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PubMed1984

1,25-Dihydroxyvitamin D production after stimulation with synthetic human parathyroid hormone (1-34) in hypoparathyroid and renal tubular disorders.

1,25-dihydroxyvitamin D production in response to two successive infusions of synthetic active 1-34 fragment of human PTH [hPTH-(1-34)] was evaluated in order to develop an understanding of the vitamin D metabolism and the rationale of vitamin D therapy in calcium disorders. Five normal controls, six hypoparathyroid patients, two patients with hypophosphatemic vitamin-D-resistant rickets, one patient with Lowe's synd. and one patient with primary Fanconi's synd. were investigated, and the following results were obtained. All normal controls showed a significant increase in serum 1,25(OH)2D[43 +/- 3.8 (m +/- SEM, n = 5, basal), 53 +/- 4.3 (three hours after the first PTH infusion), 65 +/- 7.7 (six hours) and 66 +/- 4.4 (nine hours) pg/ml]. All patients with PTH-deficient hypoparathyroidism showed a significant increase in serum 1,25(OH)2D, and serum 1,25(OH)2D values were within the normal range after hPTH-(1-34) stimulation. Serum 1,25(OH)2D remained low after hPTH-(1-34) infusions in a patient with pseudohypoparathyroidism type I who showed a significant increase in this value after infusion of dibutyryl cyclic AMP. On the other hand, a patient with normocalcemic pseudohypoparathyroidism type I had a high basal 1,25(OH)2D value, which increased further after hPTH-(1-34) infusions. An almost normal increase in serum 1,25(OH)2D was observed in two patients with hypophosphatemic vitamin-D-resistant rickets, one with Lowe's syndrome and the other with primary Franconi's syndrome. We conclude that these results ae important in obtaining an understanding of calcium and vitamin D metabolism in these disorders and that this PTH stimulation test is a useful method to use in evaluating renal responsiveness in 1,25(OH)2D production to PTH in various calcium disorders.

Adolescent↗
PubMedDate not supplied

Hypophosphatemia induced in mice by transplantation of a tumor-derived cell line from a patient with oncogenic rickets.

A cultured cell line was derived from a hemangiopericytoma obtained at surgery from a 9 year-old boy with hypophosphatemic rickets. Hypophosphatemia and metabolic bone disease were cured in the patient after tumor removal. Cells from passage 5 were transplanted into 8 week-old athymic female mice. Additional animals received innocula of cells thawed from the stored original tumor tissue, as well as MRC-5 fibroblasts. Serum phosphate levels 3-7 months post-transplantation were lowest in mice which received the cultured cell line (n = 5) 6.1 +/- 0.6 mg/dl (p < 0.05 compared to the other groups), thawed tumor cells (n = 8) 7.2 +/- 0.7 mg/dl, MRC fibroblasts (n = 4) 8.1 +/- 1.0 mg/dl, no transplant (n = 10) 8.7 +/- 1.9 mg/dl. Repeat of the experiment with cultured tumor cells from passage 12 no longer altered phosphate levels. A substance produced and release by the tumor in situ and by tumor-derived cultured cells is capable of producing hypophosphatemia. Experimental manipulation of functional tumor-derived cell lines may help elucidate the factor(s) causing hypophosphatemia in oncogenic osteomalacia/rickets.

Animals↗
PubMedDate not supplied

Hypophosphatemic rickets and osteomalacia in polyostotic fibrous dysplasia.

A 17 year-old girl with polyostotic fibrous dysplasia and hypophosphatemia had inappropriately low tubular reabsorption of phosphate. She had radiological evidence of rickets and osteomalacia. The patient showed clinical improvement after treatment with phosphate supplementation, active vitamin D (calcitriol) and alendronate. It is postulated that either a phosphaturic substance elaborated from the dysplastic bone or target-organ (kidney) unresponsiveness may interfere with phosphate reabsorption in the renal tubule.

Alendronate↗
PubMed2005

Hypophosphatemic rickets associated with epidermal nevus syndrome and giant hairy nevus.

The association of hypophosphatemic rickets and epidermal nevus or giant hairy nevus is rare. We report two patients with hypophosphatemic rickets, one associated with epidermal nevus syndrome and the other with giant hairy nevus, and describe their clinical features and variable response to treatment. The abnormal nevus tissue may have contributed to the pathogenesis of hypophosphatemic rickets. We did not find a PHEX gene mutation in these two patients, and the mechanism for their rickets may be different from that in X-linked hypophosphatemic rickets.

Adult↗
PubMed1992

Effect of testosterone on bone mineralization of the hypophosphataemic rat.

Clinical observations in patients with X-linked hypophosphataemic rickets, that bone changes can be corrected during puberty, suggest that androgen can participate actively in the process of bone mineralization. In the present study we investigated the role of testosterone on the bone mineralization of male rats placed on a low phosphorus and vitamin D diet and kept in complete darkness after weaning. After 15 days the animals presented hypophosphataemia, rickets and osteomalacia, as assessed by histomorphometry of the tibia and seventh caudal vertebra calcification fronts respectively. Testosterone propionate administration for five days, while the animals were kept on the same rachitogenic diet, induced an improvement in the bone mineralization process of the hypophosphataemic rat independently of serum phosphate levels. Testosterone-treated rats were cured of rickets but not of osteomalacia, despite the reduction in osteoid seam area.

Animals↗
PubMed2003

Effect of GH replacement therapy in two male siblings with combined X-linked hypophosphatemia and partial GH deficiency.

OBJECTIVE: X-linked hypophosphatemia (XLH) is characterized by low serum phosphorus, relative 1,25-dihydroxyvitamin D(3) deficiency and rickets. It is caused by mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). The conventional treatment of XLH includes the administration of phosphate and calcitriol; however, treated patients usually present with a short stature. Therefore, additional coexistent defects, such as GH deficiency, are under debate. PATIENTS AND METHODS: Two male siblings presented with a disproportionate growth failure and rickets. Investigation of calcium and phosphate metabolism, molecular genetic analysis of the PHEX gene and GH function tests were initiated. RESULTS: Both patients showed typical clinical and biochemical signs of XLH. Molecular genetic analysis revealed a 747 CGA (Arg)-TGA (End) mutation in exon 22 of the PHEX gene, confirming XLH. Since treatment with phosphate and calcitriol alone failed to improve growth in both patients, the GH axis was examined and a partial GH deficiency was diagnosed in both cases. Almost 3 Years of additional therapy with recombinant human GH (rhGH) led to a significant improvement of height standard deviation scores (HtSDS). CONCLUSIONS: Poor growth in XLH may, in at least some patients, be aggravated by GH deficiency. Hence, GH deficiency should be considered in extremely poorly growing patients with XLH, because these patients are likely to benefit from rhGH therapy.

Body Height↗
PubMed1997

The effect of recombinant human growth hormone in children with X-linked hypophosphatemia.

BACKGROUND: X-linked hypophosphatemia (XLH) is characterized clinically by rickets and growth retardation. Conventional treatment of XLH with oral phosphate and vitamin D fails to normalize linear growth. Objective. To determine the benefit and the potential side effects of recombinant human growth hormone (rhGH) therapy in patients with XLH. DESIGN AND METHODS: A randomized, double-blind, crossover study was performed throughout a 24-month period in five children with XLH, each patient serving as his own control. The effect of 12 months of rhGH therapy on height, mineral metabolism, glucose and lipid metabolism, hemoglobin, thyroid and parathyroid function, serum 1,25-(OH)2 vitamin D, osteocalcin, growth hormone, urinary calcium, phosphate, nephrocalcinosis, renal function, and bone density was compared with the effects of 12 months of placebo administration on the same parameters. RESULTS: The average age (mean +/- SEM) of the patients at the start of the study was 5.6 +/- 1.4 years. Growth hormone therapy improved the height standard deviation score (z-score) from a baseline of -2.66 +/- 0.21 to -2.02 +/- 0.25 and to -1.46 +/- 0.28, after 3 and 12 months, respectively. At the start of the control period the height z-score was -2.27 +/- 0.30 compared with -2.22 +/- 0.16 after 12 months of placebo administration. The growth velocity standard deviation score was -1. 90 +/- 0.40 during the 12 months of placebo administration and +4.04 +/- 1.50 during the 12 months of rhGH therapy. An increase in serum phosphate from 0.88 +/- 0.07 mmol/L to 1.17 +/- 0.14 mmol/L and tubular maximum for phosphate reabsorption (TmP/GFR) from 2.12 +/- 0. 15 to 3.41 +/- 0.25 mg/dL, was observed after 3 months of rhGH therapy. However, both serum phosphate and TmP/GFR were unchanged from baseline after 6, 9, and 12 months of rhGH therapy. Neither serum phosphate nor TmP/GFR changed from baseline during the placebo administration. Insulin-like growth factor 1 (IGF-1) increased from 114 +/- 25 to 354 +/- 51 ng/mL after 12 months of rhGH therapy. Despite the increase in IGF-1 after rhGH therapy, the value did not exceed normal serum concentration. IGF-1 did not change from baseline after 12 months of placebo administration. Neither therapy with rhGH nor with placebo had an effect on glucose and lipid metabolism, hemoglobin, thyroid and parathyroid function, serum 1, 25-(OH)2 vitamin D, alkaline phosphatase, osteocalcin, urinary calcium excretion, the grade of nephrocalcinosis, glomerular filtration rate, or urinary albumin excretion. Twelve months of rhGH therapy increased bone mass and width but not density. Twelve months of placebo administration had no effect on bone mass, width, or density. CONCLUSION: Patients with XLH have an improvement in linear growth and a transient increase in serum phosphate attributable to a transient decrease in urinary phosphate excretion when treated with rhGH.

Child↗
PubMed2004

Effects of growth hormone treatment on body proportions and final height among small children with X-linked hypophosphatemic rickets.

BACKGROUND: X-linked hypophosphatemic rickets (XLH) is characterized by rickets, disproportionate short stature, and impaired renal phosphate reabsorption and vitamin D metabolism. Despite oral phosphate and vitamin D treatment, most children with XLH demonstrate reduced adult height. OBJECTIVE: To determine the beneficial effects of recombinant human growth hormone (rhGH) therapy on body proportions and adult height among patients with XLH. METHODS: Three initially prepubertal short children (age, 9.4-12.9 years) with XLH were treated with rhGH for 3.1 to 6.3 years until adult height was attained. RESULTS: rhGH treatment led to sustained increases in standardized height for all children. The median adult height was 0.9 SD (range: 0.5-1.3 SD) greater than that at the initiation of rhGH treatment and exceeded the predicted adult height by 6.2 cm (range: 5.3-9.8 cm). However, longitudinal growth of the trunk was stimulated more than leg growth. During rhGH treatment, the standardized sitting height increased by 1.6 SD (range: 1.1-2.7 SD), compared with baseline values. In contrast, the median subischial leg length did not change consistently (median change: 0.3 SD; range: -0.1 to 0.6 SD). CONCLUSION: The increase in final height after rhGH treatment is of potential benefit for children with XLH. However, the exaggeration of disproportionate truncal growth observed for our prepubertal patients is a potential negative effect of treatment and should be confirmed with additional studies.

Body Height↗
PubMed1978

Hypophosphatemic vitamin D-resistant rickets: metabolic balance studies in a child receiving 1,25 dihydroxyvitamin D3, phosphate, and ascorbic acid.

A child with hypophosphatemic vitamin D-resistant rickets was treated for three years with the conventional vitamin D-inorganic phosphate supplementation followed by a new therapeutic regimen consisting of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) and half of the previous phosphate supplementation. The effectiveness of the two treatment regimens was compared by calcium, phosphate, and magnesium balance techniques and by serial radiological examinations as well as careful height measurements. In addition, the lowering of the urinary pH with ascorbic acid supplementation seems to be associated with improvement in the renal tubular reabsorption of phosphate, but its distinct effect, separate from the rest of the treatment modalities, was not tested in this study. The conventional treatment did not correct the hypophosphatemia and alkaline phosphatase elevation, whereas the 1,25 (OH)2 D3-inorganic phosphate regimen is well tolerated and effective in achieving a sustained normalization of these variables. In addition, the improved growth and healing of rickets further attest to the efficacy of the new treatment.

Alkaline Phosphatase↗
PubMed1998

Implant placement and guided tissue regeneration in a patient with congenital vitamin D-resistant rickets.

There continues to be increased expansion of implant services corresponding to the public's increased awareness of implant-borne prostheses as a regular part of treatment planning. This rise in public awareness as practitioners expand their skills will lead to the consideration of an implant option for growing groups of patients whose medical histories may have previously contraindicated implantology. This presentation is one such case.

Adult↗
PubMed1992

Phosphate transport by fibroblasts from patients with hypophosphataemic vitamin D-resistant rickets.

It is accepted that renal phosphate wasting is the basis of hypophosphataemia in vitamin D-resistant hypophosphataemic rickets (VDRR). Abnormal renal adaptation to phosphate deprivation has also been reported in these patients. We studied sodium-dependent phosphate transport and its modulation by phosphate deprivation in skin fibroblasts cultured from healthy subjects and patients with VDRR. Control fibroblasts exhibited high-affinity sodium-dependent phosphate transport (77 +/- 12 mumol/l) which resembled the ubiquitous transport of renal and non-renal cells. Phosphate deprivation (incubation in low phosphate medium) increased the maximal velocity (Vmax) of the transport by 2.7-fold after 24 h, with no change in the affinity. The increase in Vmax was dependent on gene transcription and protein synthesis. The sodium-dependent phosphate transport exhibited in fibroblasts from VDRR patients did not significantly differ from that of control subjects, except that the Vmax of the phosphate transport was higher in cells from patients with VDRR under normal and phosphate-deprivation conditions, although the difference was significant only after 24 h of phosphate deprivation (Vmax: 22.6 +/- 2.4 pmol/mg protein per s in VDRR vs 16 +/- 3.6 pmol/mg protein per s in controls, P less than 0.05). These data demonstrate that sodium-coupled phosphate transport in human skin fibroblasts has the properties of ubiquitous sodium-phosphate co-transport and show that this transport is not deficient in patients with VDRR. Indeed paradoxically the Vmax was 40% higher in VDRR than in control subjects after 24 h of phosphate deprivation. The transport must be either different from that of kidney cells responsible for the phosphate leak, or differently modulated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets.

MEPE (Matrix Extracellular PhosphoglycoprotEin) expression is markedly elevated in X-linked-hypophosphatemic-rickets (HYP) and tumor-induced osteomalacia (TIO). In normal individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD). Also, MEPE derived, C-terminal ASARM-peptides are candidate minhibins and/or phosphatonins. Our aims were to determine: 1. whether MEPE-ASARM-peptide(s) are abnormally elevated in HYP/hyp serum, and, 2. whether the ASARM-peptide(s) accumulate in hyp mice kidney renal-tubules. Using a specific competitive ELISA we measured a five fold increase (P=0.007) of serum ASARM-peptide(s) in human HYP patients (normal subjects 3.25 microM n=9; S.E.M.=0.51 and HYP-patients 15.74 microM, n=9; S.E.M.=3.32). A 6.23 fold increase (P=0.008) was measured in hyp male mice compared with their normal male siblings (normal-siblings, 3.73 muM, S.E.M.=0.57, n=3; and hyp-mice 23.4 microM, n=3, S.E.M.=4.01). Renal immuno-histological screening also revealed a dramatic increase of ASARM-peptides in regions anatomically consistent with the proximal convoluted tubules. This study demonstrates for the first time that markedly elevated serum levels of protease-resistant ASARM-peptide(s) occur in HYP/hyp and they accumulate in murine hyp kidneys. These peptides are thus likely responsible for the phosphaturia and defective mineralization in HYP/hyp and TIO.

Animals↗
PubMed2005

Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH), a disorder characterized by hypophosphatemia, impaired skeletal mineralization, and aberrant regulation of 1, 25(OH)(2)D(3), is caused by inactivating mutations of Phex, which results in the accumulation of putative phosphaturic factors, called phosphatonins. Matrix extracellular phosphoglycoprotein (Mepe) is a proposed candidate for phosphatonin. The authors found that Hyp mice had increased expression of the MEPE and another phosphaturic factor, Fgf23. To establish MEPE's role in the pathogenesis of the XLH, Mepe-deficient mice were back-crossed onto the Hyp mouse homologue of XLH and phenotypes of wild-type, Mepe(-/-), Hyp, and Mepe(-/-)/Hyp mice were examined. Transfer of Mepe deficiency onto the Phex-deficient Hyp mouse background failed to correct hypophosphatemia and aberrant serum 1,25(OH)(2)D(3) levels. Increased Fgf23 levels in Hyp mice were not affected by superimposed Mepe deficiency. In addition, Mepe-deficient Hyp mice retained bone mineralization defects in vivo, characterized by decreased bone mineral density, reduced mineralized trabecular bone volume, lower flexural strength, and histologic evidence of osteomalacia; however, cultures of Hyp-derived bone marrow stromal cells in the absence of Mepe showed improved mineralization and normalization of osteoblast gene expression profiles observed in cells derived from Mepe-null mice. These results demonstrate that MEPE elevation in Hyp mice does not contribute to the hypophosphatemia associated with inactivating Phex mutations and is therefore not phosphatonin.

Animals↗