Fibrous Dysplasia

Pathogenesis and Pathophysiology. Our understanding of the pathogenesis of fibrous dysplasia has advanced greatly in recent years. Several investigators have identified a point mutation in the gene that codes for the alpha subunit of the G-protein, Gsa, in affected bone and other tissues in patients with fibrous dysplasia. The absence of this mutation in non-affected tissues in patients with the disease suggests that a somatic mutation occurs early in embryogenesis to create a genetic mosaic. The mutated Gsa proteins activate adenylate cyclase and increase signaling through the cyclic adenosine monophosphate (cAMP)- protein kinase A pathway.y Recent work suggests that the resultant phosphorylation of transcription factors enhances transcription of the proto-oncogene c- fos and translation of c-fos protein in affected tissues. y These findings surely represent only part of the molecular story, and it is likely that enhanced production of other oncoproteins is yet to be discovered.y These molecular changes result in a gain of function that probably underlies the bony and endocrinological lesions characteristic of fibrous dysplasia. The functional result is a disorder of lamellar bone remodeling and repair. The pathological result is a replacement of normal bone and marrow elements by a vascular fibrous tissue composed of whorls of proliferating fibroblasts with haphazardly arranged trabeculae of metaplastic bone and fluid-filled cystic areas lined by multinucleated giant cells. The appearance is similar to that of osteitis fibrosa cystica due to hyperparathyroidism but is distinguished by the absence of osteoblasts. The abnormal bone originates from the medullary cavity and grows outward thinning the bony cortex. y The high prevalence in puberty, the accelerated expansion of lesions during pregnancy, and the association with precocious puberty in females in the McCune-Albright syndrome y , y suggest a hormonal influence that is, so far, poorly understood. Estrogen and progesterone receptors have been identified in affected bone. y Patients with fibrous dysplasia have an accelerated turnover of bone, and many have elevated serum alkaline phosphatase levels, reflecting increased osteoblastic activity. Those with extensive disease also have elevated urinary hydroxyproline, reflecting increased turnover of collagen, a measure of the activity of osteoclasts. Serum calcium and inorganic phosphorus remain normal, reflecting compensatory increases in bone formation and resorption. Fibrous dysplasia is generally considered to occur sporadically. Sassin and Rosenberg found no positive family histories among 50 cases with cranial fibrous dysplasia. y This result is consistent with the current hypothesis that the disorder results from a somatic mutation early in embryological development.

Epidemiology and Risk Factors. The age of onset is variable, but the disorder most commonly presents in childhood, especially during the period of most rapid bone

TABLE 29-3 -- FREQUENCY OF SKULL BONE INVOLVEMENT OF SKULL BONE BY FIBROUS DYSPLASIA

Bone

Number of Cases (N = 50)

Frontal

28

Sphenoid

24

Frontal and sphenoid

18

Optic canal involved

10 (3 bilateral)

Temporal

8

Parietal

6

Occipital

2

Adapted from Sassin JF, Rosenberg RN: Neurological complications of fibrous dysplasia of the skull. Arch Neurol 1968;18:363-369.

Adapted from Sassin JF, Rosenberg RN: Neurological complications of fibrous dysplasia of the skull. Arch Neurol 1968;18:363-369.

growth. However, in one series of 50 patients with fibrous dysplasia of the skull, over half came to medical attention after age 18. There is no difference in incidence based on race or sex for the most typical forms.^i However, the McCune-Albright syndrome occurs more frequently in females. As noted earlier, the bony lesions may expand at an accelerated rate during pregnancy.

Clinical Features and Associated Disorders. About 70 percent of patients have the monostotic form involving a single bone. The remainder have the disseminated polyostotic form, which is often predominantly unilateral. Sites of involvement vary, the ribs and long bones being the most common sites. The skull is involved in about 50 percent of polyostotic cases and in 10 to 27 percent of monostotic cases. y Most of the clinical manifestations that prompt neurological evaluation are due to skull involvement (.,T§.b.!.e...,2,9z3 ). Patients may present with a variety of focal neurological findings secondary to the compressive effects of the involved bone ( Fig

29-5 ). Visual impairment

Figure 29-5 Fibrous dysplasia. Sagittal T1-weighted MRI scan of the head. Fibrous tissue is seen replacing bone of the occiput and skull base. This patient presented with acute hoarseness that was presumed to be due to compression of the accessory nerve in the skull base.

followed by hearing loss and tinnitus are the most common presenting neurological deficits. Although various other cranial neuropathies may occur as a result of the compressive effects of involved bone, these are rare enough that none were seen in two large studies of cases involving the skull. y , y 20 Optic nerve compression with visual symptoms is common when the frontal and sphenoid bones are involved. A proptotic and downward displaced eye is often seen when these bones are involved and should prompt questions about visual symptoms and a radiological evaluation of the optic canal. Patients with stenosis of the optic canal may complain of decreased acuity or blurring of vision, scintillating scotoma, flashing light, or graying of vision when pressure is applied to the globe. Optic atrophy may be seen on funduscopic examination. The visual symptoms may be slowly progressive, and they have often been present for some time when the patient presents. Patients may also have progressive facial asymmetry and deformity resulting from facial nerve involvement. Patients with hearing deficits typically have conductive loss due to stenosis of the external canal and middle ear by the involved temporal bone. A nonthrobbing headache may be a common complaint as well. Sassin and Rosenberg's patients also had an increased incidence of seizures (6 of 50), confirming the findings of prior reports. y The reason for this association is not known.

Fibrous dysplasia has been associated with various other disorders. Cutaneous pigmentation occurs in over 50 percent of those with the polyostotic form. The McCune- Albright syndrome consists of polyostotic fibrous dysplasia, usually largely unilateral, with cafe(c) au lait spots, and various forms of endocrine hyperfunction, especially precocious puberty in females. y , y Rarely, other endocrine abnormalities, including hyperthyroidism, acromegaly, Cushing's syndrome, hyperparathyroidism, and diabetes mellitus, may occur. Some patients may have a progressive diffuse facial deformity called leontiasis ossea; however, this facies may be caused by other disorders as well, including Paget's disease and craniometaphyseal dysplasia. y Malignant transformation to sarcoma occurs in about 0.5 percent of patients with fibrous dysplasia and 4 percent of those with the McCune-Albright syndrome. y This tumor is rare in the skull.y

Differential Diagnosis. Fibrous dysplasia must be differentiated from benign and malignant neoplasms, including meningioma with adjacent hyperostosis, sarcomas or fibromas replacing bone, bone cysts, and various orbital masses, including eosinophilic granuloma, Hand-Schuller- Christian disease, and orbital pseudotumor. y , hi In addition, other metabolic diseases of bone must be considered, including Paget's disease, hyperparathyroidism, hyperostosis frontalis interna, osteopetrosis, and craniometaphyseal dysplasia (Pyle's disease). In general, age of onset, other clinical features, and radiological features easily distinguish these disorders. Rarely, the cranial hyperostosis found in hematological disorders causing bone marrow hyperplasia or cyanotic heart disease may cause confusion.

Evaluation. Evaluation should seek to distinguish fibrous dysplasia from other tumors or metabolic diseases and to assess the presence of deficits that require follow-up or surgical intervention. Plain x-ray films, CT, and MRI can distinguish fibrous dysplasia from tumors and characterize other metabolic disorders. Meningioma with adjacent hyperostosis is distinguishable on CT and MRI by its typical enhancement and its extension into the cranial cavity. Fibrous dysplasia expands into the outer table, leaving the inner table and cranial contents undisturbed. y Imaging dedicated to the optic foramina should be done when the frontal and sphenoid bones are involved. Skeletal survey and increased uptake on bone scintiscanning can identify asymptomatic areas of involvement. Serum alkaline phosphatase levels are often elevated, but serum calcium and inorganic phosphorus are normal, helping to differentiate hyperparathyroidism. When following patients with frontal and sphenoid involvement who have not had surgery, photographs of the head, quantitation of proptosis, documentation of acuity and visual fields, and funduscopic examinations for optic atrophy should be performed along with radiological views of the optic canal. These parameters may then be followed every 3 to 6 months until it is clearly established that no progressive visual loss has occurred. The onset of pain, increasing alkaline phosphatase levels, rapid growth, or invasion into cortical bone should raise a suspicion of possible malignant transformation. Biopsy may be needed to distinguish progression of fibrous dysplasia from malignant transformation.

Management. Treatment is indicated when clinical function is significantly threatened. When visual symptoms are present in patients with a small or diminishing optic canal, surgical decompression by unroofing the optic canal can in most cases arrest progression. Such treatment rarely leads to significant return of function; therefore, patients at risk for visual loss must be closely followed. The lesions are highly vascular, and intraoperative bleeding and intrabony hematomas may complicate surgery. Radiotherapy is contraindicated because it greatly increases the risk of malignant transformation. Because lesions may progress more rapidly during pregnancy, careful follow-up, especially for visual symptoms, must be maintained. Decisions about surgery during pregnancy should be based on the neurological status of the patient.

Prognosis and Future Perspectives. The course in most cases is benign. Leeds and colleagues followed 15 patients for 6 to 39 years and found that radiological progression was slight or equivocal in all except two patients. y Yet although the lesions become less active after skeletal maturation, progression does not necessarily stop with bone growth, and the lesions may reactivate during maturity. Recent success in elaborating the molecular mechanisms of intracellular signaling and their alterations in fibrous dysplasia and other diseases opens a rich field in which our understanding of the pathogenesis of fibrous dysplasia can be deepened. The elaboration of this work is likely to clarify the endocrinological manifestations of fibrous dysplasia. A better understanding of the molecular pathogenesis may eventually produce effective therapies, as it has in Paget's disease of bone.

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