Loss-of-function mutations of vitamin D-24 hydroxylase have recently been recognized as a cause of hypercalcaemia and nephrocalcinosis/nephrolithiasis in infants and adults. True prevalence and natural history of this condition are still to be defined. … Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)2D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25 (OH)2D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)2D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)2D and depressed PTH, and that 1,25(OH)2D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)2D levels. …. This natural model indicates that vitamin D-24 hydroxylase is a key physiologic regulator of calcitriol and plasma calcium levels, and that balanced reduction of 1,25 (OH)2D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.
