Research progress on diagnosis and treatment of craniofacial fibrous dysplasia: a narrative review

Introduction

Background

Craniofacial fibrous dysplasia (CFD) is a rare fibro-osseous structural disorder in the craniofacial region (1). As a complex and continuously progressive multi-phenotypic disorder, at present, there is still a lack of comprehensive diagnosis and treatment plans that can effectively control or alleviate the disease course in the long term for CFD.

Rationale and knowledge gap

CFD is a rare disease of fibrous bone structure abnormality with an incidence of approximately 0.01–0.05% (2), mainly manifested by the replacement of normal trabecular bone structure by hyperproliferative fibrous-like bone tissue (3). Fibrous dysplasia (FD) can occur in bones throughout the body, with the craniomaxillofacial region, femur, and rib being among the most frequently involved sites. FD can manifest as single bone involvement [monostotic fibrous dysplasia (MFD)] or as multi-bone involvement [polyostotic fibrous dysplasia (PFD)], with a small number of patients being combined with other systemic diseases, which then manifest as a syndromic form, such as McCune-Albright syndrome (MAS), Mazabraud syndrome (2-6). Because of its clinical rareness and complex disease phenotype, effective therapies are still lacking, and accurate diagnosis and standardized treatment of the disease are of great significance. Therefore, this paper reviews the research progress related to CFD, including its pathogenic mechanisms, clinical manifestations, imaging manifestations, histopathological features, and treatment strategies, by integrating the latest clinical and basic research results.

Objective

This paper reviews the latest clinical and basic progress related to CFD to provide certain references for future research, diagnosis, and treatment of CFD. Compared with the previously published systematic review, the present narrative review integrates emerging preclinical and clinical evidence published until early 2026, highlights a maxillofacial surgery-oriented refined multidisciplinary team (MDT) regimen, updates molecular pathogenesis advances based on single-cell sequencing and transgenic animal experiments, and summarizes up-to-date global CFD clinical trial landscape, providing complementary and updated evidence for CFD clinical practice and basic research. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-2026-0011/rc).

Methods

A literature search was performed for this narrative review. The search was carried out by all authors. Table 1 describes the method for this narrative review. The following section of this narrative review will discuss and appraise the evidence surrounding the pathogenic mechanisms, clinical manifestations, imaging findings, histopathological features, and treatment strategies of CFD. This narrative review aimed to include high-quality evidence from randomized controlled trials, cohort studies, and case series relevant to craniofacial management.

Pathogenic mechanism of FD

The prevalence of GNAS mutations in patients with FD ranges from 64% to 83% (7). Transgenic mouse models with GNAS mutations faithfully recapitulate key skeletal features observed in humans, including age-dependent lesion progression, expansive bone deformities, aberrant trabecular architecture, reduced medullary volume, thinning cortical bone, deposition of immature woven bone, impaired mineralization, compromised hematopoietic potential, and active bone metabolism (8-10). These findings strongly suggest that GNAS mutations play a central initiating role in FD pathogenesis. Substantial progress in both in vivo and in vitro studies has enhanced the understanding of the molecular mechanisms underlying FD (8-10). The GNAS mutations associated with FD, particularly R201H and R201C, are predominantly activating gain-of-function variants. These mutations could result in constitutive activation of the stimulatory G protein α subunit (Gsα), leading to persistent elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which is a hallmark event in FD development. Sustained activation of cAMP in osteoblasts inhibits the Wnt/β-catenin signaling pathway, leading to suppression of downstream osteogenic differentiation and bone matrix synthesis (11,12). During this process, the expression level of RUNX2, an essential transcription factor involved in osteoblast differentiation, is also downregulated (13).

Beyond this canonical pathway, emerging evidence highlights the complexity of FD pathogenesis at the cellular level. Single-cell transcriptomic analyses have revealed that GNAS mutations are not confined to osteolineage cells but are also present in endothelial cells, pericytes, and mesenchymal stromal cells within FD lesions. This multi-lineage involvement likely contributes to the complex histopathological features of FD, including hypervascularity and fibrosis (14). Furthermore, the immune microenvironment plays a significant role. Pro-inflammatory and osteoclastogenic signals, partly driven by mutant stromal cells, contribute to the pain, increased bone resorption and fibrous tissue accumulation characteristic of FD (15,16).

The phenotypic variability, including the extent of monostotic versus polyostotic involvement, disease severity, and systemic manifestations, may be influenced by the specific mutational locus or the developmental timing of the genetic alteration (10,17-19). Given that GNAS is a highly complex genetic locus, one of its key features is the generation of multiple transcripts and the presence of genomic imprinting effects. It regulates diverse physiological processes through several signaling pathways, including Wnt/β-catenin, Hedgehog, and PKA, which contribute significantly to the phenotypic heterogeneity observed in FD-related syndromes (20,21). In addition, the majority of GNAS mutations associated with FD occur in a mosaic pattern. The phenotypic expression and clinical severity in FD-related syndromes are also influenced by multiple factors, including the timing of the mutational event, allelic expression biases based on parental origin, and the spectrum of affected cell lineages (such as osteoprogenitor cells, melanocytes, and endocrine cells) (18,22,23). Transcriptomic studies in both human and murine models of GNAS-mutated lesions have identified diverse related biological processes which are strongly implicated in FD pathogenesis, including Gsα/cAMP signaling pathway, mesenchymal stem cell differentiation process, fibrosis process, inflammatory responses (particularly osteoclastogenesis), and angiogenesis regulation pathway. These processes are also closely aligned with the regulatory mechanisms underlying bone development (11,14,24-26).

In summary, GNAS mutations represent the principal pathogenic driver of FD, primarily exerting their effects through constitutive activation of the Gsα/cAMP signaling pathway. The phenotypic variability of FD is determined by a combination of factors, including the developmental timing of the mutation, mosaic distribution, and genomic imprinting effects, which collectively influence key biological processes such as mesenchymal stem cell differentiation, fibrosis, osteogenesis, and osteoclast-mediated bone remodeling (Figure 1). Despite these advances, critical questions remain. The precise mechanisms by which mutant cells in different lineages interact to drive lesion expansion are not fully understood. Furthermore, the factors determining why some lesions progress while others stabilize after puberty are yet to be elucidated.

Figure 1 Pathogenic mechanisms of FD driven by GNAS mutations. This schematic illustrates the molecular and cellular pathways involved in FD due to GNAS mutations. The R201H/C mutations cause constitutive activation of the Gsα subunit, resulting in sustained elevation of intracellular cAMP levels. This leads to suppression of the Wnt/β-catenin signaling pathway and downregulation of RUNX2, impairing osteogenic differentiation and bone matrix synthesis in osteoblasts. Concurrently, increased cAMP activates the PKA pathway, enhancing the RANK/RANKL axis and promoting osteoclastogenesis, which increases bone resorption. The mutation is not limited to osteolineage cells but also affects endothelial cells, fibroblasts, and macrophages in the lesion microenvironment. This multi-lineage involvement contributes to fibrosis through the accumulation of fibrous tissue and extracellular matrix by dysplastic fibroblasts. It also leads to hypervascularity due to endothelial cell activity and promotes chronic inflammation driven by pro-inflammatory macrophages. These processes collectively result in impaired bone formation, excessive bone resorption, fibrosis, and vascular proliferation in FD. cAMP, cyclic adenosine monophosphate; ECM, extracellular matrix; FD, fibrous dysplasia; PKA, protein kinase A; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand.

Clinical manifestations

FD-related craniomaxillofacial lesions may present as either MFD or PFD. Monostotic involvement accounts for approximately 75–85% of cases and predominantly affects individuals between the ages of 10 and 20 years (27). Disease onset and progression of MFD typically occur during adolescence, followed by stabilization after puberty. A small number of patients continue to experience lesion progression and associated pain even after reaching adulthood (27). The monostotic form is characterized by a more indolent and stable clinical course (4,28), a pattern that may be attributed to the progressive decline in the proportion of mutant cells within the lesion over time. The maxilla region is more commonly involved than the mandible, and maxillary MFD frequently extends into adjacent skeletal structures, including the temporal bone, sphenoid bone, occipital bone, and skull base (2). Due to the anatomical complexity of the craniomaxillofacial region, osseous lesions can give rise to a wide spectrum of clinical manifestations, such as painless craniofacial swelling and deformity, pathological fractures, tooth loss or displacement, malocclusion, localized pain, neurological involvement symptoms, globe displacement, visual impairment, and hearing deficits (3,4,29-31). For patients with syndromes, systemic abnormalities are commonly observed in addition to polyostotic skeletal involvement. Clinically, the diagnostic criteria for MAS require the coexistence of at least two of three core manifestations: polyostotic FD, irregular café-au-lait cutaneous macules with jagged borders, and autonomous endocrinopathies; isolated single-system involvement cannot establish MAS diagnosis. Common endocrine manifestations include precocious puberty (the most frequent endocrine abnormality in pediatric patients), hyperthyroidism, Cushing syndrome, hyperprolactinemia, growth hormone excess, and renal phosphate wasting-induced hypophosphatemia. Mazabraud syndrome is defined by the definitive co-occurrence of FD lesions and benign intramuscular myxomas, predominantly arising in the lower extremities, whereas craniofacial myxoma is extremely rare. Compared with non-syndromic FD, syndromic FD displays inherent biological aggressiveness: lesions expand continuously even after skeletal maturation, frequently cross multiple adjacent craniofacial bones and readily invade skull base, orbital apex and paranasal sinus cavities. Endocrine hyperfunction further accelerates bone turnover and fibrous lesion proliferation, which is the core reason for earlier lesion progression and higher postoperative recurrence rate in MAS patients (4,30,32,33). Furthermore, genetic counseling is also recommended for MAS patients, particularly regarding the mosaic inheritance pattern and potential reproductive implications. Therefore, the diagnosis and management of severe CFD necessitate a multidisciplinary approach, involving specialists in oral and maxillofacial surgery, plastic surgery, ophthalmology, otolaryngology-head and neck surgery, neurosurgery, endocrinology, orthopedics, radiology, and pathology to ensure comprehensive evaluation and optimal therapeutic outcomes.

CFD impairs patients’ health-related quality of life mainly via refractory pain, facial disfigurement, malocclusion, visual/auditory and airway dysfunction; facial asymmetry frequently causes psychological distress and social stigma (34). According to Berry et al. (15), FD/MAS pain can be classified into inflammatory osteoclastic pain, nerve compressive pain, and lesion-related chronic fibrotic pain with distinct pathogeneses: inflammatory pain originates from elevated RANKL/IL-6-mediated osteoclast hyperactivity; compressive pain arises from cranial foraminal stenosis and peripheral nerve entrapment; fibrotic pain correlates with abnormal interstitial hyperplasia inside lesions. Common assessment tools include visual analogue scale (VAS) and FD-specific patient-reported outcome questionnaires.

Imaging manifestations

Computed tomography (CT) offers significant advantages in the assessment of complex skeletal anatomy, establishing it as the preferred imaging modality for both the diagnosis and longitudinal monitoring of FD (5,35,36). CT demonstrates distinct advantages in the evaluation of complex anatomical regions, including the optic canal and skull base, due to its superior spatial resolution and ability to delineate bony structures with high precision. In the craniomaxillofacial region, FD lesions typically appear as diffuse, poorly defined ground-glass opacities, which may present as radiolucent or spot calcification shadow in early stage. On CT scans, the classic ground-glass appearance is observed in most cases, representing immature woven bone. However, the cyst-like and sclerotic patterns are also equally common in the craniofacial region and may indicate different stages of lesion maturity. Beyond conventional CT and radiography, nuclear medicine imaging techniques, such as emission computed tomography (ECT) and positron emission tomography-computed tomography (PET-CT), enable more precise localization and assessment of osseous lesions by visualizing regions of increased metabolic activity, thereby supporting early detection of systemic skeletal involvement (28,37,38). Compared with CT, magnetic resonance imaging (MRI) is a more appropriate examination option for assessing the compression of adjacent nerves due to the lesion’s expansile nature, particularly in skull base lesions (39). On MRI scans, FD typically demonstrates intermediate signal intensity on T1-weighted images and variable (heterogeneous) hyperintensity on T2-weighted images, which correlates with the fibrous-to-mineralized tissue ratio (40). The “milk cloud” appearance is also a characteristic sign of FD on contrast-enhanced T1-weighted MRI images (40,41).

The most critical differential diagnosis, particularly in the jaws, is ossifying fibroma (OF) (Table 2). Although OF may also present with painless craniofacial swelling, its radiographic features are typically characterized by well-circumscribed margins, occasional sclerotic borders, variable radiopaque foci, and root resorption of teeth. With the development of artificial intelligence (AI) technology and machine learning, the performance of deep convolutional neural network models has also demonstrated potential in the identification of FD and OF (42). Differentiating FD from OF is critical for surgical planning. FD typically presents with ill-defined, blending margins that merge imperceptibly with normal bone, making complete resection difficult. In contrast, OF usually exhibits a well-demarcated capsule or distinct corticated margins, allowing for enucleation. Notably, the imaging features of FD-related malignant tumors include poorly defined margins, mineralization, and osteolytic lesions with cortical destruction (43). Clinically, enhanced differential diagnosis is required for these malignant transformation characteristics.

The integration of machine learning-assisted image analysis has introduced an innovative tool for distinguishing between these differential diagnoses (44). Recent studies suggest that texture analysis based on CT images can quantitatively assess the heterogeneity of bone lesions (45). AI-assisted diagnosis shows promise in distinguishing FD from other fibro-osseous lesions with high accuracy, potentially reducing the need for invasive biopsies in typical cases. Additionally, craniomaxillofacial FD must be differentiated from a range of other maxillofacial pathologies, including congenital jaw deformities, central giant cell granuloma, osteomyelitis, aneurysmal bone cyst, Paget’s disease of bone, Langerhans cell histiocytosis, plasma cell neoplasms or other soft tissue sarcomas.

Histopathological features

The histopathological features of FD are relatively uniform, characterized by the presence of irregular, non-anastomosing trabeculae of immature bone embedded within a loosely cellular fibrous stroma, with sparse mature osteoblasts and minimal calcified matrix deposition. The lesion lacks a well-defined capsule or demarcated boundary, resulting in a gradual transition and intermingling with adjacent normal bone tissue. In certain craniofacial lesions, a tendency toward progressive osseous maturation may be observed, occasionally featuring the formation of lamellar bone (5,25,26,30,35). Histologically, OF and FD share overlapping morphological characteristics, as both consist of a fibrovascular stroma and varying amounts of mineralized tissue, including lamellar bone (46-48). However, the key distinguishing feature is that OF typically exhibits well-circumscribed margins, may be partially encapsulated, and demonstrates a more heterogeneous pattern of internal ossification, including osteoid-like or cementum-like calcifications. In diagnostically challenging cases, detection of the canonical GNAS-activating mutation can provide molecular confirmation, particularly when clinical and radiographic features are inconclusive.

Treatment strategies

The management of CFD requires an MDT involving oral and maxillofacial surgeons, neurosurgeons, ophthalmologists, endocrinologists, and radiologists to tailor treatment to the individual patient’s disease burden, symptoms, and goals. The therapeutic strategy is guided by a decision-making framework that considers lesion location, extent, growth trajectory, and symptom severity (Table 3).

Surgical intervention

Due to the absence of effective therapies capable of curing or halting the progressive course of CFD, its management remains clinically challenging (49-51). Surgical intervention currently still represents the primary therapeutic approach. Common treatment strategies include: (I) conservative observation, which may be appropriate for lesions that do not cause significant cosmetic or functional impairment; (II) complete surgical excision for small or localized lesions; (III) radical resection with immediate reconstruction in cases of extensive monostotic CFD involving recurrent infections, provided complete removal is feasible. Reconstruction of craniomaxillofacial defects primarily involves autologous bone grafts (such as fibular, iliac crest, or rib grafts), titanium mesh, hydroxyapatite, and polyetheretherketone (PEEK) (52); (IV) for extensive lesions that are not amenable to complete resection, particularly those associated with progressive neurological or functional deficits (such as ocular displacement, visual loss, hearing impairment, or anosmia) and exhibiting persistent slow progression, the timing and extent of surgery must be carefully determined. The goals of surgical intervention in these cases typically emphasize functional and aesthetic improvement, along with disease stabilization, rather than complete eradication of the lesion. Determining the optimal timing for surgical intervention remains a subject of ongoing debate. A conservative approach is generally recommended during the active growth phase (childhood and adolescence) to mitigate the risk of recurrence; therefore, surgery is ideally deferred until skeletal maturity unless severe functional impairments, such as optic nerve compression or airway obstruction, are present. When early intervention is unavoidable, contouring is often advocated over radical resection to preserve function while minimizing aesthetic morbidity. The choice of surgical strategy requires a careful risk-benefit analysis: while conservative contouring offers aesthetic improvement with lower morbidity, surgeons must weigh this against the potential for regrowth, particularly in younger patients. Conversely, radical resection provides lower recurrence rates but necessitates complex reconstruction using vascularized free flaps or bone grafts, inevitably introducing donor site morbidity. Recent technological advances have significantly refined these surgical approaches. The integration of robotic-assisted surgical workflow, virtual surgical planning (VSP) and computer-aided design/computer-aided manufacturing (CAD/CAM) has become standard practice in major craniofacial centers (53-56). These tools allow for highly precise osteotomies and the fabrication of patient-specific implants (PSIs), which are critical for accurately restoring orbital volume and facial symmetry. Furthermore, contemporary studies emphasize the importance of comprehensive long-term follow-up (34). This not only involves monitoring for osseous regrowth but also evaluating patient-reported outcome measures (PROMs) to assess quality of life and psychosocial well-being. Ultimately, operative timing and the selection of surgical techniques must be highly individualized, carefully balancing the biological aggressiveness of the disease with the patient’s functional and aesthetic goals. Malocclusion is a common clinical manifestation of craniomaxillofacial CFD, while most patients achieve the stable occlusion by adulthood. Orthodontic treatment or other dental interventions can be safely and effectively performed when indicated, provided they are supported by long-term follow-up and standardized symptomatic management (31,57). With the advancement of AI technology and machine learning, deep learning models built on multimodal data and large-sample real-world data are also likely to demonstrate enormous prospects for guiding surgical timing in the future (58).

Specific surgical decision-making principles for syndromic CFD are still a challenge. Surgical timing is more conservative for untreated active MAS patients than for patients with sporadic MFD. Elective contouring or reconstructive surgery is generally postponed until concurrent endocrine dysfunction is well-controlled via endocrinological medication. Emergency decompression is indicated only for acute optic nerve compression, airway stenosis or intracranial hypertension. Radical complete resection is rarely feasible for extensive syndromic CFD. Staged partial contouring combined with postoperative long-term drug administration has been a viable option. For Mazabraud syndrome-related CFD, concurrent intramuscular myxoma requires systemic whole-body imaging screening before craniofacial operation to exclude occult multifocal myxoma.

Drug therapy

With an increasingly deeper understanding of the pathogenic mechanisms underlying FD and bone metabolism, non-surgical therapeutic approaches for severe primary PFD have garnered growing attention (59). According to a recent meta-analysis of 56 studies, bone markers decreased in 45 of 47 patients, among which alkaline phosphatase (ALP) decreased by an average of 31%±18% (n=30) (60). A total of 31 FD-related clinical trials have been registered internationally (https://clinicaltrials.gov/), with drug therapy representing the predominant focus of investigation. Investigational agents include alendronate, risedronate, denosumab (RANKL inhibitor), tocilizumab (IL-6 receptor inhibitor), anastrozole (non-steroidal aromatase inhibitor), pegvisomant (somatostatin), and others. Bisphosphonates and RANKL inhibitors currently constitute the main areas of therapeutic exploration, though their use is primarily for symptom control rather than disease modification.

Bisphosphonates, such as alendronate, risedronate, and zoledronic acid, could inhibit osteoclastic bone resorption and attenuate osteolytic inflammatory responses, demonstrating a relatively pronounced effect in alleviating moderate to severe persistent bone pain associated with FD. However, their ability to reduce lesion size, halt progression, or prevent complications in children or adults remains unproven. Evidence is largely derived from small case series, and their long-term efficacy, optimal dosing, and risk of medication-related osteonecrosis of the jaw (MRONJ) require further evaluation in larger, controlled studies (28,32,61).

RANKL inhibitors, including denosumab and AS 2676239, have been shown in multiple clinical studies to effectively delay or halt disease progression and relieve bone pain. In murine models harboring GNAS-activating mutations, RANKL inhibitors have been confirmed to suppress osteoclastogenesis, reduce fibrotic tissue accumulation, promote bone regeneration, and prevent lesion progression. Nevertheless, clinical experience regarding the use of RANKL inhibitors in FD, particularly optimal dosing regimens and treatment duration, remains limited. Concerns about disease rebound and potential complications following discontinuation, such as hypercalcemia, warrant further investigation (8,26,61-64).

The role of drug therapy in FD is still evolving and subject to debate. As for bisphosphonates, while effective in alleviating bone pain in the short term, their long-term efficacy in halting lesion progression is unproven. We still advise caution regarding potential side effects, such as MRONJ, especially in the context of planned dental surgeries. As for denosumab, although it also shows promise in reducing lesion size and pain, recent reports highlight a significant “rebound phenomenon” upon discontinuation, characterized by hypercalcemia and accelerated lesion growth. Pain subtype of FD may guide individualized medication: bisphosphonates preferentially improve inflammatory bone pain; denosumab shows superior efficacy against progressive osteolytic pain; symptomatic nerve-related pain requires adjuvant anti-inflammatory or targeted symptomatic treatment. Therefore, based on the potential pathogenic mechanism, long-term personalized management plans and careful monitoring are mandatory.

Beyond bisphosphonates and RANKL inhibitors, other promising research avenues include fibroblast growth factor 23-targeted monoclonal antibodies (burosumab) (65), IL-6 receptor inhibitors (tocilizumab) (66), Gsα pathway inhibitors or antagonists (suramin) (67,68), and GNAS gene editing technologies, all of which represent significant directions in ongoing clinical and preclinical research on FD. These adjuvant drugs for FD provide novel multi-target approaches to restoring bone homeostasis and enhancing quality of life, but their use is currently limited to specific syndromic presentations or clinical trials. When integrated with future therapeutic strategies, they hold potential as adjunctive agents in the early intervention of CFD.

Systemic endocrine diseases

In addition to the management of FD-related bone lesions, the treatment of systemic endocrine disturbances and control of elevated growth hormone levels are critical for influencing disease progression and achieving clinical stabilization (28,30,32,50,69). Patients with severe FD, particularly those diagnosed with MAS, frequently exhibit abnormalities in calcium-phosphate metabolism, with hypophosphatemia being a prominent feature. Therefore, routine clinical follow-up should include individualized phosphate supplementation, guided by the patient’s serum phosphate levels and renal function to prevent related complications (70). Total ALP is currently recommended as a biomarker for assessing overall bone metabolic activity. Serial monitoring of ALP levels can serve as a valuable tool for evaluating the metabolic activity of FD lesions, thereby aiding in the timely initiation or adjustment of therapeutic interventions (71). Thus, an annual standardized follow-up protocol is mandatory for all patients with MAS and Mazabraud syndrome, comprising three core modules: (I) endocrine surveillance: regular detection of serum phosphorus, ALP, thyroid hormone, sex hormone and growth hormone to adjust endocrine-targeted drugs; (II) radiological surveillance: annual skull base and maxillofacial CT to monitor lesion expansion, especially for postoperative residual lesions; (III) malignancy screening: persistent sharp pain, rapid lesion enlargement or abrupt ALP elevation triggers urgent enhanced imaging and pathological biopsy to exclude sarcomatous malignant transformation, which carries significantly higher incidence in syndromic FD than in isolated monostotic FD.

Malignant transformation

FD rarely undergoes malignant transformation, which occurs predominantly in female patients and is associated with a poor overall prognosis. The most common malignancies arising from FD include osteosarcoma, chondrosarcoma, and fibrosarcoma, with osteosarcoma being the most frequently observed secondary neoplasm. Overexpression of MDM2 and CDK4 may serve as auxiliary diagnostic markers for the identification of secondary osteosarcoma in patients with FD (72-74). However, the sensitivity and specificity of these markers remain to be validated in large-scale prospective studies. Individuals with extensive or aggressively progressive FD lesions should undergo close clinical surveillance and regular radiological evaluation to monitor disease progression and enable early detection of potential malignant degeneration.

Emerging precision technologies for CFD diagnosis and treatment

AI and gene editing represent two promising emerging technologies driving the upgrade of CFD diagnosis and individualized treatment, with distinct application stages and practical values in clinical practice and basic research, respectively. For AI, mature technologies have already been translated into clinical auxiliary diagnosis and preoperative planning. Image-based machine learning and radiomics analyze CT lesion texture features, quantitatively identify tissue heterogeneity to differentiate CFD from OF and other similar fibro-osseous lesions, lowering unnecessary invasive biopsy rates (42,44). Combined with VSP, AI optimizes osteotomy path and custom implant design, improving the accuracy of craniofacial contour repair. For gene editing, current exploration stays within preclinical animal research (8-10). Researchers target pathogenic gain-of-function mutation to modify abnormal Gsα/cAMP signaling cascade, restoring normal mesenchymal stem cell osteogenic capacity and limiting abnormal fibrous hyperplasia, offering potential curative ideas for refractory syndromic CFD. Programmable gene integration in human cells has the potential to enable mutation-agnostic treatments for loss-of-function genetic diseases and facilitate many applications in the life sciences (75). Taken together, AI has achieved immediate clinical benefits while gene editing remains under translational exploration, and continuous research will expand its clinical application scope for CFD comprehensive management in the future.

Limitations

This narrative review integrates emerging preclinical and clinical evidence published until early 2026, highlights maxillofacial surgery-oriented refined MDT regimen, updates molecular pathogenesis advances based on single-cell sequencing and transgenic animal experiments, and summarizes up-to-date global FD clinical trial landscape, providing complementary and updated evidence for CFD clinical practice and basic research. Nevertheless, this review also has certain limitations: most clinical studies are small-sample retrospective case series; large-scale prospective cohort studies and head-to-head randomized controlled trials for drug therapy remain scarce, leading to inconsistent evidence of bisphosphonates and denosumab long-term efficacy; only English literature indexed in PubMed was included, potentially missing grey literature and non-English relevant clinical data; quantitative meta-analysis was not performed due to high heterogeneity among original studies. Future high-quality prospective trials are needed to optimize standardized CFD therapeutic protocols.

Conclusions

FD is a complex, progressive, and multi-phenotypic disorder with manifestations that evolve continuously throughout the lifespan. Comprehensive diagnostic and therapeutic strategies capable of effectively controlling or ameliorating the disease course over the long term hold considerable clinical promise. In recent years, as FD has received growing scientific and clinical attention, extensive basic science and clinical research efforts have been undertaken globally. Notably, the development of murine models that recapitulate the natural history, histopathological features, and clinical phenotypes of FD has significantly advanced the understanding of its underlying pathobiology. Looking forward, it is anticipated that by integrating cutting-edge findings from basic research and clinical trials, along with emerging technologies such as AI and gene editing, more effective, safe, and reliable integrated management strategies can be developed. These approaches aim to address the current limitations and leverage the strengths of existing surgical and medical interventions, ultimately offering improved therapeutic outcomes and renewed hope for patients with FD.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-2026-0011/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-2026-0011/prf

Funding: This work was supported and funded by National Natural Science Foundation of China (Nos. 82071130, 82201085, and 81870780) and Natural Science Foundation of Shanghai (No. 23ZR1437900).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-2026-0011/coif). J.W.Z. serves as the Editor-in-Chief of Frontiers of Oral and Maxillofacial Medicine from May 2019 to April 2029. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Meier ME, Vágó E, Abrahamsen B, et al. Incidence and Prevalence of Fibrous Dysplasia/McCune-Albright Syndrome: A Nationwide Registry-Based Study in Denmark. J Clin Endocrinol Metab 2024;109:1423-32. [Crossref] [PubMed]
2. Cheng J, Wang Y, Yu H, et al. An epidemiological and clinical analysis of craniomaxillofacial fibrous dysplasia in a Chinese population. Orphanet J Rare Dis 2012;7:80. [Crossref] [PubMed]
3. DiCaprio MR, Enneking WF. Fibrous dysplasia. Pathophysiology, evaluation, and treatment. J Bone Joint Surg Am 2005;87:1848-64. [Crossref] [PubMed]
4. Sweeney K, Kaban LB. Natural History and Progression of Craniofacial Fibrous Dysplasia: A Retrospective Evaluation of 114 Patients From Massachusetts General Hospital. J Oral Maxillofac Surg 2020;78:1966-80. [Crossref] [PubMed]
5. Tuompo S, Mäkitie RE, Nieminen MT. Craniofacial fibrous dysplasia: A review of current literature. Bone 2025;192:117377. [Crossref] [PubMed]
6. Wang S, Li KH, Liu ZX, et al. Research progress in the pathogenesis and treatment of craniofacial fibrous dysplasia. Zhonghua Kou Qiang Yi Xue Za Zhi 2025;60:1195-202. [Article in Chinese]. [Crossref] [PubMed]
7. Zhang AB, Zhang JY, Xue J, et al. The prevalence, diagnostic accuracy and genotype-phenotype correlation of GNAS mutations in fibrous dysplasia: a meta-analysis. Front Genet 2024;15:1377716. [Crossref] [PubMed]
8. Liu Z, Yin Y, Wang Z, et al. RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia. Bone 2022;156:116301. [Crossref] [PubMed]
9. Lung H, Hsiao EC, Wentworth KL. Advances in Models of Fibrous Dysplasia/McCune-Albright Syndrome. Front Endocrinol (Lausanne) 2019;10:925. [Crossref] [PubMed]
10. Saggio I, Remoli C, Spica E, et al. Constitutive expression of Gsα(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. J Bone Miner Res 2014;29:2357-68. [Crossref] [PubMed]
11. Shen L, He Y, Chen S, et al. PTHrP Modulates the Proliferation and Osteogenic Differentiation of Craniofacial Fibrous Dysplasia-Derived BMSCs. Int J Mol Sci 2023;24:7616. [Crossref] [PubMed]
12. Lee KK, Changoor A, Grynpas MD, et al. Increased Osteoblast GαS Promotes Ossification by Suppressing Cartilage and Enhancing Callus Mineralization During Fracture Repair in Mice. JBMR Plus 2023;7:e10841. [Crossref] [PubMed]
13. Fan QM, Yue B, Bian ZY, et al. The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone. J Pathol 2012;228:45-55. [Crossref] [PubMed]
14. Wentworth KL, Fierro FA, Moody TA, et al. Single-cell analysis of human fibrous dysplasia bone reveals a fibrotic transcriptome and GNAS variants in endothelial, perivascular, and stromal cells. Am J Hum Genet 2025;112:2067-87. [Crossref] [PubMed]
15. Berry C, Hsu EE, LeSon C, et al. Plasma proteomic markers of pain and emotional dysfunction in fibrous dysplasia/McCune-Albright syndrome. Bone 2025;201:117626. [Crossref] [PubMed]
16. Diolintzi A, Pervin MS, Hsiao EC. Immunologic Aspects in Fibrodysplasia Ossificans Progressiva. Biomolecules 2024;14:357. [Crossref] [PubMed]
17. Xie Y, Chen X, Xie Y, et al. GNAS gene mutations affecting XLαs and bone health: A long neglected relationship. Clin Genet 2023;104:279-86. [Crossref] [PubMed]
18. Turan S, Bastepe M. GNAS Spectrum of Disorders. Curr Osteoporos Rep 2015;13:146-58. [Crossref] [PubMed]
19. Giannetti C, Aouchiche K, Lagarde A, et al. Genotype-phenotype correlation and challenges in mutation detection in McCune-Albright syndrome: A retrospective study of a French cohort. Ann Endocrinol (Paris) 2026;87:102556. [Crossref] [PubMed]
20. Yang W, Zuo Y, Zhang N, et al. GNAS locus: bone related diseases and mouse models. Front Endocrinol (Lausanne) 2023;14:1255864. [Crossref] [PubMed]
21. Liu Z, Xing L, Huang W, et al. Protein kinase A is a dependent factor and therapeutic target in mouse models of fibrous dysplasia. Nat Commun 2025;16:5425. [Crossref] [PubMed]
22. Skinner JA, Cattanach BM, Peters J. The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for Gnas and Gnasxl in development. Genomics 2002;80:373-5. [Crossref] [PubMed]
23. Kuznetsov SA, Cherman N, Riminucci M, et al. Age-dependent demise of GNAS-mutated skeletal stem cells and "normalization" of fibrous dysplasia of bone. J Bone Miner Res 2008;23:1731-40. [Crossref] [PubMed]
24. Michel Z, Raborn LN, Spencer T, et al. Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia. Cells 2024;13:774. [Crossref] [PubMed]
25. Kim HY, Charton C, Shim JH, et al. Patient-Derived Organoids Recapitulate Pathological Intrinsic and Phenotypic Features of Fibrous Dysplasia. Cells 2024;13:729. [Crossref] [PubMed]
26. de Castro LF, Whitlock JM, Michel Z, et al. RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia. Bone Res 2024;12:10. [Crossref] [PubMed]
27. Diyora B, Dey S, Dubey A, et al. Cranial fibrous dysplasia: An institutional experience and review of the literature. Surg Neurol Int 2022;13:66. [Crossref] [PubMed]
28. Pan KS, Taylor J, Szymczuk V, et al. Lesion Expansion in Gnathic Fibrous Dysplasia: Natural History, Indicators of Progression, and Response to Bisphosphonates. J Bone Miner Res 2023;38:1465-71. [Crossref] [PubMed]
29. Berry C, Boyce AM, Kaban LB, et al. Identifying Pain Subtypes in Patients With Craniofacial Lesions of Fibrous Dysplasia/McCune-Albright Syndrome. J Oral Maxillofac Surg 2025;83:366-73. [Crossref] [PubMed]
30. Szymczuk V, Taylor J, Boyce AM. Craniofacial Fibrous Dysplasia: Clinical and Therapeutic Implications. Curr Osteoporos Rep 2023;21:147-53. [Crossref] [PubMed]
31. Han NA, Tolley PD, Lenz TB, et al. Demystifying Maxillomandibular Fibrous Dysplasia and Its Impact on Dental Development. Plast Reconstr Surg 2026;157:501-12. [Crossref] [PubMed]
32. Javaid MK, Boyce A, Appelman-Dijkstra N, et al. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis 2019;14:139. [Crossref] [PubMed]
33. Hagelstein-Rotman M, Appelman-Dijkstra NM, Boyce AM, et al. Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome. Calcif Tissue Int 2022;110:334-40. [Crossref] [PubMed]
34. Forestier-Zhang L, Watts L, Turner A, et al. Health-related quality of life and a cost-utility simulation of adults in the UK with osteogenesis imperfecta, X-linked hypophosphatemia and fibrous dysplasia. Orphanet J Rare Dis 2016;11:160. [Crossref] [PubMed]
35. Pandiar D, Krishnan RP, Gopinath D, et al. Benign fibro-osseous lesions of the cranio-maxillofacial bones: an updated review with special emphasis on molecular pathogenesis. J Bone Miner Metab 2026;44:1-17. [Crossref] [PubMed]
36. Pons Escoda A, Naval Baudin P, Mora P, et al. Imaging of skull vault tumors in adults. Insights Imaging 2020;11:23. [Crossref] [PubMed]
37. Hennessy G, Shetty D, Loh H, et al. Polyostotic Fibrous Dysplasia in McCune-Albright Syndrome Demonstrated on 68Ga-DOTATATE PET/CT. Clin Nucl Med 2016;41:982-5. [Crossref] [PubMed]
38. Jain S, Singh D, Jain S. The 'Eye Mask Sign' in Fibrous Dysplasia on 99mTc-MDP Skeletal Scintigraphy and SPECT/CT. Nucl Med Mol Imaging 2023;57:301-5. [Crossref] [PubMed]
39. Gozgec E, Ogul H, Akkus AT, et al. Assessment of dural involvement in calvarial and skull base fibrous dysplasia. Neurochirurgie 2026;72:101744. [Crossref] [PubMed]
40. Pozzessere C, Cicone F, Barberio P, et al. Cross-sectional evaluation of FGD-avid polyostotic fibrous dysplasia: MRI, CT and PET/MRI findings. Eur J Hybrid Imaging 2022;6:19. [Crossref] [PubMed]
41. Franz D, Wechselberger J, Rasper M, et al. Milk cloud appearance-a characteristic sign of fibrous dysplasia on contrast-enhanced MR imaging. Eur Radiol 2019;29:3424-30. [Crossref] [PubMed]
42. Achararit P, Manaspon C, Jongwannasiri C, et al. Assessment of Deep Convolutional Neural Network Models for the Classification of Benign Fibro-Osseous Lesions of the Jaws. Clin Exp Dent Res 2025;11:e70244. [Crossref] [PubMed]
43. Qu N, Yao W, Cui X, et al. Malignant transformation in monostotic fibrous dysplasia: clinical features, imaging features, outcomes in 10 patients, and review. Medicine (Baltimore) 2015;94:e369. [Crossref] [PubMed]
44. Zhang AB, Zhao JR, Wang S, et al. CT-based radiomics analysis of different machine learning models for differentiating gnathic fibrous dysplasia and ossifying fibroma. Oral Dis 2024;30:5243-54. [Crossref] [PubMed]
45. Shah N, Drubach LA, Berry C, et al. Dissecting the heterogeneity of craniofacial lesions in patients with fibrous dysplasia/McCune-Albright Syndrome. Int J Oral Maxillofac Surg 2024;53:1006-14. [Crossref] [PubMed]
46. Golden BM, Tucker SK, Carpenter M, et al. Integration of Clinical, Radiographic, Histologic, and Molecular Findings to Diagnose Craniofacial Fibrous Dysplasia. J Craniofac Surg 2025;36:2287-93. [Epub ahead of print]. [Crossref] [PubMed]
47. Davidova LA, Bhattacharyya I, Islam MN, et al. An Analysis of Clinical and Histopathologic Features of Fibrous Dysplasia of the Jaws: A Series of 40 Cases and Review of Literature. Head Neck Pathol 2020;14:353-61. [Crossref] [PubMed]
48. Nagar SR, Mittal N, Rane SU, et al. Ossifying Fibromas of the Head and Neck Region: A Clinicopathological Study of 45 Cases. Head Neck Pathol 2022;16:248-56. [Crossref] [PubMed]
49. Kim HY, Shim JH, Heo CY. A Rare Skeletal Disorder, Fibrous Dysplasia: A Review of Its Pathogenesis and Therapeutic Prospects. Int J Mol Sci 2023;24:15591. [Crossref] [PubMed]
50. Wentworth KL, Park J, Yu X, et al. Update on the medical management of fibrous dysplasia of the bone. Ther Adv Endocrinol Metab 2025;16:20420188251347350. [Crossref] [PubMed]
51. Palmisano B, Berry C, Boyce A, et al. Fibrous dysplasia/McCune-Albright syndrome: state-of-the-art advances, pathogenesis, and basic/translational research. Orphanet J Rare Dis 2025;20:414. [Crossref] [PubMed]
52. Dalle Carbonare M, Manisali M. Surgical management of syndromic versus non-syndromic craniofacial fibrous dysplasia: a systematic review and meta-analysis. Br J Oral Maxillofac Surg 2022;60:1166-75. [Crossref] [PubMed]
53. Shen S, Bao J, Shi J, et al. A novel dual-stage robotic-assisted surgical workflow for precision contouring of craniomaxillofacial fibrous dysplasia. BMC Oral Health 2026;26:863. [Crossref] [PubMed]
54. Ainuz BY, Rizvi I, Kane AA. Craniofacial Fibrous Dysplasia of the Skull Assisted by Virtual Surgical Planning. J Craniofac Surg 2022;33:e628-32. [Crossref] [PubMed]
55. Best DL, Lee KC, Reynolds RM, et al. Contemporary Surgical Management of Craniofacial Fibrous Dysplasia Using Computer-Assisted Surgery and Intraoperative Navigation. J Craniofac Surg 2024;35:1280-3. [Crossref] [PubMed]
56. Dumas BM, Nava A, Law HZ, et al. Three-Dimensional Printing for Craniofacial Surgery: A Single Institution's 5-Year Experience. Cleft Palate Craniofac J 2019;56:729-34. [Crossref] [PubMed]
57. Han NA, Tolley PD, Lenz TB, et al. Demystifying Maxillomandibular Fibrous Dysplasia and Its Impact on Dental Development. Plast Reconstr Surg 2026;157:501-12. [Crossref] [PubMed]
58. Li G, Liu H, Pan Z, et al. Predicting craniofacial fibrous dysplasia growth status: an exploratory study of a hybrid radiomics and deep learning model based on computed tomography images. Oral Surg Oral Med Oral Pathol Oral Radiol 2025;139:364-76. [Crossref] [PubMed]
59. Bertin H, Moussa MS, Komarova S. Efficacy of antiresorptive agents in fibrous dysplasia and McCune Albright syndrome, a systematic review and meta-analysis. Rev Endocr Metab Disord 2023;24:1103-19. [Crossref] [PubMed]
60. Levaillant L, Mabilleau G, Malagié A, et al. Comparison of traditional and new treatments for fibrous dysplasia: a systematic review and meta-analysis. Osteoporos Int 2026; [Epub ahead of print]. [Crossref] [PubMed]
61. Tucker-Bartley A, Selen DJ, Golden E, et al. Pharmacological Interventions Targeting Pain in Fibrous Dysplasia/McCune-Albright Syndrome. Int J Mol Sci 2023;24:2550. [Crossref] [PubMed]
62. Ormsby RT, Zhang Y, Hodys C, et al. Neutralization of Receptor activator of nuclear factor-κB ligand reduces fibrosis and promotes osteoblast differentiation in a mouse model of fibrous dysplasia driven by somatic expression of GnasR201H. JBMR Plus 2025;9:ziaf145. [Crossref] [PubMed]
63. Szymczuk V, Elbashir II, Ahmed R, et al. Safety and Efficacy of Moderate-dose Denosumab in Fibrous Dysplasia: Observational Results From a Phase 2 Clinical Trial. J Clin Endocrinol Metab 2025;110:2666-73. [Crossref] [PubMed]
64. Ouyang Q, Jiajue R, Zhou R, et al. Denosumab in pediatric patients with fibrous dysplasia/McCune-Albright syndrome: a single-center, open-labeled study. Front Endocrinol (Lausanne) 2026;17:1762370. [Crossref] [PubMed]
65. Sakka SD, Georgakopoulou D, Doulgeraki A, et al. Burosumab treatment of a child with McCune-Albright syndrome/polyostotic fibrous dysplasia: challenges and benefits. JBMR Plus 2025;9:ziaf042. [Crossref] [PubMed]
66. Chapurlat R, Gensburger D, Trolliet C, et al. Inhibition of IL-6 in the treatment of fibrous dysplasia of bone: The randomized double-blind placebo-controlled TOCIDYS trial. Bone 2022;157:116343. [Crossref] [PubMed]
67. Lv M, Li X, Huang Y, et al. Inhibition of fibrous dysplasia via blocking Gsα with suramin sodium loaded with an alendronate-conjugated polymeric drug delivery system. Biomater Sci 2016;4:1113-22. [Crossref] [PubMed]
68. Raut P, Mathivanan P, Batra SK, et al. Contract to kill: GNAS mutation. Mol Cancer 2025;24:70. [Crossref] [PubMed]
69. Zainab MJ, Khamies LL, Baladi J, et al. McCune-Albright syndrome with multiple hyperfunctional endocrinopathies: diagnosis, treatment, and long-term follow-up: a case report. Front Endocrinol (Lausanne) 2025;16:1632257. [Crossref] [PubMed]
70. Pazelli AM, Srikumar JK, Gharavi A, et al. Skeletal and endocrine manifestations of McCune-Albright syndrome in patients with fibrous dysplasia. J Plast Reconstr Aesthet Surg 2025;109:137-43. [Crossref] [PubMed]
71. Meier ME, Hagelstein-Rotman M, Streefland TCM, et al. Clinical value of RANKL, OPG, IL-6 and sclerostin as biomarkers for fibrous dysplasia/McCune-Albright syndrome. Bone 2023;171:116744. [Crossref] [PubMed]
72. Shi R, Li X, Zhang J, et al. Clinicopathological and genetic study of a rare occurrence: Malignant transformation of fibrous dysplasia of the jaws. Mol Genet Genomic Med 2022;10:e1861. [Crossref] [PubMed]
73. Xue J, Li X, Feng Y, et al. Genotype-Phenotype Correlation in Fibrous Dysplasia/McCune-Albright Syndrome Patients With Craniofacial Lesions. Oral Dis 2026;32:175-82. [Crossref] [PubMed]
74. Liu L, Sun J, Liu S, et al. Malignant transformation of craniofacial fibrous dysplasia: A clinicopathological, immunohistochemical and molecular analysis of 15 cases in one single institution. J Stomatol Oral Maxillofac Surg 2025;126:102098. [Crossref] [PubMed]
75. Witte IP, Lampe GD, Eitzinger S, et al. Programmable gene insertion in human cells with a laboratory-evolved CRISPR-associated transposase. Science 2025;388:eadt5199. [Crossref] [PubMed]