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.