Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?

J Bone Miner Res. 2017 Sep;32(9):1893-1899. doi: 10.1002/jbmr.3181. Epub 2017 Jul 13.


Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH)2 D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)2 D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D3 or alfacalcidol (1α-OH-D3 ) treatment, and we observed a dramatic increase in the 1,25-(OH)2 D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D3 ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research.


Publication types

  • Case Reports

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / deficiency
  • Adult
  • Child
  • Child, Preschool
  • Cholestanetriol 26-Monooxygenase / deficiency*
  • Cytochrome P450 Family 2 / deficiency*
  • Diagnostic Errors*
  • Ergocalciferols / administration & dosage*
  • Female
  • Humans
  • Male
  • Mutation*
  • Rickets* / diagnosis
  • Rickets* / drug therapy
  • Rickets* / enzymology
  • Rickets* / genetics
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood


  • Ergocalciferols
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • Cytochrome P450 Family 2
  • CYP2R1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • CYP27B1 protein, human