Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic Disease of Gα s Activation

Alison M Boyce; Michael T Collins

doi:10.1210/endrev/bnz011

. 2019 Nov 1;41(2):345–370. doi: 10.1210/endrev/bnz011

Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic Disease of Gα _s Activation

Alison M Boyce ^1,^✉, Michael T Collins ^1,^✉

PMCID: PMC7127130 PMID: 31673695

Abstract

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder of striking complexity. It arises from somatic, gain-of-function mutations in GNAS, leading to mosaic Gα _s activation and inappropriate production of intracellular cyclic adenosine monophosphate (cAMP). The clinical phenotype is largely determined by the location and extent of affected tissues, and the pathophysiological effects of Gα _s activation within these tissues. In bone, Gα _s activation results in impaired differentiation of skeletal stem cells, leading to discrete skeletal lesions prone to fracture, deformity, and pain. Extraskeletal manifestations include a variable combination of hyperpigmented macules and hyperfunctioning endocrinopathies. Distinctive age-related changes in disease development has key effects on histologic, radiographic, and clinical features. FD/MAS thus presents along a uniquely broad clinical spectrum, and the resulting challenges in diagnosis and management can be difficult for clinicians. This review presents FD/MAS in the context of a mosaic disorder of Gα _s activation, providing an intellectual framework within which to understand, evaluate, and treat this interesting disease. It includes a comprehensive summary of current understanding of FD/MAS pathogenesis, and a detailed discussion of clinical presentation and management. Critical areas of unmet need are highlighted, including discussion of key challenges and potential solutions to advance research and clinical care in FD/MAS.

Keywords: skeletal stem cells, metabolic bone disease, somatic mosaicism, fibroblast growth factor 23, precocious puberty, growth hormone excess

Graphical Abstract

Essential Points.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder arising from somatic activating mutations in GNAS, leading to a mosaic pattern of Gα _s activation
The clinical phenotype in FD/MAS presents along a broad spectrum, involving a variable combination of hyperpigmented skin macules, hyperfunctioning endocrinopathies, and FD of bone
Gα _s activation impairs differentiation of skeletal stem cells, leading to formation of expansile FD lesions prone to fracture and deformity, and presenting clinically with pain, functional impairment, and disability
Patients with FD have a distinctive age-related pattern of disease development: FD lesions become established in the first few years of life and expand during linear growth; final disease burden is established by early adulthood, after which the metabolic activity of FD lesions tends to decline
Complications of FD are more frequent and severe in patients with uncontrolled MAS endocrinopathies: Hypophosphatemia and hyperthyroidism increase the risk of deformities in weight-bearing bones, and growth hormone excess, which drives expansion of craniofacial FD
The development of effective medical therapies for FD is a critical area of unmet need; although reasonably effective treatments exist for most MAS endocrinopathies, no therapies have been shown to definitively improve bone quality or prevent the expansion of FD lesions

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disorder of striking complexity. Somatic gain-of-function mutations lead to mosaic activation of Gα _s, resulting in disease that may involve any part of the skeleton, and may be variably associated with cutaneous, endocrine, and other extraskeletal features. The combination of 2 or more classic features (FD of bone, café-au-lait skin macules, and/or associated hyperfunctioning endocrinopathies: gonadotropin-independent gonadal function, nonautoimmune hyperthyroidism, GH excess, neonatal hypercortisolism) is termed McCune-Albright syndrome (MAS) (1, 2). The resulting clinical presentation is remarkable for its uniquely broad spectrum. This complexity makes FD/MAS a compelling disorder with which to understand the role of Gα _s and the interplay between systems affected by its activation. However, it also poses a unique challenge for clinicians, who seek a unified approach to a disorder that causes no 2 patients to look alike. In this review, we will provide an intellectual framework for understanding FD/MAS, in which the pathophysiology, natural history, and clinical management are determined by the tissue-specific role and distribution of Gα _s signaling.

Etiology and Pathophysiology

Genetic etiology

FD/MAS results from missense mutations in the GNAS locus, located on chromosome 20q13.3 (3). This locus has a highly complex imprinted pattern of expression, with multiple alternate promoters giving rise to maternally, paternally, and biallelically expressed transcripts. Mutations associated with FD/MAS typically occur at exon 8, in which the arginine 201 is converted to either a histidine (R201H) or a cysteine (R201C). Rarely, other substitutions may occur (4), or other codons may be affected (5). GNAS mutations associated with FD/MAS are not inherited, and monozygotic twins discordant for the disease have been reported (6), consistent with a postzygotic mutational event (7). The precise timing at which the mutation occurs varies, but concomitant involvement of tissues derived from all 3 germ layers (endoderm, mesoderm, and ectoderm) in severely affected patients suggests that mutations are acquired at an early stage of development. Accordingly, the 2 most common mutations arise from aberrant methylation of the CpG dinucleotide in the R201 codon, suggesting that the mutational event may frequently take place during the active methylation phase in formation of the inner cell mass (8). This supports a model in which a disease-causing mutation acquired in a pluripotent stem cell has the potential to transmit to a broad and variable distribution of tissues. The clinical phenotype in FD/MAS therefore likely reflects the differential number, cell type, and viability of clones that arise from this mutated pluripotent cell. Epigenetic modifiers also likely contribute to phenotypic variability in FD/MAS. Random and asymmetric expression of Gα _s alleles has been observed both in mutant and wild-type clonogenic osteoprogenitors (9), suggesting that mutant Gα _s expression varies within and between affected tissues, potentially influencing the development and severity of clinical disease.

Molecular and cellular pathophysiology

Mutations associated with FD/MAS are gain-of-function, and result from impaired intrinsic GTPase activity, leading to ligand-independent signaling and production of excess intracellular cyclic adenosine monophosphate (cAMP) (10) (Fig. 1, upper and middle panels). GDP-bound Gα _s is inactive under normal physiologic conditions, however recent evidence suggests that the mutant GDP-bound Gα _s interacts with adenylyl cyclase to generate cAMP, at least in the case of the R201C variant (Fig. 1, lower panel) (11). The relative contributions of activation of the mutant GDP-bound and GTP-bound receptor conformations are unknown, and further research is needed to verify this model, particularly with respect to the R201H variant. Constitutive Gα _s signaling results in impaired differentiation of mutation-bearing osteoprogenitor cells, an observation supported by in vitro studies of cells isolated from FD lesions (12-14), and in normal human osteoprogenitors stably transduced with Gα _s^R201C (15). Proliferation of undifferentiated skeletal stem cells generates fibro-osseous tissue that expands into the marrow space, with loss of normal marrow features such as hematopoiesis and adipogenesis. Characteristic histopathologic features of FD reflect this impaired differentiation and function of osteogenic cells (16, 17) (Fig. 2). Discontinuous networks of trabeculae with woven bone result from aberrant osteoblast activity, likely through activation of Wnt/β-catenin signaling in osteoblast progenitors (13). Trabeculae are typically dense and irregularly shaped, resulting in their previous description as “Chinese characters” (Fig. 2A); however, in actuality there is little resemblance to the written Chinese language. Osteoclastogenesis is also a prominent feature and may result from local production of osteoclast-promoting factors such as interleukin-6 and receptor activator of nuclear kappa-B ligand (15, 18). Severe osteomalacic changes contribute to the structural instability of FD bone, and probably derive from an intrinsic mineralization defect as well as FD lesion production of the phosphaturic hormone fibroblast growth factor-23 (FGF23) (19).

Figure 1. — G_s G-protein-coupled signaling dysregulation in FD/MAS. In the inactive state, the αβγ-heterotrimer is bound to GDP. After ligand binding, the GTP-bound α-subunit dissociates from the βγ-complex and activates adenylyl cyclase, leading to production of intracellular cyclic AMP and activation of protein kinase A and other downstream signaling pathways. Activating *GNAS* mutations in FD/MAS results in loss of GTPase activity in the α-subunit, resulting in constitutive Gα _s protein signaling. Alternatively, the mutant GDP-bound Gα _s may also interact with adenylyl cyclase to generate cAMP. ATP indicates adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CREB, cyclic adenosine monophosphate response element-binding protein; FD/MAS, fibrous dysplasia/McCune-Albright syndrome; GDP, guanosine diphosphate; GPCR, G-coupled protein receptor; GTP, guanosine triphosphate.

Figure 2. — Representative histological features of fibrous dysplasia (FD). A and B show low-power and high-power views of an FD lesion with classic dense, irregular trabeculae and marrow fibrosis (ft). Massive de novo bone formation is apparent throughout, including areas of woven bone (wb) with prominent unmineralized osteoid (o). Collagen fibers are perpendicularly oriented along forming bone surfaces, also termed *Sharpey fibers* (black arrows). An osteoclastic giant cell is actively resorbing an area of abnormal bone (white arrow). Note the presence of high vascularity with a red blood cell-filled vessel coursing through the lesion adjacent to an area of venous pooling (black arrowhead).

Mosaicism in FD/MAS is apparent even at the tissue level and is likely requisite for the formation of FD lesions. This has been demonstrated by genetic analysis of clones of individual cells derived from FD lesions in which mutation-positive and mutation-negative osteogenic cells are present. Further, when ectopic xenographs of patient-derived osteogenic cells are implanted in immunocompromised mice, both mutated and wild-type cells are required to generate ossicles with histologic features consistent with FD (12). The specific contributions of nonmutated cells to the establishment and progression of FD lesions, and the mechanism by which mutated skeletal stem cells co-opt the behavior of wild-type cells, remain important unanswered questions. In addition, it is possible that TRAP positive, osteoclast-like giant cells, which are a prominent feature of FD lesions, may play a contributory role in generating or promoting the expansion of FD lesions.

The effects of Gα _s activation appear to be tissue specific and vary considerably in different organ systems. The downstream mechanisms that account for these differences are unknown but may relate to tissue-specific sensitivities to cAMP dysregulation. In addition, it is possible that certain cell types may not tolerate Gα _s activation, leading to deselection of GNAS-mutation–bearing cells during embryogenesis.

Clinical Description

The original description of FD/MAS in 1936 included a “classic triad” of café-au-lait macules, precocious puberty, and FD (20). However, we now know that FD/MAS can involve a broad range and combination of systems, resulting in a diversity of phenotypes. Understanding the clinical presentation in FD/MAS requires an appreciation of how various disease features influence each other, and how the mosaicism underlying these features has unique and profound effects on clinical outcomes.

Fibrous dysplasia

The clinical presentation of FD varies extensively based on the location and amount of affected bone. Monostotic FD is likely far more common than polyostotic FD; however, reliable epidemiological data are lacking, in part because of the poor characterization and classification of monostotic fibro-osseous lesions (21). In cases of polyostotic FD or MAS, the diagnosis can often be made clinically based on typical radiographic features; however, isolated monostotic lesions generally require biopsy and molecular testing if diagnostic certainty is desired (22). FD lesions are most commonly found in the skull base and proximal femurs; however, any part or combination of the skeleton can be involved. The clinical sequelae of FD are region specific, with distinct manifestations involving the appendicular, craniofacial, and axial compartments of the skeleton.

Appendicular skeleton.

Complications of appendicular FD arise primarily due to bone fragility, resulting in fractures and deformation under weight-bearing forces (Fig. 3A and 3B). Patients typically present with pain or limp. The tension placed on the femoral neck classically results in coxa vara (“shepherd’s crook”) or, less commonly, valga deformities, which are key sources of morbidity and ambulation impairment (23). Deformities may also occur in the upper extremities, but typically result in less functional sequelae. Multiple factors may contribute to the development of deformities, including malalignment from fractures and surgeries, muscle weakness, and uncontrolled MAS-associated endocrinopathies. Secondary aneurysmal bone cysts may rarely arise in the appendicular skeleton, leading to rapid deformation with severe pain or fracture.

Figure 3. — Skeletal deformities and radiographic findings in patients with fibrous dysplasia (FD). A, Images of a patient with a bowing deformity of the proximal upper extremity. Radiographs reveal extensive FD involvement, including an expansile humeral lesion demonstrating severe cortical thinning and a characteristic “ground-glass” appearance. B, A patient with coxa vara deformity proximally (at the hip) and genu valgum deformity distally (at the knees). Note the leg length discrepancy with the resulting asymmetry of the knees apparent in the photograph. This patient’s radiographs demonstrate diffuse FD involvement of the lower extremities with cortical thinning and “ground-glass” radiolucency. Plate and nail implants have been placed in the bilateral proximal femurs to correct shepherd’s crook deformities (yellow arrows). Note the presence of an 8-plate initially implanted in the distal femoral epiphyses, which has migrated proximally during skeletal growth (yellow star). This implant was intended to treat leg length discrepancy by slowing growth in the left leg, which is unfortunately now shorter than the right. C, Posterior view of a patient with severe spinal curvature, resulting in shortening of the torso and asymmetry of the shoulders and scapulae. This patient’s radiographs demonstrate severe thoracic scoliosis with loss of lung volumes bilaterally. Reproduced with permission from Hartley I et al. (24).

Craniofacial skeleton.

Complications in the craniofacial skeleton arise because of FD’s tendency to expand, leading to asymmetry and functional impairment (Fig. 4). The typical presentation is a painless “bump” or subtle asymmetry that expands during childhood; however, asymptomatic lesions are often detected incidentally on dental radiographs, computed tomography (CT), or magnetic resonance imaging. Very rarely, the initial presentation may involve new-onset functional impairment, such as vision or hearing loss. Complications of craniofacial FD are highly region-specific. The skull base is the most commonly affected location and is typically asymptomatic; however, neurologic complications from skull-base deformities such as basilar invagination and Chiari I malformation have been reported (25). Facial asymmetry is common in patients with FD affecting the frontal, maxillary, or mandibular regions, particularly in those with unilateral involvement. Hearing loss may occur in association with temporal bone FD and is generally mild and nonprogressive (26). Vision loss is an uncommon but serious complication that may result from deformation of the optic canals, or in the setting of a secondary aneurysmal bone cyst. Vision and hearing loss both occur more frequently in patients with MAS-associated growth hormone (GH) excess (27, 28). Additional sequelae of craniofacial FD include chronic nasal congestion, hyposmia, and malocclusion (22, 29).

Figure 4. — Progression of craniofacial fibrous dysplasia (FD) in a patient with uncontrolled growth hormone excess. A, B, and C, Upper panels show computed tomography (CT) images at age 4 years. Note mild expansion of the left mandible (red arrows) and zygomatic bone (green arrows) visible on A and B, 3-dimensional (3D) reconstruction. C, An axial view demonstrates the characteristic homogenous. A patent optic canal surrounded by FD is visible on the right (white arrow). The left optic canal (not depicted) is also patent. D, E, and F lower panels show images from the same patient at age 17 after 13 additional years of uncontrolled growth hormone excess. D and E, On 3D reconstruction the left mandible has massively expanded (red arrows), leading to severe malocclusion and distorted dentition. The zygomatic bones are now expanded bilaterally (green arrows) with resulting orbital asymmetry. E, Note the severe macrocephaly with enlargement of the posterior cranium leading to a scaphocephalic appearance. F, An axial view demonstrates typical age-related changes with increased heterogeneity and areas of radiolucency. The left optic canal is visible and severely narrowed (white arrow), and the patient is unfortunately now blind.

Axial skeleton.

Scoliosis is a common complication of FD affecting the axial skeleton, and in severe cases may be progressive and rarely fatal (30, 31) (Fig. 3C). Risk factors for scoliosis progression include leg length discrepancy and uncontrolled endocrinopathies (30). Expansile rib lesions are prone to fractures and pain, and in rare cases may be associated with pleural effusions (32, 33).

Fibroblast growth factor-23–mediated disease.

FGF23 overproduction is an inherent feature of FD. Although most patients have elevated circulating levels of FGF23, increased cleavage of intact FGF23 to its inactive fragments often prevents the development of frank hypophosphatemia (34). The mechanism of FGF23 overproduction in FD is unknown but is presumably related to effects of Gα _s activation in abnormally differentiated osteocytes (35) Because the degree of FGF23 overproduction is correlated with FD severity and tissue burden, frank hypophosphatemia occurs only in patients with substantial skeletal involvement (19, 36). Hypophosphatemia may wax and wane over time and may occur more frequently during periods of high phosphate requirement, such as phases of rapid linear growth in infancy and adolescence. Clinical sequelae of hypophosphatemia are substantial and include earlier and more frequent fractures (37), pain, poor surgical outcomes, and an increased propensity for deformities (25, 30). Rickets may be seen; however, it is important to note that even in the absence of frank metaphyseal changes, FD-related complications such as fractures and deformities may occur at an increased prevalence in patients with hypophosphatemia.

Endocrinological features

Gonadotropin-independent gonadal dysfunction.

Autonomous ovarian activation is the most common endocrinopathy in girls and women with MAS, affecting approximately 85% of patients in one large cohort (38). Ovarian Gα _s activation results in recurrent estrogen-producing cysts. The typical presentation in infancy and childhood includes signs of estrogen exposure in a previously prepubertal girl, such as rapid breast development, growth acceleration, and vaginal discharge (38, 39). Serum estradiol levels are typically elevated with suppressed gonadotropins. Pelvic ultrasonography reveals unilateral or bilateral ovarian cysts, which may vary in size and be simple or complex, often accompanied by an enlarged uterus with an endometrial stripe (40) (Fig. 5C). Girls frequently present for care after cyst resolution, when declining estrogen levels result in shedding of the uterine lining and vaginal bleeding. Between episodes girls typically appear prepubertal, with appropriately low serum estrogen levels and normal pelvic ultrasonography findings, which may contribute to delayed diagnoses. The onset and frequency of cysts are variable, and cysts have been detected as early as in utero (41). Untreated peripheral precocious puberty may lead to bone age advancement with compromised adult stature and the development of secondary central precocious puberty (42). In adulthood, cysts frequently result in dysfunctional uterine bleeding, which may be severe, necessitating repeated blood transfusions and early hysterectomy (43, 44). The effects of MAS ovarian disease on fertility are unclear. Spontaneous pregnancies occur; in one series of 39 women, 43% had reduced fertility, likely in part related to frequent cysts that disrupt ovulatory cycles leading to delayed time to conception (44). Pregnancy does not appear to have a clear negative impact on skeletal disease (44).

Figure 5. — Radiographic features of endocrine disease in patients with McCune-Albright syndrome. A, Testicular ultrasound images show extensive right-sided involvement with mixed radiolucent and radio-opaque lesions involving most of the testis (red arrowheads). The left side is unaffected and demonstrates a normal homogeneous echotexture. B, A thyroid ultrasound shows diffuse involvement with heterogeneous mixed radiolucent and radio-opaque lesions, resulting in a spongiform appearance. C, A pelvic ultrasound from a 2-year-old girl shows a complex ovarian cyst (white arrow). Note the enlarged, mature-appearing uterus (blue arrowheads) that has grown under the influence of hyperestrogenism. D, An MR image from a patient with growth hormone excess shows pituitary enlargement and a hypoechoic area (white arrow) consistent with an adenoma. Note the expanded skull base involved with fibrous dysplasia (yellow star).

Testicular involvement similarly affects approximately 85% of boys and men with MAS (45). Patients can present with normal testicular volume, or unilateral or bilateral macro-orchidism, and variable ultrasonographic abnormalities, including discrete lesions, diffuse heterogeneity, and microlithiasis (45) (Fig. 5A). Histopathology shows Leydig and Sertoli cell hyperplasia. Unlike MAS ovarian involvement, which appears to be necessarily associated with hyperestrogenism, autonomous testosterone production is detectable in only 15% of patients with testicular disease. In boys this presents with progressive signs of premature androgen excess, including pubic and axillary hair, body odor, penile growth, and androgen-associated behavioral changes.

Thyroid disease.

Thyroid involvement is reported in approximately two-thirds of patients with MAS, resulting in frank hyperthyroidism in around half of affected patients (38, 46). Thyrotoxicosis results from cAMP-mediated increased deiodinase activity and overproduction of triiodothyronine. Ultrasonographic features are variable and include patchy areas of heterogeneity along with discrete cystic nodules (46, 47) (Fig. 5B). The clinical presentation includes typical signs of hyperthyroidism such as tachycardia, growth acceleration, hyperactivity, and sleep disturbances. Thyroid storm has been reported, including in conjunction with anesthesia for orthopedic procedures (48, 49). Like FGF23 overproduction, hyperthyroidism in MAS has been associated with increased skeletal morbidity and progressive deformities, likely due to detrimental effects of excess thyroid hormone on bone metabolism (25, 30).

Pituitary disease.

Pituitary involvement is uncommon in MAS, affecting 10% to 15% of patients (27, 50). Approximately 85% of the patients with pituitary disease have both GH and prolactin excess, which is due and abundance of cosecreting mammosomatotroph cells (51) (Fig. 5D). GH excess may be frank, with clearly elevated GH and insulin-like growth factor-1 levels, or subtle, evident only by altered secretion dynamics on glucose tolerance testing and overnight GH sampling. GH excess fuels FD expansion, particularly in the craniofacial region, which can lead to significant morbidity (Fig. 4). Untreated GH excess has been associated with vision loss (28), hearing loss (26), macrocephaly (28, 52), facial deformity (53), and poor surgical outcomes (53). Patients are also subject to more common effects of GH excess, including diabetes, heart disease including cardiomegaly aortic root dilatation and aortic valvular insufficiency, and secondary pituitary hormone deficiencies. Prolactinemia in MAS is typically mild and asymptomatic, but in rare cases may result in hypogonadism and galactorrhea (50).

Adrenal disease.

Hypercortisolism is the rarest endocrine feature of MAS, occurring in less than 5% of patients (38, 54). Adrenocorticotropic hormone–independent adrenal Gα _s activation results in a characteristic diffuse and nodular infiltration of the adrenal glands, leading to hypercortisolism that can range from mild to severe and life threatening. Disease presents exclusively within the first year of life and may develop as early as in utero, likely reflecting involvement of fetal adrenal tissue (54, 55). Infants may present with low birth weight, failure to thrive, facial plethora, or hirsutism. Cutaneous features such as violaceous striae are typically absent in infants (56). Neonatal hypercortisolism is associated with high mortality from secondary infections, which emphasizes the need for prophylaxis against opportunistic infections, and other complications, particularly in patients with delayed diagnoses.

Dermatologic features

Café-au-lait macules affect two-thirds of patients with MAS, and are often the earliest presenting feature, visible at or shortly after birth (38). An astute clinician may recognize these as an early clue to the diagnosis; however, their significance is often appreciated only in retrospect, after additional features of FD/MAS have become apparent. Café-au-lait macules arise as a result of cutaneous Gα _s activation and constitutive melanocyte-stimulating hormone receptor signaling, leading to local increased melanin production in areas of affected skin. As such, skin lesions tend to follow a characteristic distribution reminiscent of embryonic cell migration patterns (Fig. 6). Macules often occur or reflect along the midline of the body (referred to as “respecting” the midline). Common locations include the chest, neck, and superior portion of the intergluteal cleft; however, any region may be affected. Borders tend to be jagged, resembling the “coast of Maine” (in contrast to the smooth-bordered “coast of California” lesions seen in neurofibromatosis). However, like FD, skin macules present along a broad spectrum, and many exceptions to these patterns exist. Mucosal pigmentation has also been reported involving the lips and intraoral and vaginal mucosa (57).

Figure 6. — Typical café-au-lait macules in patients with McCune-Albright syndrome. A, Lesions in a young child involving the lower back and buttocks approach but do not cross the midline of the body. Note the relatively even borders on the back lesions, whereas the buttock lesions show irregular borders. An osteotomy scar related to a femoral fixation procedure is visible on the right lateral buttock. B, A lesion involving the neck and shoulder of a young adult terminates sharply at the midline, with serpiginous borders involving the lateral aspects. C, An extensive lesion involving the neck and upper trunk of a young child extends past the midline. A port visible in the right lower chest was placed to facilitate intravenous access during a period of neonatal hypercortisolism. D, A lower extremity lesion in an adolescent extends downward from the upper medial thigh to the calf area.

Gastrointestinal involvement

GNAS is a known driver mutation for multiple gastrointestinal (GI) abnormalities in the general population (58-61); it is therefore not surprising that MAS is associated with a broad spectrum of GI involvement. Reported hepatobiliary abnormalities include hepatocellular adenomas (62, 63), inflammatory adenomas (62, 63), choledochal cysts (63), neonatal cholestasis (64), and hepatoblastoma (64). Recent cohort studies have identified a high prevalence of intraductal papillary mucinous neoplasms (IPMNs), a potentially precancerous pancreatic cyst, affecting up to 50% of patients with MAS (63, 65). The malignant potential of these cysts is discussed further in ‘’Malignancies.’’ Although most patients in these series were asymptomatic, some reported associated functional deficits, including acute and chronic pancreatitis and diabetes. A variety of upper GI pathology has been identified in patients with MAS, including gastric heterotopia/metaplasia (66), gastric hyperplastic polyps (66), fundic gland polyps (66), and hamartomatous polyps (66, 67).

Intramuscular myxomas

An association between FD and intramuscular myxomas was first noted in 1926 (68), and later characterized by Mazabraud and colleagues in 1967 (69). The constellation of FD and soft tissue myxomas has since been widely referred to as Mazabraud syndrome. However, given the multisystemic nature of Gα _s activation, it is more pathophysiologically consistent to consider these myxomas as a feature of MAS rather than a distinct syndrome. In a retrospective multicenter review that included 1446 patients with a diagnosis of FD, myxomas were present in 32 patients, for a prevalence of 2.2% (70). Most myxomas present as a painless, palpable mass that is firm in consistency and partially movable. Uncommonly, lesions may progressively enlarge causing pain and functional impairment, particularly when located near joints or weight-bearing structures such as the buttocks. Myxomas can be visualized radiographically on ultrasound, CT, or magnetic resonance imaging, where they appear as distinct hypoechoic or low-density lesions with well-demarcated borders (71). On histopathology they present as well-encapsulated, hypovascular fibrous lesions composed of relatively hypocellular mucoid material (72). Most reported patients with myxomas have polyostotic as opposed to monostotic FD, likely reflecting a larger tissue distribution of mutated GNAS in these individuals (70). Case reports have associated the presence of myxomas with malignant transformation of FD lesions (73-76); however, this was not noted in larger series (70) and likely represents reporting bias.

Malignancies

G-protein dysregulation is a frequent contributor to tumorigenesis, and recent studies have identified that up to 4.2% of all cancers in the general population harbor gain-of-function GNAS mutations (77). These mutations are also commonly associated with sporadic, hyperfunctioning pituitary tumors (28%) and thyroid adenomas (5%) (10), which is unsurprising given their causative role in the development of MAS-related endocrinopathies.

Pancreatic tumors.

GNAS plays a key role in driving pancreatic tumorigenesis, with 66% of IPMNs harboring gain-of-function GNAS mutations (60, 61). IPMNs occur in up to 2% of the general population and are considered a precursor lesion to pancreatic adenocarcinoma (78). GNAS mutations have been identified as early driver mutations for IPMN development, particularly in the setting of concurrent KRAS mutations (79, 80). IPMNs occur in up to 50% in patients with MAS; however, pancreatic adenocarcinoma appears to be a rare development in this population, with only 1 reported case (81). It is unclear whether this reflects an inherently low malignant potential of pancreatic tumorigenesis in MAS, or whether the transformation of Gα _s-associated IPMNs to invasive adenocarcinomas may be less common than previously thought (82).

Breast cancer.

Breast cancer is another malignancy that has been associated with MAS. In 1 series combining Dutch and US cohorts, women with MAS had a 3.5- to 4-fold increased risk of breast cancer compared to the general population (83). Cancers developed at the notably young age of 36 to 46 years; however, outcomes were favorable, with 100% survival and no cases of recurrence or distal metastases. Thoracic FD was identified as a risk factor, and GNAS mutations were identified in affected tissues, pointing to a potentially causative role for Gα _s activation. Women with breast cancer had a high prevalence of MAS-associated precocious puberty, suggesting that, as in the general population, increased estrogen exposure in MAS may play a role in tumorigenesis. Results of this study led to the recommendations to initiate breast cancer screening in MAS at an earlier age compared to the general population, that is, at age 40 years both for the United States and the Netherlands.

Skeletal malignancies.

The transformation of FD into bone cancers has been well documented, including osteosarcoma, chondrosarcoma, fibrous histiocytoma, and others (84-87). Malignant transformation typically presents with new expansion and/or focal pain in a previously quiescent lesion, and radiographs may demonstrate expansion of the lesion through the cortex. Determining the prevalence of malignant transformation in FD is difficult because of the absence of rigorous epidemiologic studies. In the National Institutes of Health (NIH) cohort of 250 patients, 2 cases of osteosarcoma have been identified for a prevalence of less than 1%. The abandoned practice of therapeutic external beam radiation was clearly demonstrated to be a risk factor for malignant transformation as was seen in a large retrospective review of the Mayo Clinic data (85). An additional risk factor may be GH excess, both as NIH patients and several published cases report GH excess in association with malignant transformation (88-90). Pituitary irradiation for treatment of GH excess has been associated with sarcomatous transformation of skull base FD in 2 patients (88, 90), consistent with the tumorigenic effects of ionizing radiation.

Other malignancies.

Additional rarely reported tumors in MAS patients include testicular cancer (45), thyroid cancer (91, 92), ovarian virilizing sclerosing-stromal tumor (93), ovarian epithelial tumor (94), and hepatoblastoma (64). Although additional epidemiologic studies are clearly needed, the existing evidence points to a relatively low prevalence of malignancies associated with MAS, despite a potentially large and longstanding tissue burden of Gα _s activation in many patients. This may reflect relatively weak prototumorigenic effects of GNAS mutations, which may require the presence of coalterations in other oncogenic pathways to produce clinical disease. It is also possible that (outside IPMN development, where GNAS is known to be an early driver mutation), Gα _s mutations may occur as late events in already dedifferentiated cancers, making them less likely to be associated with malignancies in the setting of congenital mutations. More speculative is the possibility of protective mechanisms in patients with MAS, potentially related to apoptosis or senescence in mutation-bearing cells. This is discussed further in “Clinical Description,’’ which addresses age-related changes in disease activity.

Quality of life

Quality of life in FD/MAS has been studied in several large European and North American cohorts (95-97), all of which reported significant impairments in measures of physical function, bodily pain, and general health, with mental health and emotional domains within general population norms. A Dutch cohort reported impairments in vitality and social function (95); however, these domains were not different from the general population in the North American cohort (96). Impairments in quality of life indices were associated with psychosocial factors, including negative patient illness perceptions (98) and use of passive coping strategies (99). Total skeletal disease burden was negatively correlated with quality of life; however, interestingly, bone pain did not show a direct relationship with quality of life indices (95).

Age-Related Changes

FD/MAS is characterized by distinct age-related features that affect nearly every aspect of the disease, from molecular and cellular activity to long-term clinical outcomes. Defining these changes is central to understanding systemic and local effects of Gα _s activation, and, importantly, provides a critical perspective in developing effective approaches to clinical evaluation, monitoring, and treatment.

Establishment of fibrous dysplasia burden

The establishment of FD follows a characteristic and predictable time course. Although GNAS mutations are acquired early in embryogenesis, skeletal development appears to occur relatively normally in utero, with no frank clinical signs of FD present at birth. FD lesions become apparent over the first several years of life and expand during childhood and adolescence. One study of patients who underwent serial scintigraphy scans showed that FD burden was established in a region-specific pattern, with 90% of craniofacial FD present by age 3.4 years, 90% of extremity FD by 13.7 years, and 90% of axial FD by 15.5 years (100). Approximately 90% of future clinically significant FD was apparent in some form by age 5 years (100). These data support a course in which FD burden is established at a young age, roughly corresponding to the period during which patients undergo skeletal growth. The appearance of new lesions or expansion of existing lesions in adulthood is atypical with the natural history of FD and should raise suspicions for secondary processes.

Age-related clinical and radiographic features of fibrous dysplasia

Clinical sequelae in FD/MAS also reflect age-related patterns. Fractures peak around age 6 to 10 years before declining steadily in adulthood (37); this is particularly true of femoral fractures, which decline precipitously after adolescence (37). When it occurs, significantly impaired ambulation is also established early. In 1 large series the median age for initiating assistive devices was approximately 6 years, with 92% of assistive devices initiated by age 17 years (100).

Age-related changes are also apparent in the radiographic appearance of FD (71). During infancy FD is typically heterogeneous with streak-like features on X-ray; however, by school-age it has transitioned to the classic, homogeneous “ground-glass” appearance. In adulthood, lesions again become heterogeneous, often with sclerotic areas along the borders (Fig. 7A, 7B, and 7C). During childhood, craniofacial FD appears as homogenous “ground-glass” lesions on CT, but by adolescence lesions begin to develop progressive heterogeneity, with focal lucent areas reminiscent of cyst-like structures (Fig. 4C and 4F).

Figure 7. — Radiographic features of fibrous dysplasia (FD). A, B, and C, Upper panels demonstrate age-related radiographic changes in 3 patients with diffuse femoral involvement. A, In a 6-month-old patient, FD appears heterogeneous with streak-like features. Note the irregular metaphyses resulting from uncontrolled FGF23-mediated hypophosphatemia (yellow arrowhead). B, Radiograph from a 6-year-old demonstrates the classic “ground-glass” homogeneity. C, In a 31-year-old, FD again appears heterogeneous, with sclerotic areas interspersed with areas of radiolucency. D and E, Lower panels depict nuclear medicine scan images used to evaluate total skeletal FD burden. D, Technetium-99 scintigraphy scan in a young child with near panostotic disease shows increased tracer uptake in most of the skeleton, including the skull, spine, and long bones (red arrows). Note the symmetric increased uptake at the metaphyses in this growing child. E, ¹⁸F-NaF PET/CT scan in an adult with mild disease shows tracer uptake in areas of FD involving the skull, ribs, and left tibia (red arrows). Note the superior resolution and anatomical characterization of ¹⁸F-NaF in comparison to technetium.

Age-related biochemical and histologic features of fibrous dysplasia

Evaluation of biochemical markers can provide insight into the skeletal processes underlying age-related clinical and radiographic changes. Bone turnover markers increase in early childhood while FD lesions are established and begin a steady decline through adolescence and adulthood (101). A similar pattern holds true for receptor activator of nuclear factor kappa-Β ligand (RANKL) and FGF23 production (101). In vitro studies support this pattern of activity, with FD lesions from older individuals demonstrating the recurrence of histological features of normal bone with restoration of hematopoiesis, and decreased prevalence of mutated cells (102, 103).

Taken together, these clinical, radiographic, biochemical, and histological findings support a potential model in which FD lesions increase in childhood as a result of a greater proliferation of mutation-bearing stromal cells relative to unaffected cells. After final disease burden is established, the metabolic activity of FD lesions decreases over time, potentially because of a shortened life span of mutated stromal cells through apoptosis or senescence. This decrease in mutated cell proliferation allows the proportion of nonmutated stromal cells within FD lesions to increase over time, corresponding to improvements in histology, decreased biochemical bone turnover, changes in radiographic appearance, and clinical improvements. If this model is accurate, it has important implications for potential therapeutic strategies. Treatments designed to prevent the development or expansion of FD lesions would need to be targeted to childhood and initiated soon after FD development becomes apparent. In patients with established disease, a potential strategy may be to harness the natural decrease in FD activity by promoting proliferation and ultimately apoptosis of mutated stromal cells, with the goal of shortening the time during which lesions are metabolically active.

Bone pain and age-related changes

Bone pain in FD is common and poorly understood. In 1 large, cross-sectional study, 80% of adults and 50% of children reported the presence of bone pain, suggesting a tendency for pain to increase with age (104). Interestingly, neither the presence nor severity of pain was associated with total disease burden (104) or with serum bone turnover markers (101, 105). These findings suggest that the pathophysiology of FD pain is distinct from other skeletal complications and is not directly related to increased skeletal activity or stromal cell proliferation. The potential contribution of neuropathic or other extraskeletal elements to FD-related bone is an important unmet research need.

Age-related features of endocrine disease

Unlike FD, which follows a waxing and waning pattern of activity, MAS endocrinopathies appear persistent across the lifespan and do not improve over time. However, endocrinopathies manifest at variable times and may have profound effects on growth and development; thus, they have inherent age-related clinical implications. The timing of disease establishment has been less well elucidated for endocrinopathies in comparison to FD; however, most endocrinopathies appear to present in childhood before age 10 years (personal observations, A.M.B. and M.T.C.). GH excess and hyperthyroidism may infrequently become apparent in adulthood; however, in most cases, these patients likely had longstanding subclinical disease that could have been detected in childhood through careful evaluation. Linear growth changes are a hallmark feature of MAS endocrinopathies in children, and untreated disease may result in bone age advancement and disabling short stature. However, interpretation of linear growth in MAS is complex and affected by multiple variables. Growth acceleration is common in early precocious puberty, hyperthyroidism, and GH excess, whereas growth may be impaired by advanced puberty, hypophosphatemia, and skeletal deformities. Behavior changes are also common manifestations of endocrinopathies in children; these may also be affected by bone pain.

Model Systems

The ideal model system in FD/MAS would reflect all critical disease-specific and clinically relevant aspects, such as mosaicism, multisystem involvement (bone and endocrine), and age-related changes. Realistically it may be impractical for any single model to encompass all these features, and multiple models may be necessary to investigate various aspects of pathophysiology, and to develop and test therapeutics. The following sections will discuss the benefits and limitations of currently available models.

In vitro models

Primary cultures from patient tissue.

Attempts to isolate mutation-bearing stromal cells from patient tissue highlight the essential mosaic nature of FD lesions. In one study, single cell suspensions isolated from FD tissue and plated at low density led to colony-forming units that were a mixture of mutated and wild-type stromal cells (12). Further, in an established in vivo ossicle model, when clones of mutant, wild-type, or mixed mutant + wild-type cells implanted in immunocompromised mice, FD-like ossicles developed only in mice that received a combination of mutant + wild-type clones (12). This suggests that mutant GNAS-bearing stromal cells are unable to propagate clonally in the absence of wild-type cells, supporting a critical, thus far unelucidated contribution of wild-type stromal cells to FD lesion formation. Mixed cultures can also be useful for evaluating FD cell expression profiles and behavior, evidenced by studies of increased RANKL production in FD cells and osteoclastogenic induction in cocultured monocytes, consistent with the high levels of osteoclastogenesis present in FD tissue (106). Evaluation of specific transcriptional targets in these mixed cultures is also possible, as shown in studies demonstrating upregulated Wnt/β-catenin signaling in patient-derived tissue and cell cultures (13). However, the degree of heterogeneity seen in FD lesions, which are an admixture mutant and wild-type cells, must be considered and presents a challenge in interpreting data and developing informative models (102). One approach to overcoming this limitation has been to generate mixtures of homogeneous, clonally derived strains both of wild-type and GNAS-mutated stromal cells from individual FD lesions. This approach demonstrated increased basal and induced interleukin-6 (IL-6) production in clonally derived mutation-bearing stromal cells compared to cognate wild-type cells (18, 107), suggesting that Gα _s activation specific to mutant cells (as opposed to wild-type) is a source of osteoclast-promoting factors in FD. Recent evidence that demonstrated osteoclasts have paracrine effects on osteogenic cells via osteoclast-produced vesicular RANK raise the question of whether osteoclasts, which are so prevalent in active FD lesions, may play a role in FD lesion formation and/or expansion (108).

Transfected cells.

Targeting activating GNAS mutations to normal human stromal cells is a strategy that limits the variability found in patient-derived cells and more easily facilitates investigation of molecular pathways downstream from Gα _s activation. One study used lentiviral vectors to engineer stably transfect normal human skeletal progenitor cells with R201C mutations. Transfected cells demonstrated enhanced cAMP production consistent with constitutive Gα _s activation (15). These cells displayed altered osteogenic differentiation in vitro and, like findings in patient-derived cells, showed dramatic upregulation of the osteoclast promotor RANKL. This model also identified upregulation of several phosphodiesterase isoforms in transfected cells that could potentially inform development of therapeutic targets (15).

Animal models

Transplanted models.

Cellular models have been used to generate FD-like tissue (ossicles) ex vivo through transplantation of patient-derived stromal cells into immunocompromised mice (12). Subcutical transplants of clonally derived mutant and wild-type cells resulted in formation of ossicles that recapitulated key histologic aspects of FD, including abnormal bone tissue devoid of adipocytes and hematopoietic marrow. Transplantation of stromal cells stably transfected with R201C mutations produced similar findings (15). As mentioned above, it is important to note that in experiments of patient-derived cells, a mixture both of mutant and wild-type cells was required for FD-like ossicle formation; wild-type cells alone generated ossicles resembling normal bone, whereas transplantation of only mutant cells resulted in transplant loss and no ossicle. This model provides experimental evidence for the hypothesis that GNAS mutation-bearing cells are less viable than wild-type cells and necessitate mosaicism for survival. Additional advantages of this model include the potential to investigate Gα _s activation effects on wild-type cells. As such, this model may prove useful in studying FD lesion expansion and in testing therapies to prevent lesion growth. However, this model has important limitations inherent to use of patient-derived tissue, including availability and adequacy of samples, the growth restriction typical of most GNAS-mutated colonies, and variability in mutational loads between samples. Additional limitations include the inability to account for developmental features of FD and nonskeletal features associated with MAS.

Germline models.

Germline animal models offer practical advantages that bypass some of the limitations posed by cell culture-based methods. Saggio et al used lentiviral constructs to generate transgenic mice that constitutively express the R201C mutation found in human disease in all tissues, resulting in inherited, panostotic skeletal disease that histopathologically replicates FD (109). Like human disease, skeletal lesions in these mice developed postnatally, with normal development and cell differentiation during the embryonic and neonatal periods. Lesions developed through a distinct sequence of histopathological stages, including a primary phase of increased bone formation and a secondary remodeling phase with marked narrowing of the marrow cavity. The tertiary phase, which most resembled human FD, was not established until mice were well into adulthood at age 1 year or older; the equivalent of approximately 50 years in a human. Although this model demonstrates a developmental context to disease expression in FD, the late onset of disease is markedly different from the human phenotype, in which lesions develop in early childhood. It is possible that differences in the relative number of cell divisions in humans and mice may confound the ability of murine models to replicate this age-related phenotype. Interestingly, transgenic germline expression of R201C targeted to mature osteoblasts by a 2.3 kb Col1a1 promoter resulted in mice with progressive high bone mass without features of FD, suggesting that Gα _s activation involving less-differentiated skeletal progenitors is required for FD lesion formation (110). By modeling an age-related pattern of development, transgenic germline models may prove useful for investigating the pathogenesis of FD lesion formation and expansion, and to test preventive therapies. Further work is needed to determine whether these models reproduce the multisystem involvement characteristic of MAS. The lack of embryonic lethality in these models indicates that key pathogenic aspects of human disease, including those related to obligate mosaicism, may not be captured in these systems and require other methods of investigation.

Inducible models.

Inducible animal models offer the ability to modify the timing of Gα _s activation, providing another approach to replicating developmental patterns of disease expression. The first inducible model of FD was developed through use of a G-coupled protein receptor (Rs1) engineered to constitutively activate Gα _s signaling in osteoblasts (111, 112). Constitutive Rs1 expression led to dramatically increased trabecular bone mass with histopathologic features reminiscent of FD; however, the presentation varied widely depending on the timing of induction, with delayed expression leading to a progressively attenuated phenotype, and no skeletal abnormalities with induction after age 4 weeks (111, 112). Withdrawal of tetracycline-induced Rs1 expression in adult mice led to a marked reversion of skeletal disease (112). This important finding supports 3 important hypotheses: 1) There is a critical postnatal window during which osteoblasts respond to Gα _s activation, consistent with the age-related phenotype observed in human disease; 2) ongoing Gα _s activation may be required to maintain a disease state in FD, and 3) if a therapy could “turn off” mutant Gα_s activation, lesion regression could take place.

Two recently developed models show promise in recapitulating FD both pathogenically and phenotypically. Zhao et al created a conditional doxycycline-inducible model expressing the human R201C mutation in skeletal stem cells under a Prrx1-Cre promoter, resulting in rapid development of skeletal lesions both in embryonic and postnatal mice (113). Like in human disease, conditional mutant Gα _s expression resulted in increased cAMP production and proliferation of skeletal progenitor cells without differentiation into mature osteoblasts. The resulting skeletal lesions demonstrated multiple histopathologic features of FD, including abnormal woven bone, increased RANKL expression, and prominent osteoclastogenesis. Consistent with the tissue-specific distribution of Cre-recombinase expression, lesions developed exclusively in the long bones and calvarium, locations frequently associated with morbidity in human disease. The presence and degree of mosaicism within skeletal lesions in this model is unclear; however, the variable Cre-recombinase (and therefore mutant Gα _s) expression in the skull offers a potential opportunity to investigate the interface between mutant and wild-type cells. Like the Rs1 FD mouse, doxycycline withdrawal resulted in resolution of skeletal lesions, adding support for Gα _s inhibition as a potential treatment strategy.

Khan and colleagues concurrently published a model in which the human R201H mutation was conditionally knocked in to the endogenous mouse GNAS locus (114). Pre-embryonic induction targeted to mouse oocytes resulted in embryonic lethality; however, expression targeted to osteochondral progenitor cells, early osteoblasts, and bone marrow stromal cells under a Prrx1-Cre promoter resulted in rapid formation of severe skeletal lesions, which like FD were characterized by increased trabecular volume and loss of marrow space. Wnt/β-catenin signaling was increased in skeletal tissue, consistent with findings in patient-derived tissues and cells (13), and the pathogenic role of Wnt/β-catenin was further confirmed by rescue of the FD phenotype in mice missing 1 copy of LRP6, a Wnt coreceptor gene. An inducible mosaic state was created by crossing R201H knock-in mice with a Sox9-CreER line, leading to selective mutant Gα _s expression in bone marrow stromal cells and the development of a similar but attenuated skeletal phenotype. The spatial and temporal control of Gα _s activation offered by this model is particularly useful in investigating Gα _s’s role in skeletal formation and differentiation. For example, further work in this system demonstrated Gα _s regulation of intramembranous ossification through Hedgehog and Wnt1/β-catenin, and reduced cartilage dissolution associated with Gα _s activation in cranial bones (115). This knock-in approach could also potentially be targeted to extraskeletal tissues, providing an opportunity to investigate multisystemic involvement in MAS.

Treatment

Clinical management of fibrous dysplasia

Surgical management.

Surgery is the mainstay approach to treatment for FD. Techniques must be highly individualized, tailored both to the area of the affected skeleton and the specific patient characteristics. The timing of surgical intervention is a critical aspect of decision making that cannot be overemphasized. Skeletal complications characteristically become apparent in childhood; however, FD tends to be more metabolically active during this period, and surgical techniques appropriate for use in a growing skeleton are limited. Together these factors conspire to produce poorer surgical outcomes and contribute to long-term disability.