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

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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.

Section snippets

Genetic mosaicism

Mosaic organisms harbor 2 or more genetically distinct cell types. The generation of a mosaic requires a nonlethal somatic mutation in 1 cell of a developing embryo; this mutant cell divides and gives rise to mutant daughters that populate 1 or more parts of the organism.1 Germline mosaicism occurs when a mutation affects germ cell progenitors, allowing the mutation to be inherited by subsequent generations, whereas pure somatic mosaicism spares germ cells and is thus noninheritable. Genetic

Nevus syndromes: a spectrum of genetic mosaicism

Congenital melanocytic nevi and epidermal nevi that include both keratinocytic and sebaceous subtypes are examples of somatic mosaicism arising via postzygotic activating RAS mutations.2, 3, 4 Laser capture microdissection and whole exome sequencing found causative RAS mutations in epidermal keratinocytes and sebocytes of the lesions, whereas the underlying dermis, blood leukocytes, and adjacent, unaffected skin were wild type. In phacomatosis pigmentokeratotica, RAS mutations are found in both

Cutaneous skeletal hypophosphatemia syndrome

Cutaneous skeletal hypophosphatemia syndrome (CSHS) features epidermal or melanocytic nevi and hypophosphatemic rickets with elevated levels of a serum phosphatonin, fibroblast growth factor (FGF)-23.13 Patients often require phosphate and calcitriol supplementation to maintain mineral homeostasis.

In 1977, Aschinberg et al14 reported the first case of CSHS in a 5-year-old boy with linear verrucous nevi and severe rickets. Serum phosphate and tubular resorption of phosphate were low, indicating

FGF-23 in CSHS

FGF-23 is a 30-kd phosphatonin normally secreted from osteocytes, which regulates both phosphate and vitamin-D homeostasis by modulating the expression of renal phosphate transporters and calcitriol-metabolizing enzymes, respectively.20, 21, 22, 23, 24 Transgenic mice that overexpress FGF-23 demonstrate reduced levels of sodium phosphate cotransporter 2a (NaPi-2a) and 2c (NaPi-2c) in the proximal tubules, increasing urinary excretion of phosphate, whereas ablation of FGF-23 leads to

Management of CSHS

Given our current understanding of the pathogenesis of CSHS, excision or ablation of nevi as treatment for hypophosphatemia is not advised. Although some case reports suggest a therapeutic response, the results are confounded by concomitant oral medication or lack of follow-up. Patients with CSHS/nevus syndrome 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

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      In most patients with CSHS, these features lead to frequent fractures, limb deformities, and scoliosis [1,5]. Despite the original hypothesis that epidermal nevi were the origin of FGF23, excision of affected skin areas does not correct phosphorus metabolism, and neither FGF23 protein nor mRNA have been detected in these lesions [1,6]. Therefore, removal of skin lesions subjects patients to potentially painful surgical procedures with no clear symptomatic improvement [1,6].

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      These focal changes also have extensive unmineralized osteoid, characteristic of osteomalacia (de Castro et al., 2020). The DNA from the dysplastic bone lesions, but not healthy lamellar bone tissue, harbor the same HRAS or NRAS mutations that are found in DNA extracted from the nevoid skin cells or circulating leucocytes (Lim et al., 2016). It is known that gain-of-function mutations in members of the RAS signaling pathway cause the increased expression of FGF23 through increased activation of the fibroblast growth factor receptor 1 (de Castro et al., 2020).

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    Supported in part by a Clinical Scientist Development Award (Dr Choate) and Medical Student Research Fellowship (Mr Lim) from the Doris Duke Charitable Foundation, the Medical Scientist Training Program at Yale University (National Institutes of Health T32 GM007205) (Mr Lim), and the Yale Center for Mendelian Genomics (National Institutes of Health U54 HG006504).

    Conflicts of interest: None declared.

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