Rousseau-Nepton Isabelle, Jones Glenville, Schlingmann Karlpiet, Kaufmann Martin, Zuijdwijk Caroline S, Khatchadourian Karine, Gupta Indra R, Pacaud Danièle, Pinsk Maury N, Mokashi Arati, Nour Munier A, Alexander R Todd, Rodd Celia J
Department of Pediatrics, CHU de Québec, Université Laval, Québec, Québec, Canada.
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Horm Res Paediatr. 2021;94(3-4):124-132. doi: 10.1159/000517548. Epub 2021 Jul 28.
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.
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.
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.
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.
CYPA24A1和SLC34A1的双等位基因致病性变异是特发性婴儿高钙血症的病因。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，且之前无高钙血症（肾脏组）。我们的目的是研究CYP24A1或SLC34A1变异在早期高钙血症或迟发性高钙尿症儿童中的发生率。
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D3与24,25-二羟基维生素D3的比值（25-OH-D3:24,25-(OH)2D3），该比值升高是CYP24A1酶功能丧失的特征性表现。进行了突变分析。如果在先证者中检测到致病性变异，则进行家系级联筛查。
29名儿童患有早发性高钙血症；无一例25-OH-D3:24,25-(OH)2D3升高或有变异。有趣的是，肾脏组的12名儿童中有2名25-OH-D3:24,25-(OH)2D3升高，且为青春期前儿童。在病例1中，级联检测发现一名同胞和一名父母在CYP24A1中有无症状致病性变异。在这2名先证者中鉴定出4个CYP24A1致病性变异：3个已在欧洲人群中描述，1个是外显子7中的罕见变异（c931delC），可能具有致病性。未检测到SLC34A1致病性变异。
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-D3:24,25-(OH)2D3比值是筛查CYP24A1双等位基因致病性变异的极佳工具。我们证实级联检测对这些变异很重要。
