Fibrous Dysplasia

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Fibrous Dysplasia
Classification and external resources
ICD-10 [1]85.0,[2]78.1
ICD-9 733.29

,756.54

DiseasesDB 7880



Disease Entity

Fibrous dysplasia is a benign disorder of bone. It can involve any bone, but most commonly affects the long bones of the extremities or the craniofacial skeleton. There are three forms of fibrous dysplasia: monostotic (involving a single skeletal site), polyostotic (multiple sites), and the McCune Albright Syndrome (polyostotic fibrous dysplasia with endocrine and skin changes). In all three forms, normal bone is replaced by fibrous-osseous tissue.

Disease

  • Fibrous dysplasia monostotic (ICD-9 # 733.29)
  • Polyostotic fibrous dysplasia (ICD-9 # 756.54)
  • Osteodystrophy NEC (ICD-9 756.59)
  • McCune-Albright syndrome (ICD-9 #756.59)

Etiology

Fibrous dysplasia occurs due to an activating somatic missense mutation of a G protein that interferes with normal bone maturation and resorption. (WHO 2005) 

Risk Factors

An equal distribution is noted between sexes in monostotic and polyostotic fibrous dysplasia, and the disease can be found among all racial groups. (WHO 2002, Feller, Selva) McCune-Albright Syndrome may be seen more commonly in female patients. (Lustig, WHO 2005)

General Pathology

Monostotic fibrous dysplasia is the most frequent form, and accounts for approximately 75% of all cases. (Riddle, Papay, Lustig) The remaining 20-30% are of the polyostotic variant, which tends to produce more severe bone deformity. (Lustig, Parekh)

A small subset of polyostotic fibrous dysplasia associated with endocrine dysfunction and characteristic café-au-lait skin pigmentation is known as the McCune-Albright Syndrome. This syndrome accounts for approximately 3% of polyostotic disease. (Chapurlat) Precious puberty is the most frequent hyperfunctioning endocrinopathy; others include acromegaly, hyperthyroidism, diabetes, hyperparatuitarism, hypercalcemia, and adrenal disorders. (Cutler, Riddle)

The most common sites of involvement in monostotic fibrous dysplasia are the craniofacial skeleton, ribcage, femurs and tibias. (WHO 2002) By contrast, in polyostotic disease, dysplasia most often occurs in the femurs and tibias, followed by the craniofacial skeleton, pelvis, ribs, humeri, and spine. (WHO 2002, Parekh, Riddle) No evidence supports the progression of monostotic to polyostotic dysplasia.

Twenty to thirty percent of all fibrous dysplasia involves the craniofacial skeleton. Commonly affected sites include the maxilla, ethmoid, sphenoid and frontal bones. (Papay, Nerad, Lustig, Selva). Craniofacial dysplasia may be seen in over half of polyostotic patients and 10-35% of monostotics. (Sassin, Lustig, WHO 2002) Fibrous dysplasia of multiple adjacent craniofacial bones is considered monostotic disease. (WHO 2005, Nerad)


Primary bone tumors of the orbit represent a small percentage of all orbital tumors (0.6-2%). (Selva) Fibrous dysplasia represents approximately 18% of all primary orbital bone tumors. (Selva) The majority of cases with orbital involvement have monostotic fibrous dysplasia of the frontal, sphenoid or ethmoid bones. (Selva)

Pathophysiology

Fibrous dysplasia is thought to result from an activating somatic missense mutation of the GNAS1 gene on chromosome 20. The protein transcript of GNAS1 is a stimulatory signaling G protein, Gs-alpha, and the mutated protein causes prolonged adenylyl cyclase activity and overproduction of intracellular cyclic adenoside monophosphate, (cAMP). (Lee, Collins, Cutler, Riddle, Selva, WHO 2005, WHO 2002). More recent studies have also implicated the WNT/ β-catenin signaling pathway. (Riddle)

This mutation triggers the replacement of normal bone by immature bone marrow stromal cells in a fibrous matrix. An arrest of typical bone maturation leads to abnormal, functionally impaired osteoblasts that produce spicules of poorly organized bone. (Collins, Lee, Papay, Feller) Increased levels of IL-6 stimulate osteoclastic bone resorption at fibrous dysplasia sites, resulting in poor mineralization. (Feller, Chapurlat) 

Primary prevention

No known prevention exists for fibrous dysplasia. 

Diagnosis

The diagnosis of fibrous dysplasia can often be made based on the clinical and radiographic appearance, but in some cases may be confirmed with a tissue biopsy.

History

Monostotic fibrous dysplasia patients present symptomatically between age ten to thirty, on average, whereas the majority of polyostotic patients present prior to the age of ten.

The natural course of fibrous dysplasia is a matter of some debate. Historically, it was often regarded as a disease of childhood that tended to become quiescent following puberty. Multiple studies, however, have reported both active disease and progression in adults. (Davies, Nerad, Lee, Cutler)
 

Physical examination

The exam will vary based on the site of involvement and degree of dysplasia. Patients with craniofacial FD should receive a full ophthalmologic exam, including detailed external exam with attention to any facial asymmetry, pupillary function, extraocular movements, visual fields, exophthalmometry, visual acuity, color vision, intraocular pressure measurement, slit-lamp and fundus exam. Decreased visual acuity may not present until late in the course of optic neuropathy associated with fibrous dysplasia. 

Signs and Symptoms

The most common presenting symptoms of fibrous dysplasia include pain, swelling and disfigurement due to fibroblastic expansion of the affected sites. Within the craniofacial skeleton, this can manifest as headaches, proptosis, and facial asymmetry. (Sassin, Nerad, Michael). Visual impairment and hearing loss are the most common reported neurologic complications of fibrous dysplasia. (Sassin, Lee, Nerad, Michael) In addition to vision changes and globe displacement, bony thickening of the skull, its bony canals and foramena, and adjacent sinuses may also produce sinus collapse, nasal obstruction, extraocular muscle palsies, trigeminal neuralgia, anomia, and epiphora. (Gass, Liakos) 

Clinical diagnosis

Clinical diagnosis relies on both facial changes and imaging characteristics. Symptoms can include long standing facial asymmetry, proptosis, orbital pain, diffuse headache, double vision, visual loss, hearing loss, malocclusion, cranial nerve palsies, or tearing. (Selva) Careful attention to facial symmetry, cranial nerve function, visual acuity, visual fields, external ocular adnexal exam as well as orbital evaluation helps to support the diagnosis. Skin should be checked for café-au-lait spots (seen in McCune-Albright Syndrome).

Diagnostic procedures

Fibrous dysplasia was initially studied using plain X-rays, and its characteristic mottled, sclerotic appearance described as resembling “ground-glass.” Today, lesions may be well characterized on computed tomography. The radiographic features vary based on the proportion of normal, mineralized bone to fibrous tissue in any given lesion. Early in the disease course, cystic and sclerotic areas are noted. As dysplasia progresses, a heterogeneous “pagetoid” pattern of radiolucent and radiopaque areas is seen, reflecting regions of fibrous stroma and opaque, osseous changes, respectively. (Nerad, Selva) Typically, fibrous dysplasia has smooth cortical margins and no soft tissue involvement. (Feller, Nerad, WHO 2002) On MRI, lesions are low to isointense on T1 and T2-weighted images, and demonstrate moderate enhancement with gadolinium. (Lustig, Selva, WHO 2005)

Radiographic optic nerve bony encasement is exceedingly common in craniofacial fibrous dysplasia, and may approach rates as high as 50-90% of patients. (Collins, Lee) The relationship between optic canal stenosis and visual compromise is uncertain, however, as large studies have demonstrated that the majority of patients with completely encased nerves remain asymptomatic without evidence of optic neuropathy. {Figures 1 and 2} (Cutler, Collins, Michael)
Bony optic nerve encasement in craniofacial fibrous dysplasia.                                            FD3.jpeg

Figure 1. Bony optic nerve encasement in craniofacial fibrous dysplasia.                       Figure 2. Craniofacial fibrous dysplasia.

Firm, gritty, pink or white tissue is seen on gross sectioning. (Selva, WHO 2002). Histologically, dysplastic bone has a classic appearance of dense fibrous stroma of low to moderate cellularity surrounding irregularly shaped bony trabeculae. This pattern has been described as resembling “Chinese characters.” {Figure 3} (Riddle, Selva) No osteoblastic rimming of trabeculae is seen, which is of note in distinguishing fibrous dysplasia from other malignant entities, such as ossifying fibroma. (Selva, Riddle, WHO 2005) The surrounding stroma may contain aneurysmal bone cysts, cartilaginous nodules, and myxomatous areas. (Selva)

Fibrous Dysplasia Histology.jpg

Figure 3. Dense fibrous stroma with irregular bony trabeculae. Courtesy of Riddle et al. 
                                                 

Laboratory test

Serum alkaline phosphatase may be elevated in up to one third of FD patients, regardless of disease severity or the presence of fractures. (WHO 2005)

Differential diagnosis

Fibrous dysplasia can resemble other entities including meningioma, Paget’s disease or other osteodystrophies of the skull base, eosinophilic granuloma, Hand-Schuller-Christian disease, and low-grade central osteosarcoma. (Gass, Feller, Lustig) Unlike fibrous dysplasia, meningiomas will exhibit a homogenous, sclerotic appearance if hyperostosis is present {Figure 3}, may involve surrounding soft tissue, and display rapid contrast enhancement on MRI. (Nerad)


Meningioma.jpeg

Figure 3. Meningioma initially diagnosed as fibrous dysplasia. 

Management

The treatment of fibrous dysplasia is guided by the severity of the disease and its complications, and options include careful observation and surgical intervention. No proven therapy is currently known for halting disease progression or preventing malignant transformation. The disease seems to stablilze with skeletal maturity. (WHO 2005) 

Medical therapy

Patients with minimal or mild symptoms may be observed with periodic CT or MRI imaging, and encouraged to maintain bone density through diet and exercise. (Lustig, Riddle). Bisphosphonates have been utilized in efforts to halt bone resorption, and some studies suggest some improvement in pain, biochemical markers of turnover, and radiographic lesions. (Chapurlat) 

Medical follow up

Visual impairment in fibrous dysplasia may be acute or chronic in nature. Multiple mechanisms for its development have been advanced, including progressive canal stenosis, compression by an external mass, optic nerve traction secondary to displacement of the globe, and rarely, vascular compromise of the optic nerve. (Seiff, Michael) Visual loss attributed to progressive canal narrowing tends to follow a chronic, gradual course. Many case reports describe acute vision loss due to external compression of the optic nerve by mucoceles, hemorrhage into an area of dysplastic bone, and aneurysmal bone cysts. (Liakos, Chen, Nerad, Michael, Lee) 

Surgery

Surgical intervention remains the mainstay of treatment for symptomatic fibrous dysplasia, and may be undertaken in the setting of severe disfigurement, pathologic fractures, and other sequelae, including vision loss.


In patients with evidence of visual impairment and optic nerve encasement on imaging, therapeutic optic nerve decompression is advocated in efforts to preserve visual function. Less consensus exists regarding the treatment of asymptomatic patients with radiographic optic nerve encasement. Many experts recommend expectant management with careful follow-up as most individuals will retain full visual function. (Cutler, Collins, Lee). Others, however, support the practice of prophylactic optic nerve decompression given the risk of irreversible visual loss. (Chen, Papay).


Studies examining recurrence after surgical removal have found that residual tissue exhibits relatively normal growth rates, and that increased rates of malignancy are not seen following partial removal of dysplastic bone. (Papay)

Complications

Visual impairment and hearing loss are the most common reported neurologic complications of fibrous dysplasia. (Sassin, Lee, Nerad, Michael)


Malignant degeneration of fibrous dysplasia has been reported to occur in 0.5-1% of cases (Edgerton, Michael). This risk is increased in polyostotic disease, particularly in McCune-Albright patients, and following radiation (Parekh, Papay). Transformation more frequently occurs in lesions within the craniofacial bones and femur. (Parekh) The most common malignancy is osteogenic sarcoma, followed by fibrosarcoma, chondrosarcoma, and malignant fibrous histiocytoma. (Papay, Riddle) The mean time interval from diagnosis to malignancy is 13.5 years, and clinical signs include rapid increase in lesion size or pain, intralesional necrosis or bleeding, and elevation of serum alkaline phosphatase levels. (Papay, Parekh)
 

Prognosis

Fibrous dysplasia has a good prognosis with low rates of malignant transformation. The disease may stabilize with bone maturation. (WHO 2005)

Additional Resources

References

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