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11/176. prenatal diagnosis of congenital hypophosphatasia in a consanguineous Bedouin couple. A case report.

    BACKGROUND: hypophosphatasia is a rare autosomal recessive metabolic disorder characterized by low serum and tissue alkaline phosphatase activity, increased urinary excretion of phosphoethanolamine and ricketslike changes in the bone. CASE: We present a case of prenatal diagnosis of congenital hypophosphatasia in a consanguineous Bedouin couple. The case was diagnosed at 24.5 weeks of gestation. Sonographic evaluation revealed a fetus with short and deformed bones and a hypoechogenic skull. Based on the sonographic findings and the obstetric history of the couple, hypophosphatasia was diagnosed. The parents opted for pregnancy termination. Feticide was accomplished uneventfully. Laboratory findings confirmed the diagnosis. CONCLUSION: This couple was prone to this metabolic disorder due to their consanguineous marriage and previous affected fetus. Early-first-trimester prenatal diagnosis by first-trimester chorionic villus sampling or second-trimester measuring of alkaline phosphatase activity in the amniotic fluid is required to exclude this lethal disease in subsequent pregnancies. ( info)

12/176. Familial hypophosphatemic vitamin d-resistant rickets: dental findings and histologic study of teeth.

    A case of familial hypophosphatemic vitamin d-resistant rickets or X-linked hypophosphatemia (XLH) accompanied by specific systemic and dental findings is reported. A 15-year-old boy with XLH visited our facility complaining of a toothache in the left lower canine region. Two other family members of the patient, his younger sister and their mother, also had XLH, whereas the other 2 members, his younger brother and father, are healthy. Those with XLH show systemic signs of the disease, such as growth retardation, limb deformity, and spinal curvature disorders; however, these symptoms are more severe in the patient than in the others. The patient had multiple periodontal abscesses, but no evidence of dental caries, trauma, or periodontal disease on the corresponding teeth at the time of his oral examination. A radiographic examination showed root dysplasia and enlarged pulp chambers.A histologic examination of an extracted third molar showed marked globular dentin and an increased predentin width. The abscess was thought to be caused by pulpal infection, which came from bacterial invasion through enamel cracks and dentinal microcleavage of the teeth. The treatments provided in this case are discussed. ( info)

13/176. Three novel PHEX gene mutations in Japanese patients with X-linked hypophosphatemic rickets.

    X-linked hypophosphatemic rickets (XLH) is an X-linked dominant disorder characterized by renal phosphate wasting, abnormal vitamin d metabolism, and defects of bone mineralization. The phosphate-regulating gene on the X-chromosome (PHEX) that is defective in XLH has been cloned, and its location identified at Xp22.1. It has been recognized to be homologous to certain endopeptidases. So far, a variety of PHEX mutations have been identified mainly in European and North American patients with XLH. To analyze the molecular basis of four unrelated Japanese families with XLH, we determined the nucleotide sequence of the PHEX gene of affected members. We detected a new nonsense mutation (R198X) in exon 5, a new 3 nucleotides insertion mutation in exon 12 and a new missense mutation (L160R) in exon 5 as well as a previously reported nonsense mutation in exon 8 (R291X). These results suggest that: 1) PHEX gene mutations are responsible for XLH in Japanese patients, and 2) PHEX gene mutations are heterogeneous in the Japanese population similarly to other ethnic populations. ( info)

14/176. Axial osteomalacia with sacroiliitis and moderate phosphate diabetes: report of a case.

    We report a new case of axial osteomalacia diagnosed in a 51-year-old white Caucasian male, made particular by its association with sacroiliitis, positive hla-b27 antigen, and also moderate phosphate diabetes responsible for a decreased appendicular bone mass. The diagnosis was suspected when X-ray evaluation showed increased density and coarse trabeculation mainly involving the pelvis and spine. Dual energy X-ray absorptiometry confirmed the elevated bone density at the lumbar spine (T score: 1.92) contrasting with a decreased bone mass at the femoral neck (T score: -2.33). The diagnosis was confirmed by histomorphometry of the iliac crest showing marked thickening of the cortices (2190 microns /- 0.574, N = 780 /- 40) and an increased trabecular bone volume (33.24%, N = 14 /- 3). Osteoid parameters were also markedly increased with an osteoid volume of 2.1% (N = 1.2 /- 0.5) and a mean osteoid thickness of 28.7 microns (N = 13 /- 2.5), with a normal bone fluoride content (0.082%, N < 0.10). bone resorption as assessed on bone biopsy and by the measurement of markers of bone remodeling (serum procollagen type I C-terminal telopeptide and 24 hr urinary cross-laps to creatinine ratio) was increased. This latter finding was not necessarily due to axial osteomalacia and could be the consequence of moderate phosphate diabetes. The patient was treated with calcitriol which was promptly discontinued due to gastrointestinal symptoms and replaced by calcidiol without any significant effect on the low back pain. ( info)

15/176. Effect of dipyridamole on serum and urinary phosphate in X-linked hypophosphatemia.

    X-linked hypophosphatemia (XLH) is characterized clinically by rickets, hypophosphatemia and hyperphosphaturia. Conventional treatment of XLH with oral phosphate and vitamin d is associated with hypercalcuria and nephrocalcinosis. Recently, intravenous and oral dipyridamole has been reported to decrease fractional excretion of phosphate in adults with idiopathic hyperphosphaturia. Our objective was to determine whether oral dipyridamole therapy reduces urinary phosphate excretion and increases serum phosphate concentration in children with XLH. A prospective study was performed in six children with XLH. The average age of the patients at the start of the study was 12.5 /-1.0 years. The effects of 12 weeks of oral dipyridamole therapy, at 4.4 /-0.4 mg/kg body weight per day, on serum phosphorous, parathyroid hormone (PTH), 1,25 (OH)2 vitamin d, osteocalcin, tubular maximum for phosphate reabsorption (TmP/GFR), urinary calcium excretion, and cyclic adenosine 3',5'-monophosphate (cAMP) excretion, were compared to baseline levels. Our results show that there was no change in serum phosphorous concentration or TmP/GFR after 12 weeks of dipyridamole therapy. dipyridamole therapy also had no effect on serum PTH, serum 1,25 (OH)2 vitamin d, alkaline phosphatase, osteocalcin levels, urinary calcium or cAMP excretion. We therefore concluded that in children with XLH, a 12-week course of dipyridamole had no effect on serum phosphorous or its urinary excretion. dipyridamole therapy is unlikely to improve the bone disease in children with XLH. ( info)

16/176. X-linked hypophosphatemic rickets--a report of 2 cases and review of literature.

    We report two cases of x-linked dominant hypophosphatemic rickets involving a man and his daughter. The family tree consists of 44 members with 13 of them having short stature and bowing of the lower limbs. The study of this family tree strongly suggests an x-linked dominant inheritance. ( info)

17/176. Ossification of the posterior longitudinal ligament in vitamin d-resistant rickets: case report and review of the literature.

    STUDY DESIGN: A case report of cervical myelopathy caused by ossification of the posterior longitudinal ligament in a patient with vitamin d-resistant rickets is presented together with a review of literature. OBJECTIVE: To report the diagnosis of ossification of the posterior longitudinal ligament in a white woman with vitamin d-resistant rickets. SUMMARY OF BACKGROUND DATA: The association between ossification of the posterior longitudinal ligament and untreated vitamin d-resistant rickets has been reported in japan, but infrequently in white populations. In whites, ossification of the posterior longitudinal ligament is closely associated with diffuse idiopathic skeletal hyperostosis. A clear association between ossification of the posterior longitudinal ligament and vitamin d-resistant rickets in white populations has not yet been established. methods: The medical record and imaging studies of a patient treated at the authors' institution for cervical myelopathy caused by ossification of the posterior longitudinal ligament in the setting of treated vitamin d-resistant rickets were reviewed. A medline search of the medical literature between 1966-1999 was performed to identify pertinent studies and similar case reports. RESULTS: The occurrence of spinal stenosis in untreated adults with vitamin d-resistant rickets has been reported in all regions of the spine in Japanese patients. The association between ossification of the posterior longitudinal ligament and untreated vitamin d-resistant rickets was first reported in japan, where ossification of the posterior longitudinal ligament is endemic. This association may be incidental, because reports on ossification of the posterior longitudinal ligament in whites are not as frequent as in Japanese, reflecting the higher prevalence of this condition in japan. CONCLUSION: Ossification of the posterior longitudinal ligament and ossification of the posterior longitudinal ligament associated with deranged calcium or phosphate metabolism may be different pathologic entities sharing a common outcome. Adequate treatment of vitamin d-resistant rickets may not always prevent or reverse ossification of the posterior longitudinal ligament. ( info)

18/176. Hereditary hypophosphatemic rickets with hypercalciuria: report of a new kindred.

    We report a new kindred of hereditary hypophosphatemic rickets with hypercalciuria. The symptomatic child and several relatives had increased renal phosphate clearance leading to hypophosphatemia, hyperabsorptive hypercalciuria, low PTH and increased 1,25-(OH)2D serum level. However, association with vitamin D deficiency and normal urinary excretion of cyclic amp might suggest another tubular defect in phosphate transport. ( info)

19/176. A novel inborn error in the ligand-binding domain of the vitamin d receptor causes hereditary vitamin d-resistant rickets.

    Mutations in the vitamin d receptor (VDR) cause hereditary vitamin d-resistant rickets (HVDRR), an autosomal recessive disease resulting in target organ resistance to 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. In this report, we describe the clinical case and molecular basis of HVDRR in an Asian boy exhibiting the typical clinical features of the disease including alopecia. Using cultured dermal fibroblasts from the patient, 1,25(OH)(2)D(3) resistance was demonstrated by a shift in the dose response required for 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) mRNA induction. Western blot showed that the cells express a normal size VDR but contained reduced levels of receptor compared to normal cells. At 24 degrees C, the affinity of the patient's VDR for [(3)H]1,25(OH)(2)D(3) was 50-fold lower than the VDR in normal fibroblasts. sequence analysis identified a unique T to G missense mutation in exon 6 that changed phenylalanine to cysteine at amino acid 251 (F251C). The recreated F251C mutant VDR showed reduced transactivation activity using a 24-hydroxylase promoter-luciferase reporter. Maximal transactivation activity exhibited by the WT VDR was not achieved by the mutant VDR even when the cells were treated with up to 10(-6) M 1,25(OH)(2)D(3). However, the transactivation activity was partially rescued by addition of RXRalpha. In the yeast two-hybrid system and GST-pull-down assays, high concentrations of 1,25(OH)(2)D(3) were needed to promote F251C mutant VDR binding to RXRalpha, indicating defective heterodimerization. In conclusion, a novel mutation was identified in the VDR LBD that reduces VDR abundance and its affinity for 1,25(OH)(2)D(3) and interferes with RXRalpha heterodimerization resulting in the syndrome of HVDRR. ( info)

20/176. Hypophosphatemic rickets accompanying McCune-Albright syndrome: evidence that a humoral factor causes hypophosphatemia.

    McCune-Albright syndrome (MAS) is sometimes complicated by hypophosphatemia. However, it remains unclear whether a humoral factor is associated with the cause of hypophosphatemia. We isolated cells with mutations of the Gsalpha gene from fibrous bone dysplasia tissues of two MAS patients (MAS cells). severe combined immunodeficiency (SCID) mice were subjected to experiments using from one of these cells patients. Effects of conditioned media (CM) isolated from MAS cells (MAS-CM) on phosphate transport were investigated by using rat renal slices, the renal cell line OK-B, rat intestinal rings and the human intestinal cell line Caco-2. In addition, the effects of MAS-CM on human sodium-dependent phosphate transporter (NPT2) gene promoter activity expression were investigated in the renal cell line OK-B2400 and were compared with the effects of CM isolated from a patient with oncogenic hypophosphatemic osteomalacia (OHO). MAS cells caused significant hypophosphatemia (P < 0.05) and elevated serum alkaline phosphatase activity (P < 0.05) in SCID mice. The MAS-CM significantly inhibited phosphate uptake in everted intestinal rings (P < 0.01), whereas it had no effect on glucose uptake. The MAS-CM had no effect on either phosphate uptake in the kidney or NPT2 gene promoter activity. In contrast, the CM of the OHO patient significantly inhibited phosphate uptake and NPT2 gene promoter activity. These results indicate that the humoral factor derived from fibrous dysplasia cells of the MAS patient is different to that from OHO patients, because the humoral factor from the MAS patient inhibited phosphate transport not in the kidney but in the intestine. ( info)
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