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Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function

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Abstract

Two cases of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) were reported in Japanese female siblings. Both of them manifested short stature and bowed legs, and biochemical examination revealed hypophosphatemia, phosphaturia, and hypercalciuria. The serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)2D) were elevated. In the oral phosphate loading test, serum phosphate levels were markedly increased in the HHRH patients, and the elevation was much higher than that in patients affected with X-linked hypophosphatemic rickets (XLH), suggesting the increased gastrointestinal absorption of phosphate in HHRH. Bone histology studies showed increased osteoid surface and width in HHRH, which was compatible with osteomalacia. In the HHRH patients, there were no hypomineralized periosteocytic lesions, which was a hallmark of XLH in bone histology. In one of the HHRH patients, phosphate administration alone almost completely cured the osteomalacia within a year, although pharmacological doses of 1,25(OH)2D3 had little effect. In osteoblasts isolated from a HHRH patient, basal alkaline phosphatase (ALP) activities and osteocalcin syntheses by a physiological concentration of 1,25(OH)2D3 were not stimulated by the increased medium phosphate concentrations from 0.5 to 4 mM. In contrast, these two parameters were stimulated by the increased medium phosphate concentrations both in normal and XLH osteoblasts, although the regulatory patterns of increased osteocalcin syntheses were different from normal to XLH osteoblasts; 2 and 4 mM of phosphate concentrations at least were necessary for normal and XLH osteoblasts, respectively. The gene analysis of phosphate transporter revealed a novel heterozygous mutation (R564C) in the exon of phosphate transporter NPT type IIc. These lines of evidence suggested that the pathogenesis of osteomalacia in HHRH was different from XLH in terms of the utility of phosphate in osteoblasts. These abnormalities were speculated to be associated with the abnormal functions of phosphate transporter gene type IIc, although the exact roles of this phosphate transporter in the human osteoblast are still unknown.

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Authors and Affiliations

  1. Department of Pediatrics, Minoh City Hospital, 5-7-1 Kayano, Minoh, Osaka, 562-8562, Japan

    Takehisa Yamamoto

  2. Division of Environmental Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan

    Toshimi Michigami

  3. Department of Molecular Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan

    Fumito Aranami, Hiroko Segawa & Ken-ichi Miyamoto

  4. Department of Orthopedics, Sasayama Hospital, Hyogo Medical College, Sasayama, Japan

    Kousei Yoh

  5. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan

    Shigeo Nakajima & Keiichi Ozono

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  1. Takehisa Yamamoto
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  2. Toshimi Michigami
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  3. Fumito Aranami
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  4. Hiroko Segawa
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  6. Shigeo Nakajima
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  7. Ken-ichi Miyamoto
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  8. Keiichi Ozono
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Correspondence to Takehisa Yamamoto.

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Yamamoto, T., Michigami, T., Aranami, F. et al. Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function. J Bone Miner Metab 25, 407–413 (2007). https://doi.org/10.1007/s00774-007-0776-6

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  • DOI: https://doi.org/10.1007/s00774-007-0776-6

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