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

Ovejero, Diana; Lim, Young Hee; Boyce, Alison M.; Gafni, Rachel I; McCarthy, Edward F.; Nguyen, Thao Thi Thu; Eichenfield, Lawrence F.; DeKlotz, Cynthia M. C.; Guthrie, Lori C.; Tosi, Laura L.; Thornton, Paul; Choate, Keith; Collins, Michael T.

doi:10.1007/s00198-016-3702-8

Cited by 50 publications

(49 citation statements)

References 58 publications

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“…Notably, the mosaic metabolic bone disorder “cutaneous skeletal hypophosphatemia syndrome”, that comprises epidermal/melanotic nevus associated with FGF23 overproduction and thus hypophosphatemic bone disease, (73) is caused by postzygotic activating NRAS or HRAS mutations in codons 13 and 61. (37) However, in 2016, (73) no direct evidence seemed to implicate the nevi of this disorder in its hypophosphatemia.…”

Section: V) Discussionmentioning

confidence: 99%

“…(37) However, in 2016, (73) no direct evidence seemed to implicate the nevi of this disorder in its hypophosphatemia. Indeed, in 2005, we had postulated (56) instead that the hypophosphatemia emanated from the associated focal skeletal lesions in this disorder.…”

Section: V) Discussionmentioning

confidence: 99%

“…Our current patient with a large LEN instead harbors at codon 61 a postzygotic KRAS mutation, and showed no rickets radiographically and had normal blood levels of phosphorus and FGF23. (73) Thus, why he manifested MEL and SLS remains puzzling, but he carried a germline LEMD3 defect as well.…”

Section: V) Discussionmentioning

confidence: 99%

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Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS

Whyte

Griffith

Trani

et al. 2017

Bone

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Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3 gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient’s mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of him and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using five algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.

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Section: V) Discussionmentioning

confidence: 99%

Section: V) Discussionmentioning

confidence: 99%

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Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS

Whyte

Griffith

Trani

et al. 2017

Bone

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“…These therapies, however, are not currently available for clinical use. In addition, strategies to increase phosphate levels include use of calcitriol to increase gut phosphate absorption and have also been recommended recently [13,17,18]. Further understanding of the pathways involved will allow for a more precise treatment and allow patients such as this one not only to reduce recurrent stress fractures but also to enjoy a better quality of life.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 23 and Hypophosphatemia: A Case of Hypophosphatemia along the Rickets-Osteomalacia Spectrum

et al. 2016

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Phosphorus is a key component of bone, and a deficiency results in poor mineralization along with other systemic symptoms of hypophosphatemia. Various causes of hypophosphatemia with renal wasting of phosphorus have been identified. These include the Fanconi syndrome, various genetic mutations of fibroblast growth factor 23 (FGF23) handling and the sodium/phosphate cotransporter, and those due to FGF23 secretion by mesenchymal tumors. Depending on the cause, vitamin D metabolism may also be impaired, which may amplify the deficiency in phosphorus and render treatment more challenging. Here, we report a case of hypophosphatemia and multiple stress fractures in a 20-year-old male college student living with chronic bone pain and anxiety about suffering further fractures. We further review the literature regarding this spectrum.

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“…Elevated plasma FGF23 concentrations cause the hypophosphatemia and resultant osteomalacia . Although the skin lesions were proposed as the source of FGF23 and some studies suggested improvement in hypophosphatemia after resection of the nevus, subsequent studies have not demonstrated convincing improvement after resection of these generally large skin lesions . In contrast, the FGF23 expression was not detectable in the skin lesions .…”

Section: Conditions Of Localized Increased Fgf23 Productionmentioning

confidence: 99%

FGF23, Hypophosphatemia, and Emerging Treatments

2019

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FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co‐receptor Klotho, it modulates phosphate reabsorption and both 1α‐hydroxylation and 24‐hydroxylation in the renal proximal tubules. The most common FGF23‐mediated hypophosphatemia is X‐linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23‐mediated forms of hypophosphatemia are characterized by phosphaturia and low or low‐normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23‐mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor‐induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23‐mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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

Abstract: An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.

Cited by 50 publications

References 58 publications

Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS

Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS

Fibroblast Growth Factor 23 and Hypophosphatemia: A Case of Hypophosphatemia along the Rickets-Osteomalacia Spectrum

FGF23, Hypophosphatemia, and Emerging Treatments

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