Hormone-nuclear receptor interactions in health and disease. Vitamin D resistance.

Tissue resistance to vitamin D, or vitamin D-dependent rickets (VDDR), can be classified as two separate conditions--VDDR type I and VDDR type II--both of which present with the classical clinical, radiological and biochemical features of rickets despite adequate vitamin D intake. VDDR II can also be associated with alopecia, for reasons that are not clear. The two syndromes result from distinct disorders of vitamin D metabolism or action. Both are inherited in an autosomal recessive fashion. VDDR I is caused by decreased production of the active form of vitamin D, 1,25-dihydroxycholecalciferol, with the proposed defect being in the gene encoding the enzyme 1 alpha-hydroxylase. VDDR II results from mutations in the gene for the intracellular receptor for 1,25-dihydroxycholecalciferol (vitamin D receptor), resulting in changes in hormone or DNA binding, depending on the mutation. These mutations are analogous to those affecting receptors for other steroid-thyroid hormones, which have also been shown to cause resistance to hormone action.

Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D.

Studies were done to determine the cause for hypocalcemia, secondary hyperparathyroidism, osteomalacia and osteitis fibrosa cystica in a 22-year-old black woman. The patient had normal serum 25-hydroxyvitamin D (14 ng per milliliter) and markedly elevated serum 1,25-dihydroxyvitamin D (137 pg per milliliter). Vitamin D3, 4000 units per day for four weeks, increased the serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to as high as 29 and 297 pg per milliliter, respectively, and corrected the hypocalcemia and secondary hyperparathyroidism. The results suggest that the disorder results from impaired end-organ response to 1,25-dihydroxyvitamin D. We propose that the entity be called vitamin-D-dependent rickets Type II.