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.

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

“…CSHS features epidermal or melanocytic nevi and hypophosphatemic rickets with elevated levels of a serum phosphatonin, fibroblast growth factor-23 (FGF23) [13]. Patients often require phosphate and calcitriol supplementation to maintain mineral homeostasis.…”

“…Our investigation included 5 CSHS patients (CSHS101-105, Table 1), with keratinocytic, sebaceous, or giant congenital melanocytic nevi (GCMN) occurring in association with hypophosphatemic rickets [13]. All epidermal nevi appeared in a Blaschkoid pattern, while the GCMN had a coat-like pattern.…”

“…While some case reports suggest a therapeutic response, the results are confounded by concomitant oral medication or lack of follow-up. CSHS/nevus syndrome patients may undergo potentially painful removal procedures with no improvement [13, 19]. Not all patients in whom phosphate levels normalized were subject to nevi removal and there is evidence that phosphaturia improves over time [44].…”

Stability and degradation of fibroblast growth factor 23 (FGF23): the effect of time and temperature and assay type

“…Deranged levels of circulating FGF23 have been found in several diseases of phosphate metabolism, such as tumor-induced osteomalacia (TIO) [3], X-linked hypophosphatemic rickets (XLH) [3], autosomal dominant hypophosphatemic rickets (ADHR) [1], autosomal recessive hypophosphatemic rickets (ARHR) [4], fibrous dysplasia (FD) [5], hyperphosphatemic familial tumoral calcinosis (FTC) [6], and the recently described cutaneousskeletal hypophosphatemia syndrome (CSHS) [7]. FGF23 levels are also markedly elevated in patients with end-stage renal disease [8].…”

1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

“…(1) Alterations in FGF23 levels were subsequently identified as the common abnormality in a number of phosphate homeostasis disorders, including X-linked hypophosphatemic rickets (XLH), (2) tumor-induced osteomalacia (TIO), (3) fibrous dysplasia of bone, (4) autosomal recessive hypophosphatemic rickets (ARHR), (5) cutaneous skeletal hypophosphatemia syndrome (CSHS), (6) familial tumoral calcinosis, (7) and others. The primary actions of FGF23 are to regulate blood phosphate and 1,25-dihydroxyvitamin D 3 (1,25-D) levels by its actions on renal sodium/phosphate cotransporters and 25-hydroxyvitamin D hydroxylation.…”