title: Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome.
abstract: BACKGROUND
  Hypophosphatemia and increased serum fibroblast growth factor 23 (FGF23) levels have been reported in young brothers with compound heterozygous mutations for the FAM20C gene; however, rickets was not observed in these cases. We report an adult case of Raine syndrome accompanying hypophosphatemic osteomalacia with a homozygous FAM20C mutation (R408W) associated with increased periosteal bone formation in the long bones and an increase in bone mineral density in the femoral neck.
  
  
  METHODS
  The patient, a 61-year-old man, was born from a cousin-to-cousin marriage. A short stature and severe dental demineralization were reported at an elementary school age. Hypophosphatemia was noted inadvertently at 27years old, at which time he started to take an active vitamin D metabolite (alphacalcidol) and phosphate. He also manifested ossification of the posterior longitudinal ligament. On bone biopsy performed at the age of 41years, we found severe osteomalacia surrounding osteocytes, which appeared to be an advanced form of periosteocytic hypomineralized lesions compared to those reported in patients with X-linked hypophosphatemic rickets. Laboratory data at 61years of age revealed markedly increased serum intact-FGF23 levels, which were likely to be the cause of hypophosphatemia and the decreased level of 1,25(OH)2D. We recently identified a homozygous FAM20C mutation, which was R408W, in this patient. When expressed in HEK293 cells, the R408W mutant protein exhibited impaired kinase activity and secretion.
  
  
  CONCLUSIONS
  Our findings suggest that certain homozygous FAM20C mutations can cause FGF23-related hypophosphatemic osteomalacia and indicate the multiple roles of FAM20C in bone.
authors: Department of Pediatrics, Minoh City Hospital, Osaka 562-8562, Japan.
authors: Shinji
authors: S
authors: Takeyari
authors: Department of Pediatrics, Minoh City Hospital, Osaka 562-8562, Japan. Electronic address: t.yamamoto@minoh-hp.jp.
authors: Takehisa
authors: T
authors: Yamamoto
authors: Division of Nephrology and Endocrinology, Department of Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors: Yuka
authors: Y
authors: Kinoshita
authors: Division of Nephrology and Endocrinology, Department of Medicine, The University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors: Seiji
authors: S
authors: Fukumoto
authors: Genetics Unit, Shriners Hospitals for Children, Montreal H3G 1A6, Canada.
authors: Francis H
authors: FH
authors: Glorieux
authors: Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1011, Japan.
authors: Toshimi
authors: T
authors: Michigami
authors: Department of Pediatrics, Okayama University Hospital, Okayama 700-8558, Japan.
authors: Kosei
authors: K
authors: Hasegawa
authors: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors: Taichi
authors: T
authors: Kitaoka
authors: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors: Takuo
authors: T
authors: Kubota
authors: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
authors: Yasuo
authors: Y
authors: Imanishi
authors: Department of Pediatrics, Minoh City Hospital, Osaka 562-8562, Japan.
authors: Tsunesuke
authors: T
authors: Shimotsuji
authors: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors: Keiichi
authors: K
authors: Ozono
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D047389:Casein Kinase I / Q000235:genetics*; D002972:Cleft Palate / Q000150:complications* / Q000235:genetics; D005094:Exophthalmos / Q000150:complications* / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D017674:Hypophosphatemia / Q000150:complications / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000150:complications* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010018:Osteomalacia / Q000150:complications / Q000235:genetics*; D010026:Osteosclerosis / Q000150:complications* / Q000235:genetics; D012598:Sclerosis / Q000150:complications / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D047389:Casein Kinase I; C524449:FAM20C protein, human
keywords: Cortical hyperostosis; FAM20C; FGF23; Hypophosphatemic rickets; Loss of teeth; OPLL