Fibrous Dysplasia

Fibrous dysplasia is a benign fibro-osseous developmental disorder (not a true neoplasm) caused by a postzygotic somatic GNAS mutation at Arg201 codon, leading to constitutive cAMP activation and replacement of normal bone with fibrous tissue and immature woven bone. Monostotic disease (70%) affects ribs/femur and stabilizes at skeletal maturity; polyostotic (30%) presents earlier in childhood and may progress. The ground-glass radiographic appearance with endosteal scalloping is pathognomonic. Shepherd's crook deformity (proximal femur varus) results from repetitive microfractures in polyostotic disease. McCune-Albright syndrome comprises polyostotic FD, café-au-lait macules (coast of Maine irregular borders), and precocious puberty. Histology shows Chinese letters pattern—irregular woven bone without osteoblastic rimming.

Fibrous dysplasia is a benign fibro-osseous developmental disorder characterized by replacement of normal medullary bone with fibrous tissue and immature woven bone. It is caused by a postzygotic somatic mutation in the GNAS gene, leading to abnormal bone remodeling and structural weakness.

Genetic Basis

GNAS mutation:

• Postzygotic somatic mutation at Arg201 codon of GNAS gene
• Causes constitutive activation of Gsα protein
• Leads to excess cyclic AMP (cAMP) production
• Results in abnormal osteoblast differentiation
• Not inherited - occurs sporadically during early development

Consequences of mutation:

• Replacement of normal bone with fibrous tissue
• Production of immature woven bone (not lamellar)
• Loss of normal trabecular architecture
• Structural weakness and deformity
• Variable expressivity based on timing of mutation

Epidemiology

Incidence:

• Accounts for 5-7% of benign bone tumors
• No sex predilection for monostotic disease
• Slight female predominance for polyostotic (McCune-Albright)

Age distribution:

• Monostotic: presents in adolescence to young adulthood (teens to 20s)
• Polyostotic: presents in childhood (often under 10 years)
• Lesions usually stabilize after skeletal maturity

Distribution:

• Monostotic (70%): single bone involvement
• Polyostotic (30%): multiple bones
• Craniofacial (25%): skull and facial bones common in polyostotic

Molecular Pathophysiology

GNAS mutation cascade:

1. Mutation at Arg201: Prevents GTPase activity of Gsα
2. Constitutive activation: Gsα remains in active GTP-bound state
3. Excess cAMP: Adenylyl cyclase continuously activated
4. Abnormal signaling: Dysregulated osteoblast function
5. Fibro-osseous metaplasia: Normal marrow replaced by fibrous tissue

Bone remodeling effects:

• Increased RANKL: Promotes osteoclast activity
• Decreased OPG: Reduces inhibition of bone resorption
• Abnormal osteoblasts: Produce immature woven bone
• Structural weakness: Loss of normal lamellar architecture

Gross Pathology

Macroscopic appearance:

• White-tan fibrous tissue replacing marrow
• Gritty texture from bone spicules
• No distinct capsule - blends with normal bone
• Vascular stroma - can be hemorrhagic

Histology

Microscopic features (Chinese letters pattern):

1. Irregular bone trabeculae: C-shaped, S-shaped, alphabet-like
2. Woven bone: Immature bone, not lamellar
3. No osteoblastic rimming: Key differentiator from ossifying fibroma
4. Fibrous stroma: Bland spindle cells, fibroblastic
5. Variable bone content: From minimal to extensive

Differential diagnosis on histology:

• Ossifying fibroma: Has osteoblastic rimming on trabeculae
• Low-grade osteosarcoma: Cytologic atypia, permeative growth
• Osteofibrous dysplasia: Cortical location, osteoblastic rimming

Monostotic Fibrous Dysplasia

Definition: Single bone involvement (70% of cases)

Common sites:

1. Ribs (most common monostotic site)
2. Proximal femur
3. Tibia
4. Craniofacial bones
5. Humerus

Clinical presentation:

• Often asymptomatic (incidental finding)
• Pathological fracture through weakened bone
• Bone pain (dull, aching)
• Deformity if progressive (rare)
• Stabilizes at skeletal maturity in most cases

Polyostotic Fibrous Dysplasia

Definition: Multiple bone involvement (30% of cases)

Distribution patterns:

• Unilateral predominance (especially in McCune-Albright)
• Craniofacial involvement common
• Long bones (femur, tibia) frequently affected
• May involve 20-30+ bones in severe cases

Clinical presentation:

• Earlier onset than monostotic (childhood)
• Progressive deformity (shepherd's crook)
• Multiple fractures
• Limb length discrepancy
• Cranial nerve compression if craniofacial

McCune-Albright Syndrome

Classic triad:

1. Polyostotic fibrous dysplasia (unilateral predominance)
2. Café-au-lait macules (irregular "coast of Maine" borders)
3. Endocrinopathy (precocious puberty most common)

Endocrine manifestations:

• Precocious puberty (75% of patients, more common in girls)
• Hyperthyroidism
• Cushing syndrome (excess cortisol)
• Acromegaly (excess growth hormone)
• Hypophosphatemia (renal phosphate wasting)

Dermatologic features:

• Café-au-lait spots with irregular borders
• Coast of Maine appearance (vs smooth "coast of California" in neurofibromatosis)
• Unilateral distribution following Blaschko lines
• Present at birth or early infancy

Mazabraud Syndrome

Definition: Fibrous dysplasia (monostotic or polyostotic) associated with intramuscular myxomas

Features:

• Intramuscular myxomas in skeletal muscle
• Same GNAS mutation as fibrous dysplasia
• Soft tissue masses adjacent to affected bones
• Rare syndrome (fewer than 100 reported cases)

Presenting Symptoms

Monostotic disease:

• Asymptomatic (50-70% of cases, incidental finding)
• Bone pain (dull, aching, worse with activity)
• Pathological fracture (sudden pain, deformity)
• Swelling if expansile (craniofacial lesions)

Polyostotic disease:

• Progressive deformity (shepherd's crook, limb bowing)
• Multiple fractures (recurrent, different sites)
• Limb length discrepancy (unilateral involvement)
• Gait abnormality (limp, antalgic gait)
• Cranial nerve symptoms (vision, hearing loss)

Physical Examination

Inspection:

• Visible deformity (varus femur, tibial bowing)
• Limb length discrepancy (measure true vs apparent length)
• Café-au-lait macules (check for McCune-Albright)
• Gait assessment (antalgic, Trendelenburg)

Palpation:

• Bony expansion over affected area
• Tenderness if symptomatic
• Warmth not typical (unless fracture)

Special findings:

• Shepherd's crook deformity: Proximal femur varus with lateral bowing
• Leonine facies: Craniofacial expansion in severe polyostotic
• Limb atrophy: If chronic pain/disuse

Radiography

Classic X-ray appearance:

Ground-glass opacity:

• Homogeneous hazy density - pathognomonic finding
• Loss of normal trabecular pattern
• Smoky, frosted glass appearance
• Well-defined margins

Bone changes:

• Endosteal scalloping with cortical thinning
• Expansion of medullary cavity
• Loss of corticomedullary differentiation
• No periosteal reaction (unless fracture)

Specific patterns by location:

Proximal femur:

• Shepherd's crook deformity - varus with lateral bowing
• Involves metaphysis and diaphysis
• Pathological fractures common

Skull/craniofacial:

• Expansion of diploe
• Loss of normal contour
• Can cause orbital/sinus obliteration

Ribs:

• Expansile lucency with ground-glass matrix
• Most common monostotic site

CT Scan

Indications:

• Evaluate extent of craniofacial involvement
• Assess cortical thickness for fracture risk
• Pre-operative planning for curettage

CT findings:

• Ground-glass attenuation (100-150 HU)
• Endosteal scalloping clearly visible
• 3D reconstruction helpful for deformity assessment

MRI

Indications:

• Differentiate from malignancy if atypical
• Assess soft tissue extension (Mazabraud syndrome)
• Evaluate spinal canal involvement

MRI signal characteristics:

• T1: Low to intermediate signal
• T2: Variable (low to high depending on fibrous vs cystic content)
• STIR: High signal (edema-like)
• Enhancement: Mild to moderate, heterogeneous

Bone Scan (Tc-99m)

Utility:

• Screen for polyostotic disease when single lesion found
• Shows increased uptake in active lesions
• Helps identify all sites of involvement

Laboratory Tests

Serum markers:

• Alkaline phosphatase: Often elevated (reflects bone turnover)
• Calcium and phosphate: Usually normal
• Endocrine screening if McCune-Albright suspected:
  • Thyroid function (TSH, T4)
  • Cortisol (24-hour urine free cortisol)
  • Growth hormone, IGF-1
  • Bone age (if precocious puberty)

Biopsy

Indications for biopsy:

• Atypical radiographic features (rule out malignancy)
• Pain without fracture (concern for sarcomatous transformation)
• Progressive lesion after skeletal maturity
• First diagnosis in polyostotic disease

Technique:

• Core needle biopsy usually sufficient
• Open biopsy if inadequate sample
• Send for histology (Chinese letters pattern)

Other differentials:

Paget disease:

• Older age (over 50 years)
• Blade of grass advancing lytic front
• Cotton wool appearance in later stages
• Elevated alkaline phosphatase (markedly high)

Aneurysmal bone cyst:

• Eccentric location
• Fluid-fluid levels on MRI
• Blown-out appearance on X-ray
• No ground-glass matrix

Low-grade osteosarcoma:

• Permeative growth pattern
• Cytologic atypia on histology
• Periosteal reaction (Codman, sunburst)
• Older age or history of radiation

📊 Management Algorithm

Click to expand

Conservative Management

Indications for observation:

• Asymptomatic monostotic lesions
• Small lesions without fracture risk
• Stable disease after skeletal maturity

Follow-up protocol:

• X-rays every 6-12 months initially
• Annual imaging once stable
• Monitor for growth, pain, deformity

Medical Therapy

Bisphosphonates:

Indications:

• Symptomatic polyostotic disease
• Bone pain not responding to NSAIDs
• Reduce fracture risk in high-risk sites

Agents and dosing:

• Pamidronate: 30-60 mg IV every 3-6 months
• Zoledronic acid: 4-5 mg IV annually
• Duration: Several years, reassess periodically

Evidence:

• Reduces bone pain in 60-80% of patients
• Decreases alkaline phosphatase levels
• May reduce fracture risk (limited data)
• Does not reverse deformity

Side effects:

• Flu-like symptoms after infusion
• Hypocalcemia (supplement calcium/vitamin D)
• Osteonecrosis of jaw (rare, dental hygiene important)

Surgical Management

Indications for surgery:

1. Pathological fracture (treat fracture, then address lesion)
2. Impending fracture (cortical thinning over 50%, over 2.5cm lesion)
3. Progressive deformity (shepherd's crook)
4. Neurological compromise (craniofacial lesions)
5. Refractory pain despite medical therapy

Surgical options:

Treatment Algorithm

Decision pathway:

1. Asymptomatic monostotic: Observe with serial X-rays
2. Symptomatic monostotic: NSAIDs, consider bisphosphonates or surgery
3. Polyostotic non-syndromic: Bisphosphonates, prophylactic fixation as needed
4. McCune-Albright syndrome: Endocrine management, bisphosphonates, selective surgery
5. Pathological fracture: Treat fracture conservatively, then address lesion after healing

Surgery timing:

• After skeletal maturity when possible (lower recurrence)
• Emergency: Fractures, neurological compromise
• Prophylactic: High-risk proximal femur lesions

Complications

Skeletal complications:

Pathological fracture (most common):

• Occurs in 20-50% of polyostotic patients
• Most common in proximal femur and tibia
• Usually minimally displaced
• Treat conservatively if possible (cast/brace)
• Consider prophylactic fixation after healing

Progressive deformity:

• Shepherd's crook - proximal femur varus
• Limb length discrepancy - up to 5-10 cm in severe cases
• Angular deformity - tibial bowing

Cranial nerve compression:

• Optic nerve - vision loss (10% of craniofacial cases)
• Auditory nerve - hearing loss
• Facial nerve - facial weakness
• Surgical decompression if progressive

Malignant Transformation

Incidence:

• Under 0.5% overall
• Under 1% in non-irradiated lesions
• 5-10% in previously irradiated lesions (historical data)

Risk factors:

• Radiation therapy (major risk factor - avoid if possible)
• Polyostotic disease (slightly higher risk)
• Craniofacial lesions

Types of sarcoma:

• Osteosarcoma (most common transformation)
• Fibrosarcoma
• Chondrosarcoma
• Malignant fibrous histiocytoma

Warning signs:

• New pain in long-standing lesion
• Rapid growth after skeletal maturity
• Soft tissue mass on imaging
• Periosteal reaction or cortical destruction

Prognosis

Monostotic disease:

• Excellent prognosis - lesions stabilize at skeletal maturity
• Surgery curative in most cases
• Recurrence low after maturity (under 10%)

Polyostotic disease:

• Variable prognosis depending on extent
• May progress through adulthood
• Bisphosphonates improve quality of life
• Functional outcomes good with management

McCune-Albright syndrome:

• Prognosis depends on endocrine complications
• Skeletal disease managed similarly to polyostotic
• Endocrinopathy management critical
• Multidisciplinary follow-up lifelong

Multidisciplinary Management: Complex fibrous dysplasia cases, particularly McCune-Albright syndrome, require coordinated care involving orthopaedic surgery, endocrinology, craniofacial surgery, and genetics. Major children's hospitals have relevant multidisciplinary clinics.

Bisphosphonate Access: Pamidronate and zoledronic acid are available through hospital pharmacy for severe symptomatic disease. PBS subsidisation is available for specific indications. Treatment requires specialist supervision.

Genetic Testing: GNAS mutation testing is available through specialised genetics laboratories. Useful for confirming diagnosis in atypical presentations and for genetic counselling (sporadic, not inherited).

Surveillance Imaging: Regular surveillance with plain radiographs and MRI as indicated. CT useful for surgical planning. Bone scintigraphy can map polyostotic involvement.

Craniofacial Surgery: Severe craniofacial involvement may require specialist craniofacial surgery input available at major paediatric centres for optic nerve decompression or reconstructive procedures.