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Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect

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Abstract

Summary

Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations.

Introduction

The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het.

Methods

Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects’ medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed.

Results

The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations.

Conclusions

In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.

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Fig. 1

Abbreviations

25-Hydroxyvitamin D:

25(OH)D

1,25-Dihydroxyvitamin D:

1,25(OH)2D

24,25-Dihydroxyvitamin D:

24,25(OH)2D

ACE:

Angiotensin-converting enzyme

B-CTx:

Carboxyterminal cross-linking telopeptide of bone collagen

PCR:

Polymerase chain reaction

PTH:

Parathyroid hormone

TSH:

Thyroid stimulating hormone

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Acknowledgments

Study design: DOK, RW, and PT. Study conduct: DOK; data collection: DOK; data analysis: DOK, RW, PT, and RK; data interpretation: DOK, RW, PT, RK, RS, and YW; drafting manuscript: DOK, RW, and PT; revising manuscript content: RK, RS, and YW; approving final version of manuscript: DOK, PT, and RW. DOK takes responsibility for the integrity of the data analysis.

Author information

Authors and Affiliations

  1. Division of Endocrinology, Diabetes, Metabolism and Nutrition/Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    D. T. O’Keeffe, P. J. Tebben, R. Kumar & R. A. Wermers

  2. Division of Pediatric Endocrinology/Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    P. J. Tebben

  3. Division of Nephrology and Hypertension/Department of Medicine and Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    R. Kumar

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    R. J. Singh & Y. Wu

Authors
  1. D. T. O’Keeffe
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  2. P. J. Tebben
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  3. R. Kumar
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  4. R. J. Singh
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  5. Y. Wu
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  6. R. A. Wermers
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Corresponding author

Correspondence to R. A. Wermers.

Ethics declarations

This study was made possible using the resources of CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Science (NCATS).

Conflicts of interest

Derek O’Keeffe, Peter Tebben, Rajiv Kumar, Ravinder Singh, Yanhong Wu, and Robert Wermers state that they have no conflicts of interest.

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O’Keeffe, D.T., Tebben, P.J., Kumar, R. et al. Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect. Osteoporos Int 27, 3121–3125 (2016). https://doi.org/10.1007/s00198-016-3615-6

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  • DOI: https://doi.org/10.1007/s00198-016-3615-6

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