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

Yale Center for Mendelian Genomics

Research output: Contribution to journalReview articlepeer-review

26 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)420-427
Number of pages8
JournalJournal of the American Academy of Dermatology
Issue number2
StatePublished - Aug 1 2016
Externally publishedYes


  • congenital melanocytic nevus
  • cutaneous skeletal hypophosphatemia syndrome
  • epidermal nevus
  • fibroblast growth factor-23
  • mosaicism
  • nevus syndrome
  • rickets

ASJC Scopus subject areas

  • Dermatology


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