ReviewCutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy
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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Inherited fibroblast growth factor 23 excess
2024, Best Practice and Research: Clinical Endocrinology and MetabolismPhacomatosis spilosebacea: A new name for a distinctive binary genodermatosis
2023, Journal of the American Academy of DermatologyThe efficacy and safety of burosumab in two patients with cutaneous skeletal hypophosphatemia syndrome
2023, BoneCitation Excerpt :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].
Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report
2021, Bone ReportsCitation Excerpt :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).
The phosphaturic mesenchymal tumor as a cause of oncogenic osteomalacia. Three cases and review of the literature
2021, Revista Espanola de Cirugia Ortopedica y Traumatologia
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.