Skeletal changes in epidermal nevus syndrome: Does focal bone disease harbor clues concerning pathogenesis?

Heike, Carrie L.; Cunningham, Michael L.; Steiner, Robert D.; Wenkert, Deborah; Hornung, Robin L.; Gruss, Joseph S.; Gannon, Francis H.; McAlister, William H.; Mumm, Steven; Whyte, Michael P.

doi:10.1002/ajmg.a.30915

Cited by 45 publications

(49 citation statements)

References 68 publications

(79 reference statements)

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“…A subset of these patients have ipsilateral focal bone disease associated with hypophosphatemic rickets, elevated circulating FGF23 levels, and aberrant 1,25(OH) 2 D levels, similar to other syndromes that are caused by elevated FGF23. Treatment with the somatostatin agonist octreotide and excision of the nevus have been reported to normalize FGF23 (63)(64)(65).…”

Section: Sporadic/acquired Disordersmentioning

confidence: 99%

How Fibroblast Growth Factor 23 Works

Liu

Quarles

2007

Journal of the American Society of Nephrology

366

341

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There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1 Fibroblast Growth Factor 23 Gene and Protein StructureThe fibroblast growth factor (FGF) family consists of 22 members with varied functions (2). FGF23 is an approximately 32-kD (251 amino acids) protein with an N-terminal region that contains the FGF homology domain and a novel 71-amino acid C-terminus that was originally discovered by homology-based PCR screening of a mouse embryonic cDNA library (3). The FGF23 gene is located on Chr 12p13 and is phylogenetically grouped with FGF19 and 21 gene products (2,3), with which it has approximately 24% and approximately 22% amino acid identities, respectively. FGF23 principally acts as a phosphaturic factor and suppressor of 1␣-hydroxylase activity in the kidney (4,5), making it functionally distinct from other members of this family. Tissue Expression and Function: Evidence for a Bone-Kidney AxisFGF23 is predominately expressed in osteocytes in bone (6,7), but it is also expressed in pericyte-like cells that surround the venous sinuses in the bone marrow, in the ventrolateral thalamic nucleus, and in thymus and lymph nodes (Figure 1). The relative contribution of these sites to circulating FGF23 levels is not known, but the high levels of expression in the osteocyte and that osteocytes are the most abundant cell in bone suggest that the serum levels of FGF23 are derived mainly from bone. In addition, the production of FGF23 by osteocytes, cells that are central to the regulation of osteoblast function and mineralization, likely has functional significance (8). In this regard, osteocytes secrete sclerostin, an inhibitor of bone formation and the phosphaturic factor FGF23, as well as other gene products, such as phosphate-regulating endopeptidase homolog, X-linked (Phex), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE), that regulate bone mineralization and FGF23 expression. Phex is a type I cell surface zinc metalloprotease that is involved in the regulation of FGF23 levels and is mutated in X-linked hypophosphatemic rickets (9). Both DMP1 and MEPE are glycophosphoproteins that belong to the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. MEPE and DMP1 are predominately expressed in bones and/or teeth, where they respectively inhibit and induce mineralization of extracellular matrix (10). These associations suggest that osteocytes coordinate osteoblast-mediated bone formation with renal regulation of systemic phosphate homeostasis through the regu...

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Section: Sporadic/acquired Disordersmentioning

confidence: 99%

How Fibroblast Growth Factor 23 Works

Liu

Quarles

2007

Journal of the American Society of Nephrology

366

341

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“…Linear sebaceous or epidermal nevus syndrome (ENS) is caused by a mosaicism of activating FGFR3 mutations in the human epidermis in some patients (101). A subset of these patients have ipsilateral focal bone disease associated with hypophosphatemic rickets, elevated circulating FGF23 levels, and aberrant 1,25(OH) 2 D levels, similar to other syndromes caused by elevated FGF23 (102).…”

Section: Role Of Fgf23 In Our Understanding Of Disorders Of Phosphatementioning

confidence: 99%

Endocrine functions of bone in mineral metabolism regulation

2008

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Biological importance of phosphate regulationIntracellular phosphate is involved in intermediary metabolism and other essential cellular functions (1), whereas extracellular phosphate is necessary for matrix mineralization (2). Since both extremes of hypophosphatemia and hyperphosphatemia have negative effects (1, 3), adaptive mechanisms have evolved to protect organisms from hypophosphatemia and hyperphosphatemia and to coordinate the changing phosphate needs for bone mineralization and phosphate homeostasis. Historically, phosphate homeostasis has been viewed from the perspective of the parathyroid hormone/1,25-dihydroxy vitamin D [PTH/1,25(OH) 2 D] axis, which regulates both systemic calcium and phosphate homeostasis ( Figure 1A). In response to hypocalcemia, the parathyroid gland (PTG) increases the production and secretion of PTH, which targets the renal distal tubule to decrease renal calcium excretion and the proximal tubule to inhibit phosphate reabsorption and to stimulate 1,25(OH) 2 D production. Action of 1,25(OH) 2 D on the small intestines increases active calcium and phosphate transport (4). PTH also has direct effects on bone via PTH receptors in osteoblasts, resulting in increased calcium and phosphate efflux from the exchangeable bone fluid compartment (5) and through RANKL-dependent, osteoclast-mediated bone resorption of mineralized bone (6). The direct kidney and bone effects of PTH, along with the concomitant actions of 1,25(OH) 2 D, restore serum calcium levels to normal. The phosphaturic actions of PTH offset vitamin D-mediated gastrointestinal phosphate absorption (4) and PTH-dependent phosphate efflux from bone (7), thereby preventing the development of hyperphosphatemia.Recently, a novel hormonal cascade involving FGF23 and Klotho has been identified that principally regulates phosphate, vitamin D homeostasis, and mineralization of bone ( Figure 1B) (8-13). FGF23 and Klotho participation in a bone-kidney axisFGF23 is a 32-kDa protein with an N-terminal region, containing the FGF-homology domain and a novel 71-amino acid C terminus (8, 9). FGF23 is phylogenetically grouped with FGF19 (mouse FGF15) and FGF21 gene products (8, 10), members of a subfamily of FGFs that act as hormones/systemic factors due to their ability to interact with FGF receptor (FGFR) in the presence of members of the Klotho family of proteins. FGF23 binds to Klotho (KL), which encodes a type I membrane, β-glycosidase-like protein (11, 12) that is an essential cofactor for FGF23 binding to . In vitro studies indicate that the N-terminal region of FGF23 binds to and activates FGFR1, -3, and -4 at physiological concentrations only in the presence of Klotho, which binds to FGFR and the C terminus of FGF23 to convert the canonical FGFRs to a specific receptor for FGF23 (14)(15)(16). This is in contrast with the more typical paracrine/local functions of other FGFs that require extracellular acidic glycosaminoglycans (e.g., heparin) for receptor activation (17).FGF23 principally functions as a phosphaturic factor (9, 18, 19...

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“…In this sense, the FGF23 level would be helpful in the workup of this type of rickets (Dermatologia et The skeletal changes associated with ENS were highly addressed in a study conducted in 2005. The study gathered 27 case reports of patients with ENS in addition to different types of skeletal abnormalities, such as osteopenia, osteoporosis, osteomalacia, rickets, Cystic lesions and fractures or pseudo-fractures (Heike et al 2005). …”

Section: Discussion:-mentioning

confidence: 99%

“…Typically, ENS has complex and highly variable phenotypes that cause focal or generalized skeletal disease. The skeletal changes include bone cysts, kyphoscoliosis, joint, vitamin-D-resistant rickets, cranial deformities (Heike et al 2005;Aschinberg et al 1977). Hypophosphatemic rickets is considered a rare presentation of ENS.…”

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confidence: 99%