Session: OR45-What Is New in Vitamin D?
Room 29 (San Diego Convention Center)
Objective : 1) Evaluation of the frequency of CYP24A1 mutation in a cohort of patients; 2) Evaluation of the clinical utility of simultaneous assay of multiple vitamin D metabolites by liquid chromatography tandem mass spectrometry (LC-MS/MS); 3) Investigation of patients harboring CYP24A1 mutation in a heterozygous state to better understand the role of CYP24A1 haploinsufficiency in the occurrence of hypercalcemia.
Patients and Methods: We studied 72 index cases (38 males (53%) and 34 females (47%)), presenting with hypercalcemia (>2.6 mmol/L) and low PTH levels (<20 pg/mL). We also included 22 relatives. Biochemical data and CYP24A1 sequencing were obtained with routine methods. Serum 25-hydroxyvitamin D3 (25-OH-D3) and 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) were assessed by LC-MS/MS using 100 µL of serum (1); results were expressed as a ratio (R) of 25-OH-D3:24,25-(OH)2D3. Values under 25 were considered as normal.
Results: We identified 25 patients (35%) harboring mutations in the coding sequence of CYP24A1. Twenty patients (28%) have bi-allelic mutations that were found more frequently in patients with renal disease (67%) (nephrocalcinosis or renal stones) than in patients without renal symptoms (23%). Patients with bi-allelic CYP24A1 mutations have very low 24,25-(OH)2 D3 levels and exhibit a dramatic increase in R (mean [range] :105 [48.8-173.4] n = 7) providing evidence “in vivo” for the loss of 24-hydroxylase activity. We found 5 patients (7%), all neonates, harboring CYP24A1 mutations in a heterozygous state raising the question of a dominant trait. In contrast with children harboring bi-allelic mutations, none presented with renal pathology. Probands (n=3) as well as relatives (n=14) harboring heterozygous mutations, have measurable amounts of 24,25-(OH)2D3 and R below 25, suggesting functional CYP24A1 activity. Last, probands without CYP24A1 mutations have measurable amounts of 24,25-(OH)2D3 and normal R.
Conclusion: CYP24A1 mutation are frequently found in patients presenting hypercalcemia with low or suppressed PTH especially in patients with nephrocalcinosis or renal stones. We confirm the accuracy and effectiveness of a novel blood test estimating the ratio between relevant vitamin D metabolites 25-OH-D3 and 24,25-(OH)2D3 as a useful screening tool for CYP24A1 mutation. Even so most of heterozygous patients with CYP24A1 mutation remain asymptomatic, this study leads to recommend preventive measures including restriction of vitamin D supplementation that could protect affected relatives particularly during the neonatal period.
Nothing to Disclose: MLK, AM, MK, AT, GJ
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