The calciferols were the first class of hormonally active steroids to be discovered and also the first for which subjects with hormone resistance could be identified. With recognition that vitamin D is the precursor for 1,25-dihydroxyvitamin D, it has become possible to characterize defects in the activation (1-hydroxylation) of vitamin D and defects in the target action of activated (1,25-dihydroxy)vitamin D. We have demonstrated a broad spectrum of manifestations of hereditary resistance to 1,25(OH)2D ranging from infantile rickets with alopecia and no intestinal response to calciferols to adult onset osteomalacia with satisfactory intestinal response to high doses of calciferols and with no epidermal abnormalities. A similar disorder has been recognized in new world monkeys. Cases with total lack of responses to calciferols have been treated with extroadinary doses of calcium administered intravenously. Cultured skin fibroblasts display many components of the 1,25(OH)2D effector system. Skin fibroblasts from all subjects with hereditary resistance to 1,25(OH)2D display abnormalities in this effector system, and defects in many discrete steps of this pathway have been identified with these cells. Other cells, such as bone cells, lymphocytes, and parathyroid cells can also be used to evalute actions of 1,25(OH)2D in vitro.
