title: Raine Syndrome (OMIM #259775), Caused By FAM20C Mutation, Is Congenital Sclerosing Osteomalacia With Cerebral Calcification (OMIM 259660).
abstract: In 1985, we briefly reported infant sisters with a unique, lethal, autosomal recessive disorder designated congenital sclerosing osteomalacia with cerebral calcification. In 1986, this condition was entered into Mendelian Inheritance In Man (MIM) as osteomalacia, sclerosing, with cerebral calcification (MIM 259660). However, no attestations followed. Instead, in 1989 Raine and colleagues published an affected neonate considering unprecedented the striking clinical and radiographic features. In 1992, "Raine syndrome" entered MIM formally as osteosclerotic bone dysplasia, lethal (MIM #259775). In 2007, the etiology emerged as loss-of-function mutation of FAM20C that encodes family with sequence similarity 20, member C. FAM20C is highly expressed in embryonic calcified tissues and encodes a kinase (dentin matrix protein 4) for most of the secreted phosphoproteome including FGF23, osteopontin, and other regulators of skeletal mineralization. Herein, we detail the clinical, radiological, biochemical, histopathological, and FAM20C findings of our patients. Following premortem tetracycline labeling, the proposita's non-decalcified skeletal histopathology after autopsy indicated no rickets but documented severe osteomalacia. Archival DNA revealed the sisters were compound heterozygotes for a unique missense mutation and a novel deletion in FAM20C. Individuals heterozygous for the missense mutation seemed to prematurely fuse their metopic suture and develop a metopic ridge sometimes including trigonocephaly. Our findings clarify FAM20C's role in hard tissue formation and mineralization, and show that Raine syndrome is congenital sclerosing osteomalacia with cerebral calcification. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.|Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.affiliation: Department of Pediatric Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.affiliation: Department of Surgical Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fallon
authors.affiliation: Department of Pediatrics, University of Minnesota School of Medicine, and Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
authors.forename: Mary Ella
authors.initials: ME
authors.lastname: Pierpont
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.
authors.forename: Vinieth N
authors.initials: VN
authors.lastname: Bijanki
authors.affiliation: Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Duan
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.|Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.|Department of Clinical Genetics, Division of Human Genetics and Genome Research, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Ghada A
authors.initials: GA
authors.lastname: Otaify
authors.affiliation: E.A. Doisey Department of Biochemistry, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.|Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D000328:Adult; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism; D054022:Cerebrum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D002972:Cleft Palate / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D005094:Exophthalmos / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008831:Microcephaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D010018:Osteomalacia / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D010026:Osteosclerosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; D047389:Casein Kinase I; C524449:FAM20C protein, human
keywords: CRANIOFACIAL DYSOSTOSIS; CRANIOSYNOSTOSIS; CROUZON SYNDROME; DENTIN MATRIX PROTEIN; HYPOPHOSPHATEMIA; KINASE; METOPIC SUTURE; MINERALIZATION; OSTEOMALACIA; OSTEOPETROSIS; OSTEOPONTIN; OSTEOSCLEROSIS; PHOSPHOPROTEOME; RICKETS; SIBLING PROTEINS; TRIGONOCEPHALY