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Orthopedic Surgery > NEOPLASMS
Fibrous Dysplasia
Article Last Updated: Aug 13, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 12  
Author: Bernardo Vargas, MD, Consulting Staff, Unité Pédiatrique de Chirurgie Orthopédique et Traumatologie (UPCOT), Department of Orthopedic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Coauthor(s):
Mark Clayer, MD, MBBS, FRACS, FAOrthA, Head of Musculoskeletal Tumor Service, Department of Orthopaedics and Trauma, Queen Elizabeth Hospital; Senior Visiting Medical Specialist, Royal Adelaide Hospital and Women's and Children's Hospital, Australia
Editors: Howard A Chansky, MD, Associate Professor, Department of Orthopedics and Sports Medicine, University of Washington Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Sean P Scully, MD, PhD, Professor, Department of Orthopedics, University of Miami; Dinesh Patel, MD, FACS, Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital; Harris Gellman, MD, Consulting Surgeon, Broward Hand Center, Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami School of Medicine
Author and Editor Disclosure
Synonyms and related keywords:
fibrous dysplasia, bone dysplasia, osteochondrodysplasia, Albright disease, bone disease, dysplasia, fibrous dysplasia of bone, fibrous dysplasia bone, cherubism, dysplastic disorder, connective tissue, fibroosseous tissue, lamellar bone, monostotic fibrous dysplasia, polyostotic fibrous dysplasia, precocious puberty, skin pigmentation, McCune-Albright syndrome, Mazabraud syndrome, McCune-Albright's syndrome, Mazabraud's syndrome, Albright's disease, Albright syndrome, Albright's syndrome
Fibrous dysplasia of bone is a nonheritable disease in which abnormal tissue develops in place of normal bone. 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 20.1, 2 As a consequence of this mutation, there is a substitution of the cysteine or the histidine—amino acids of the genomic DNA in the osteoblastic cells—by another amino acid, arginine.3 Consequently, the osteoblastic cells will elaborate a fibrous tissue in the bone marrow instead of normal bone.
Abnormalities may involve 1 bone in the monostotic form (70% of cases ) or many bones in the 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).4, 5, 6, 7, 8
Related eMedicine topics:
Albright Syndrome
McCune-Albright Syndrome (Endocrinology)
McCune-Albright Syndrome (Pediatrics)
Osteofibrous Dysplasia
Related Medscape topics:
Specialty Site Orthopaedics
CME Bone Mineral Parameters, Vitamin D, and Outcomes in Chronic Kidney Disease
History of the Procedure
The term fibrous dysplasia was suggested by Lichtenstein and Jaffe in 1942.9
Problem
In 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 risk of fracture. Incidence of fractures is around 50% of cases.10 This risk of fractures or bone deformity is higher in the long bones, such as the 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.11 The incidence of this risk has been evaluated to be reduced to 1%.11, 12 This risk is higher in patients with the polyostotic form, or McCune–Albright syndrome.12
Frequency
Fibrous dysplasia represents about 5% of all benign bone tumors.2 The monostotic form is more common than the polyostotic form. Many patients are asymptomatic, so 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.
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.2 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.
Pathophysiology
As a consequence of the mutation of GNAS1, there is a substitution of cysteine or histidine, amino acids of the genomic DNA in the osteoblastic cells, by another amino acid, arginine.3 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 cAMP levels are increased and osteocalcin is decreased.13 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.
Clinical
Pain is a common sign of fibrous dysplasia in symptomatic patients.14 Most commonly, patients are asymptomatic. Patients usually seek medical care because of either painful swelling and deformity or a pathologic fracture through a weakened bone. Long bones are commonly affected. The femur is the most common localization. Other sites typically affected are the tibia, maxilla, and skull. Nonskeletal manifestations include abnormal cutaneous pigmentation, precocious puberty, hyperthyroidism, Cushing disease, hyperparathyroidism, and hypophosphatemic rickets. McCune-Albright syndrome is defined as the triad of precocious puberty, polyostotic fibrous dysplasia, and cutaneous pigmentation. Typically, only females are affected by precocious puberty, but the other endocrine abnormalities occur equally in males and females. All of these abnormalities are thought to be due to the same underlying mutation.
- Surgical treatment of fibrous dysplasia is indicated in the prevention or treatment of fractures or major deformity.15 The most common surgical indications are fracture of a weight-bearing bone or a progressive disease.
- Asymptomatic patients do not need treatment.
- A needle biopsy can be performed if there is doubt about the diagnosis before the initial management.
- Upper-extremity lesions rarely require surgical management. Nevertheless, vascularized bone grafting has been proposed.16
- Several studies have shown that bisphosphonates are useful in alleviating chronic pain in patients with fibrous dysplasia,17, 18, 19, 20 but further studies are necessary to confirm these promising results.
Fibrous dysplasia can affect almost any bone in the body. The relevant anatomy is that of the bone involved.
There are no specific contraindications to surgical intervention in patients with fibrous dysplasia. However, care must be used in the skeletally immature patient. Internal fixation of long bones with intramedullary nails may be proposed.
Lab Studies
- Molecular diagnosis using the techniques of polymerase chain reaction (PCR) analysis with peptide nucleic acid (PNA) has shown that fibrous dysplasia patients have blood cells with the G protein gene (GNAS) mutation. Diagnosis of fibrous dysplasia or McCune-Albright syndrome could be helped by identification of this mutation in the peripheral blood.21 Utility of this technique is still being evaluated.
- Serum alkaline phosphatase levels are often elevated during active phases of this disease. This test could be useful to asses the evolution of disease in patients treated with bisphosphonates.
- About 25% of patients may have a vitamin D deficiency.18 Serum calcium, phosphate, and vitamin D levels are useful to exclude rickets.
- Pituitary gonadotropins and gonadosteroids are assessed to assist in the workup of precocious puberty.
- Patients with the polyostotic form, particularly McCune-Albright syndrome, must be evaluated to exclude hyperthyroidism, pituitary gigantism, or hypercortisolism (possible autonomous endocrine hyperfunction).
Imaging Studies
Plain radiographs - The most common site of involvement in both the monostotic and polyostotic forms of fibrous dysplasia is the femur.10
- Lesions in the long bones are medullary and usually affect the diaphysis and extend toward the metaphysis (see Image 2).
- Typically, the matrix of the lesion has a ground-glass appearance. The lesion produces endosteal scalloping with a thin intact cortical shell. The contour of the bone may be expanded by the lesion.
- The classic deformity that results with involvement of the proximal femur is described as a shepherd's crook deformity due to the deformation into varus.
Technetium-99m methylene diphosphonate (MDP) bone scan. - Increased uptake of the label that corresponds to osteoblastic activity in the area of involvement is seen on radiographs (see Image 3).
- This study is useful in determining whether disease is monostotic or polyostotic.
CT scan (see Image 4)
- CT scan confirms a lesion confined to the interior of bone with no soft-tissue component. It is helpful in distinguishing fibrous dysplasia from a malignancy.22
- CT scan can show a homogeneous matrix.
MRI - Intermediate signal intensity is present on T1-weighted images (see Image 5)
- High signal intensity is present on T2-weighted images (see Image 6).
Diagnostic Procedures
Biopsy - Needle biopsy is used to establish the diagnosis of fibrous dysplasia, especially in monostotic cases.
- Open biopsy should be performed only as part of a multidisciplinary team approach, with personnel experienced in the management of both benign and malignant bone and soft-tissue sarcomas.
Histologic Findings
- The gross findings of fibrous dysplasia include a centrally located, tan-to-gray-white, gritty-feeling lesion.
- The microscopic appearance shows a fibrous/collagenous matrix with randomly oriented bone or fiber trabeculae that are formed by osseous metaplasia of spindled stromal cells.
- The spicules of immature bone that are produced are short and irregular and are not lined by osteoblasts.
- The appearance has been described as that of Chinese letters.
- Small nodules of cartilage are found within the fibrous matrix in 10% of cases.
Staging
- 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.
Medical therapy
Although there is no specific medical therapy for fibrous dysplasia, studies have shown decreased pain after treatment with bisphosphonates. Bisphosphonates inhibit bone resorption by their action on osteoclasts (see also Future And Controversies). The most common drug therapy is intravenous pamidronate. An intravenous infusion of pamidronate (total dose of 1 mg/kg/day over 3 days, repeated every 3-6 mo) has been proposed. The total dose must be administered over a 4-hour period. Vitamin D and calcium supplements must be added to this therapy. This therapy in children seems to be safe, but longer follow-up is needed to confirm the absence of collateral effects on the growth plate. An increased growth-plate thickness has been reported in children treated with bisphosphonates.2 The PROFIDYS study (Oral Bisphosphonate Effect on Osseous Symptoms in Fibrous Dysplasia of Bone) is a double-blind study evaluating the long-term safety and results of treatment with an oral bisphosphonate (risedronate [Actonel]), which has been ongoing since 2007. The study is evaluating bone pain and the evolution of osteolytic lesions in patients with fibrous dysplasia, and it is expected to be completed by 2013.
Surgical therapy
- If surgical treatment is required for fibrous dysplasia in long bones, intramedullary nails are recommended.
- This technique provides good stabilization and could prevent deformation.
- Conservative treatment, use of plates, curettage, or bone grafting should be discouraged.10, 14
- Deformity-correction surgery is indicated in patients with mechanical axis deviation of the lower limbs.
Intraoperative details
- The dysplastic bone in fibrous dysplasia can be quite difficult to ream.
- Fibrous dysplasia is associated with a high tendency of bone bleeding during surgery.10
Follow-up
- The main role of the follow-up is to prevent deformity as a result of the disease.
- The authors recommend yearly radiographs of the involved area or areas until skeletal maturity.
- Fibrous dysplasia rarely undergoes remission. For this reason, it is appropriate to periodically monitor the disease progression, especially in the skeletally immature patient.
- Once skeletal maturity has been achieved, it is unusual for monostotic fibrous dysplasia to progress.
- Early intervention with internal fixation of involved bones may be important in the prevention of deformity.
- Referral to an endocrinologist for endocrine and metabolic testing is suggested so that endocrine anomalies can be diagnosed and treated.
- Fracture is the most common complication of fibrous dysplasia. In polyostotic disease, fracture occurs in more than 50% of cases.
- Deformity may occur in weight-bearing bones.
- Malignant transformation occurs in less than 0.5% of cases. It is more likely to occur if polyostotic disease exists or following treatment with radiation therapy. Typically, malignant transformation occurs during the third or fourth decade of life.12 Benign tumors have also been associated with fibrous dysplasia.23
- Patients with McCune-Albright syndrome have a high incidence of scoliosis (probably more than 50%).2
- The recurrence rate for fibrous dysplasia has been reported to be 21% following curettage and grafting, but if patients are monitored for many years, the rate is probably closer to 100% .
- Unless malignant transformation develops, fibrous dysplasia is not a life-threatening disease. The lesions tend to stabilize as skeletal maturity is reached.
- The majority of the monostotic cases have a good evolution regardless of treatment.
- Polyostotic lesions are very often associated with one or more fractures.14
- Malignant transformation develops in a minority of patients (< 0.5%)
Major advances have occurred in understanding the molecular basis of fibrous dysplasia. The mutation has been identified, but the actual pathways that lead to abnormal osteoblast differentiation and function are just beginning to be understood.
In the future, effective nonsurgical treatments may be possible. The risk of local recurrence is high, so the decision to treat must be made with informed consent to avoid inappropriate expectations. In general, the goals of surgery should be to stabilize the bone and relieve pain, rather than to excise the involved bone. The condition often is found incidentally, and the need for prophylactic treatment may be difficult to accept for an asymptomatic or minimally symptomatic patient. The PROFIDYS study (Oral Bisphosphonate Effect on Osseous Symptoms in Fibrous Dysplasia of Bone) is double-blind study evaluating the long-term safety and results of treatment with an oral bisphosphonate (risedronate [Actonel]), which has been ongoing since 2007. The study is evaluating bone pain and the evolution of osteolytic lesions in patients with fibrous dysplasia, and it is expected to be completed by 2013.
| Media file 1:
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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Media type: Electron Microscopy
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| Media file 2:
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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Media type: Radiograph
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| Media file 3:
Technetium-99m methylene diphosphonate (MDP) bone scan demonstrating increased uptake in the tibia corresponding to the radiographic margins. |
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Media type: Nuclear Image
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| Media file 4:
CT scan of the tibia demonstrating expansion of the tibia due to an expanding intramedullary lesion. |
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Media type: CT
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| Media file 5:
A T1-weighted MRI image demonstrating intermediate signal intensity and no soft tissue component. |
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Media type: MRI
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| Media file 6:
A T2-weighted MRI image demonstrating increased signal intensity of the matrix of the lesion. |
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Media type: MRI
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| Media file 7:
The metaplastic bone formed by fibrous dysplasia has the appearance of Chinese letters. |
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Media type: Electron Microscopy
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Fibrous Dysplasia excerpt Article Last Updated: Aug 13, 2008
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