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Updated: Feb 28 2024

Fibrous Dysplasia

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  • 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 for 75% of patients at <30 years of age
        • 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
          • 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
      • 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 in response to mechanical stress due to GNAS mutation
      • results in an isolated area of immature trabecular bone in dysplastic fibrous tissue that does not mineralize normally or remodel
      • 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
      • associated with GNAS mutation
        • GS α-protein (chromosome 20q13) activating mutation (affects cAMP signaling pathway leading to increased production of cAMP)
          • the time of mutation is associated with the extent and severity of disease
        • this leads to bone marrow stromal cells with impaired ability to terminally differentiate into mature osteoblasts, and hematopoietic supporting stroma
        • upregulation of NF-kB and IL-6 from mutated osteoblastic cells increases bone resorption and production of disorganized collagenous matrix
          • increases FGF-23 leading to renal phosphate wasting, hypophosphatemia, and osteomalacia
    • Associated conditions
      • orthopedic manifestations
        • McCune Albright syndrome
          • condition defined by the presence of
            • café-au-lait lesions
              • jagged and irregular borderer macules
                • "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 AP 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 (80%) or polyostotic (20%)
      • Fibrous Dysplasia
      • Defining characteristic
      • Incidence
      • Monostotic
      • involvement of only a single bone
      • 80%
      • Polyostotic
      • involvement of multiple bones
      • 20%
  • 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 fibrous dysplasia
        • 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
      • findings
        • three main appearances include cystic/lytic, sclerotic, or mixed ("ground glass" appearance) 
          • expansile, intramedullary lesion, often centrally located, with well-defined borders and smooth cortices
        • 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
      • AP and lateral of the hip/proximal femur
        • Shepherd's crook deformity
          • coxa vara deformity of the proximal femur
        • lateral bowing and anterior angulation of the 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 thyroid panel, and hormone panel (IGF-1, growth hormone, and prolactin) to evaluate for McCune Albright Syndrome
    • 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 
      • oral analgesics and bisphosphonate 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
    • majority of monostotic lesions become inactive after reaching skeletal maturity
    • 50% of patients with monostotic disease will experience at least one fracture through the lesion 
    • 1% risk of malignant transformation to osteosarcoma, fibrosarcoma, or malignant fibrous histiocytoma
      • poor prognosis
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