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Defect in the vitamin D receptor results in hypocalcemia, tetanic seizures, and rickets.

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Rickets-Alopecia Syndrome; Hypocalcemic Vitamin D-Resistant Rickets; Pseudo-Vitamin D Deficiency Type II.

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Fewer than 50 kindreds are known.

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Autosomal recessive transmission, with parental consanguinity as a risk factor. It seems to be more common in people of Mediterranean origin. The defect has been mapped to 12q12-q14.

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Vitamin D is well known to have biologic effects that extend far beyond the control of mineral metabolism. This is supported by the fact that vitamin D receptors are present in a wide variety of cells and can be induced by increased cell proliferation, the ontogenetic state, or exposure to calcitriol. The name vitamin D refers to a group of steroid molecules whose intake is possible in two forms: as vitamin D2 (ergocalciferol), which is derived from plants, and as vitamin D3 (cholecalciferol), which is produced in humans (skin) and animals. However, neither vitamin D2 nor D3 has significant biologic activity. Therefore, a two-step activation in the body is necessary. The first step takes place in the liver and results in hydroxylation of cholecalciferol, resulting in 25-hydroxycholecalciferol (or calcidiol). Passing through the enterohepatic circulation, this molecule is reabsorbed and then transported to the kidneys, where further hydroxylation results in 1,25-dihydroxycholecalciferol (calcitriol), which is the biologically active form of vitamin D. Although hydroxylation in the liver is not under very tight control, control of the enzyme 1-α-hydroxylase in the kidney (responsible for the hydroxylation on carbon molecule 1 of cholecalciferol) is regulated within very narrow limits and represents the key control point in the production of the active vitamin D3. The main activator of 1-α-hydroxylase is parathormone, which stimulates the enzyme in the proximal tubules of the kidney. Calcitonin also results in an activation of 1-α-hydroxylase, but further distally in the proximal tubule. Inhibitors of 1-α-hydroxylase are calcium, phosphate, and calcitriol. The main function of activated vitamin D is to increase calcium serum concentration. This is achieved in three ways:

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  • 1. Increased intestinal absorption of dietary vitamin D3 and calcium by activation of a specific calcium-binding protein (calbindin, cholecalcin, or vitamin D-dependent calcium-binding protein) in the duodenal mucosa
  • 2. Increased release of calcium from the bone into the bloodstream by (indirect) activation of osteoclasts
  • 3. Increased renal reabsorption of calcium Steps 2 and 3 require the simultaneous action of parathormone.

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The specific physiologic effects of calcitriol are mediated by the vitamin D receptor (VDR), a 50-kDa phosphoprotein member of the steroid/thyroid/retinoid receptor gene superfamily of transcription factors that regulates gene expression. Calcitriol enters the target-cell nucleus to form a complex with the VDR. This complex further combines with the so-called retinoic acid X receptor, forming a heterodimer. This heterodimer then regulates the biosynthesis of vitamin D-dependent calcium transport proteins in the small bowel and in osteoblasts. Mutations in the ...

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