Murine models of HRAS-mediated cutaneous skeletal hypophosphatemia syndrome suggest bone as the FGF23 excess source

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and FGF23-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels. This study aims to elucidate whether the source of FGF23 excess in CSHS is RAS mutation-bearing bone or skin lesions. Toward this end, we analyzed the expression and activity of Fgf23 in two mouse models expressing similar HRAS/Hras activating mutations in a mosaic-like fashion in either bone or epidermal tissue. We found that HRAS hyperactivity in bone, not skin, caused excess of bioactive intact FGF23, hypophosphatemia, and osteomalacia. Our findings support RAS-mutated dysplastic bone as the primary source of physiologically active FGF23 excess in patients with CSHS. This evidence informs the care of patients with CSHS, arguing against the practice of nevi removal to decrease circulating, physiologically active FGF23.

Automated summary

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a disorder characterized by dysplastic skeletal lesions, congenital skin nevi, and FGF23-mediated hypophosphatemia. This study found that RAS-mutated dysplastic bone, not skin, is the primary source of excess FGF23 in CSHS patients. These findings have implications for the treatment of CSHS patients and argue against the removal of skin lesions to decrease FGF23 levels.