背景:数据有限,主要来自小案例系列,关于临床概况,遗传变异,和WDR72相关的远端肾小管酸中毒(WDR72-dRTA)的结果。
方法:我们的研究招募了来自9个印度中心的18岁以下被诊断为WDR72-dRTA的儿童,并分析了他们的临床特征,遗传概况,和结果。探讨了潜在的基因型-表型相关性。
结果:我们报告了22例WDR72-dRTA患者(59%为女性),他们的中位年龄为5.3(3,8)岁,患有多尿(n=17;77.3%),增长不佳(16;72.7%),和病(9;40.9%)。21例(95.5%)存在成色不全症。在介绍时,所有患者均有正常的阴离子间隙代谢性酸中毒;低钾血症和肾钙质沉着各17例(77.3%).7例(31.8%)患者伴有近端肾小管功能障碍。遗传分析确定了18例(81.8%)患者的双等位基因无义变异,包括6例新型变种。以前报道的变体,c.88C>T,和一个新颖的变体,c.655C>T,是最常见的变体,占10例(45.5%)。在1.3(1,8)年的中位随访中,高度速度提高了0.74(0.2,1.2)个标准差分数,而3名儿童(13.6%)进展为慢性肾脏病(CKD)2期,eGFR分别为67至76mL/min/1.73m2,经过11.3-16年的随访。无法建立特定的基因型-表型相关性。
结论:WDR72-dRTA应适用于具有牙釉质发育不全和dRTA典型特征的儿童。双等位基因无义变体在亚洲人中很常见。虽然大多数患者对改善生长和保持eGFR的治疗反应良好,在长期随访中,可能出现eGFR下降。
BACKGROUND: Limited data, primarily from small case series, exist regarding the clinical profile, genetic variants, and outcomes of WDR72-associated distal renal tubular acidosis (WDR72-dRTA).
METHODS: Our study enrolled children diagnosed with WDR72-dRTA below 18 years of age from 9 Indian centers and analyzed their clinical characteristics, genetic profiles, and outcomes. Potential genotype-phenotype correlations were explored.
RESULTS: We report 22 patients (59% female) with WDR72-dRTA who were diagnosed at a median age of 5.3 (3, 8) years with polyuria (n = 17; 77.3%), poor growth (16; 72.7%), and rickets (9; 40.9%). Amelogenesis imperfecta was present in 21 (95.5%) cases. At presentation, all patients had normal anion gap metabolic acidosis; hypokalemia and nephrocalcinosis were seen in 17 (77.3%) patients each. Seven (31.8%) patients had concomitant proximal tubular dysfunction. Genetic analysis identified biallelic nonsense variants in 18 (81.8%) patients, including novel variants in 6 cases. A previously reported variant, c.88C > T, and a novel variant, c.655C > T, were the most frequent variants, accounting for 10 (45.5%) cases. Over a median follow-up of 1.3 (1, 8) years, the height velocity improved by 0.74 (0.2, 1.2) standard deviation scores, while 3 children (13.6%) progressed to chronic kidney disease (CKD) stage 2, with eGFR ranging from 67 to 76 mL/min/1.73 m2, respectively, after 11.3-16 years of follow-up. No specific genotype-phenotype correlation could be established.
CONCLUSIONS: WDR72-dRTA should be considered in children with typical features of amelogenesis imperfecta and dRTA. Biallelic nonsense variants are common in Asians. While most patients respond well to treatment with improved growth and preserved eGFR, on long-term follow-up, a decline in eGFR may occur.