title: Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function.
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)(2)D) 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)(2)D(3) 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)(2)D(3) 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.
authors.affiliation: Department of Pediatrics, Minoh City Hospital, 5-7-1 Kayano, Minoh, Osaka 562-8562, Japan. takehisa_yamamoto@maple.city.minoh.lg.jp
authors.forename: Takehisa
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Toshimi
authors.initials: T
authors.lastname: Michigami
authors.forename: Fumito
authors.initials: F
authors.lastname: Aranami
authors.forename: Hiroko
authors.initials: H
authors.lastname: Segawa
authors.forename: Kousei
authors.initials: K
authors.lastname: Yoh
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakajima
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D016022:Case-Control Studies; D002469:Cell Separation; D004252:DNA Mutational Analysis; D003955:Diagnostic Tests, Routine; D053098:Familial Hypophosphatemic Rickets / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D040181:Genetic Diseases, X-Linked; D006801:Humans; D053565:Hypercalciuria / Q000150:complications*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015675:Osteocalcin / Q000096:biosynthesis; D010710:Phosphates / Q000494:pharmacology; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000737:chemistry / Q000235:genetics*
chemical_list: D010710:Phosphates; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D015675:Osteocalcin; D000469:Alkaline Phosphatase