0A4 group it was 0；there was statistical difference among the four groups （P<0.001）. Three patients had sensorineural hearing loss （1 of ATP6V0A4，2 of ATP6V1B1）. The proportion of patients with ATP6V0A4 mutations combined with sensorineural hearing loss was significantly lower than that reported abroad. After treatment with citric acid preparation，68.42% of the patients had a height and weight of more than - 2SD，which were significantly positively correlated with the time of treatment （related coefficients 0.627），but had no significant relationship with genotype. After treatment， blood potassium remained normal，and 71.43% of patients' blood bicarbonate remained normal. Only one patient had eGFR lower than 90ml/min/1.73m2 after 8 years of treatment. There was no significant genotypic difference in treatment outcome. In addition，the allele frequency of SLC4A1 c.2102G>A （p.G701D） was 83.33%，which was a hot spot mutation in SLC4A1 recessive patients. All patients carrying this mutation in this study came from southern China. ATP6V0A4 c.580C>T （p.R194X） mutation gene frequency was 28.57%，which was considered to be a hot mutation in Chinese population，and all patients with this mutation came from North China. Conclusion    Different genotypes of primary dRTA have different phenotypes. Patients with SLC4A1 mutation have a late onset age and more bone involvement. Patients with SLC4A1 recessive mutations often suffer from severe acidosis. After appropriate treatment，the condition of patients with all genotypes improved，and prognosis in childhood is good without end point. This study reveals 9 new mutations，which have enriched the human gene mutation database. The ATP6V0A4 c.580C>T （p.R194X） mutation and SLC4A1 c.2102G>A （p.G701D） are consistent with the hot spot mutation of Chinese population，and there are hot spot regional differences. There is no end event under the current follow-up age and current treatment.

Key words: distal renal tubular acidosis, gene, rickets, growth retardation

摘要： 目的    总结儿童原发性远端肾小管酸中毒（distal renal tubular acidosis，dRTA）患儿的临床以及治疗转归，分析不同基因表型患儿表观差异，以提高对儿童dRTA认识。方法    对2011年4月至2022年11月首都医科大学附属北京儿童医院诊断为dRTA并有基因确诊的原发性dRTA患儿共19例进行临床及实验室数据收集，总结患儿的临床特点，并进行基因型和表型的关联研究以及临床及生化转归因素分析。结果    19例患儿，男8例，女11例，发病年龄10 d至4岁，末次随访年龄8月龄至17岁1月龄。临床以生长迟缓多见，身高或体重低于-2SD占78.94%，100%存在低钾血症、高氯性代谢性酸中毒、碱性尿、尿钙增高以及肾髓质钙质沉着。19例患儿共发现来自3个基因SCL4A1、ATP6V0A4和ATP6V1B1 的20个变异，共有9个未报道的变异。SLC4A1常染色体隐性遗传（AR）、SLC4A1常染色体显性遗传（AD）、ATP6V0A4和ATP6VB1遗传患儿比例分别为31.58 %、15.79%、36.84%和15.79%。基因型表型分析，SLC4A1 AR及SLC4A1 AD患儿发病年龄明显高于ATP6V0A4及ATP6VB1变异患儿（P=0.029）；SLC4A1 AR患儿实际碳酸氢根水平明显低于其他组（P=0.01）；合并骨骼异常：SLC4A1 AD患儿66.67%，而SLC4A1 AR患儿100%，ATP6V1B1患儿33.33%，ATP6V0A4患儿0，4组存在差异具有统计学意义（P<0.001）；3例患儿存在感音神经性耳聋（1例ATP6V0A4，2例ATP6V1B1），ATP6V0A4基因变异患儿合并感音神经性耳聋比例明显低于国外报道。经枸橼酸制剂规律治疗后，68.42%患儿身高、体重均达-2SD以上，与治疗时间显著正相关（相关系数0.627），与基因型无明显关系。治疗后血钾均维持正常，71.43%患儿治疗后血实际碳酸氢根维持正常。仅1例患儿治疗8年后eGFR低于90 mL/（min・1.73m2）。治疗结局无明显基因型间差异。SLC4A1 c.2102G>A（p.G701D）等位基因频率83.33%，是SLC4A1 AR患儿中热点变异，研究中携带该变异患儿均来自中国南部地区。ATP6V0A4基因c.580C>T（p.R194X）变异位基因频率28.57%，考虑为中国人群热点变异，该变异患儿均来自我国华北地区。结论    原发性dRTA不同基因型表型不同，SLC4A1变异患儿发病年龄晚、骨骼受累多，SLC4A1常染色体隐性患儿酸中毒程度较重。经恰当的治疗后，各基因型患儿病情均可获得改善，儿童期预后良好未见终点事件。该研究发现9个未报道变异，丰富了人类基因突变数据库，ATP6V0A4基因c.580C>T（p.R194X）变异和SLC4A1 c.2102G>A（p.G701D）符合中国人群热点变异，且存在热点地域差异。在目前随访年龄和当前治疗下未见终末事件。

关键词: 原发性远端肾小管酸中毒, 基因, 佝偻病, 生长迟缓