Rickets vitamin D-resistant

There tire a number of rachitic syndromes that do not respond to normal amounts of vitamin D  

Tumor-induced osteomedacia (oncogenic hypophosphatemic osteomalacia) is tdso chtuacterized by excessive urintiry excretion of phosphate, tmd hence hypophosphatemia emd low circulating ctdcitriol. Removed of the tumor results in normalization of phosphate excretion and 

Type I vitamin D-resistant rickets is due to a genetic defect in calcidiol 1 -hydroxylase, so that little or no calcitriol is formed. Patients respond well to the administration of la-hydroxycholectilciferol, which is a substrate for 25-hydroxylation in the liver, leading to normtil circulating concentrations of calcitriol. 

Type II vitamin D-resistant rickets is chtu acterized hy a lack of responsiveness of target tissues to calcitriol and is caused hy a genetic defect in the calcitriol receptor. Affected children develop more or less normally until about 9 months of age, then develop severe rickets with tilopecia and a wide variety of disorders, including immune system dysfunction. Three variants are known  

Strontium intoxication can cause vitamin D-resistant rickets because strontium is a potent inhibitor of calcidiol 1-hydroxylase (Omdahl and DeLuca, 1971). 

Renal failure is associated with an osteomalacia-like syndrome, renal osteodystrophy, as a result of the loss of calcidiol 1-hydroxylase activity. The condition may be complicated by defective reabsorption of calcium and phosphate from the urine. Furthermore, the half-life of parathyroid hormone is increased, because the principal site of its catabolism is the kidney, so there is increased parathyroid hormone-stimulated osteoclastic action without the compensatory action of calcitriol (Mawer etal., 1973). 

Hypoparathyroidism is also associated with a failure of calcidiol 1-hydroxylation, in this case because the major stimulus for induction of 1-hydroxylase is parathyroid hormone. 

X-linked hypophosphatemic rickets is caused by abnormal reabsorption of phosphate in the proximal renal tubule, resulting in excessive excretion of phosphate and hence hypophosphatemia. There may also be blunting of the normal increase in calcidiol 1 -hydroxylase activity in response to hypophosphatemia. The gene responsible for the condition has been identified (the PHEX gene) its product is a membrane-bound endopeptidase that normally acts to clear the hormone phosphatonin from the circulation. Phosphatonin acts to decrease the activity of the sodium/phosphate cotransporter in the kidney (Drezner, 2000). 

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Phosphorus Disorders. Phosphoms nutrient deficiency can lead to rickets, osteomalacia, and osteoporosis, whereas an excess can produce hypocalcemia. Faulty utilisation of phosphoms results in rickets, osteomalacia, osteoporosis, and Paget s disease, and renal or vitamin D-resistant rickets. 

Chronic renal disease Hypophosphatemic vitamin D-resistant rickets Vitamin D-dependent rickets... 

Malloy PJ, Eccleshall TR, Gross C, Van Maldergem L, Bouillon R, Feldman D. Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest 1997 99[2] 297-304. 

I. A 25-year-olcl female suspected of having vitamin D-resistant rickets has decreased blood phosphate levels. Aside from high-dose vitamin D and oral phosphate, an alternative therapeutic approach might be the use of which of the following ... 

Most convincing with respect to variable needs, however, are well authenticated cases of "vitamin D-resistant rickets" which respond only when enormous doses of vitamin D, sometimes up to 100,000, 500,000 or even 1,500,000 units, are administered.39,40 Lower levels, which are wholly adequate even for mildly susceptible children, are without any beneficial effect on highly resistant cases so far as calcium and phosphorus retention is concerned. When extremely high levels are used, toxicity is liable to develop.40... 

On the basis of the concepts which we have developed, it appears most probable that, for various and diverse structural and biochemical reasons, the needs for vitamin D vary greatly from individual to individual. Children who are nonsusceptible to rickets require small amounts susceptible children require many times more children afflicted with vitamin D-resistant rickets require for a time, at least, extremely high doses. There are probably no sharp dividing lines between normals, susceptible individuals, and cases of vitamin D-resistant rickets. The susceptible individuals may make up an appreciable percentage of the population, for Park has found in postmortems on 230 children that about 46.5 per cent of children between 2 and 14 years have histological signs of rickets.41... 

Genetic defldency of the la-hydroxylase (vitamin D-resistant rickets)... 

Vitamin D-resistant rickets PO 250-1,500 meg/day (with phosphate supplements). Osteoporosis prevention PO 400-600 units/day. Maximum 2,000 units/day. 

It is indicated in osteoporosis, hypoparathyroidism, hyperparathyroidism (with bone disease), renal osteodystrophy, nutritional and malabsorptive rickets, hypophosphataemic vitamin D resistant rickets and osteomalacia. 

A human Na+/ P cotransporter in the kidney is also essential. An X-linked trait leading to inadequate synthesis of the transporter causes hypophosphatemic vitamin D-resistant rickets 499... 

Vitamin D resistant rickets associated with mutant Vitamin D receptor 14... 

Vitamin D 1,25 Dihydroxyvitamin Vitamin D-resistant rickets in A variety of mutations, mainly in the DNA-... 

Calcidiol la-hydroxylase is not restricted to the kidney, but is also found in placenta, bone cells (in culture), mammary glands, and keratinocytes. The placental enzyme makes a significant contribution to fetal calcitriol, but it is not clear whether the calcidiol 1-hydroxylase activity of other tissues is physiologically significant or not. Acutely nephrectomized animals given a single dose of calcidiol do not form any detectable calcitriol, but there is some formation of calcitriol in anephric patients, which increases on the administration of cholecalciferol or calcidiol. However, thus extrarenal synthesis is not adequate to meet requirements, so that osteomalacia develops in renal failure (Section 3.4.1). The enzyme is inhibited, or possibly repressed, by strontium ions this is the basis of strontium-induced vitamin D-resistant rickets, which responds to the administration of calcitriol or la-hydroxycalciol, but not calciferol or calcidiol (Omdahl and DeLuca, 1971). 

Type II vitamin D-resistant rickets (Section 3.4.2) is associated with target tissue resistance to calcitriol. Most cases are from either a lack of calcitriol receptors or impaired binding of calcitriol to the receptor. Thus, higher than normal concentrations of calcitriol are required to saturate the receptor. Some affected families show normal binding of calcitriol to the receptor, with an apparent defect in the DNA binding domain (Griffin and Zerwekh, 1983). 

Hair follicles also have calcitriol receptors and type 11 vitamin D-resistant rickets (Section 3.4.2), which is caused hy lack of calcitriol receptor function, is associated with total alopecia, suggesting that calcitriol has a role in their development. 

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