cholecalciferol and Familial-Hypophosphatemic-Rickets

This review mainly describes on childhood vitamin D deficiency and x-linked hypophosphatemic rickets. Though nutritional state has improved dramatically, 25 (OH) D level, which is a good indicator of vitamin D status, is marginal especially in winter, and vitamin D deficiency is not rare in Japan. The PTH/Vitamin D axis does not account for the entire picture of x-linked hypophosphatemic rickets, and a new bone (osteocyte) -renal metabolic milieu has emerged and loss of PHEX, mostly expressed in osteocytes, is proposed to result in inappropriate processing of MEPE and consequent reduction in bone mineralization and an increase in circulating FGF23 to give rise to phosphaturia and hypophosphatemia.

Topics: Animals; Calcitriol; Child; Cholecalciferol; Extracellular Matrix Proteins; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Genetic Diseases, X-Linked; Glycoproteins; Humans; Osteocytes; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphoproteins; Phosphorus; Vitamin D Deficiency

Hypophosphatemic rickets (HR) is a genetic disorder with various types of inheritance. It results mainly from defects in factors that control mineral ion homeostasis such as 1,25(OH)

Topics: Child; Cholecalciferol; Dental Arch; Dentition, Mixed; Esthetics, Dental; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Humans; Malocclusion, Angle Class I; Malocclusion, Angle Class II; Malocclusion, Angle Class III; Orthodontic Wires; Orthodontics, Corrective; Palatal Expansion Technique; Rare Diseases; Rickets, Hypophosphatemic

Pseudovitamin D-deficiency rickets is a rare disease which is caused by CYP27B1. In this study, we identified 9 mutations in 7 PDDR patients. In addition, we observed the response to long-term treatment of calcitriol in 15 Chinese patients with PDDR, which showed that the biochemical abnormalities had been corrected satisfactorily after 1-year treatment.. Pseudovitamin D-deficiency rickets is a rare autosomal recessive disorder resulting from a defect in 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by CYP27B1. The purpose of this study was to identify the CYP27B1 mutations and investigate the response to long-term treatment of calcitriol in Chinese patients with PDDR.. We investigated CYP27B1 mutations in seven individuals from six separate families. To investigate the response to long-term (13 years) treatment with calcitriol in PDDR patients, we additionally collected clinical data of eight families from our previous report and analyzed their biochemical parameter and radiographic changes during the treatment.. Nine different mutations were identified: two novel missense mutations (G194R, R259L), three novel and one reported deletion mutations (c1442delA, c1504delA, c311-321del, and c. 48-60del), two novel nonsense mutations (c.85G>T, c.580G>T), and a reported insertion mutation (c1325-1332insCCCACCC). The statistical analysis revealed that parathyroid hormone (PTH) and ALP significantly decreased after 6-month and 1-year treatment with calcitriol respectively. Urine calcium was measured in all the patients without kidney stones being documented. After 6-year treatment, the radiographic abnormalities had also been improved. Two patients who had reached their final height are both with short stature (height Z-score below - 2.0).. We identified seven novel mutations of CYP27B1 gene in seven Chinese PDDR families. Our findings revealed after 1-year treatment of active vitamin D

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adolescent; Alkaline Phosphatase; Body Height; Calcium-Regulating Hormones and Agents; Child; Child, Preschool; Cholecalciferol; DNA Mutational Analysis; Drug Administration Schedule; Familial Hypophosphatemic Rickets; Female; Humans; Male; Mutation; Parathyroid Hormone; Pedigree; Radiography; Treatment Outcome; Young Adult

X-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and autosomal recessive hypophosphatemic rickets/osteomalacia (ARHR1 or ARHR2) are hereditary fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets showing similar clinical features. We here show a patient with hypophosphatemic rickets and widespread ossification of posterior longitudinal ligament (OPLL). The proband is a 62-year-old female. Her parents are first cousins and showed no signs of rickets or osteomalacia. She showed hypophosphatemic rickets with elevated FGF23 level and had been clinically considered to be suffering from XLH. However, direct sequencing of all coding exons and exon-intron junctions of phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX), FGF23 and dentin matrix protein 1 (DMP1) genes, responsible genes for XLH, ADHR and ARHR1, respectively, showed no mutation. A novel homozygous splice donor site mutation was found at the exon-intron junction of exon 21 of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene responsible for ARHR2 (IVS21+1_3(GTA>CACC)). Subsequent analysis of mRNA revealed that this mutation caused skipping of exon 21 which created a premature stop codon in exon 22. These results indicate that genetic analysis is mandatory for the correct diagnosis of hereditary FGF23-related hypophosphatemic rickets. Because Enpp1 knockout mouse is a model of OPLL, this case also suggests that OPLL is associated with ARHR2.

Topics: Base Sequence; Cholecalciferol; DNA Mutational Analysis; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Gene Expression Regulation, Enzymologic; Genetic Diseases, X-Linked; Homozygote; Humans; Middle Aged; Molecular Sequence Data; Mutation; Ossification of Posterior Longitudinal Ligament; Phosphates; Phosphoric Diester Hydrolases; Pyrophosphatases; RNA, Messenger

Severe dental troubles are associated with X-linked hypophosphatemic rickets and are mainly related to impaired dentin mineralization. In dentin matrix, matrix extracellular phosphoglycoprotein (MEPE) may be protected from proteolysis by a specific interaction with PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome). The objective of our work was to determine whether PHEX impairment induces MEPE cleavage in dentin and the subsequent release of the C-terminal acidic serine- and aspartate-rich motif (ASARM) peptide, which is known to inhibit mineralization. By Western blot analysis, we explored dentin extracts from seven hypophosphatemic patients with mutations of the PHEX gene. A proteomic approach combining immunoprecipitation, surface-enhanced laser desorption/ionization-time of flight-mass spectrometry and matrix-assisted laser desorption ionization-time of flight analysis of the samples completed this exploration. This study shows a 4.1-kDa peptide containing the MEPE-derived ASARM peptide in hypophosphatemic samples. The presence of ASARM was less marked in patients treated with 1-hydroxylated vitamin D and phosphate during growth. Moreover, recombinant ASARM implanted in a rat pulp injury model disturbed the formation of the reparative dentin bridge. These results suggest that abnormal MEPE cleavage occurs when PHEX activity is deficient in humans, the ASARM peptide may be involved in the mineralization defects and the PHEX-MEPE interaction may be indirect, as ensuring a better phosphate and vitamin D environment to the mineralizing dentin prevents MEPE cleavage.

Topics: Adolescent; Adult; Amino Acid Sequence; Animals; Calcification, Physiologic; Child; Child, Preschool; Cholecalciferol; Dentin; Extracellular Matrix Proteins; Familial Hypophosphatemic Rickets; Female; Genetic Diseases, X-Linked; Glycoproteins; Humans; Male; Molecular Sequence Data; Mutation; Peptides; PHEX Phosphate Regulating Neutral Endopeptidase; Phosphoproteins; Rats; Vitamins