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Thomas O. Carpenter, Take Another CYP: Confirming a Novel Mechanism for “Idiopathic” Hypercalcemia, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 3, 1 March 2012, Pages 768–771, https://doi.org/10.1210/jc.2012-1110
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Three recent studies have described a novel mechanism of hypercalcemia related to the effects of vitamin D on calcium homeostasis. These studies collectively confirm that loss of function of the vitamin D 24-hydroxylase enzyme may result in significant clinical hypercalcemia. The initial studies of this disorder, by Schlingmann et al. (1) and Dauber et al. (2), identify homozygous loss-of-function mutations in CYP24A1, the gene encoding the 24-hydroxylase, in the setting of otherwise unexplained infantile hypercalcemia. The report by Schlingmann et al. (1) identified several loss-of-function mutations in eight hypercalcemic infants who were investigated at 6–8 months of age. Their data are most consistent with recessive transmission of the syndrome. Transfection experiments document impaired in vitro 24-hydroxylase activity using constructs of six mutations identified clinically; clinical evidence of impaired enzyme activity was not reported. The Dauber et al. (2) study identified a hypercalcemic infant with a homozygous loss-of-function mutation identical to one of the mutations observed in a compound heterozygote presented by the Schlingmann group (1) and provided strong in vivo evidence relating this mutation to disease. The 10-month-old proband had low circulating 24,25-dihydroxyvitamin D [24,25(OH)2D] levels compared with age-matched normal children and markedly elevated fractional intestinal absorption of calcium (∼90% vs. ∼45% in age-matched controls). The absence of a coding region mutation in 27 other hypercalcemic infants examined by the Dauber team would suggest that loss of function of CYP24A1 is probably an uncommon cause of this syndrome. In the current issue of the JCEM, Tebben et al. (3) extend these observations, reporting a similar syndrome in adults with presumed loss-of-function mutations in the same enzyme. Several interesting features in the current report differ from the pediatric studies. First, the severity of the hypercalcemia in the infants decreased or corrected with age. Secondly, the Tebben et al. (3) study reports an overt clinical phenotype in the heterozygous state. Of interest, the possibility of a partial or mild phenotype in heterozygotes is raised by the maternal history of nephrolithiasis in the Dauber et al. (2) report, and the identification of a (deletion) abnormality of only one allele in a proband is reported by Schlingmann et al. (1). Finally, the current report describes a clinical response to therapy with the cytochrome inhibitor, ketoconazole, an agent also used in a report of 20 infants with idiopathic hypercalcemia by Nguyen et al. (4). Decreased enzymatic function of the 24-hydroxylase was identified in skin fibroblasts from one of the patients in the Nguyen et al. (4) study.
