Fibrous dysplasia

Fibrous dysplasia (FD) is a benign, non-neoplastic fibro-osseous disorder in which normal medullary bone is progressively replaced by structurally unsound fibrous tissue and irregularly formed woven bone.[1][2] The disease arises from postzygotic, somatic gain-of-function mutations in the GNAS gene (chromosome 20q13), which encodes the α-subunit of the stimulatory G protein (Gαs).[2][3] These mutations—most commonly at codon Arg201—constitutively activate adenylyl cyclase, elevate intracellular cyclic AMP, and impair differentiation of skeletal stem cells, resulting in the formation of discrete fibro-osseous lesions.[2][4] Because the mutation occurs after conception and is mosaic, FD is not heritable.[5] In the jaws, FD characteristically produces a diffuse, ground-glass opacity with ill-defined margins that blend into adjacent normal bone, most often in the posterior maxilla.[1] Management ranges from observation to surgical recontouring or resection, guided by symptoms, growth behavior, and patient age.[2]

The current WHO classification of bone tumors categorizes fibrous dysplasia among benign fibro-osseous lesions.[6] Accepted subtypes include:

• Monostotic fibrous dysplasia — involvement of a single bone; the most common form
• Polyostotic fibrous dysplasia — involvement of two or more bones
• Craniofacial fibrous dysplasia — the preferred term when maxillary FD extends contiguously into adjacent craniofacial bones (e.g., zygoma, sphenoid, ethmoid) without extracraniofacial skeletal involvement, distinguishing it from true polyostotic disease[1][2]

FD occurring with café-au-lait macules and hyperfunctioning endocrinopathies constitutes McCune–Albright syndrome (MAS).[2] The rare association of FD with intramuscular myxomas is termed Mazabraud syndrome.[7] Older terms such as "Jaffe–Lichtenstein disease" for polyostotic FD are largely historical.

FD is rare, with an estimated prevalence of approximately 61 per million and an incidence of roughly 3.6 per million person-years.[8] The monostotic form accounts for approximately 80–85% of all cases.[1] There is no sex predilection.[1][8] Diagnosis peaks during the second and third decades of life for monostotic disease, although clinically significant lesions typically manifest during childhood and adolescence.[1][2] In the maxillofacial region, the posterior maxilla is the most frequently affected site, followed by the mandible.[1][9] Maxillary lesions predominate in craniofacial FD overall, representing the most affected facial bone.[9] Jaw involvement is unilateral, and bilateral jaw disease, when present, is associated with polyostotic FD or MAS.[2]

Presentation and symptoms

The hallmark presentation is painless, slowly progressive, unilateral bony swelling. Approximately 90% of patients with gnathic FD present with tumefaction, while pain is reported in a minority.[1] Lesions expand during childhood and adolescence and typically become more quiescent after skeletal maturity, although craniofacial lesions may continue to grow into adulthood.[1][2]

Examination findings

• Firm, non-tender, fusiform expansion of the alveolar ridge or body of the jaw, often causing facial asymmetry[1][2]
• Overlying mucosa is normal in color and intact
• Teeth within the lesion may be displaced or rotated, but the arch form generally maintains its shape[2]
• Dental anomalies include malocclusion, crowding, spacing, taurodontism, enamel hypoplasia, and dentin dysplasia[2]

Complications and red flags

• Maxillary lesions may obliterate the maxillary sinus and extend to involve the orbit, causing proptosis, dystopia, or visual disturbance[1][2]
• Skull base involvement can compress cranial nerves, producing visual loss, hearing impairment, or facial numbness[1][5]
• Rapid growth, new-onset pain, paresthesia, or cortical destruction should raise concern for secondary aneurysmal bone cyst or, rarely, sarcomatous transformation[2]

Location and distribution

FD of the jaws most commonly involves the posterior maxilla, followed by the mandibular body and ramus.[1][9] Lesions are characteristically unilateral. Maxillary FD frequently extends beyond the alveolar bone to involve the hard palate, zygomatic buttress, and maxillary sinus floor.[1][2]

Periphery and shape

A defining radiographic feature is the absence of a distinct border: the lesion merges imperceptibly with surrounding normal bone through a gradual transition zone.[1] This ill-defined periphery distinguishes gnathic FD from ossifying fibroma, which typically demonstrates a well-defined, often corticated margin. Extragnathic FD lesions tend to have somewhat better-defined margins than those in the jaws.[1]

Internal architecture

The classic internal pattern is a diffuse, homogeneous ground-glass opacity—a hazy radiopacity without discrete internal trabeculation, resulting from superimposition of fine woven bone on a fibrous matrix.[1][2] Descriptive synonyms include "orange-peel" and "fingerprint" patterns.[1] The radiographic appearance evolves with patient age:

• Early (immature) lesions — predominantly radiolucent due to abundant fibrous tissue; FD is seldom considered in the differential at this stage[1]
• Intermediate lesions — mixed radiolucent–radiopaque with the characteristic ground-glass quality; most common during childhood and adolescence[2]
• Mature lesions — increasingly radiopaque, heterogeneous, and occasionally densely sclerotic, particularly in older patients or those treated with bisphosphonates[2]

On cross-sectional imaging, ground-glass density is the most common finding, while expansion with sclerosis or expansion with lytic areas are less frequent patterns.[10]

Effects on teeth and adjacent structures

• Lamina dura: loss of definition of the lamina dura around teeth embedded in the lesion is common[1]
• Tooth displacement: teeth may be displaced or rotated; root splaying around the lesion is characteristic[2]
• Root resorption: not a typical feature, which helps distinguish FD from more aggressive lesions
• Inferior alveolar nerve canal: superior displacement of the canal is considered a pathognomonic sign of mandibular FD[1]
• Maxillary sinus: progressive superior displacement and eventual complete obliteration of the sinus floor is characteristic of maxillary FD[1]

Cortical involvement and expansion

The buccal and lingual cortices become expanded and thinned but are characteristically preserved—cortical interruption is rare in uncomplicated FD.[1] Endosteal scalloping is a typical feature on cross-sectional imaging.[2] Cortical destruction, when present, should prompt consideration of secondary pathology such as aneurysmal bone cyst or malignant transformation.[2]

Growth pattern and extent

FD produces a fusiform, centrifugal expansion of the affected bone. Growth is most active during childhood and adolescence. Cross-sectional imaging is the technique of choice for delineating the full extent of disease, particularly when maxillary lesions extend into the skull base, orbit, or paranasal sinuses.[1][2]

Variants

• Cystic degeneration: rarely, gnathic FD develops internal cystic change[1]
• Pagetoid pattern: occasional lesions show a coarsened, mixed sclerotic and lytic pattern resembling Paget disease on imaging[11]
• Secondary aneurysmal bone cyst: an aneurysmal bone cyst may develop within a pre-existing FD lesion, producing a rapidly expanding, destructive component[2]

MRI

FD lesions are characteristically hypointense on T1-weighted sequences.[12] Signal on T2-weighted sequences is variable: lesions with abundant bony trabeculae appear hypointense, while those with greater fibrous or cystic components are hyperintense.[12] A hypointense peripheral rind is common. Contrast-enhanced T1-weighted images may demonstrate a "milk cloud appearance"—a diffuse, cloud-like enhancement pattern that correlates with the ground-glass appearance on CT and may aid diagnosis when radiographs are equivocal.[13] MRI is particularly valuable for evaluating suspected hemorrhagic or cystic degeneration and for assessing possible malignant transformation, where cortical destruction and a soft tissue mass may be identified.[1][14]

Nuclear medicine

Technetium-99m bone scintigraphy demonstrates intense radiotracer uptake in FD lesions and is useful for identifying subclinical or polyostotic disease, confirming multifocal involvement, and assessing whether lesions remain metabolically active. 18F-sodium fluoride PET/CT provides superior spatial resolution and quantitative assessment of lesion activity, and multimodal imaging classification using PET, MRI, and CT has been explored to characterize lesion heterogeneity and potentially predict clinical behavior.[1][15]

FD belongs to the benign fibro-osseous lesion family, and the differential centers on entities sharing a fibrous stroma with mineralized product. The key diagnostic anchor is the combination of ill-defined margins blending into normal bone, ground-glass internal pattern, and fusiform cortical expansion without interruption.

The highest-risk diagnostic pitfall is misidentifying a low-grade central osteosarcoma as FD, given overlapping ground-glass density and medullary location. When clinical or imaging features are atypical—particularly cortical destruction, soft tissue extension, or rapid growth—biopsy with GNAS mutation analysis and MDM2/CDK4 testing is essential to exclude malignancy.[6]

Microscopic findings

The hallmark is a cellular fibrous stroma composed of bland, fusiform fibroblastic cells without atypia, interspersed with irregularly shaped trabeculae of woven bone.[1][2] The bony trabeculae are characteristically curvilinear, branching, and serpentine, classically described as resembling "Chinese characters" or "alphabet soup".[1][2] Key features include:

• Osteoblastic rimming is typically absent or inconspicuous, distinguishing FD from ossifying fibroma, in which prominent osteoblastic rimming is the rule[1]
• Peritrabecular clefting (artifactual separation of trabeculae from stroma during processing) is a characteristic finding that further aids distinction from ossifying fibroma[1]
• Microscopic homogeneity: the ratio of fibrous tissue to bony trabeculae is relatively uniform throughout a given lesion[1]
• The lesion is non-encapsulated and merges with peripheral cortical bone without a demarcation line, correlating with the ill-defined radiographic margins[1][2]

Variants and secondary changes

In craniofacial FD, lamellar maturation of bone may occur in older lesions.[1] Secondary changes include hemorrhage, myxoid degeneration, foamy macrophage aggregates, and dense stromal collagenization, all of which can complicate histologic interpretation.[17] Cementum-like ovoid calcifications are rare in FD, in contrast to ossifying fibroma and cemento-osseous dysplasia.[1]

Molecular findings

Activating GNAS mutations at codon R201 (R201H or R201C) are detectable in approximately 50–70% of cases by standard PCR-based methods, with sensitivity limited by the mosaic nature of the mutation and variable concentration of mutation-bearing cells.[6][17] Detection of a GNAS mutation is highly specific for FD among fibro-osseous lesions and is absent in ossifying fibroma, osteofibrous dysplasia, and low-grade central osteosarcoma.[6] Rare high-grade osteosarcomas arising within FD may retain the GNAS mutation.[6]

Workup and referral

When clinical and radiographic findings are characteristic, biopsy may not be required.[1][2] Biopsy is indicated when the diagnosis is uncertain or when atypical features such as rapid growth, pain, or cortical destruction raise concern for malignancy.[2] All patients with confirmed FD should undergo screening for polyostotic disease (bone scintigraphy) and, if polyostotic features or endocrine signs are present, comprehensive evaluation for MAS including biochemical analysis and thyroid/gonadal ultrasonography.[2] Baseline and periodic audiologic and ophthalmologic examinations are indicated when the skull base, auditory canal, or orbit is involved.[2]

Surgical management

Surgery remains the cornerstone of treatment for symptomatic craniofacial FD.[2][9] Lesions are classified by clinical behavior as quiescent, nonaggressive (slow growth), or aggressive (rapid growth with or without pain or paresthesia).[2]

• Observation is appropriate for asymptomatic, quiescent lesions and yields excellent outcomes[9]
• Conservative recontouring/debulking is the most frequently performed procedure for cosmetic or functional indications but carries a substantial risk of postoperative regrowth[2]
• Radical resection with reconstruction has lower recurrence rates than recontouring but greater morbidity; it is considered for aggressive or recurrent disease[9][18]
• Elective procedures are often deferred until after skeletal maturity, when lesions tend to stabilize[2]

Risk factors for recurrence include younger age at surgery, polyostotic disease, and elevated preoperative alkaline phosphatase.[7]

Medical therapy

• Intravenous bisphosphonates (zoledronic acid, pamidronate) are effective for FD-related bone pain; oral alendronate has not demonstrated efficacy[16]
• Denosumab (anti-RANKL antibody) reduces bone turnover markers and lesion activity and may improve pain in patients refractory to bisphosphonates, but carries risks of mineral metabolism disturbances and rebound phenomena upon discontinuation. Its use is recommended only in experienced centers, ideally within clinical studies[16][19][20]

Prognosis

The overall prognosis is favorable. Sarcomatous transformation—most commonly to osteosarcoma—is rare, estimated at less than 1% for monostotic disease, with higher risk in polyostotic FD, MAS, and patients with prior radiation exposure.[1][21] Radiotherapy is contraindicated due to this risk.[1] Red flags for malignant transformation include abrupt onset of pain, rapid swelling, cortical destruction, and soft tissue mass formation.[14][22] Long-term clinical and radiographic surveillance is recommended for all patients.[23]

McCune–Albright syndrome

Polyostotic FD with one or more extraskeletal features (café-au-lait macules, precocious puberty, hyperthyroidism, growth hormone excess, Cushing syndrome) defines MAS.[2] Patients with MAS tend to present earlier, have more aggressive craniofacial disease, undergo more surgical procedures, and have higher recurrence rates than those with isolated monostotic or polyostotic FD.[9][24] Untreated growth hormone excess is associated with increased postoperative regrowth; screening and treatment of all endocrinopathies prior to elective surgery is strongly recommended.[2] Growth hormone excess has also been linked to dental anomalies including taurodontism.[2]

Pediatric considerations

Most FD lesions become clinically apparent during childhood. Surgical intervention in growing patients must balance the need for functional or aesthetic correction against the higher recurrence risk associated with operating before skeletal maturity.[2][7] Denosumab use in pediatric patients has shown efficacy but carries a relatively high incidence of rebound hypercalcemia upon discontinuation, necessitating close monitoring.[25]