summary Fibrous dysplasia is a developmental abnormality caused by a Gs alpha protein mutation that leads to failure of the production of normal lamellar bone and arrest as woven bone. The condition usually presents in patients who are less than 30 years of age with an asymptomatic lesion that is found incidentally on radiographs. Diagnosis is made with radiographs showing a lesion with a ground glass appearance or a "punched-out" lytic lesion with a well-defined margin of sclerotic bone. Treatment is usually nonoperative with oral analgesics and bisphosphonates for pain control. Surgical management is indicated in the setting of pathologic fracture or impending pathologic fracture and lesions leading to bony deformities including coxa vara, scoliosis, and limb length discrepancy. Epidemiology Incidence 1 in 5,000 to 10,000 accounts for approximately 2.5% of all bone lesions and 5% of all benign bone lesions Demographics age can affect all age groups onset at <30 years of age for 75% of patients monostotic form commonly affects individuals between 10 and 30 years of age polyostotic form presents earlier and is more likely to affect children younger than the age of 10 due to pain or pathologic fracture 60% of children under the age of 10 with polyostotic form will be symptomatic sex no difference in incidence between male and female Location can occur in any bone in the body, but most commonly in flat bones and long bones proximal femur is most common location monostotic form ribs (28%) and proximal femur (23%) are most common skull, craniofacial bones, tibia and humerus are also common polyostotic form often unilateral and affecting only one limb most commonly affects the femur, skull and craniofacial bones, pelvis and spine Risk factors no known risk factors Etiology Pathophysiology failure of primitive bone to remodel to mature lamellar bone and reorganize results in an isolated area of immature trabecular bone in dysplastic fibrous tissue that does not mineralize normally or remodel in response to mechanical stress due to GNAS mutation lesions typically are active and expand during childhood before becoming inactive upon skeletal maturity monostotic lesions grow in proportion to skeletal growth polyostotic lesions grow in proportion to the extent of disease severity Genetics inheritance pattern spontaneous missense mutation results in somatic mosaicism no risk of vertical transmission the time of mutation is associated with the extent and severity of the disease associated with an activating GNAS missense mutation Gs α-protein (chromosome 20q13) activating mutation causes upregulation of WNT/B-catenin pathway increased WNT/B-catenin proteins inhibits maturation/differentiation of osteoprogenitor cells upregulation of NF-kB and IL-6 from mutated osteoclastic cells increases bone resorption and production of disorganized collagenous matrix increases FGF-23 leading to renal phosphate wasting, hypophosphatemia, and osteomalacia this leads to bone marrow stromal cells with impaired ability to terminally differentiate into mature osteoblasts and hematopoietic supporting stroma Associated conditions orthopedic manifestations McCune Albright syndrome condition defined by the presence of: café-au-lait lesions jagged and irregularly bordered macules found most commonly on the trunk/back "coast of Maine" pattern typically respect and do not cross the midline endocrine abnormalities precocious puberty most common presenting symptom in females 85% of females with McCune Albright Syndrome recurrent ovarian cysts autonomous testosterone production excess growth hormone thyroid abnormalities 66% of patients with McCune Albright Syndrome neonatal hypercortisolism polyostotic fibrous dysplasia obtain spine radiographs to look for scoliosis 60% will have spinal involvement, most commonly in the posterior elements Mazabraud syndrome polyostotic fibrous dysplasia soft-tissue intramuscular myxomas Jaffe-Lichenstein syndrome polyostotic fibrous dysplasia café-au-lait lesions distinguished from McCune Albright syndrome by lack of endocrinopathies Osteofibrous dysplasia rare form that primarily affects the tibia and is confined to the cortices non-orthopedic manifestations severe cranial deformities leading to cosmetic deformities, blindness, hearing loss, and airway obstruction Classification Bone lesions may be monostotic (70%) or polyostotic (30%) Fibrous Dysplasia Defining characteristic Incidence Monostotic involvement of only a single bone 70% Polyostotic involvement of multiple bones 30% Presentation History most lesions are asymptomatic and found incidentally on radiographs patients should be screened for endocrinopathies and dermatologic ailments Symptoms usually asymptomatic and discovered as an incidental finding may have swelling or deformity primarily in setting of pathologic fracture localized pain more common in lesions in high-stress areas female patients can have increased pain during pregnancy and their menstrual cycle due to estrogen receptors within the fibrous dysplasia Physical exam inspection café-au-lait spots larger and more irregular borders ("coast of Maine") than neurofibromatosis (“coast of California”) may or may not be present with fibrous dysplasia presence is diagnostic of McCune-Albright syndrome in setting of polyostotic fibrous dysplasia typically found on trunk or back and do not cross midline swelling around lesion leg length discrepancy most common skeletal deformity bowing of lower extremities most commonly seen with fibrous dysplasia of proximal femur causing classic “shepherd’s crook” deformity characterized by widening of the hip, lateral bowing of proximal thigh, and shortening of the limb scoliosis Imaging Radiographs recommended views orthogonal views of the affected bone AP and lateral of the hip/proximal femur findings expansile, intramedullary lesion, often centrally located, with well-defined borders and smooth cortices three main appearances include cystic/lytic, sclerotic, or mixed ("ground glass" appearance) may have cortical thinning depending on the size of expansile lesions endosteal scalloping may be present no periosteal reaction “rind sign” "punched-out" lesion with a well-defined margin of sclerotic bone is common pseudofractures or Looser zones (“milkman lines”) transverse lucencies with sclerotic borders perpendicular to the cortex typically seen in the setting of osteomalacia Shepherd's crook deformity lateral bowing and anterior angulation of the femur coxa vara deformity of the proximal femur best seen on an AP and lateral of the hip/proximal femur AP and lateral of the tibia “saber shin” anterior bowing of the tibia useful in differentiation from osteofibrous dysplasia AP and lateral of the spine vertebral collapse kyphoscoliosis thoracolumbar scoliosis CT scan indications provides greater detail of osseous morphology of the lesion findings variable findings ground glass opacities (56%) homogenous sclerosis (23%) cystic/lytic (21%) similar to an x-ray showing well-defined borders of the expansile, intramedullary lesion enhances with contrast MRI indications can be used to delineate fibrous dysplasia from malignancy and identification of soft tissue component findings T1: dark T2: variable signal T1 with contrast: heterogenous with moderate contrast enhancement Bone scan indications utility in the evaluation of pediatric patients with concern for polyostotic fibrous dysplasia or McCune Albright syndromes findings lesions are usually warm until adulthood when they become typically become inactive Studies Labs monostotic fibrous dysplasia does not require any laboratory studies polyostotic fibrous dysplasia requires a lab workup to evaluate for McCune Albright Syndrome including a thyroid panel hormone panel IGF-1 growth hormone prolactin Biopsy gross appearance yellow/tannish-white with gritty tissue texture cystic changes present in older lesions ~10% of lesions contain cartilage and may have blue-tinge histology curvilinear trabeculae of woven bone with irregular branching the characteristic look of "alphabet soup" or "Chinese letters" varied proportion of osseous and fibrous tissue with fibrous stroma background fibroblast proliferation surrounding islands of woven bone woven bone lacks osteoblastic rimming (osteofibrous dysplasia has osteoblastic rimming) trabeculae of osteoid and bone in fibrous stroma with metaplastic cartilage or areas of cyst degeneration mitotic figures are common in the setting of fracture Differential Fibrous Dysplasia Differential Multiple lesions in young patients Treatment is Observation alone Benefits from Bisphonate therapy Fibrous Dysplasia o o o Eosinophilic granuloma o o Lymphoma o Leukemia o Enchondroma / Olliers / Maffucci's o o Osteochondroma / MHE o o NOF /Jaffe-Campanacci syndrome o o Hemangioendothelioma o Paget's o o Metastatic Disease o Myeloma o Paget Disease disorder of abnormal bone remodeling with coarsened, broad and irregular trabeculae with increased osteoclast activity may appear similar to fibrous dysplasia on radiographs can be distinguished from fibrous dysplasia by patient demographics and histology Paget disease commonly affects individuals >50 years of age Fibrous dysplasia commonly affects individuals <30 years of age Neurofibromatosis type 1 caused by an autosomal dominant mutation on chromosome 17q11.2 manifesting with neurofibromas, café-au-lait spots, and osseous abnormalities can be distinguished from McCune Albright Syndrome by the appearance of café-au-lait spots, the presence of neurofibromas, and genetic testing Osteofibrous dysplasia (ossifying fibroma) bone lesion occurring in patients under 30 years old, and appears as a lytic cortical defect with a well-defined sclerotic border most commonly occurs in the tibia, specifically the anterior cortex leading to anterior bowing can be differentiated from fibrous dysplasia by location within the cortex and the presence of osteoblastic rimming on histological analysis not seen in fibrous dysplasia Adamantinoma low-grade malignancy primarily occurring in the tibia (80%) along the anterior cortex of the diaphysis appears similar to fibrous dysplasia on radiographs as an expansile lytic lesion without periosteal reaction can be differentiated from fibrous dysplasia by MRI and histological analysis histology of adamantinoma shows nest of epithelioid cells in a background of fibrous stroma Diagnosis Can be made based on history, physical examination, and plain radiographs Advanced imaging (MRI and CT) and biopsy of the lesion may be useful when there is suspicion for polyostotic fibrous dysplasia/McCune Albright Syndrome, or malignancy cannot be excluded. Treatment Nonoperative observation indications asymptomatic upper extremity lesions and lower extremity lesions with low risk for fracture techniques bi-annual clinical examination and serial radiographs until skeletal maturity after skeletal maturity, routine follow-up is not indicated unless the lesion becomes symptomatic outcomes most monostotic lesions become inactive once skeletally maturity is reached more than 50% of upper extremity lesions will have at least one fracture low threshold for radiographic evaluation in skeletally mature patients with lesions that become symptomatic due to risk of fracture and malignant transformation bisphosphonate or denosumab therapy indications symptomatic lesions with minimal risk of pathologic fracture in polyostotic fibrous dysplasia modalities IV bisphosphonate bi-annually hypothesized mechanism is decreased bone turnover mediated by bisphosphonates outcomes overall mixed results with some studies showing improved pain control no current consensus on bisphosphonate in the setting of fibrous dysplasia and considered off-label by the FDA pain and serum biomarkers of bone turnover (i.e alkaline phosphatase) used to monitor response to treatment immobilization alone (+/- closed reduction) indications fracture involving the lesion that fall within acceptable criteria for nonoperative management pediatric upper extremity fractures and tibial shaft fractures modalities upper extremity fractures can be managed with a sling (humerus) or cast (forearm/hand) tibia fractures immobilized in a cast Operative intramedullary nail fixation (+/- osteotomy) considered the gold standard due to load-sharing properties indications recalcitrant bone pain impending or pathologic fracture in weight-bearing area progressive skeletal deformity more likely in younger patients with polyostotic fibrous dysplasia technique long intramedullary nails should be used when possible to protect the entire bone and prevent construct failure elastic nails may be used when rigid intramedullary nails are contraindicated or the medullary canal is too small proximal femoral osteotomy may be performed if coxa vara deformity present intertrochanteric osteotomy internal fixation and bone grafting indications symptomatic lesions impending or pathologic fractures in areas where intramedullary fixation is contraindicated technique titanium plate with locking screw constructs are preferred construct of choice titanium more closely mimics the modulus of elasticity of bone compared to stainless steel locking plate and screws act as internal fixator to allow the dysplastic bone to heal the longest plate that spans the entire bone should be selected to prevent the creation of stress riser the maximum number of screws possible should be used to increase total pull-out strength graft choice calcium phosphate cement may be favorable as it has the longest resorption time in dysplastic bone and provides immediate stability synthetic bone graft, and cortical/cancellous allograft may also be utilized autologous bone graft should be avoided due to high rate of resorption transformation into dysplastic woven bone intramedullary device more effective than a plate in the lower extremity isolated curettage and bone grafting indications monostotic fibrous dysplasia in the upper extremity with low risk of fracture typically not recommended due to poor outcomes including high rate of graft resorption, fracture, and need for subsequent reoperation Complications Pathologic fracture Incidence 50% of humeral lesions will have at least one fracture risk factors pathologic humeral fracture >50% cortical involvement >30mm in diameter presence of cystic degeneration pathologic femur fracture large lesion located in the femoral neck and trochanteric region Coxa vara common complication of fibrous dysplasia risk factors polyostotic fibrous dysplasia high mechanical stress multiple fractures of the proximal femur diagnosis made radiographically and classified into one of six subtypes Type 1 (24%) limited to the neck and trochanteric region normal neck-shaft angle (120-140°) Type 2 (6%) limited to the neck and trochanteric region coxa valgus (neck-shaft angle >140°) Type 3 (7%) limited to the neck and trochanteric region coxa vara (neck-shaft angle <120°) Type 4 (20%) lateral bowing of proximal femoral shaft normal neck-shaft angle (120-140°) Type 5 (14%) lateral bowing of the proximal femoral shaft coxa valgus (neck-shaft angle >140°) Type 6 (29%) lateral bowing of proximal femoral shaft coxa vara (neck-shaft angle <120°) treatment operative intervention with fixation +/- corrective osteotomies goals achieve neck shaft angle 120-140° correct lateral bowing (if present), sagittal plane deformity (usually apex anterior), and restore rotational alignment and version total bone fixation with load-sharing device address cystic degeneration of fibrous dysplasia prognosis type 1 and type 2 deformities tend to remain stable after skeletal maturity is reached type 3 to type 6 deformities tend to progress and worsen over time Malignant transformation incidence approximately 1% risk of malignant transformation risk factors polyostotic fibrous dysplasia diagnosis most commonly occurs in the diaphysis of long bones presenting symptoms include increased pain, swelling, and enlarging mass elevated alkaline phosphatase levels may be seen in the presence of malignant transformation advanced imaging (CT and MRI) and biopsy required for diagnosis treatment surgical resection of lesion +/- neoadjuvant/adjuvant chemotherapy and/or radiation therapy prognosis >50% mortality rate lower overall survival rate compared with primary sarcomas Scoliosis incidence low incidence in monostotic fibrous dysplasia 40% in polyostotic fibrous dysplasia diagnosis AP and lateral radiographs of the spine treatment management dependent on degree of deformity no current consensus on the role of bracing and spinal instrumentation and fusion Prognosis Resolution the majority of monostotic lesions become inactive after reaching skeletal maturity Pathologic fractures 50% of patients with monostotic disease will experience at least one fracture through the lesion Malignancy 1% risk of malignant transformation to osteosarcoma fibrosarcoma malignant fibrous histiocytoma poor prognosis when malignant transformation occurs