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At least 487 records · Page 27Linked to original sources
PubMed1989

Hypophosphataemic rickets: final height and clinical symptoms in adults.

The heights and symptoms of 52 patients, aged at least 18 years, with X-linked hypophosphataemic rickets were analysed retrospectively; 47 had been seen as children and 5 were adult at their first examination. 2 patients were lost to follow-up. 3 patients had died but their adult heights were known. There was no evidence that any form of treatment (ie, vitamin D in high doses, vitamin D plus phosphate supplements, or calcitriol plus phosphate) had any effect on adult height, symptoms, or alkaline phosphatase levels. There was a negative relation between adult height and the number of osteotomies undergone. The complications of treatment, such as renal failure, which occurred secondary to vitamin D intoxication in 3 patients in their twenties, may outweight any possible benefits. Until a treatment is established as effective in controlled trials, it may be better that these patients remain untreated.

Adolescent↗
PubMed1981

Histomorphometric study of bone remodeling in hypophosphatemic vitamin D-resistant rickets.

Static and dynamic histomorphometric parameters were evaluated on undecalcified iliac crest bone biopsies obtained from eight children with untreated hypophosphatemic vitamin D resistant rickets (VDRR) in an attempt to evaluate whether a primary metabolic bone defect contributes to the skeletal disorder observed in that disease. When compared to normal age-matched controls the trabecular calcified bone volume was not decreased and there was no evidence of excessive osteoclastic resorption. Both trabecular and cortical bone envelopes had an excess of osteoid tissue and a decreased extent of the mineralization front. Dual tetracycline labeling revealed a decrease in the osteoblastic calcification rate and a marked prolongation of the mineralization lag time and of the formation period. In the intracortical Haversian system the birthrate of new Basic Multicellular remodeling Units (BMU) was markedly reduced, leading to a marked depression of the bone formation rate at the whole tissue level. The combination of the decreased birthrate of new BMU and the prolonged formation period appears to be characteristic of the disease. These results indicate that abnormal differentiation and function of the osteoblast contribute to the osteomalacic lesion present in VDRR. Defective mineralization and impaired osteoblastic function might be the consequence of the chronic hypophosphatemic state. However, the existence of a primary disorder of the bone cell line cannot be excluded as an explanation of the defective recruitment and function of the bone forming cells.

Adolescent↗
PubMed2000

Phex cDNA cloning from rat bone and studies on phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo.

Phosphate regulating gene with homology to endopeptidases on the X chromosome (Phex) inactivating mutations cause X-linked hypophosphatemia (XLH). The disorder is characterized by decreased renal phosphate (Pi) reabsorption in both humans and mice, in the latter shown to be due to a reduction in mRNA and protein of type II sodium-dependent phosphate cotransporter (NadPi-II). To gain insight into the physiological role of Phex, we cloned the rat cDNA and examined tissue-specific and age-dependent mRNA expression. The rat full-length cDNA (2247 nucleotides) shares 96 and 90% identity with the mouse and human cDNA, respectively. We found 6.6 kb Phex transcripts in calvarial bone and lungs, and a weaker signal in liver of newborn rats. In adult animals, Phex mRNA signals were weaker in bone and lungs and absent in liver. Phex mRNA expression in bones and NadPi-I and -II cotransporter mRNA expression in kidney were also determined in hypophysectomized rats. These rats, which lack GH and IGF I, stop growing and exhibit decreased serum Pi levels. Treatment during 6 days with IGF I stimulated growth and increased serum Pi. Phex and NadPi-II cotransporter mRNA levels were higher in IGF I than in vehicle-treated animals, while mRNA expression of NadPi-I, 1alpha-hydroxylase and 24-hydroxylase and serum levels of calcitriol remained unaffected. Age-dependency of Phex expression suggests a role for Phex in Pi retention during growth. Moreover, our findings indicate that an increase in Phex expression in bones under the influence of IGF I may contribute to increased serum Pi by enhancing renal phosphate reabsorption. Because IGF I treatment increased NadPi-II mRNA expression and serum Pi, IGF I appears to act at least partially at pretranslational levels to increase NadPi-II mediated renal Pi retention in growing rats.

Aging↗
PubMed2002

Hypophosphatemic osteomalacia in neurofibromatosis 1: hypotheses for pathogenesis and higher incidence of spinal deformity.

Osteomalacia is rarely encountered in association with neurofibromatosis 1, characterized by phosphate loss in the urine and its pathogenesis is still unknown. Incidence of spinal deformities in cases of neurofibromatosis 1 associated with osteomalacia seems to be high. Spinal deformities are unlikely to be due to osteomalacia itself. Melatonin deficiency was proposed to be present in cases of neurofibromatosis 1 and to be an operating factor in progression of spinal deformities. We might hypothesize that putative melatonin deficiency in cases of neurofibromatosis 1 might play a role in the pathogenesis of hyperphosphaturea by decreasing sodium-phosphate cotransport, increasing the level of cAMP, the un-antagonized effect of dopamine on phosphate reabsorption and increasing glucocorticoid levels. Parathyroid overactivity that may occur secondary to osteomalacia might have synergistic effects with dopamine and further exaggerate phosphate loss in urine. On the other hand, excess corticosteroid secretion would decrease nocturnal melatonin level. Moreover, in the presence of hypophosphatemia, hypercortisolism might further inhibit melatonin secretion that might lead to progression of spinal deformities in these cases.

Hypophosphatemia, Familial↗
PubMed2005

[Hereditary hypophosphatemia in adults].

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).

Adult↗
PubMed2000

Disorders of phosphate metabolism.

Correct identification of the disorders of hypophosphatemia and hyperphosphatemia is important for determining therapy. Further research will provide insights into normal phosphate homeostasis, a complex and fascinating process.

Animals↗
PubMed1994

Hormone-nuclear receptor interactions in health and disease. Vitamin D resistance.

Tissue resistance to vitamin D, or vitamin D-dependent rickets (VDDR), can be classified as two separate conditions--VDDR type I and VDDR type II--both of which present with the classical clinical, radiological and biochemical features of rickets despite adequate vitamin D intake. VDDR II can also be associated with alopecia, for reasons that are not clear. The two syndromes result from distinct disorders of vitamin D metabolism or action. Both are inherited in an autosomal recessive fashion. VDDR I is caused by decreased production of the active form of vitamin D, 1,25-dihydroxycholecalciferol, with the proposed defect being in the gene encoding the enzyme 1 alpha-hydroxylase. VDDR II results from mutations in the gene for the intracellular receptor for 1,25-dihydroxycholecalciferol (vitamin D receptor), resulting in changes in hormone or DNA binding, depending on the mutation. These mutations are analogous to those affecting receptors for other steroid-thyroid hormones, which have also been shown to cause resistance to hormone action.

Drug Resistance↗
PubMed2003

Molecular basis for pseudo vitamin D-deficiency rickets in the Hannover pig.

The molecular basis for pseudo vitamin D deficiency rickets (PDDR) in the Hannover pig model was determined in the current study. Consistent with the inability of Hannover PDDR pigs to maintain ambient levels of 1,25-dihydroxyvitamin D (i.e., 1,25D), the bioactivation enzyme cytochrome P450C1 (or CYP27B1) was determined to contain coding-region deletions that rendered the enzyme ineffective due to frame-shift mutations and expression of a premature termination codon. Expression levels of P450C1mRNA were up-regulated in response to the low-1,25D high-parathyroid hormone state of the PDDR animals. In a complementary manner, cytochrome P450C24 mRNA was not detectable in PDDR pigs. Two different deletions were detected within the Hannover pig strain in which the P450C1 coding region contained either 173 bp or 329 bp deletions that resulted in the expression of non-sense products beginning within the I-helix region and extending through the truncated C-terminal domains. The boundaries for the deletion segments aligned with derived mRNA processing sites. This observation was consistent with an mRNA processing error as the causative factor for the coding-region deletions. Based upon the expression of a non-functional P450C1 enzyme, the Hannover pig model for PDDR was determined to be identical to the human disease in which enzyme-inhibitory mutations are the molecular basis for the calcium disorder.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2002

Augmenting vitamin D to combat genetic disease.

Vitamin D-resistant rickets is a genetic disease that causes severe bone underdevelopment due to mutations in the vitamin D receptor. Orthogonal analogs of vitamin D were recently identified that correct defects in the ligand binding pocket of a mutant receptor associated with this disease.

Humans↗
PubMed1996

Pathohistology of undecalcified primary teeth in vitamin D-resistant rickets: review and report of two cases.

The basic dental defects in vitamin D-resistant rickets seem to be manifested in dentin. Enamel is usually reported to be normal. This histologic examination showed the penetration of microorganisms through the calcified structures of the enamel layer without visible caries. The microorganisms passed through the dentinoenamel junction and invaded dentin, which was characterized by calcospherites and large amounts of interglobular dentin. Furthermore, microorganisms could be detected in dentinal tubules, which were exposed to the oral cavity when enamel was removed. However, large areas of tertiary dentin extended between such tubules and the pulp. These light microscopic results suggest that clinical manifestations, such as, pulp recrosis and periapical lesions (without carious defects) may be caused by the penetration of microorganisms through microclefts of the enamel layer as well as pathologically altered enamel microstructures of affected teeth.

Adult↗
PubMed2002

A novel nonsense mutation in the ligand binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). In this report, we present our findings on a young girl who exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25(OH)(2)D(3)]. The patient also had total body alopecia. Fibroblasts from the patient were cultured for analysis of the VDR structure and function. In [3H]1,25(OH)(2)D(3) binding assays, no significant specific binding to the VDR was observed in cytosols from the patient's fibroblasts. The patient's fibroblast were also totally resistant to high doses of 1,25(OH)(2)D(3) as demonstrated by their failure to induce expression of the 24-hydroxylase gene, a marker of 1,25(OH)(2)D(3) activity. DNA sequence analysis of the VDR gene uncovered a unique C to T mutation in exon 8. The mutation changed the codon for glutamine to a premature stop codon at amino acid 317 (Q317X). Restriction enzyme analysis showed that the patient was homozygous for the mutation. Both parents were heterozygous for the mutant allele. In conclusion, we have identified a novel mutation in the VDR, Q317X, as the molecular defect in a patient with HVDRR. The Q317X mutation deletes 110 amino acids of the ligand-binding domain of the VDR and results in the loss of [3H]1,25(OH)(2)D(3) binding and target gene transactivation.

Child, Preschool↗
PubMed2001

Management of male osteoporosis.

UNLABELLED: The objective of this study was to evaluate the efficacy of treatments for male osteoporosis selected based on the cause of the disease. METHODS: Sixty-three men with osteoporosis (T-score at the lumbar spine and/or femoral neck lower than -2.5) with a mean age of 53+/-11 years were studied. Forty-three (68.3%) had a history of fracturing without trauma (vertebral fractures, 37 patients, 57%). Treatments were as follows: idiopathic osteoporosis: calcium and vitamin D supplements (N = 10) or cyclical etidronate for 2 weeks followed by calcium and vitamin D supplements for 76 days (N = 29); moderate idiopathic phosphate diabetes: calcitriol and phosphate (N = 15); idiopathic hypercalciuria: hydrochlorothiazide (N = 6); and hypogonadism: testosterone (N = 3). RESULTS: Percentage change in bone mineral density (mean +/- standard error of the mean) after 18 months: calcium and vitamin D (lumbar spine: 0.6+/-2; femoral neck: 2.2+/-2.2); etidronate (lumbar spine: 3.6+/-1.4*; femoral neck: 0.5+/-1); calcitriol (lumbar spine: 7.0+/-3.5*; femoral neck: 0.0+/-1.4); thiazide diuretic (lumbar spine: 1+/-3.2; femoral neck: -2.3+/-3.7); and testosterone (lumbar spine: 6.8+/-6.4; femoral neck: 2.5+/-2.7), where *P < 0.05 versus baseline. Gastrointestinal side effects occurred in three patients (4.8%), including two on calcitriol-phosphate therapy and one on etidronate therapy. Of the six (9.5%) patients who experienced incident fractures, four were on etidronate, one on calcitriol-phosphate, and one on calcium-vitamin D. No patients discontinued their treatment because of side effects. CONCLUSION: Etidronate and the combination of calcitriol-phosphate produce a significant increase in lumbar spine bone mass in men with idiopathic osteoporosis or moderate idiopathic phosphate diabetes.

Absorptiometry, Photon↗
PubMed2001

Phosphate, the renal tubule, and the musculoskeletal system.

A component of ATP, phosphate is at the hub of the energy-related mechanisms operative in muscle cells. Together with calcium, phosphate is involved in bone tissue mineralization: thus, a chronic alteration in the metabolism of phosphate can induce bone and joint disorders. Diagnosis of chronic hypophosphatemia. Serum phosphate, calcium, and creatinine should be assayed simultaneously. Serum calcium is increased in hypophosphatemia caused by hyperparathyroidism and decreased in osteomalacia. Urinary phosphate excretion should be measured in patients with a normal serum calcium level and a serum phosphate level lower than 0.80 mmol/L. A decrease in urinary phosphate excretion to less than 10 mmol/24 h strongly suggests a gastrointestinal disorder, such as malabsorption, antacid use, or chronic alcohol abuse. In patients with a urinary phosphate excretion greater than 20 mmol/24 h, the maximal rate of tubular reabsorption of phosphate (TmPO4) and the ratio of TmPO4 over glomerular filtration rate (GFR) should be determined to look for phosphate diabetes. Manifestations and causes of phosphate diabetes in adults. Moderately severe phosphate diabetes in adults manifests as chronic fatigue, depression, spinal pain, and polyarthralgia, with osteoporosis ascribable to increased bone resorption. Although many cases are idiopathic, investigations should be done to look for X-linked vitamin D-resistant rickets missed during childhood, a mesenchymatous tumor, or Fanconi's syndrome with renal wasting of phosphate, glucose, and amino acids. Management of phosphate diabetes. Phosphate supplementation and, in patients with normal urinary calcium excretion, calcitriol produce some improvement in the symptoms and increase the bone mineral density. Whether dipyramidole is clinically effective remains unclear.

Humans↗
PubMed2003

Disorders of phosphate metabolism--pathomechanisms and management of hypophosphataemic disorders.

Hypophosphataemia does not necessarily indicate phosphate (Pi) depletion. In acute emergencies such as septicaemia, alkalosis or re-feeding, hypophosphataemia may result from redistribution of Pi from the extracellular to the intracellular space. Hypophosphataemia from true Pi depletion gives rise to skeletal (osteomalacia) and extraskeletal (myopathy, cardiomyopathy) disorders. It is practically never the result of diminished nutritional intake. The most severe syndromes of Pi depletion result from diminished tubular Pi re-absorption and renal Pi wasting. In the differential diagnosis mainly four conditions have to be considered: (i) tumour-associated osteomalacia, (ii) X-linked hypophosphataemia (XLH), (iii) autosomal dominant hypophosphataemia, and (iv) hypercalcaemic renal phosphate wasting. Recent molecular insight has put fibroblast growth factor (FGF-23) into the centre of pathophysiological considerations because of (i) overproduction (tumour-associated osteomalacia) or (ii) hypothetically, accumulation resulting from mutations causing resistance to processing or degradation (autosomal dominant hypophosphataemia) or (iii) loss-of-function of a protease (PHEX) interfering with FGF-23 breakdown (XLH). In oncogenic osteomalacia the treatment of choice is resection of the tumour. Recently, pharmacological treatment has also become possible, i.e. administration of octreotide. XLH and autosomal dominant hypophosphataemia must be managed by oral administration of phosphate and calcitriol. In patients with gastrointestinal intolerance to phosphate or with severely symptomatic bone disease, prolonged intravenous administration of Pi is necessary.

Diagnosis, Differential↗