1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis

Clin J Am Soc Nephrol. 2013 Apr;8(4):649-57. doi: 10.2215/CJN.05360512. Epub 2013 Jan 4.


Background and objectives: Elevated serum vitamin D with hypercalciuria can result in nephrocalcinosis and nephrolithiasis. This study evaluated the cause of excess 1,25-dihydroxycholecalciferol (1α,25(OH)2D3) in the development of those disorders in two individuals.

Design, setting, participants, & measurements: Two patients with elevated vitamin D levels and nephrocalcinosis or nephrolithiasis were investigated at the National Institutes of Health (NIH) Clinical Center and the NIH Undiagnosed Diseases Program, by measuring calcium, phosphate, and vitamin D metabolites, and by performing CYP24A1 mutation analysis.

Results: Both patients exhibited hypercalciuria, hypercalcemia, low parathyroid hormone, elevated vitamin D (1α,25(OH)2D3), normal 25-OHD3, decreased 24,25(OH)2D, and undetectable activity of 1,25(OH)2D-24-hydroxylase (CYP24A1), the enzyme that inactivates 1α,25(OH)2D3. Both patients had bi-allelic mutations in CYP24A1 leading to loss of function of this enzyme. On the basis of dbSNP data, the frequency of predicted deleterious bi-allelic CYP24A1 variants in the general population is estimated to be as high as 4%-20%.

Conclusions: The results of this study show that 1,25(OH)2D-24-hydroxylase deficiency due to bi-allelic mutations in CYP24A1 causes elevated serum vitamin D, hypercalciuria, nephrocalcinosis, and renal stones.

Publication types

  • Case Reports
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Calcium / blood
  • Child
  • Family Health
  • Female
  • Humans
  • Hypercalciuria / etiology
  • Hypercalciuria / genetics
  • Hypercalciuria / metabolism
  • Male
  • Nephrocalcinosis / etiology
  • Nephrocalcinosis / genetics*
  • Nephrocalcinosis / metabolism
  • Nephrolithiasis / etiology
  • Nephrolithiasis / genetics*
  • Nephrolithiasis / metabolism
  • Pedigree
  • Phosphates / blood
  • Primary Cell Culture
  • Steroid Hydroxylases / deficiency
  • Steroid Hydroxylases / genetics*
  • Vitamin D / blood
  • Vitamin D3 24-Hydroxylase


  • Phosphates
  • Vitamin D
  • Steroid Hydroxylases
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase
  • Calcium