Pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter 2a and 2c are rare causes of phosphate wasting. Since data on presentation and outcomes are scarce, we collected clinical, biochemical and genetic data via an online questionnaire and the support of European professional organizations. One hundred thirteen patients (86% children) from 90 families and 17 countries with pathogenic or likely pathogenic variants in SLC34A1 or SLC34A3 and a median follow-up of three years were analyzed. Biallelic SLC34A1 variant carriers showed polyuria, failure to thrive, vomiting, constipation, hypercalcemia and nephrocalcinosis in infancy, while biallelic SLC34A3 carriers presented in childhood or even adulthood with rickets/osteomalacia and/or osteopenia/osteoporosis, hypophosphatemia and, less frequently, nephrocalcinosis, while the prevalences of kidney stones were comparable. Adult biallelic SLC34A3 carriers had a six-fold increase chronic kidney disease (CKD) prevalence compared to the general population. All biallelic variant carriers shared a common biochemical pattern including elevated 1,25(OH)2D and alkaline phosphatase levels, suppressed parathyroid hormone (PTH), and hypercalciuria. Heterozygous carriers showed similar but less pronounced phenotypes. In biallelic SLC34A1 carriers, an attenuation of clinical features was observed after infancy, independent of treatment. Phosphate treatment was given in 55% of patients, median duration two years, and resulted in significant reduction, although not normalization, of alkaline phosphatase and of hypercalciuria but an increase in PTH levels, while 1,25(OH)2D levels remained elevated. Thus, our study indicates that biallelic SLC34A1 and SLC34A3 carriers show distinct, albeit overlapping phenotypes, with the latter having an increased risk of CKD in adulthood. Phosphate treatment may promote kidney phosphate loss and enhance 1,25(OH)2D synthesis via increased PTH production.

中文翻译：

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编码磷酸钠转运蛋白 NPT 2a 和 2c 的 SLC34A1 和 SLC34A3 致病性变异携带者的表现和结局


编码磷酸钠转运蛋白 2a 和 2c 的 SLC34A1 和 SLC34A3 的致病性变异是磷酸盐消耗的罕见原因。由于有关表现和结果的数据稀缺，我们通过在线问卷和欧洲专业组织的支持收集了临床、生化和遗传数据。分析了来自 90 个家庭和 17 个国家的 113 名患者 （86% 儿童），这些患者在 SLC34A1 或 SLC34A3 中具有致病性或可能的致病性变异，中位随访时间为 3 年。双等位基因SLC34A1变异携带者在婴儿期表现为多尿、生长迟缓、呕吐、便秘、高钙血症和肾钙质沉着症，而双等位基因SLC34A3携带者在儿童期甚至成年期表现为佝偻病/骨软化症和/或骨质减少/骨质疏松症、低磷血症和肾钙质沉着症，而肾结石的患病率相当。与普通人群相比，成人双等位基因 SLC34A3 携带者的慢性肾脏病 （CKD） 患病率增加了 6 倍。所有双等位基因变异携带者都有一个共同的生化模式，包括 1,25（OH）2D 和碱性磷酸酶水平升高、甲状旁腺激素 （PTH） 抑制和高钙尿症。杂合子携带者表现出相似但不太明显的表型。在双等位基因 SLC34A1 携带者中，在婴儿期后观察到临床特征的减弱，与治疗无关。55% 的患者接受了磷酸盐治疗，中位持续时间为 2 年，导致碱性磷酸酶和高钙尿症显着降低，但未恢复正常，但 PTH 水平增加，而 1,25（OH）2D 水平仍然升高。 因此，我们的研究表明，双等位基因 SLC34A1 和 SLC34A3 携带者表现出不同的，尽管重叠的表型，后者在成年后患 CKD 的风险增加。磷酸盐处理可能会促进肾脏磷酸盐流失，并通过增加 PTH 的产生来增强 1,25（OH）2D 合成。