Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

TitleMultilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsLim, YH, Ovejero, D, Sugarman, JS, Deklotz, CMC, Maruri, A, Eichenfield, LF, Kelley, PK, Jüppner, H, Gottschalk, M, Tifft, CJ, Gafni, RI, Boyce, AM, Cowen, EW, Bhattacharyya, N, Guthrie, LC, Gahl, WA, Golas, G, Loring, EC, Overton, JD, Mane, SM, Lifton, RP, Levy, ML, Collins, MT, Choate, KA
JournalHum Mol Genet
Date Published2014 Jan 15
KeywordsAdolescent, Child, Exome, Female, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, GTP Phosphohydrolases, Humans, Hypophosphatemia, Male, Membrane Proteins, Mutation, Nevus, Nevus, Pigmented, Osteomalacia, Proto-Oncogene Proteins p21(ras), Sequence Analysis, DNA, Skin, Skin Neoplasms

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.

Alternate JournalHum. Mol. Genet.
PubMed ID24006476
PubMed Central IDPMC3869357
Grant ListP30 DK079310 / DK / NIDDK NIH HHS / United States
R01 DK046718 / DK / NIDDK NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States