Clinical phenotype and bone microarchitecture of cutaneous-skeletal hypophosphatemia syndrome: experience from a single center in China.

CONTEXT: Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare mosaic RASopathy characterized by epidermal or melanocytic nevi, skeletal dysplasia, and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets. However, its bone microarchitectural features remain underdefined.

OBJECTIVES

The study aimed to characterize the clinical, genetic, and skeletal microarchitectural features of CSHS.

METHODS

We summarized clinical findings of 6 CSHS patients with genetically confirmed somatic RAS mutations. Skeletal involvement was assessed by whole-body bone scintigraphy. High-resolution peripheral quantitative computed tomography parameters at the distal radius and tibia were compared with age- and sex-matched XLH controls (1:3). Literature review of 24 genetically confirmed CSHS patients was performed to assess genotype-phenotype correlation.

RESULTS

All patients were confirmed to carry somatic HRAS or NRAS mutation in affected skin. Hypophosphatemia, elevated alkaline phosphatase and elevated FGF23 were found in all patients. Genotype-phenotype correlation analysis did not identify any significant biochemical or systemic burden differences across 3 genotypes. Compared with XLH controls, CSHS patients exhibited significantly reduced total and trabecular volumetric BMD (vBMD), with relatively preserved cortical vBMD. Bone cross-sectional geometry was less expanded than in XLH at the tibia. In addition, thinner trabeculae with greater separation were found at the radius, and the distal tibia showed thinner cortices and decreased cortical porosity. Estimated bone stiffness and failure load were significantly lower at both the radius and tibia.

CONCLUSIONS

CSHS is associated with pronounced trabecular vBMD impairment and reduced bone strength compared with XLH controls. These findings are consistent with a combined contribution of intrinsic skeletal dysplasia and chronic hypophosphatemia on bone, although further studies are needed to elucidate these mechanisms.