Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study

Bone. 2015 Dec:81:89-96. doi: 10.1016/j.bone.2015.06.018. Epub 2015 Jun 25.


Background: Bi-allelic CYP24A1 mutations can cause idiopathic infantile hypercalcemia (IIH), adult-onset nephrocalcinosis, and possibly bone metabolism disturbances. It is currently unclear if heterozygous carriers experience clinical problems or biochemical abnormalities. Our objective is to gain insight in the biochemical profile and health problems in CYP24A1 heterozygotes.

Study design: Cross-sectional evaluation of participants. Data of previously reported carriers are reviewed.

Setting and participants: Outpatient clinic of a tertiary care hospital. Participants were eight family members of an infant with a well-characterized homozygous CYP24A1 mutation c.1186C>T p.(Arg396Trp).

Outcomes: Serum vitamin D metabolites. Symptoms or biochemical signs of hypercalcemia, hypercalciuria or nephrocalcinosis. Bone health in heterozygous as compared to wild type (WT) subjects.

Measurements: Genotyping by Sanger sequencing; vitamin D metabolites by liquid chromatography tandem mass spectrometry; renal, calcium and bone markers by biochemical analyses; presence of nephrocalcinosis by renal ultrasound; bone health by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography.

Results: Six participants were heterozygous carriers of the mutation. None of the heterozygous subjects had experienced IIH. One had a documented history of nephrolithiasis, two others had complaints compatible with this diagnosis. No major differences between WT and heterozygous subjects were found regarding bone health, serum or urinary calcium or 25OHD/24,25(OH)2D ratio. Literature reports on three out of 33 heterozygous cases suffering from IIH. In all three, the 25OHD/24,25(OH)2D ratio was highly elevated. Nephrocalcinosis was frequently reported in family members of IIH cases.

Limitations: Small sample size, lack of a large control group.

Conclusions: Our and literature data suggest that most heterozygous CYP24A1 mutation carriers have a normal 25OHD/24,25(OH)2D ratio, are usually asymptomatic and have a normal skeletal status but may possibly be at increased risk of nephrocalcinosis. A review of the available literature suggests that an elevated 25OHD/24,25(OH)2D ratio may be associated with symptoms of IHH, irrespective of carrier status.

Keywords: CYP24A1; Heterozygous; Idiopathic infantile hypercalcemia; Mutation; Nephrocalcinosis; Nephrolithiasis.

MeSH terms

  • Absorptiometry, Photon
  • Bone and Bones / metabolism*
  • Calcium / metabolism*
  • Chromatography, Liquid
  • Cross-Sectional Studies
  • Dihydroxycholecalciferols / blood
  • Female
  • Genotype
  • Heterozygote*
  • Homeostasis* / genetics
  • Humans
  • Hypercalcemia / epidemiology
  • Hypercalcemia / genetics
  • Hypercalciuria / epidemiology
  • Hypercalciuria / genetics
  • Incidence
  • Male
  • Mutation
  • Nephrocalcinosis / epidemiology
  • Nephrocalcinosis / genetics
  • Nephrolithiasis / epidemiology
  • Nephrolithiasis / genetics
  • Pedigree
  • Tandem Mass Spectrometry
  • Vitamin D3 24-Hydroxylase / genetics*


  • Dihydroxycholecalciferols
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase
  • Calcium