title: Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment.
abstract: Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found.
  
  
  
  CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia.
  
  
  
  Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed.
  
  
  
  Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported.
  
  
  
  An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.
authors: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National ADDRESSES, references BRACKETS, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA.|Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors: D
authors: D
authors: Ovejero
authors: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors: Y H
authors: YH
authors: Lim
authors: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National ADDRESSES, references BRACKETS, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA.
authors: A M
authors: AM
authors: Boyce
authors: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National ADDRESSES, references BRACKETS, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA.
authors: R I
authors: RI
authors: Gafni
authors: Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA.
authors: E
authors: E
authors: McCarthy
authors: Albert Einstein College of Medicine, Bronx, NY, USA.|Departments of Dermatology and Pediatrics, San Diego and Rady Children's Hospital, University of California, San Diego, CA, USA.
authors: T A
authors: TA
authors: Nguyen
authors: Departments of Dermatology and Pediatrics, San Diego and Rady Children's Hospital, University of California, San Diego, CA, USA.
authors: L F
authors: LF
authors: Eichenfield
authors: Division Dermatology, Department of Medicine and Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA.
authors: C M C
authors: CM
authors: DeKlotz
authors: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National ADDRESSES, references BRACKETS, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA.
authors: L C
authors: LC
authors: Guthrie
authors: Bone Health Program, Division of Orthopaedics and Sports Medicine, Children's National Health System, Washington, DC, USA.
authors: L L
authors: LL
authors: Tosi
authors: Department of Endocrinology and Diabetes, Cook Children Medical Center, Fort Worth, TX, USA.
authors: P S
authors: PS
authors: Thornton
authors: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors: K A
authors: KA
authors: Choate
authors: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National ADDRESSES, references BRACKETS, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA. mc247k@nih.gov.
authors: M T
authors: MT
authors: Collins
mesh_terms: D001842:Bone and Bones / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D006801:Humans; D017674:Hypophosphatemia / Q000175:diagnosis* / Q000473:pathology* / Q000628:therapy; D007223:Infant; D008297:Male; D009508:Nevus, Pigmented / Q000209:etiology; D010018:Osteomalacia / Q000209:etiology; D010710:Phosphates; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000209:etiology
chemical_list: C000717427:FGF23 protein, human; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: Epidermal nevus syndrome; FGF23; Hypophosphatemic rickets; RASopathies; Skeletal dysplasia