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  1. Normal calciferol physiology includes activation through 25-hydroxylation in the liver and 1α-hydroxylation in the renal proximal tubule; the most active metabolite is 1α,25-dihydroxyvitamin D [1α,25(OH)2D], which acts on target tissues by a mechanism analogous to that of the true steroid hormones. Two distinct hereditary defects have been recognized: (1) selective deficiency (which implies normal concentrations of the immediate precursor) and simple deficiency (which implies that other metabolic pathways are not abnormal) of 1α,25(OH)2D, and (2) generalized resistance (which means that all target tissues are affected) to 1α,25(OH)2D. Hereditary defects in calciferol metabolism or action show all the features of the calciferol deficiency states beginning early in life. These features are intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia results in impaired mineralization of bone (rickets and osteomalacia).

  2. Hereditary selective and simple deficiency of 1α,25(OH)2D is an autosomal recessive trait (MIM 264700). Patients respond to any doses of calciferol analogues that maintain normal circulating bioactivity of equivalents of 1α,25 (OH)2D. The cellular basis is a deficiency of the renal 25-hydroxyvitamin D [25(OH)D] 1α-hydroxylase.

  3. Hereditary selective deficiency of 1α,25(OH)2D also can occur as part of complex disorders that affect additional metabolic pathways not related to calciferols. Examples include X-linked hypophosphatemia, pseudohypoparathyroidism, and some forms of Fanconi syndrome.

  4. Hereditary generalized resistance to 1α,25(OH)2D is an autosomal recessive trait (MIM 277440). The cellular basis is an abnormality in the vitamin D receptor. Point mutations in the vitamin D receptor gene have been implicated in almost every kindred studied and, depending on its location, will affect DNA binding, hormone binding, heterdimerization with the retinoid X receptors, or all of the above. The type of defect is not correlated with the clinical features, and it seems likely that each defect could produce varying severity of clinical dysfunction. Approximately half of patients show alopecia; these are usually the more severely affected patients. Depending on the severity of the defect, patients may respond to treatment with (1) calciferol analogues that allow for endogenous regulation of 1α,25(OH)2D production, (2) calcium plus high doses of calciferol analogues that bypass 25(OH)D 1α-hydroxylase, or (3) extremely high doses of calcium orally or intravenously (for patients unresponsive to maximal doses of all calciferols).

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