title: A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene.
abstract: 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.
authors: Division of Pediatrics, University of Tokyo Hospital, Tokyo, Japan.
authors: Tasuku
authors: T
authors: Saito
authors: Yuichiro
authors: Y
authors: Shimizu
authors: Michiko
authors: M
authors: Hori
authors: Manabu
authors: M
authors: Taguchi
authors: Takashi
authors: T
authors: Igarashi
authors: Seiji
authors: S
authors: Fukumoto
authors: Toshiro
authors: T
authors: Fujitab
mesh_terms: D001483:Base Sequence; D002762:Cholecalciferol / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D053098:Familial Hypophosphatemic Rickets / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D015971:Gene Expression Regulation, Enzymologic; D040181:Genetic Diseases, X-Linked; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017887:Ossification of Posterior Longitudinal Ligament / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology*; D010710:Phosphates / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D012333:RNA, Messenger; D002762:Cholecalciferol; D000089703:Fibroblast Growth Factor-23; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases