Abstract
Vitamin D–mediated hypercalcemia may be due to benign or malignant conditions. Recently, loss-of-function mutations in the gene CYP24A1, which encodes 25-hydroxyvitamin D3-24-hydroxylase, have been described which result in reduced degradation of the active 1,25-(OH)2 D3, causing hypercalcemia and hypercalciuria. We describe four patients in whom we identified a novel CYP24A1 homozygous germline mutation (NM_000782.4: c.323A>G; p.(His108Arg). Three of the four patients had a long history of recurrent renal stones. One patient had nephrocalcinosis with significant renal impairment. The other three patients had intermittent hypercalcemia, which in two female patients predominantly occurred during pregnancy with severe gestational hypercalcemia. Germline CYP24A1 mutations are a rare but important cause of vitamin D–mediated hypercalcemia and demonstrate a core phenotype of renal stones, hypercalciuria, and PTH-independent hypercalcemia. However, even in the setting of a homozygous CYP24A1 germline mutation, hypercalcemia may be intermittent with a normal PTH level during the periods of normocalcemia resulting in the need for a high degree of clinical suspicion. Measurement of vitamin D metabolites, in particular the 25-(OH)D3/24,25-(OH)2D3 ratio which is elevated in patients with homozygous CYP24A1 germline mutations, may help provide a clue as to the underlying diagnosis. In women with a history of recurrent calcium-containing renal stones or nephrocalcinosis, we would recommend measurement of serum calcium levels prior to conception and each trimester due to the potential for severe adverse effects on mother and baby if an unidentified CYP24A1 mutation is present.
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MSE—conception and design of the project, arranging testing and interpretation of results, drafting the manuscript and critical revision, and approval of the final version.
SDT—acquisition of data (biochemistry) and interpretation, revising the manuscript for critically important intellectual content, and final approval of the version to be published.
SA—acquisition of data (genetics) and interpretation, revising the manuscript for critically important intellectual content, and final approval of the version to be published.
JS—acquisition of data (genetics) and interpretation, revising the manuscript for critically important intellectual content, and final approval of the version to be published.
JVC—conception and design of the project, revising the manuscript for critically important intellectual content, and final approval of the version to be published.
JAUT—testing and interpretation of results, revising the manuscript for critically important intellectual content, and final approval of the version to be published.
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The local institutional review board (Waikato District Health Board) granted permission for the study. Written, informed consent was obtained from all patients for investigation and publication. Ethics approval for gene sequencing was given by the Newcastle and North Tyneside Research Ethics Committee, UK 2003/163.
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Elston, M.S., Du Toit, S., Alkanderi, S. et al. Variable Phenotypes Seen with a Homozygous CYP24A1 Mutation: Case Report. SN Compr. Clin. Med. 2, 995–1002 (2020). https://doi.org/10.1007/s42399-020-00351-8
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DOI: https://doi.org/10.1007/s42399-020-00351-8