Objectives: Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria. Method: Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D₃ to 24,25-dihydroxyvitamin D₃, (25-OH-D₃:24,25-(OH)₂D₃), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. Results: Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D₃:24,25-(OH)₂D₃ or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D₃:24,25-(OH)₂D₃ and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected. Conclusion: In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D₃:24,25-(OH)₂D₃ ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.
Horm Res Paediatr

中文翻译：

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CYP24A1 和 SLC34A1 致病性变异在加拿大高钙血症或高钙尿症儿童队列中并不常见

目的： CYPA24A1和SLC34A1中的双等位基因致病变异是特发性婴儿高钙血症的原因。两者的致病性变异也可能导致高钙尿症伴肾钙质沉着症或肾结石而无既往高钙血症（肾组）。我们的目标是检查CYP24A1或SLC34A1变异在早期高钙血症或迟发性高钙尿症儿童中的频率。方法：招募了来自加拿大 7 个中心的 41 名儿童。进行了当地调查。通过液相色谱串联质谱法评估血清中 25-羟基维生素 D ₃与 24,25-二羟基_{维生素 D 3的比例}, (25-OH-D ₃ :24,25-(OH) ₂ D _{3 )，} CYP24A1酶功能丧失的升高特征。进行了突变分析。如果在先证者中检测到致病变异，则进行家庭级联筛查。结果： 29名儿童出现早发性高钙血症；没有人升高 25-OH-D ₃ :24,25-(OH) ₂ D ₃或变体。有趣的是，肾组 12 人中有 2 人的 25-OH-D ₃ :24,25-(OH) ₂ D ₃升高并表现为青春期前的儿童。在案例 1 中，级联检测显示兄弟姐妹和父母在CYP24A1。在这 2 名先证者中鉴定出4种 CYP24A1致病性变异：3 种已在欧洲人群中被描述，1 种是外显子 7 (c931delC) 中可能致病的罕见变异。未检测到SLC34A1致病变异。结论：在加拿大，CYP24A1的致病性变异似乎表现为迟发性高钙尿症及其后遗症。25-OH-D ₃ :24,25-(OH) ₂ D ₃比率是筛选CYP24A1中双等位基因致病变异的绝佳工具。我们确认级联测试对这些变体很重要。
儿科荷尔蒙