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

Abstract

Background We recently demonstrated multilineage somatic mosaicism in cutaneous-skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor-23 (FGF23) and hypophosphatemia, finding identical RAS mutations in affected skin and bone. Objective 1) To provide an updated overview of CSHS; 2) To review its pathobiology; 3) To present a new CSHS patient; and 4) To 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 FGF23. For our additional CSHS patient, 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.G13R mutation in affected tissue, consistent with previous findings. While the mechanism of FGF23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF23 antibody KRN23 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 FGF23. Further studies investigating the role of RAS in FGF23 regulation are needed.

Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis

“…However, NRAS p.Q61R mutation has never been identified in Noonan syndrome patients, suggesting that patients with germline p.Q61R mutation do not survive to birth because of its strong activation of the downstream pathway. In mosaic RASopathies, NRAS p.Q61R mutations have been identified in a patient with Schimmelpenning syndrome [19], patients with neurocutaneous melanosis [20], and patients with cutaneous–skeletal hypophosphatemia syndrome [21]. These results suggest that somatic or mosaic NRAS p.Q61R mutations cause a broad spectrum of disorders, which depend on the lineages or cells in which they occur.…”

Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment

“…Cutaneous skeletal hypophosphatemia syndrome (CSHS) refers to the association of epidermal and/or melanocytic nevi, mosaic skeletal dysplasia, and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia [1]. We reported the finding of somatic activating RAS mutations in nevoid skin and dysplastic bone in six CSHS subjects establishing a role of RAS hyperactivity in the syndrome’s pathogenesis [1, 2]. However, the clinical spectrum and natural history of this disease remain poorly described.…”

Rickets in association with skin diseases and conditions: A review with emphasis on screening and prevention

“…49 Hypophosphatemic rickets was described in patients with extensive epidermal and/or melanocytic nevi and phakomatosis pigmentokeratotica. [50][51][52][53][54][55][56][57][58][59][60] Strikingly, all these cases share the same features (…”

“…Cutaneous skeletal hypophosphatemia syndrome is caused by somatic mutations in RAS genes (NRAS or HRAS) in the affected skin (epidermal and congenital melanocytic nevi) and the underlying dysplastic bone 56. Dysplastic bone is likely to be the source of FGF23 overproduction 49,56,57,58. However, it is unclear whetherFGF 23 was secreted by RAS mutant or wild type mesenchymal cells of the dysplastic bone.…”