133: The Search for CYP24A1 Mutations in Canadian Children: An Unexpected Presentation with Nephrocalcinosis Despite Normal 1, 25(OH)2d and Serum Calcium. Issue 6 (1st June 2014) - Rousseau-Nepton, I
Abstract: BACKGROUND: Idiopathic Hypercalcemia of Infancy (IIH) has been associated with mutations in the vitamin D degrading enzyme CYP24A1. The classic phenotype involves infants who present with hypercalcemia although individuals without an apparent infantile hypercalcemic phase have presented later in life. Typically, at least one vitamin D metabolite is elevated at the time of presentation, and usually CYP24A1 mutations described to date have completely abrogated enzyme activity. The frequency of CYP24A1 mutations and their phenotype is still poorly documented. OBJECTIVES: To recruit children from across Canada with presumed IIH to examine their vitamin D metabolite profile using sensitive LC-MS/MS profiling and mutational analyses. DESIGN/METHODS: Endocrinologists and nephrologists across Canada were contacted to identify potential cases of hypercalcemia or hypercalciuria without another identifiable etiology. LC-MS/MS was used to determine the ratio of 25(OH)D: 24, 25(OH)2D, a marker of CYP24A1 activity. A ratio greater than 80 (ng/mL/ng/mL) is suggestive of CYP24A1 mutations. Mutational analyses were then carried out in all children. RESULTS: To date, five children have been recruited and 25 other cases are pending analyses. Three were infants with serum total calcium >2.90 mM and urine calcium: creatinine ratio >95th CI for age, and two were adolescents presenting with nephrocalcinosis or nephrolithiasis. Almost all had elevated 1, 25(OH)2D concentrations and suppressed PTH. All vitamin D metabolite ratios were normal except in one girl who presented at nine years of age with an incidental finding of nephrocalcinosis on ultrasound performed for urinary tract infection. Her labs demonstrated intermittent hypercalciuria (peak 6.2 mmol/d), sporadically suppressed PTH, normal serum calcium, and normal vitamin D metabolites in the clinical laboratory. Family history was positive on both sides for nephrolithiasis. Her vitamin D metabolite ratio was 121; the mutational analysis demonstrated a known homozygous mutation E143del. CONCLUSIONS: The full phenotype of CYP24A1 mutations is not yet fully described. Likely other gene mutations are associated with IIH. Clinicians need to consider CYP24A1 mutations in the presence of suppressed PTH concentrations and incidental hypercalciuria or nephrocalcionosis.