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Variable Phenotypes Seen with a Homozygous CYP24A1 Mutation: Case Report

Lookup NU author(s): Sumaya Alkanderi, Professor John SayerORCiD

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Abstract

© 2020, Springer Nature Switzerland AG.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.

Publication metadata

Author(s): Elston MS, Du Toit S, Alkanderi S, Sayer JA, Conaglen JV, Tamatea JAU

Publication type: Article

Publication status: Published

Journal: SN Comprehensive Clinical Medicine

Year: 2020

Volume: 2

Pages: 995-1002

Print publication date: 01/07/2020

Online publication date: 19/06/2020

Acceptance date: 08/06/2020

ISSN (electronic): 2523-8973

Publisher: Springer

URL: https://doi.org/10.1007/s42399-020-00351-8

DOI: 10.1007/s42399-020-00351-8

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