title: Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy.
abstract: BACKGROUND
  We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone.
  
  
  OBJECTIVE
  We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3) present a new patient with CSHS; and (4) discuss treatment modalities.
  
  
  METHODS
  We searched PubMed for "nevus AND rickets," and "nevus AND hypophosphatemia," identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations.
  
  
  RESULTS
  Our new case harbored somatic activating HRAS p.G13 R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS.
  
  
  CONCLUSIONS
  Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable.
  
  
  CONCLUSIONS
  Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed.
authors.affiliation: Departments of Dermatology, Pathology, and Genetics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Young H
authors.initials: YH
authors.lastname: Lim
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Ovejero
authors.affiliation: Division of Pediatric Endocrinology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Derrick
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Disease Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.affiliation: Departments of Dermatology, Pathology, and Genetics, Yale University School of Medicine, New Haven, Connecticut. Electronic address: keith.choate@yale.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D009030:Mosaicism; D009508:Nevus, Pigmented / Q000188:drug therapy / Q000235:genetics*; D010018:Osteomalacia / Q000188:drug therapy / Q000235:genetics*; D063730:Rickets, Hypophosphatemic / Q000188:drug therapy / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics*; D013577:Syndrome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C000601956:burosumab
keywords: congenital melanocytic nevus; cutaneous skeletal hypophosphatemia syndrome; epidermal nevus; fibroblast growth factor-23; mosaicism; nevus syndrome; rickets