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PubMed1986

Hereditary resistance to 1,25-dihydroxyvitamin D: clinical and radiological improvement during high-dose oral calcium therapy.

A 6-year-old boy, of consanguinous parents, presented with severe rickets and alopecia; he was found to have hypocalcaemia and elevated circulating 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels. He showed no calcaemic response to 1,25-(OH)2D3 or ergocalciferol given for 3 or more months in daily doses as high as 48 micrograms and 6 X 10(6) IU, respectively. Analyses with cultured skin fibroblasts revealed a normal capacity and affinity for 1,25-(OH)2D3 in soluble extracts ('cytosol') and in nuclei of intact cells but no detectable response of 25-(OH)D3 24-hydroxylase to 1,25-(OH)2D3 in high concentration. Treatment with high doses of calcium (3-4 g elemental calcium orally per day) produced a striking clinical and radiological improvement. We conclude that high oral doses of calcium can replace many of the actions of calciferols. Therapy with high doses of calcium should be tried in similarly affected cases that appear totally or partially unresponsive to calciferols.

Calcitriol↗
PubMed1985

Renal magnesium and phosphate wastage in a patient with hypercalciuria and nephrocalcinosis: effect of oral phosphorus and magnesium supplements.

We report a 29-year-old man with a mild decrease in glomerular filtration, nephrocalcinosis, hypercalciuria and a renal magnesium leak. He had other features of 'congenital magnesium-losing kidney', such as arthritis and hyperuricemia, short stature and recurrent urinary tract infections, but had no radiological chondrocalcinosis. In addition, pallidal calcification was found. The patient also had a renal phosphate leak. Phosphorus supplements resulted in a decrease in urinary calcium excretion, indicating that hypercalciuria was at least partially a consequence of phosphorus depletion. Plasma and urine magnesium were not affected by phosphorus supplements. Addition of magnesium supplements resulted in a transient and modest decrease in urinary calcium excretion, with no modification in plasma magnesium.

Administration, Oral↗
PubMed1993

Demeclocycline-induced phosphate diabetes in a patient with inappropriate ADH secretion and systemic sarcoidosis.

We report a case of phosphate diabetes in a patient with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with sarcoidosis. Our patient was affected by systemic sarcoidosis and he fits the criteria of Schwartz for the diagnosis of SIADH. He presented with phosphate diabetes which appeared during demeclocycline (DMC) therapy and persisted for about 1 month from the end of DMC. It constitutes the fourth case of phosphate diabetes induced by tetracycline described in the literature and it is the third case of SIADH associated with sarcoidosis.

Demeclocycline↗
PubMed1993

Hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets.

The treatment of X-linked hypophosphatemia (XLH) consists of phosphate and vitamin D3 derivatives. Transient hypercalciuria and hypercalcemia are well-known signs of vitamin D intoxication. Despite urinary calcium excretion control, the danger of nephrocalcinosis in treated patients has been emphasized. It has recently been suggested that hyperoxaluria might be a causative factor of nephrocalcinosis other than calcium in phosphate-treated XLH patients. We measured urinary oxalate and phosphate excretion in 12 patients with the syndrome of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) receiving only oral phosphates and in 5 XLH patients receiving both oral phosphates and vitamin D. No correlation was found between the dosage of phosphate supplements or urinary phosphate excretion and urinary oxalate excretion, in either group of patients. Nephrocalcinosis, presenting as hyperechogenicity of the medullary pyramids, was found in 2 of the 5 XLH patients and only in 2 HHRH patients who had been treated with excessive doses of vitamin D2 and calcium, prior to the true diagnosis being established. We conclude: (1) hyperoxaluria is not a cause of nephrocalcinosis in phosphate-treated patients with hereditary hypophosphatemic rickets; (2) prolonged phosphate treatment alone does not induce nephrocalcinosis in HHRH patients, and (3) we believe that in XLH patients, nephrocalcinosis is essentially due to vitamin D overdosage at some stage, or noncompliance in phosphate intake, leading to repeated undetected hypercalciuric periods.

Adolescent↗
PubMed1994

Extensive linear epidermal nevus associated with hemangiomas of bones and vitamin-D-resistant rickets.

The association of connate, left-sided, extensive epidermal verrucous nevus, multiple isolated bone tumors and vitamin-D-resistant rickets since childhood seen in a 20-year-old male patient corresponded to an epidermal nevus syndrome (ENS). However, other organ involvement occasionally associated with ENS could not be found in this patient, and his intraosseous tumors represented histologically benign hemangiomas. Serum analysis revealed hypophosphatemia (together with phosphaturia), decreased levels of 1,25-dihydroxycholecalciferol and elevated levels of alkaline phosphatase indicating hypophosphatemic osteomalacia. Therefore we suppose that vitamin-D-resistant rickets combined with skeletal tumors represents a peculiar type of osteomalacia caused by unilateral mesenchymomas.

Adult↗
PubMed1980

Vitamin D metabolism in hypophosphatemic vitamin D-resistant rickets.

Plasma levels of 1,25-(OH)2-D were low in children with hypophosphatemic vitamin D-resistant rickets (HVDRR), but increased after very large doses of 1 alpha-OH-D3. These results suggest that the metabolism of 1,25-(OH)2-D is accelerated in HVDRR. In addition, the lower level of plasma 1,25-(OH)2-D in untreated HVDRR was correlated with the lower level of serum phosphate and renal threshold phosphate concentration (TmP/GFR). The administration of 1 alpha-OH-D3 to the patients with HVDRR could enhance the renal threshold phosphate concentration.

Alkaline Phosphatase↗
PubMed1993

Genetic mapping in the Xp11.2 region of a new form of X-linked hypophosphatemic rickets.

Human X-linked dominant hypophosphatemic rickets (HPDR I) is characterized by hypophosphatemia, hyperphosphaturia, abnormal vitamin D metabolism, and rickets/osteomalacia. Two closely linked hypophosphatemic genes, hypophosphatemia (Hyp) and Gyro (Gy), are known on the mouse X chromosome. The Hyp phenotype is the equivalent of the human X-linked hypophosphatemia, while the human equivalent of the Gyro mouse has not been unambiguously identified. We observed an Italian four-generation pedigree with a new form of X-linked recessive hypophosphatemic rickets (XLRH). We demonstrated that HPDR I and XLRH are two different X-linked genes and that XLRH maps in the Xp11.2 region at 0% recombination fraction from the DXS1039 locus. We discuss this new finding in relation to the identification of the human equivalent of the Gyro mouse and to the recent mapping in Xp11.22 of another X-linked recessive renal disorder named Dent disease.

Adult↗
PubMed1972

25-Hydroxycholecalciferol. A comparative study in deficiency rickets and different types of resistant rickets.

The effects of 25-hydroxycholecalciferol were studied in 4 children with deficiency rickets and 22 children with D-resistant rickets, including patients with hereditary hypophosphatemic D-resistant rickets, "pseudo-deficiency" rickets, and rickets secondary to cystinosis or to tyrosinosis. Three protocols were used. (a) 8 days after a single oral dose of 16,000 IU of 25-hydroxycholecalciferol, normalization of all biological parameters was observed in all cases of deficiency rickets. A complete lack of response was observed in the different types of resistant rickets. (b) Under prolonged administration of 2,640 IU/day for 2 months, clinical-biological symptoms and X-ray lesions disappeared, and a catch-up growth pattern was observed in deficiency rickets; no relapse of rickets occurred up to 5 months after therapy was stopped. The same dose had no significant effect in 10 patients with hereditary hypophosphatemic D-resistant rickets. A bone biopsy performed in one case showed the persistence of characteristic lesions. (c) With increasing doses of 25-hydroxycholecalciferol varying from 6,000 to 30,000 IU/day and a follow-up of 6 months up to 2 yr duration, clinical-biological-radiologic recovery and catch-up growht was obtained in all cases of "pseudo-deficiency" rickets. In hypophosphatemic hereditary D-resistant rickets, 5 out of 13 patients' serum concentration of phosphorus reached at least 30 mg/liter, but a catch-up growth pattern was not observed. These results indicate that (a) 25-hydroxycholecalciferol is highly active in deficiency rickets; (b) a defect in the conversion of vitamin D(3) to its active 25-hydroxy metabolite is probably not the metabolic defect in any of the different types of vitamin D-resistant rickets studied.

Administration, Oral↗
PubMed1975

Orthophosphate transport in the erythrocyte of normal subjects and of patients with X-linked hypophosphatemia.

We have examined the mechanism of TCA-soluble orthophosphate (Pi) transfer across the membrane of mature human erythrocytes in normal subjects and in patients with X-linked hypophosphatemia (X-LH). The studies were carried out largely at pH 7.4 and 37 degrees C, in partial stimulation of conditions in vivo. (a) At physiological concentrations (1-2 mM) Pi enters the intact normal erythrocyte down its chemical gradient and under no conditions could we identify a steady-state trans-membrane gradient for Pi greater than 0.6. Calculations of the phosphate anion distribution ratio using the Nernst equation yield theoretical values that closely approximate observed values. (b) Glycolytic inhibitors have little effect on total entry of 32Pi inti erythrocytes but they do affect the intracellular distribution of Pi. In the presence of iodoacetamide, label accumulates almost exclusively in the orthophosphate pool and less than 1% enters the organic phosphate pool. (c) Specific activity measurements in unblocked cells indicate that Pi anion equilibrates first with its intracellular Pi pool. These initial findings imply that neither group translocation, nor energy coupling, influence Pi permeation into the human erythrocytes. (d) The relationship between 32P entry and extracellular Pi concentration is parabolic in the presence of chloride, and linear in the presence of sulfate. The kinetics of concentration dependent entrance cannot be examined and saturability of Pi entry cannot be identified under these conditions. (e) The competitive inhibitor arsenate partially inhibits the initial rate and steady-state flux of orthophosphate in erythrocytes treated with iodoacetamide to inhibit glycolysis. However, a significant portion of Pi transport escapes arsenate inhibition. (f) Activation energies for Pi entry, in nonglycolizing erythrocytes are much higher than those required by simple diffusion in an aqueous system. (g) Neither the inward or outward movement of Pi is modulated by trans-phosphate. These latter findings suggest that transport of phosphate across the human erythrocyte is compatible with slow facilitated diffusion with symmetry for influex and efflux. The transmembrane chemical distribution ratio, and the equilibrium flux of Pi were not different from normal in the X-LH erythrocyte. Nor did the extracellular Pi concentration, arsenate, or temperature affect Pi entry differently in the two types of cells. We dedjce that different gene products serve the diffusional type of Pi transport in the erythrocyte membrane and the saturable component of transepithelial absorption in the gut and kidney. Only the latter is affected by the X-LH mutation. The former is apparently present not only in erythrocytes but also in epithelial tissue, where it can serve the absorption of pharmacologic amounts of Pi in the therapeutic repair of the depleted phosphate pools in X-LH.

Amides↗
PubMed1979

Evidence for an intrinsic renal tubular defect in mice with genetic hypophosphatemic rickets.

To investigate the role of parathyroid hormone (PTH) and(or) an intrinsic renal tubular reabsorptive defect for phosphate in mice with hereditary hypophosphatemic rickets, we performed clearance and micropuncture studies in hypophosphatemic mutants and nonaffected littermate controls. Increased fractional excretion of phosphate in mutants (47.2+/-4 vs. 30.8+/-2% in controls) was associated with reduced fractional and absolute reabsorption in the proximal convoluted tubule and more distal sites. Acute thyropara-thyroidectomy (TPTX) increased phosphate reabsorption in both mutants and controls with a fall in fractional phosphate excretion to congruent with7.5% in both groups indicating that PTH modified the degree of phosphaturia in the intact mutants. Absolute reabsorption in the proximal tubule and beyond remained reduced in the mutants, however, possibly because of the reduced filtered load. Serum PTH levels were the same in intact mutants and normals as was renal cortical adenylate cyclase activity both before and after PTH stimulation. To evaluate the possibility that the phosphate wasting was caused by an intrinsic tubular defect that was masked by TPTX, glomerular fluid phosphate concentration was raised by phosphate infusion in TPTX mutants to levels approaching those of control mice. Phosphate excretion rose markedly and fractional reabsorption fell, but there was no change in absolute phosphate reabsorption in either the proximal tubule or beyond, indicating a persistent reabsorptive defect in the absence of PTH. We conclude that hereditary hypophosphatemia in the mouse is associated with a renal tubular defect in phosphate reabsorption, which is independent of PTH and therefore represents a specific intrinsic abnormality of phosphate transport.

Animals↗
PubMed1980

Evaluation of a role for 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia.

Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristic of this disease. Thus, in the present study, we investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D(3) therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, ages 14-30 yr, had normocalcemia (9.22+/-0.06 mg/dl); hypophosphatemia (2.25+/-0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12+/-0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D(3) concentration was 33.9+/-7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D(3) was not increased, but was normal at 30.3+/-2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotypic expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the long-term response to pharmacological amounts of 1,25-dihydroxyvitamin D(3) therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D(3) in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. We, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D(3) is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotypic expression of this disease.

Adolescent↗
PubMed1981

Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse.

The hypophosphatemic male mouse, an animal model for human vitamin D-resistant rickets, is characterized by low serum phosphorus concentration due to increased urinary phosphate excretion, rickets, osteomalacia, and dwarfism. Because phosphate administration can heal rickets but not osteomalacia in the human disease, we have compared the effect of phosphate supplementation on the epiphyseal and endosteal bone mineralization in the mutant animal. Phosphate was given in drinking water for 137 d and the biochemical and bone responses were assessed by analytical and histomorphometric methods. Treatment with phosphate normalized the endochondral calcification (vertebral growthplate thickness: 83 +/- 5 SD vs. controls [+/Y] 73 +/- 8 micrometers, NS), but did not correct the endosteal bone mineralization (mineralization front: 13.6 +/- 2.7 vs. +/Y 67.1 +/- 6.9% osteoid surface, P less than 0.001, endosteal mean osteoid seam thickness: 46.4 +/- 6.1 vs. +/Y 3.3 +/- 0.3 micrometers, P less than 0.001). In addition, both osteoblastic and osteoclastic recruitment and activity were stimulated, as a result of a probable increase in parathyroid hormone secretion following the phosphate induced fall in serum calcium. Our results show that in the hypophosphatemic mouse, phosphate supplementation can heal the epiphyseal, but not the endosteal defective bone mineralization. Then, the biochemical and skeletal response to phosphate therapy appear to be similar to what we have observed in the human disease, further stressing the interest of the animal model.

Animals↗
PubMed1983

Abnormal regulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the X-linked hypophosphatemic mouse.

Abnormal vitamin D metabolism has been suspected in patients with X-linked hypophosphatemic rickets (XLH) and X-linked hypophosphatemic mice (Hyp-mice), the murine homologue of the human disease. We compared 25(OH)D-1 alpha-hydroxylase activity in the Hyp-mouse kidney to that in normal and phosphate-depleted mouse kidney. Weanling normal and Hyp-mice were fed a 0.6% phosphorus diet; phosphate-depleted mice received a 0.02% phosphorus diet. At 8-10 wk of age the serum phosphorus values in Hyp (3.35 +/- 0.12 mg/dl) and phosphate-depleted mice (3.83 +/- 0.56) were not significantly different. Despite the similar magnitude of phosphate depletion, however, the maximum levels of 25(OH)D-1 alpha-hydroxylase activity were disparate: phosphate-depleted mouse kidney had profoundly increased activity compared to normal (17.04 +/- .104 vs. 4.96 +/- 0.23 fmol 1,25(OH)2D3 produced/mg kidney per min) while Hyp-mouse kidney had a fourfold lesser increment (8.18 +/- 0.62). These data indicate that phosphate depletion is a potent stimulus of 25(OH)D-1 alpha-hydroxylase activity in the (C57BL6J) mouse. Moreover, the results show that abnormal regulation of 25(OH)D-1 alpha-hydroxylase activity is manifest in the Hyp-mouse.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗