Calcitriol-resistant rickets due to vitamin D receptor defects

Calcitriol-resistant rickets (CRR) is an autosomal recessive disease due to a defect in the vitamin D receptor (VDR) or a site distal to it. The main characteristics are extreme rickets, with growth attenuation, osteomalacia, secondary hyperparathyroidism, severe dental caries, and alopecia. Serum studies reveal hypocalcemia, hypophosphatemia, very high calcitriol, and increased alkaline phosphatase levels. The clinical and chemical abnormalities do not respond to therapy with high-dose vitamin D, indicating target organ unresponsiveness. Eleven different mutations in the gene-encoding VDR have thus far been reported. They affect either the C-terminal ligand-binding region or the N-terminal DNA binding zinc-fingers sequences, with mutation hot spots identified at conserved sequences among the steroid-thyroid receptors superfamily. These result in impaired calcitriol binding to target organs, signified in vitro as failure of fibroblasts to bind [(3)H]calcitriol or to respond to calcitriol by 24-hydroxylase activity enhancement. Receptor studies and mutational analyses are used for prenatal diagnosis of CRR. Therapy with high-dose calcium overcomes the VDR defect, normalizes serum calcium, and maintains bone remodeling and mineral apposition. These responses to therapy have interesting implications upon our understanding of the potential role of calcium alone and that of vitamin D in bone physiology. Like other hormone-resistant diseases, CRR, with its various mutations, provides the opportunity for investigating the nature of vitamin D and of VDR physiology, which has been only partially explored to date.