Fibrous Dysplasia

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The immature trabeculae are usually not lined with osteoblasts (as in ossifying fibroma) ... can be detected in the peripheral blood of 75 to 90% of patients using ...

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Fibrous Dysplasia Steven A. Lietman1, MD, Michael A. Levine2, MD 1Co-Director, Musculoskeletal Tumor Center, Cleveland Clinic, Cleveland, OH, 2Chief, Division of Endocrinology and Diabetes;

Director, Center for Bone Health, The Children’s Hospital of Philadelphia, Philadelphia, PA; Professor of Pediatrics and Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA Corresponding Author: Steven A. Lietman, MD, Co-Director of the Musculoskeletal Tumor Center, Cleveland Clinic Main Campus Mail Code A41, 9500 Euclid Avenue Cleveland, OH 44195, Tel: 216.444.2606, Email: [email protected]

Abstract

F

ibrous dysplasia is a developmental abnormality of bone that is characterized by a highly disorganized mixture of immature fibrous tissue and fragments of immature trabecular bone. Fibrous dysplasia may arise as a single, discrete (monostotic) lesion or can occur with a more widespread distribution with multiple lesions that affect many bones (oligoor polyostotic). Fibrous dysplasia is usually an isolated skeletal finding but can sometimes occur as a component of a multisystem developmental disorder known as McCune-Albright syndrome (MAS) that is also associated with endocrine hyperfunction (e.g. precocious puberty) and café au lait cutaneous macules. The identification of activating mutations in GNAS in a subset of human GH-secreting pituitary tumors and autonomously functioning human thyroid tumors provided the initial basis for understanding the molecular pathophysiology of McCune-Albright syndrome and fibrous dysplasia. These observations led to the concept that activating mutations of the GNAS gene convert it into a putative oncogene referred to as gsp(Gsα or Gαs). The classic radiographic feature of fibrous dysplasia is a h a z y, r a d i o l u c e n t , o r g r o u n d - g l a s s , p a t t e r n resulting from the defective mineralization of immature dysplastic bone; it is usually strikingly different from the radiographic appearance of normal bone, calcified cartilage, or soft tissue. The surgical approach to fibrous dysplasia should

in general be conservative. Recent research suggests that the Wnt/β-catenin pathway may play a role in fibrous dysplasia as patients with activating GNAS mutations specifically showed that Gαs mutations activated Wnt/βcatenin signaling. Thus inhibition of β-catenin signaling or silencing GNAS alleles that encode constitutively active Gsα molecules in fibrous dysplasia and McCune-Albright syndrome offer potential therapeutic promise and deserve further study. In summary fibrous dysplasia is a developmental abnormality of bone with a known molecular etiology; Further knowledge about the molecular pathology of fibrous dysplasia may lead to improved conservative therapies in the near future. Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 389-396 Key Words: McCune-Albright syndrome, GNAS, bisphosphonates, denosumab, Wnt/β-catenin pathway, gsp mutation

Clinical Features Fibrous dysplasia (OMIM 174800) is a developmental abnormality of bone that is characterized by a highly disorganized mixture of immature fibrous tissue and fragments of immature trabecular bone. Fibrous dysplasia may arise as a single, discrete (monostotic) lesion or can occur with a more widespread distribution with multiple lesions that affect many bones (oligo- or polyostotic). Fibrous dysplasia is usually an isolated skeletal finding but can sometimes occur as a component of a multisystem

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Fibrous Dysplasia Bone Involvement Single Monostotic X Polyostotic McCune-Albright Disease Mazabraud Disease

Multiple

Café Au Lait spots

Endocrine disorders Soft Tissue Masses

X X X

X

X X

Table 1: Fibrous Dysplasia Presentation

developmental disorder known as McCune-Albright syndrome (MAS) that is also associated with endocrine hyperfunction (e.g. precocious puberty) and café au lait cutaneous macules.(Table 1) (1, 2) In addition, fibrous dysplasia lesions can occur in patients who have intramuscular myxomas, an association now known as Mazabraud syndrome.(3) Fibrous dysplasia accounts for 7% of benign bone tumors and most commonly arises during periods of bone growth in older children and adolescents. Enlargement of lesions is slow and the natural history of fibrous dysplasia is highly variable(4), but spontaneous regression of lesions does not occur. Lesions may remain stable for decades, but can also progress relentlessly, and result in multiple fractures and severe bone deformities. Most patients are diagnosed with fibrous dysplasia in the first three decades of life. Fibrous dysplasia is somewhat more common in females, with onset typically during adolescence.(5) Fibrous dysplasia can occur anywhere but is usually found in the proximal femur, tibia, humerus, ribs, and craniofacial bones in decreasing order of incidence. Monostotic fibrous dysplasia accounts for 75 to 80% of cases. Monostotic lesions most commonly occur in the proximal femur, proximal tibia, mandible, and ribs, and many patients with monostotic fibrous dysplasia are asymptomatic.(5) Polyostotic disease usually presents earlier and may be unilateral or widespread, and can affect multiple adjacent bones or multiple extremities. The result of the dysplastic process is a weakened bone that becomes deformed by normal stress or sustains a pathologic fracture. Painful stress fractures are especially common in the proximal femur. While the dysplastic bone in fibrous dysplasia heals at a normal rate after fracture, the resulting callus is also dysplastic, and the disease persists and the deformity may worsen.(6) Extensive proximal femoral involvement results in the distinctive “shepherd’scrook” deformity that is characteristic of fibrous dysplasia. (6) In some cases, bone may be further weakened due to impaired mineralization that results from hypophosphatemia induced by excessive production of FGF-23. (Figures 1 & 2)

from analyses of patients with McCune-Albright syndrome. Early investigators noted that the pattern of cutaneous lesions in patients with McCune-Albright syndrome follow the developmental lines of Blaschko with dorso-ventral outgrowth of two different populations of cells during early embryogenesis.(7) These observations led to the hypothesis that the disease represents a post-zygotic mutation with subsequent mosaic distribution. As all cases of McCuneAlbright syndrome are sporadic, a further refinement was the proposal that germline transmission of the mutation would be lethal in utero. The identification of activating mutations in GNAS in a subset of human GH-secreting pituitary tumors and autonomously functioning human thyroid tumors provided the initial basis for understanding the molecular pathophysiology of McCune-Albright syndrome and fibrous dysplasia.(8, 9) These somatic mutations in GNAS were missense mutations that led to amino acid substitutions for Arg201 in exon 8 and Gln227 in exon 9. The abnormal Gαs proteins have markedly reduced GTPase activity and are able to stimulate adenylyl cyclase to synthesize the second messenger cyclic AMP constitutively, i.e., in the absence of ligands that are normally required to activate G-protein coupled receptor signaling. These observations led to the concept that activating mutations of the GNAS gene convert it into a putative oncogene referred to as gsp.(8, 9) Because the affected tissues in McCune-Albright syndrome exhibit excessive cellular growth or function that might be explained by autonomous overproduction

Molecular Pathology Insights into the molecular pathology of fibrous dysplasia have come from both direct study of the bone lesions and

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Fibrous Dysplasia of cyclic AMP, investigators sought gsp mutations in these patients. The initial hypothesis that McCune-Albright syndrome was caused by a post-zygotic somatic mutation was fulfilled when it was demonstrated that cells within affected endocrine tissues, café au lait macules, and fibrous dysplasia lesions, but not adjacent normal tissues, contained gsp mutations that led to replacement of Arg201, typically by His or Cys.(10, 11) Other mutations that replace Arg201 of GNAS have rarely been identified in patients with MAS. To date, no mutations in Gln227 have been reported in patients with MAS. The extent of mosaicism with cells containing the gsp mutation is variable from patient to patient, and correlates with the severity of the clinical phenotype of MAS. These observations suggest that a somatic mutation that arises within the inner cell mass early in development may lead to a more widespread distribution of abnormal cells and a greater number of affected tissues and bone lesions. Skeletal lesions from patients with isolated fibrous dysplasia also contain gsp mutations, primarily affecting Arg201(12) but also Gln227 in a small subset of patients.(13) The development of fibrous dysplasia is associated with the presence of the gsp mutation in skeletal progenitors, which leads to persistent proliferation and either incomplete or dysfunctional differentiation of osteoblastic precursors. (14) Moreover, in the growth plate cyclic AMP prevents chondrocyte differentiation.(15) Fibrous dysplasia lesions are complex collections of multiple cell types. The fibrotic areas consist of an excess of cells with phenotypic features of pre-osteogenic cells, whereas the lesional bone formed de novo within fibrotic areas represents the biosynthetic output of mature but abnormal osteoblasts. Fibrous dysplasia lesions contain cells that over express c-fos (12), which is most likely the result of the increased production of cyclic AMP in bone cells with the gsp mutations. c-Fos is a cellular protooncogene belonging to the immediate early gene family of transcription factors. Transcription of c-Fos is upregulated in response to many extracellular signals such as growth factors. In addition, phosphorylation by MAP kinase, protein kinase A or protein kinase C, and cdc2 alters the activity and stability of c-Fos. Members of the Fos family dimerize with C-jun to form the AP-1 transcription factor which upregulates transcription of a diverse range of genes involved in proliferation and differentiation. On a cellular level, the result is abnormal osteoblast differentiation and increased osteoclastic activity. Fibrous dysplasia appears to be a disease of the osteogenic lineage.(16) The proliferative cells in the marrow stroma express alkaline phosphatase, an early marker of osteoprogenitor cells.(6, 16, 17) Furthermore, Riminucci et al. have demonstrated that the fibrotic lesions within the affected bones consist of mature, but abnormally differentiated, osteoblasts.(16, 18) The

osteoclastic response contributes to progressive weakening of the affected bones, and with the stress of weight bearing, or as a result of repeated fractures, patients are likely to develop significant skeletal deformities. Osteosarcomas eventually develop in about 0.5 percent of patients with fibrous dysplasia and 4 percent of patients with the McCune–Albright syndrome.(18) Similarly, transgenic mice overexpressing c-fos have abnormal bone remodeling and osteosarcomas develop in some. The increased expression of c-fos mRNA in lesions caused by fibrous dysplasia suggests that the overexpression of c-fos may represent the first step in the multistep carcinogenesis of bone sarcomas. It is likely that at least some of the phenotypic changes in affected osteogenic cells result from increased expression of interleukin-6 (IL-6)(11, 12, 16, 19-21), which is induced by c-Fos via the constitutive expression of cyclic AMP. Increased IL-6 expression also causes increased osteoclast activity.(22-24) In addition, increased cyclic AMP induced by the gsp mutation may activate the Wnt/β-catenin pathway, which appears also to be involved in the development of the fibrous dysplasia lesions.(14) In addition, an important role for RANKL in the development of fibrous dysplasia has also been established using transduced skeletal precursor cells that were designed to express a constitutively active R201C Gs alpha protein. These cells showed increased production of cAMP, and could generate bone but not adipocytes or the hematopoietic microenvironment on in vivo transplantation. In addition, these transduced cells also showed a robust upregulation of RANKL mRNA expression.(25) Finally, the mosaic distribution of lesions in fibrous dysplasia may also play an important pathogenic role since close contact between transplanted normal bone cells and osteogenic cells containing the gsp mutation is necessary to reproduce the fibrous dysplasia lesion in mice.(26, 27) These studies point to a critical role for excessive and unregulated production of cyclic AMP in the affected cells. Several factors can influence the clinical severity of fibrous dysplasia. First, unbalanced (i.e. unequal) expression of the two GNAS alleles, which appears to be randomly determined.(28) Hence, in some fibrous dysplasia lesions cells can preferentially express the GNAS allele bearing the gsp mutation, which leads to a more aggressive bone lesion. Second, genomic imprinting of alternative transcripts encoded by the GNAS gene can also affect the clinical severity of the phenotype in patients with McCuneAlbright syndrome or isolated fibrous dysplasia. GNAS is a highly complex locus with alternative first exons that are spliced to exons 2-13 to generate various proteins.(29) These transcripts exhibit tissue-specific imprinting, which suggests that the parental origin of the allele containing the gsp mutation may influence the phenotype.

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Fibrous Dysplasia Transcripts starting with exon 1 encode Ga s and are expressed from both alleles in most tissues but in some cells (e.g. renal proximal tubule cells, thyroid follicular cells, and pituitary somatotrophs) imprinting leads to preferential expression of the maternal allele.(30-32) Hence, maternal gsp mutations are more likely to lead to pituitary or thyroid adenomas and excessive secretion of growth hormone or thyroid hormone, respectively.(33, 34) A second alternative first exon, XLαs, located approximately 38kb upstream from exon 1, generates transcripts that are expressed exclusively from the paternal allele, and encode two distinct proteins with extensively overlapping reading frames, XLa s and ALEX. XLas shares carboxyl terminal sequences with Gas but has a larger amino terminal end encoded by the alternate first exon.(33, 34) The experimental introduction of gsp mutations in XLas affects signal transduction and cyclic AMP generation in vitro, which has suggested that activation of XLas may play a role in fibrous dysplasia, particularly when gsp mutations occur on paternal GNAS alleles.(35)

Imaging Studies and Histopathology  The classic radiographic feature of fibrous dysplasia is a hazy, radiolucent, or ground-glass, pattern resulting from the defective mineralization of immature dysplastic bone; it is usually strikingly different from the radiographic appearance of normal bone, calcified cartilage, or soft tissue.(36) (Figures 3-4)

on radiographs. CT scans help visualize the ground-glass density of the lesion and MRI can delineate the extent of involvement and show the characteristic fat or cystic nature of some of the lesion.(36) The typical histologic pattern is an irregular collection of small pieces of immature bone within a matrix of fibrous tissue. (Figure 5) The overall appearance has been likened to that of alphabet soup. The immature trabeculae are usually not lined with osteoblasts (as in ossifying fibroma) and typically do not contain cement lines, and are obviously not aligned according to stress.(37) The fibrous stroma is loosely arranged and immature, replacing the normal marrow. A variable degree of capillary vasculature is seen within the stroma.(6) The differential diagnosis of fibrous dysplasia lesions includes osteoblastoma, osteosarcoma, ossifying fibroma, hyperparathyroidism, and Paget’s disease of bone. However, low grade osteosarcoma does not have a reactive shell, and has denser bone and more aggressive features with bone permeation over time.(6) Paget’s disease is associated with markedly elevated levels of alkaline phosphatase compared to those with fibrous dysplasia, and the appearance of these lesions more commonly occurs after the fifth decade of life.(6)

Molecular Diagnosis The molecular diagnosis of fibrous dysplasia can be achieved by identification of the gsp mutation in abnormal cells in the fibrous dysplasia lesion using polymerase chain reaction (PCR)-based techniques (13), particularly in concert with quantitative pyrosequencing.(38) Because fibrous dysplasia represents a somatic mutation in GNAS, the abnormal cells are typically restricted to the skeletal lesion(s). Nevertheless, small numbers of cells that contain the gsp mutation are present in the circulation of patients

Figures 3 & 4

The lesion has also been described as “a long lesion in a long bone” based on its common occurrence in the diaphysis of long bones. A small monostotic lesion may be difficult to distinguish from other benign lesions, but extensive polyostotic involvement is likely to produce the characteristic ground-glass density and significant deformity. The lesions, which develop in the center or intramedullary aspect of the bone, are trabeculated and surrounded by a thickened margin of reactive bone. With progression of the disease, the tumor enlarges. Bone scans demonstrate an intense radioisotope uptake that corresponds exactly to the extent of the tumor visible Figures 5

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Fibrous Dysplasia with fibrous dysplasia, but it is unknown whether these are osteogenic cells or leukocytes. Accordingly, gsp mutations can be detected in the peripheral blood of 75 to 90% of patients using modifications of PCR that greatly increase sensitivity and specificity. (15, 39, 40) Most assays are based on the use of peptide nucleic acid (PNA) primers to specifically block synthesis from the nonmutant or wildtype allele and thereby detect low copy numbers of mutant GNAS allele.(15, 41, 42)

Production of Phosphatonin by Fibrous Dysplasia Hypophosphatemia and/or decreased renal tubular reabsorption of phosphate occurs in more than 50% of subjects with MAS, and may lead to the development of rickets or osteomalacia.(43) A similar syndrome of hypophosphatemic rickets has been described in patients with fibrous dysplasia who lack other features of MAS. The basis of hypophosphatemia in patients with fibrous dysplasia is overproduction of circulating phosphaturic factors, termed phosphatonins, that are reminiscent of the pathophysiology of hyopophosphatemia that has been described in patients with genetic forms of hypophosphatemic rickets, patients with oncogenic osteomalacia owing to a variety of mesenchymal tumors, and patients with epidermal nevus syndrome.(44-47) Fibroblast growth factor 23 (FGF23) is the best characterized of the phosphatonins, and is produced by the abnormal osteogenic precursors present in fibrous dysplasia lesions. The concentration of total FGF-23 (c-terminal and intact FGF-23) in the circulation correlates with the extent of fibrous dysplasia throughout the skeleton.(21, 48) However, the relatively low prevalence of hypophosphatemia and osteomalacia has suggested that the ratio of cleaved c-terminal FGF-23 to intact FGF23 may be greater than normal.(49) Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells from patients with fibrous dysplasia has shown that cells with gsp mutations had higher cyclic AMP levels. Moreover, levels of ppGalNAcT3, which glycosylates FGF23, were lower and furin activity, which cleaves FGF-23 was greater. These observations are consistent with a model wherein fibrous dysplasia lesions secrete greater amounts of bioinactive c-terminal fragments of FGF-23 than normal bone due to decreased glycosylation of FGF-23 and increased FGF-23 cleavage by furin.(49) An alternative explanation for hypophosphatemia in patients with MAS is the presence of the gsp oncogene in the proximal renal tubule, where it induces increased cyclic AMP production and an intrinsic defect in reabsorption of phosphate.(50)

Treatment and Prognosis of Fibrous Dysplasia The natural history of fibrous dysplasia is variable, and some patients experience no untoward skeletal effects.(51) Occasional patients may experience a spontaneous decrease in bone pain and a corresponding reduction in markers of bone turnover that has been attributed to “burn out” of the fibrous dysplasia lesions. (52) Nevertheless, fractures, disfigurement and progressive bone deformity do occur in many patients, and these disabilities have stimulated interest in medical therapies that might alter the disease progression. Although cells of the osteoblast lineage carry the gsp mutation in fibrous dysplasia, medical therapy has been based on the use of inhibitors of osteoclastic bone resorption in part due to the observation that the fibrotic lesions produce substances that stimulate bone resorption, which leads to expansion of the lesion and potential fracture. The use of potent bisphosphonates to treat fibrous dysplasia is well described in the literature but outcomes are somewhat controversial, as studies have consisted principally of case reports and observational and uncontrolled studies of small numbers of children and adults. (53) These reports generally show that bisphosphonates are well tolerated and most useful for reducing bone pain. Bisphosphonates can decrease bone turnover and increase bone density, but the impact of these agents on the course of fibrous dysplasia, particularly the incidence of fractures and deformity, remains unclear. Both oral and intravenous nitrogen-containing bisphosphonates have been used, with greater success described for intravenous bisphosphonates such as pamidronate.(34, 54) (55) One series described 6 patients who had decreased pain, decreased fractures and decreased n-telopeptide levels after treatment with pamidronate or the oral bisphosphonate alendronate.(56) Studies have shown that patients with headaches ascribed to fibrous dysplasia affecting the skull experience a significant reduction in pain after treatment with high doses of alendronate. These studies have shown although pain is reduced, the fibrous dysplasia lesions are not altered.(53, 56) Encouraging results have come from other adult studies in which pamidronate was administered as cycles (60 mg/ day on 3 successive days) every 6 months for 18 months and every 12 months thereafter.(34) The follow-up time ranged from 18 to 64 months. Overall, there was a decreased intensity of bone pain, a decreased number of painful sites, a decrease in biochemical markers of bone turnover, and a radiographically apparent “refilling of osteolytic sites” in about one half of the patients.(57) Similar observations have also been made in several smaller series of adult patients.(35, 36, 56, 58)

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Fibrous Dysplasia There is much less experience with the use of bisphosphonates to treat children with fibrous dysplasia. In most studies, cyclic intravenous pamidronate infusions were given every 6 months. Reports have documented consistent decreases in bone pain and in markers of bone metabolism, but direct improvement of bone lesions with “refilling” of lytic lesions or thickening of bone cortex rarely if ever occurs.(58-60). The most extensive study of children and adolescents with fibrous dysplasia reported that within 1-4 months after the first cycle, bone pain decreased and sometimes disappeared, and the patient experienced a sense of well-being and increased stamina.(60) There was no improvement in the radiological appearance of bone lesions and limb deformities did not regress. In the 13 patients with well-delimited lesions, there was a significant increase in lesion width.(59) A significant increase in lumbar spine L1-4 volumetric bone density was noted in the 10 patients who received cyclical pamidronate therapy for at least three years, with bone density reported as 22% higher than expected for normal children. Histomorphometric analysis showed no obvious effect of treatment on the dysplastic lesions.(60) In addition to bisphosphonates, there have been recent reports on the use of denosumab, a human monoclonal antibody to the osteoclast stimulatory factor RANKL. Administration of denosumab to a young boy with fibrous dysplasia over seven months led to a marked reduction in pain, bone turnover markers, and tumor growth rate.(61) Moreover, denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment.(61) Surgical treatment remains the mainstay for prevention or treatment of fracture. Because more dysplastic bone usually forms and pain does not predictably resolve after curettage, the goal of management should be conservative and aimed to prevent deformity and fracture. This is best accomplished using cortical bone autografts (taken from the fibula), which minimally remodel after incorporation. Alternative treatment methods are reconstruction with cortical bone allografts or fixation with an intramedullary rod.(6) Rarely lesions are painful and need to be resected (Figure 6). This patient had intractable chronic weight bearing pain and would consent only to resection of the entire involved bone. The figure demonstrates the lesion grossly and microscopically. A special note is warranted for patients with craniofacial fibrous dysplasia. Most patients with craniofacial fibrous dysplasia will remain asymptomatic during long-term followup, including those with involvement of the optic nerve canal. Hence, conservative and expectant management is recommended in asymptomatic patients.(62-64)

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Future Directions The recent research that suggests that the Wnt/β-catenin pathway may play a role in the observed phenotype in patients with activating GNAS mutations specifically showed that Gαs mutations activated wnt/β-catenin signaling. (14) Moreover wnt/β-catenin activation led to a fibrous dysplasia-like phenotype in osteoblast progenitors and inhibition of β-catenin signaling rescued the osteoblast progenitors from the fibrous dysplasia derived patient stromal cells.(14) Thus, inhibition of β-catenin signaling or silencing GNAS alleles that encode constitutively-active Gsα molecules(25) in fibrous dysplasia and McCune-Albright syndrome offer potential therapeutic promise and deserve further study.

Disclosure Authors in this article declare no conflict of interest. Steven Lietman, MD Michael A. Levine, MD

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Fibrous Dysplasia 7. Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clinical genetics. 1986;29(4):321-324 8. Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 1989;340(6236):692-696 9. Lyons J, Landis CA, Harsh G, Vallar L, Grunewald K, Feichtinger H, Duh Q-Y, Clark O, Kawasaki E, Bourne HR, McCormick F. Two G protein oncogenes in human endocrine tumors. Science (New York, NY. 1990;249(4969):655-659 10. Malchoff CD, Reardon G, MacGillivray DC, Yamase H, Rogol AD, Malchoff DM.An unusual presentation of McCune-Albright syndrome confirmed by an activating mutation of the Gs alpha-subunit from a bone lesion. The Journal of clinical endocrinology and metabolism. 1994;78(3):803-806 11. Shenker A, Weinstein LS, Sweet DE, Spiegel AM. An activating Gs alpha mutation is present in fibrous dysplasia of bone in the McCune-Albright syndrome. The Journal of clinical endocrinology and metabolism. 1994;79(3):750-755 12. Candeliere GA, Glorieux FH, Prud’homme J, St-Arnaud R. Increased expression of the c-fos proto-oncogene in bone from patients with fibrous dysplasia. The New England journal of medicine. 1995;332(23):1546-1551 13. Idowu BD, Al-Adnani M, O’Donnell P, Yu L, Odell E, Diss T, Gale RE, Flanagan AM.. A sensitive mutation-specific screening technique for GNAS1 mutations in cases of fibrous dysplasia: the first report of a codon 227 mutation in bone. Histopathology. 2007;50(6):691-704 14. Regard JB, Cherman N, Palmer D, Kuznetsov SA, Celi FS, Guettier JM, Chen M, Bhattacharyya N, Wess J, Coughlin SR, Weinstein LS, Collins MT, Robey PG, Yang Y. Wnt/beta-catenin signaling is differentially regulated by Galpha proteins and contributes to fibrous dysplasia. Proc Natl Acad Sci U SA 108(50): 20101-20106 15. Lietman SA, Ding C, Levine MA. A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia. J. Bone Joint Surg. Am. 2005;87(11):2489-2494 16. Riminucci M, Fisher LW, Shenker A, Spiegel AM, Bianco P, Robey PG. Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation. Am J Pathol. 1997;151(6):1587-1600 17. Chanson P, Salenave S, Orcel P. McCune-Albright syndrome in adulthood. Pediatr Endocrinol Rev. 2007;4 Suppl 4:453-462 18. Yabut SM, Jr., Kenan S, Sissons HA, Lewis MM. Malignant transformation of fibrous dysplasia. A case report and review of the literature. Clin Orthop Relat Res. 1988;(228):281-289 19. Mandrioli S, Carinci F, Dallera V, Calura G. [Fibrous dysplasia. The clinico-therapeutic picture and new data on its etiology. A review of the literature]. Minerva stomatologica. 1998;47(1-2):37-44 20. Motomura T, Kasayama S, Takagi M, Kurebayashi S, Matsui H, Hirose T, Miyashita Y, Yamauchi-Takihara K, Yamamoto T, Okada S, Kisimoto T. Increased interleukin-6 production in mouse osteoblastic MC3T3-E1 cells expressing activating mutant of the stimulatory G protein. J Bone Miner Res. 1998;13(7):1084-1091 21. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gukpta A, Hannon T, Econs JM, Bianco P, Robey PG. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest. 2003;112(5):683-692 22. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992;257(5066):88-91 23. Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, Smith JF, Singer FR. Interleukin 6. A potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest. 1992;89(1):46-52 24. Kishimoto T. The biology of interleukin-6. Blood. 1989;74(1):1-10

25. Piersanti S, Remoli C, Saggio I, Funari A, Michienzi S, Sacchetti B, Robey PG, Riminucci M, Bianco P. Transfer, analysis, and reversion of the fibrous dysplasia cellular phenotype in human skeletal progenitors. J Bone Miner Res. 2010; 25(5):1103-1116 26. Bianco P, Kuznetsov SA, Riminucci M, Fisher LW, Spiegel AM, Robey PG. Reproduction of human fibrous dysplasia of bone in immunocompromised mice by transplanted mosaics of normal and Gsalpha-mutated skeletal progenitor cells. J Clin Invest. 1998;101(8):1737-1744 27. Sakamoto A, Chen M, Kobayashi T, Kronenberg HM, Weinstein LS. Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J Bone Miner Res. 2005;20(4):663-671 28. Michienzi S, Cherman N, Holmbeck K, Funari A, Collins MT, Bianco P, Robey PG, Riminucci M. GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs alpha. Hum Mol Genet. 2007;16(16):1921-1930 29. Bastepe M, Weinstein LS, Ogata N, Kawaguchi H, Jüppner H, Kronenberg HM, Chung UI.Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc Natl Acad Sci U S A. 2004;101(41):14794-14799 30. Germain-Lee EL, Ding CL, Deng Z, Crane JL, Saji M, Ringel MD, Levine MA. Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochemical and biophysical research communications. 2002;296(1):67-72 31. Liu B, Yu SF, Li TJ. Multinucleated giant cells in various forms of giant cell containing lesions of the jaws express features of osteoclasts. J Oral Pathol Med. 2003;32(6):367-375 32. Liu J, Erlichman B, Weinstein LS. The stimulatory G protein alphasubunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. The Journal of clinical endocrinology and metabolism. 2003;88(9):4336-4341 33. Kehlenbach RH, Matthey J, Huttner WB. XL alpha s is a new type of G protein. Nature. 1994;372(6508):804-809 34. Linglart A, Mahon MJ, Kerachian MA, Berlach DM, Hendy GN, Jüppner H, Bestepe M. Coding GNAS mutations leading to hormone resistance impair in vitro agonist- and cholera toxin-induced adenosine cyclic 3’,5’-monophosphate formation mediated by human XLalphas. Endocrinology. 2006;147(5):2253-2262 35. Mariot V, Wu JY, Aydin C, Mantovani G, Mahon MJ, Linglart A, Bestepe M. Potent constitutive cyclic AMP-generating activity of XLalphas implicates this imprinted GNAS product in the pathogenesis of McCune-Albright syndrome and fibrous dysplasia of bone. Bone. 2011;48(2):312-320 36. Sundaram M. Imaging of Paget’s disease and fibrous dysplasia of bone. J Bone Miner Res. 2006;21Suppl 2:28-30 37. Riminucci M, Fisher LW, Majolagbe A, Corsi A, Lala R, De Sanctis C, Robey PG, Bianco P. A novel GNAS1 mutation, R201G, in McCunealbright syndrome. J Bone Miner Res. 1999;14(11):1987-1989 38. Liang Q, Wei M, Hodge L, Fanburg-Smith JC, Nelson A, Miettinen M, Foss RD, Wang G. Quantitative analysis of activating alpha subunit of the G protein (Gsalpha) mutation by pyrosequencing in fibrous dysplasia and other bone lesions. J Mol Diagn. 2011;13(2):137-142 39. Candeliere GA, Roughley PJ, Glorieux FH. Polymerase chain reactionbased technique for the selective enrichment and analysis of mosaic arg201 mutations in G alpha s from patients with fibrous dysplasia of bone. Bone. 1997;21(2):201-206 40. Karadag A, Riminucci M, Bianco P, Cherman N, Kuznetsov SA, Nguyen N, Collins MT, Robey GP, Fisher LW. A novel technique based on a PNA hybridization probe and FRET principle for quantification of mutant genotype in fibrous dysplasia/McCune-Albright syndrome. Nucleic acids research. 2004;32(7):e63. 41. Murdock DG, Wallace DC. PNA-mediated PCR clamping. Applications and methods. Methods Mol Biol. 2002;208:145-164

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Fibrous Dysplasia 42. Orum H, Nielsen PE, Egholm M, Berg RH, Buchardt O, Stanley C. Single base pair mutation analysis by PNA directed PCR clamping. Nucleic acids research. 1993;21(23):5332-5336 43. Collins MT, Chebli C, Jones J, Kushner H, Consugar M, Rinaldo P, Wientroub S, Bianco P, Robey PG. Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia. J Bone Miner Res. 2001;16(5):806-813 44. Drezner MK. Decade of the bone and joint. J Bone Miner Res. 1999;14(1):2 45. Econs MJ, Drezner MK. Tumor-induced osteomalacia--unveiling a new hormone. The New England journal of medicine. 1994;330(23):16791681 46. Econs MJ, Samsa GP, Monger M, Drezner MK, Feussner JR. X-Linked hypophosphatemic rickets: a disease often unknown to affected patients. Bone Miner. 1994;24(1):17-24 47. Kumar D, Duggan MB, Mueller RF, Karbani G. Familial aplasia/ hypoplasia of pelvis, femur, fibula, and ulna with abnormal digits in an inbred Pakistani Muslim family: a possible new autosomal recessive disorder with overlapping manifestations of the syndromes of Fuhrmann, Al-Awadi, and Raas-Rothschild. Am J Med Genet. 1997;70(2):107-113 48. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007;22(4):520-526 49. Bhattacharyya N, Wiench M, Dumitrescu C, Connolly BM, Bugge TH, Patel HV, Gafni RI, Cherman N, Cho M, Hager GL, Collins MT. Mechanism of FGF23 processing in fibrous dysplasia. J Bone Miner Res. 2012; 27(5):1132-1141 50. Zung A, Chalew SA, Schwindinger WF, Levine MA, Phillip M, Jara A, Counts DR, Kowarski AA. Urinary cyclic adenosine 3’,5’-monophosphate response in McCune-Albright syndrome: clinical evidence for altered renal adenylate cyclase activity. J Clin Endocrinol Metab 1995;80(12):3576-3581 51. Akintoye SO, Kelly MH, Brillante B, Cherman N, Turner S, Butman JA, Robey PG, Collins MT. Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome. J Clin Endocrinol Metab. 2006;91(8):2960-2966 52. Kuznetsov SA, Cherman N, Riminucci M, Collins MT, Robey PG, Bianco P. Age-dependent demise of GNAS-mutated skeletal stem cells and “normalization” of fibrous dysplasia of bone. J Bone Miner Res. 2008;23(11):1731-1740

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53. Chao K, Katznelson L. Use of high-dose oral bisphosphonate therapy for symptomatic fibrous dysplasia of the skull. J Neurosurg. 2008;109(5):889-892 54. Kochar IP, Kulkarni KP. Pamidronate for fibrous dysplasia due to McCune Albright Syndrome. Indian Pediatr. 47(7):633-635 55. Ippolito E, Bray EW, Corsi A, DeMaio F, Exner UG, Robey PG, Grill F, Lala R, Massobrio M, Pinggera O, Riminucci M, Snela S, Zambakidis C, Bianco P, European Pediatric Orthopedic Society. Natural history and treatment of fibrous dysplasia of bone: a multicenter clinicopathologic study promoted by the European Pediatric Orthopaedic Society. J Pediatr Orthop B. 2003;12(3):155-177 56. Lane JM, Khan SN, O’Connor WJ, Nydick M, Hommen JP, Schneider R, Tomin E, Brand J, Curtin J. Bisphosphonate therapy in fibrous dysplasia. Clin Orthop Relat Res. 2001;(382):6-12 57. Chapurlat RD, Delmas PD, Liens D, Meunier PJ. Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. J Bone Miner Res. 1997;12(10):1746-1752 58. Pfeilschifter J, Ziegler R. [Effect of pamidronate on clinical symptoms and bone metabolism in fibrous dysplasia and McCune-Albright syndrome]. Med Klin (Munich). 1998;93(6):352-359 59. Lala R, Andreo M, Pucci A, Matarazzo P. Persistent hyperestrogenism after precocious puberty in young females with McCune-Albright syndrome. Pediatr Endocrinol Rev. 2007;4 Suppl 4:423-428 60. Plotkin H, Rauch F, Zeitlin L, Munns C, Travers R, Glorieux FH. Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone. J Clin Endocrinol Metab. 2003;88(10):4569-4575 61. Boyce A, Chong W, Yao J, Gafni RI, Kelly MH, Chamberlain CE, Bassim C, Cherman N, Ellsworth M, Kasa-Vubu JZ, Farley FA, Molinolo AA, Bhattacharyya N, Collins MT. Denosumab treatment for fibrous dysplasia. J Bone Miner Res.2012;27(7):1462-1470 62. Collins MT. Spectrum and natural history of fibrous dysplasia of bone. J Bone Miner Res. 2006;21 Suppl 2:99-104 63. Ashcroft AJ, Cruickshank SM, Croucher PI, Perry MJ, Rollinson S, Lippitt JM, Child JA, Dunstan C, Felsburg PJ, Morgan GJ, Carding SR. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity. 2003;19(6):849-861 64. Amit M, Collins MT, FitzGibbon EJ, Butman JA, Fliss DM, Gil Z. Surgery versus watchful waiting in patients with craniofacial fibrous dysplasia-a meta-analysis. PLoS One.2011; 6(9):e25179

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