Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure.
BACKGROUND
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.


METHODS
We describe two adult patients with homozygous mutations and six related heterozygous carriers. Mineral and hormonal data in these patients were compared with that in 27 patients with stage 2-3 chronic kidney disease and 39 healthy adult kidney donors.


RESULTS
Probands had recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four). Corticosteroids did not reduce plasma and urine calcium levels, but ketoconazole did, indicating that 1,25(OH)(2)D production is not maximally depressed despite coexisting hypercalcaemia, high 1,25(OH)(2)D and depressed PTH, and that 1,25(OH)(2)D degradation through vitamin D-24 hydroxylase is a regulator of plasma 1,25(OH)(2)D levels. Both probands had vascular calcifications and high bone mineral content. One developed stage 3b renal failure: in this patient 1,25(OH)(2)D decreased within normal limits as glomerular filtration rate (GFR) fell and PTH rose to high-normal values, yet hypercalcaemia persisted and the ratio of 1,25(OH)(2)D to GFR remained higher than normal for any degree of GFR.


CONCLUSIONS
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)(2)D and GFR is instrumental for the maintenance of physiologic calcium levels and balance in chronic kidney diseases.
Division of Nephrology, Dialysis and Renal Transplantation, A.O. Ospedale Niguarda-Ca' Granda, Milan, Italy.
Giacomo
G
Colussi
Liat
L
Ganon
Silvana
S
Penco
Maria Elisabetta
ME
De Ferrari
Federica
F
Ravera
Marialuisa
M
Querques
Paola
P
Primignani
Eli J
EJ
Holtzman
Dganit
D
Dinour
D016022:Case-Control Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D006934:Hypercalcemia / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics*
D010281:Parathyroid Hormone; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
CYP24A1; hypercalcaemia; hypercalciuria; nephrocalcinosis; nephrolithiasis; vitamin D-24 hydroxylase