Craniofacial Fibrous Dysplasia: Causes and Treatment Options

Craniofacial fibrous dysplasia (CFD) is a rare bone disorder in which normal bone is replaced by fibrous tissue, leading to deformities and functional impairments. It primarily affects the skull and facial bones, with symptoms ranging from asymptomatic lesions to significant disfigurement and complications. While it can occur in isolation, CFD is also linked to genetic syndromes like McCune-Albright syndrome.

Early diagnosis and appropriate management are key to minimizing complications and preserving function. Understanding its underlying mechanisms, clinical presentation, imaging characteristics, treatment approaches, and potential risks helps guide effective care strategies.

Genetic And Cellular Mechanisms

CFD results from postzygotic activating mutations in the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα). This mutation causes continuous activation of adenylate cyclase, leading to excessive cyclic adenosine monophosphate (cAMP) production. Elevated cAMP disrupts normal osteoblast differentiation, replacing mature bone with fibro-osseous tissue. Because the mutation occurs postzygotically, CFD exhibits a mosaic pattern, meaning only some cells carry the mutation, contributing to variable phenotypic expression depending on when and where the mutation occurs during development.

This aberrant signaling disrupts bone remodeling by affecting RANKL (Receptor Activator of Nuclear Factor Kappa-Β Ligand) and OPG (Osteoprotegerin), two key regulators of osteoclast activity. Increased RANKL promotes osteoclast differentiation and bone resorption, while reduced OPG fails to counterbalance this effect. The result is weak, disorganized bone that lacks normal lamellar structure, increasing the risk of deformity and fracture.

Osteogenic progenitor cells in CFD lesions exhibit impaired maturation, preventing the transition from woven to mature lamellar bone. Histological studies reveal irregular trabeculae within a fibrous stroma, devoid of normal hematopoietic marrow. The fibrous component, composed of spindle-shaped fibroblasts and collagen-rich extracellular matrix, further weakens bone integrity. Additionally, CFD-affected osteoblasts overexpress fibroblast growth factor 23 (FGF23), a hormone regulating phosphate homeostasis. Elevated FGF23 leads to hypophosphatemia, exacerbating skeletal fragility and increasing the risk of fractures.

Clinical Manifestations

The presentation of CFD varies widely depending on the extent and location of bone involvement. Some individuals remain asymptomatic, with lesions discovered incidentally on imaging, while others develop progressive deformities that impact function and appearance. The most commonly affected regions include the maxilla, mandible, frontal, sphenoid, and temporal bones, with unilateral involvement being more frequent. Expanding lesions can cause facial asymmetry, malocclusion, or difficulty with mastication.

Pain is common, often due to microfractures, nerve compression, or secondary cystic changes. A study in The Journal of Bone and Mineral Research reported that about 60% of patients experience chronic pain, which can worsen with mechanical stress or hormonal fluctuations, particularly during puberty. The pain is typically dull and persistent, though acute exacerbations may occur from structural instability. The abnormal bone architecture also increases the risk of pathological fractures, particularly in weight-bearing skull base regions.

Neurological complications arise when expanding fibrous tissue compresses cranial nerves. Optic nerve involvement is particularly concerning when the sphenoid bone is affected, potentially leading to visual disturbances or blindness if untreated. A prospective study in Ophthalmology found that up to 30% of patients with spheno-orbital involvement exhibit some degree of optic nerve compression, with early intervention improving outcomes. Similarly, temporal bone involvement can cause conductive hearing loss due to ossicular disruption or external auditory canal narrowing.

In cases associated with McCune-Albright syndrome, CFD coexists with hyperfunctioning endocrinopathies. Hormonal excess can accelerate lesion growth, worsening skeletal deformities. Elevated FGF23 levels contribute to phosphate wasting and osteomalacia-like symptoms, further weakening bone structure and increasing fracture risk.

Radiological Assessment

Imaging plays a central role in diagnosing CFD, guiding management, and monitoring progression. Computed tomography (CT) is the preferred modality due to its ability to characterize bone architecture with high resolution. Affected regions typically display a “ground-glass” appearance due to the disorganized fibro-osseous matrix. Lesions can range from homogeneously sclerotic to a heterogeneous, cystic pattern. High-resolution CT is particularly useful for assessing skull base involvement, where foraminal narrowing or orbital encroachment can have significant clinical implications.

Magnetic resonance imaging (MRI) is less commonly used for primary diagnosis but provides valuable information on soft tissue extension and potential complications. MRI can delineate neurovascular compression more effectively than CT. CFD lesions typically appear hypointense on T1-weighted sequences and show variable signal intensity on T2-weighted imaging, depending on mineralization and fibrous content. Contrast-enhanced MRI may help differentiate CFD from other fibro-osseous lesions or malignancies, particularly in cases of rapidly expanding lesions.

Bone scintigraphy with technetium-99m methylene diphosphonate (Tc-99m MDP) can assess lesion activity, especially in younger patients where growth potential remains uncertain. Increased radiotracer uptake suggests heightened osteoblastic activity, which tends to decrease with skeletal maturity. While not routinely used for diagnosis, scintigraphy can help detect multifocal disease, such as polyostotic fibrous dysplasia. Positron emission tomography (PET) with fluorodeoxyglucose (FDG) has been investigated in CFD assessment, though its role remains unclear. Some studies suggest FDG uptake may correlate with lesion progression, but distinguishing benign metabolic activity from malignant transformation is challenging.

Management Strategies

Treatment depends on symptom severity, lesion progression, and functional impairment. Asymptomatic cases with stable lesions often require only periodic monitoring with clinical evaluations and imaging, particularly in growing children. Maintaining bone health through adequate calcium and vitamin D intake is recommended to minimize fracture risk, though no pharmacological intervention has been proven to halt lesion progression definitively.

For pain management, bisphosphonates such as pamidronate or zoledronic acid have been explored. These drugs inhibit osteoclast-mediated bone resorption, potentially reducing microfractures within dysplastic bone. Some studies suggest bisphosphonates provide symptomatic relief, though robust clinical trials validating long-term efficacy in CFD are limited. Since fibrous dysplasia lesions do not remodel into normal bone, bisphosphonates should be used selectively, particularly in cases where pain is refractory to conventional analgesics.

Surgical intervention is reserved for patients with significant functional impairment, progressive deformity, or complications such as optic nerve compression. Contour remodeling can restore facial symmetry, while decompressive surgery may be necessary for neural compression. The timing of surgery is critical, as early procedures in pediatric patients carry a higher risk of recurrence due to continued skeletal growth. In extensive reconstruction cases, autologous bone grafts or alloplastic materials may be used, though their long-term integration within dysplastic bone remains a challenge.

Potential Complications

CFD progression can lead to complications, particularly when lesions expand or weaken critical skull structures. While some individuals experience mild deformities, others develop significant morbidity due to mechanical compression, pathological fractures, or secondary changes within the affected bone.

Optic nerve compression occurs when fibrous tissue encroaches on the optic canal, potentially leading to vision loss. Some studies estimate that up to 30% of patients with sphenoid involvement experience optic neuropathy. The decision to intervene surgically is complex, as some cases remain stable while others deteriorate rapidly. Sudden vision loss requires urgent decompression to prevent permanent damage. Temporal bone involvement can cause conductive hearing loss due to external auditory canal narrowing or ossicular chain disruption. In rare cases, skull base involvement can lead to cerebrospinal fluid leaks, increasing the risk of meningitis.

Bone fragility increases the likelihood of pathological fractures, particularly in weight-bearing skull base regions. These fractures may occur spontaneously or after minor trauma, often causing chronic pain and structural instability. The altered bone mechanics also make CFD lesions more susceptible to secondary changes, such as aneurysmal bone cyst formation. While malignant transformation to osteosarcoma or fibrosarcoma is rare—occurring in less than 1% of cases—it remains a serious concern, especially in long-standing disease or prior radiation exposure. Signs of malignancy include rapid lesion expansion, new-onset pain, and cortical destruction on imaging, necessitating prompt biopsy and intervention.