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Biallelic CYP24A1 variants presenting during pregnancy: Clinical and biochemical phenotypes

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



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


© 2020 the authors.Introduction: Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants. Methods: The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine. Results: The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2 D ratios (>50) during follow-up. Conclusions: W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

Publication metadata

Author(s): Griffin TP, Joyce CM, Alkanderi S, Blake LM, O'Keeffe DT, Bogdanet D, Islam MN, Dennedy MC, Gillan JE, Morrison JJ, O'Brien T, Sayer JA, Bell M, O'Shea PM

Publication type: Article

Publication status: Published

Journal: Endocrine Connections

Year: 2020

Volume: 9

Issue: 6

Pages: 530-541

Print publication date: 01/06/2020

Online publication date: 06/05/2020

Acceptance date: 06/05/2020

Date deposited: 02/07/2020

ISSN (electronic): 2049-3614

Publisher: BioScientifica Ltd.


DOI: 10.1530/EC-20-0150


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Funder referenceFunder name
J A S is supported by Kidney Research UK and the Northern Counties Kidney Research Fund.