title: Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.
abstract: Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
authors.affiliation: Department of Dermatology.
authors.forename: Young H
authors.initials: YH
authors.lastname: Lim
authors.forename: Diana
authors.initials: D
authors.lastname: Ovejero
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Sugarman
authors.forename: Cynthia M C
authors.initials: CM
authors.lastname: Deklotz
authors.forename: Ann
authors.initials: A
authors.lastname: Maruri
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Eichenfield
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Kelley
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.forename: Michael
authors.initials: M
authors.lastname: Gottschalk
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.forename: Alison M
authors.initials: AM
authors.lastname: Boyce
authors.forename: Edward W
authors.initials: EW
authors.lastname: Cowen
authors.forename: Nisan
authors.initials: N
authors.lastname: Bhattacharyya
authors.forename: Lori C
authors.initials: LC
authors.lastname: Guthrie
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.forename: Erin C
authors.initials: EC
authors.lastname: Loring
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Moise L
authors.initials: ML
authors.lastname: Levy
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
mesh_terms: D000293:Adolescent; D002648:Child; D059472:Exome; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017674:Hypophosphatemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009506:Nevus; D009508:Nevus, Pigmented / Q000097:blood / Q000235:genetics* / Q000473:pathology; D010018:Osteomalacia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: C000717427:FGF23 protein, human; D008565:Membrane Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)