CYP24A1 and SLC34A1 Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria

Abstract

<b><i>Objectives:</i></b> Biallelic pathogenic variants in <i>CYPA24A1</i> and <i>SLC34A1</i> 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 <i>CYP24A1</i> or <i>SLC34A1</i> variants in children with early hypercalcemia or late-onset hypercalciuria. <b><i>Method:</i></b> 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 <i>CYP24A1</i> enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. <b><i>Results:</i></b> 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 <i>CYP24A1.</i> Four <i>CYP24A1</i> 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 <i>SLC34A1</i> pathogenic variants were detected. <b><i>Conclusion:</i></b> In Canada, pathogenic variants in <i>CYP24A1</i> 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 <i>CYP24A1</i>. We confirm that cascade testing is important for these variants.