Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy.

TitleCutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy.
Publication TypeJournal Article
Year of Publication2016
AuthorsLim, YH, Ovejero, D, Derrick, KM, Collins, MT, Choate, KA
Corporate AuthorsYale Center for Mendelian Genomics
JournalJ Am Acad Dermatol
Date Published2016 Aug
KeywordsAntibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Fibroblast Growth Factors, Genes, ras, Humans, Mosaicism, Nevus, Pigmented, Osteomalacia, Rickets, Hypophosphatemic, Skin Neoplasms, Syndrome

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.

LIMITATIONS: Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable.

CONCLUSION: 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.

Alternate JournalJ. Am. Acad. Dermatol.
PubMed ID27444071
PubMed Central IDPMC5004488
Grant ListU54 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States