title: Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.
abstract: Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3(1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mary Scott
authors.initials: MS
authors.lastname: Ramnitz
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Pravitt
authors.initials: P
authors.lastname: Gourh
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.affiliation: Musculoskeletal Tumor Surgery, Virginia Cancer Specialists, Fairfax, VA, USA.
authors.forename: Felasfa
authors.initials: F
authors.lastname: Wodajo
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Marcus Y
authors.initials: MY
authors.lastname: Chen
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jaydira
authors.initials: J
authors.lastname: Del Rivero
authors.affiliation: Division of Nephrology and Hypertension, Pediatric Specialists of Virginia and Georgetown University School of Medicine, Fairfax, VA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Seo-Mayer
authors.affiliation: Department of Rheumatology, Pediatric Specialists of Virginia, Fairfax, VA, USA.
authors.forename: Bita
authors.initials: B
authors.lastname: Arabshahi
authors.affiliation: Department of Pediatric Endocrinology, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: Malaka B
authors.initials: MB
authors.lastname: Jackson
authors.affiliation: Department of Pediatric Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hatab
authors.affiliation: Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: McCarthy
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lori C
authors.initials: LC
authors.lastname: Guthrie
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Brillante
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. mcollins@mail.nih.gov.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
mesh_terms: D000293:Adolescent; D000328:Adult; D002114:Calcinosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002648:Child; D015331:Cohort Studies; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D015576:Hyperostosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy; D006958:Hyperostosis, Cortical, Congenital / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy; D054559:Hyperphosphatemia / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000090265:Klotho Proteins; D008297:Male; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human
keywords: FAMILIAL TUMORAL CALCINOSIS; FIBROBLAST GROWTH FACTOR 23; HYPEROSTOSIS-HYPERPHOSPHATEMIA SYNDROME; HYPERPHOSPHATEMIA