Practice Essentials
Fibrous dysplasia (a term first suggested by Lichtenstein and Jaffe in 1942 [1] ) of bone is a nonheritable disease in which abnormal tissue develops in place of normal bone. [2] Abnormalities may involve a single bone (monostotic form; 70% of cases) or many bones (polyostotic form; 30% of cases). The polyostotic form is occasionally associated with precocious puberty, fibrous dysplasia, and cafe-au-lait skin lesions (McCune-Albright syndrome, Albright syndrome) or with myxomas of skeletal muscle (Mazabraud syndrome). [3, 4, 5, 6, 7, 8]
The etiology of this abnormal growth process is related to a mutation in the gene that encodes the subunit of a stimulatory G protein (Gsα) located on chromosome 20. [9, 10] As a consequence of this mutation, a substitution occurs in which the cysteine or the histidine—amino acids of the genomic DNA in the osteoblastic cells—is replaced by arginine. [11]
Fibrous dysplasia lesions are characterized by woven ossified tissue and extensive marrow fibrosis. Mechanical quality of bones is decreased. As a consequence of this bone fragility, patients have an increased (~50%) risk of fracture. [12] This risk of fractures or bone deformity is higher in the long bones (eg, femur, tibia, and humerus), but all the bones can be affected.
Pain is a common symptom of patients with fibrous dysplasia. Patients also have an increased risk of malignant tumors such as osteosarcoma, fibrosarcoma, chondrosarcoma, and malignant fibrohistiocytoma. [13] The incidence of this risk has been evaluated to be reduced to 1%. [13, 14] The risk is higher in patients with the polyostotic form, or McCune-Albright syndrome. [14]
Asymptomatic patients do not need treatment. Surgical treatment of fibrous dysplasia is indicated in the prevention or treatment of fractures or major deformity. The most common surgical indications are fracture of a weightbearing bone and progressive disease. Upper-extremity lesions rarely require surgical management. There are no specific contraindications for surgical intervention in patients with fibrous dysplasia; however, care must be exercised in the skeletally immature patient.
Pathophysiology
As a consequence of the mutation of GNAS1 (see Etiology), there is a substitution in which cysteine or histidine (amino acids of the genomic DNA in the osteoblastic cells) is replaced by another amino acid, arginine. [11]
Osteoblastic cells expressing this mutation have a higher DNA synthesis than normal bone cells. The growth of these cells is faster, leading to an inappropriate differentiation of mesenchymal cells. At the molecular level, intracellular cyclic adenosine monophosphate (cAMP) levels are increased and osteocalcin is decreased. [15] Osteocalcin is a late marker of osteoblast differentiation. Involved bone cells are immature. They fail to produce normal amounts of collagen or to orientate appropriately to the lines of mechanical stress.
Etiology
Fibrous dysplasia is caused by the sporadic mutation of the GNAS1 gene, which encodes the alpha subunit of the stimulatory G protein (G1) located on chromosome 20q13.2-13.3 of the osteoblastic cells. [10] Although the mutation is known, the actual pathways that lead to abnormal osteoblast differentiation and function remain to be fully elucidated.
The consequence of this mutation is an inappropriate cell differentiation resulting in a disorganized fibrotic bone matrix. Cancellous bone maintenance is perturbed, and bone undergoing physiologic remodeling is replaced by an abnormal proliferation of fibrous tissue.
The extent and pattern of disease depend on the stage of development and the location at which the mutation occurs. All the bones can be affected.
Epidemiology
Fibrous dysplasia accounts for about 5% of all benign bone tumors. [10] The monostotic form is more common than the polyostotic form. Because many patients are asymptomatic, the true incidence of this disorder is unknown. Usually, fibrous dysplasia presents clinically in children and adolescents, with a median onset age of 8 years. Most cases manifest themselves before the age of 30 years. Males are affected more often than females, except in McCune-Albright syndrome, in which females are affected more often than males.
Monostotic fibrous dysplasia is active while it is growing but often becomes inactive after puberty. It may reactivate during pregnancy. Polyostotic disease typically remains active throughout life.
Prognosis
Unless malignant transformation develops, fibrous dysplasia is not a life-threatening disease. The lesions tend to stabilize as skeletal maturity is reached. Malignant transformation develops in a small minority of patients (< 0.5%).
The majority of the monostotic cases have a good evolution regardless of treatment. Polyostotic disease tends to have a poorer prognosis. [16] Polyostotic lesions are very often associated with one or more fractures. [17] A single-center study of 114 patients with craniofacial fibrous dysplasia found that those who had McCune-Albright syndrome, as compared with those who had polyostotic or monostotic fibrous dysplasia, were more likely to have aggressive disease, complications, and a greater number of operations. [18]
The recurrence rate for fibrous dysplasia has been reported to be 21% after curettage and grafting, but if patients are monitored for many years, the rate is probably closer to 100%.
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Intermediate-power view of typical histology of fibrous dysplasia. Note the bland fibrous stromal tissue with islands of disorganized, immature osteoid. A key feature is the absence of rimming osteoblasts around the osteoid. While not present in this slide, foci of cartilage also may occasionally be present.
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Plain radiograph of a tibia in a patient who is skeletally mature, demonstrating expansion of the metaphysis and diaphysis, endosteal scalloping, and a ground-glass appearance of the matrix.
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Technetium-99m methylene diphosphonate (MDP) bone scan demonstrating increased uptake in the tibia corresponding to the radiographic margins.
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CT scan of the tibia demonstrating expansion of the tibia due to an expanding intramedullary lesion.
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A T1-weighted MRI image demonstrating intermediate signal intensity and no soft tissue component.
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A T2-weighted MRI image demonstrating increased signal intensity of the matrix of the lesion.
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The metaplastic bone formed by fibrous dysplasia has the appearance of Chinese letters.
