# CIM Case: Fibrous Dysplasia - McCune-Albright Syndrome ## Clinical Scenario **Patient:** 15-year-old female **Presentation:** Bilateral hip pain and progressive waddling gait over 2 years, worsening with activity **Relevant history:** Reached menarche at age 8 (precocious puberty), multiple café-au-lait spots noticed since infancy, previous pathological fracture of left femur at age 10, no family history **Examination findings:** - Multiple café-au-lait spots with irregular "coast of Maine" borders - Bilateral coxa vara deformity with limited hip internal rotation - Shortened limbs (5cm LLD, left shorter) - Waddling gait with positive Trendelenburg bilaterally - Tenderness over proximal femora - No lymphadenopathy or masses - Thyroid not enlarged - Tanner stage 5 (early development) --- ## Investigations Provided ### Laboratory Results | Test | Result | Normal Range | Interpretation | |------|--------|--------------|----------------| | Haemoglobin | 128 g/L | 115-145 | Normal | | WCC | 6.8 x 10⁹/L | 4-11 | Normal | | Calcium | 2.35 mmol/L | 2.15-2.55 | Normal | | Phosphate | 0.65 mmol/L | 0.8-1.5 | LOW | | ALP | 420 U/L | 40-150 | Elevated | | PTH | 4.5 pmol/L | 1.5-6.5 | Normal | | 25-OH Vitamin D | 75 nmol/L | >50 | Normal | | TSH | 0.3 mU/L | 0.4-4.0 | Low-normal | | Free T4 | 22 pmol/L | 10-20 | High-normal | | IGF-1 | 450 ng/mL | 200-600 | Normal | | FGF23 | 180 RU/mL | <100 | Elevated | ### Imaging **Image 1: Pelvis and Bilateral Hip X-rays** **Radiological features:** - Bilateral "shepherd's crook" deformity of proximal femora - Coxa vara (neck-shaft angle 90° bilaterally) - Ground-glass matrix throughout proximal femora - Expansile lesions with smooth endosteal scalloping - Previous healed fracture left femoral shaft with varus malunion - Acetabula appear involved - No aggressive periosteal reaction **Image 2: Whole Body Bone Scan** **Findings:** - Increased uptake in bilateral proximal femora - Increased uptake in skull base, left humerus, multiple ribs - Pattern consistent with polyostotic fibrous dysplasia **Image 3: CT Skull** **Findings:** - Extensive fibrous dysplasia of skull base - Sphenoid bone involvement - No optic canal encroachment currently - Ground-glass appearance typical ## Questions & Model Answers **Diagnosis: McCune-Albright Syndrome** **The Classic Triad:** | Feature | This Patient | |---------|--------------| | **Polyostotic fibrous dysplasia** | Yes - bilateral femora, skull, humerus, ribs | | **Café-au-lait spots** | Yes - with coast of Maine (irregular) borders | | **Precocious puberty** | Yes - menarche at age 8 | **Genetics:** | Aspect | Detail | |--------|--------| | **Mutation** | GNAS gene (Gsα subunit of G-protein) | | **Type** | Activating mutation | | **Inheritance** | NOT inherited - post-zygotic somatic mosaic | | **Mechanism** | Constitutive activation of adenylyl cyclase → increased cAMP | | **Distribution** | Patchy due to mosaicism | **Endocrine Abnormalities (Hormone-Independent):** | Endocrinopathy | Mechanism | Features | |----------------|-----------|----------| | **Precocious puberty** | Most common (50-80%) | Early breast development, menarche | | **Hyperthyroidism** | Autonomous thyroid function | Goitre, tremor, weight loss | | **Growth hormone excess** | Pituitary autonomy | Acromegaly, gigantism | | **Cushing syndrome** | Adrenal autonomy | Rare, poor prognosis in infants | | **Hypophosphataemia** | FGF23 overproduction | Rickets/osteomalacia | | **Hyperparathyroidism** | Rare | Hypercalcaemia | **This Patient's Endocrine Status:** - Precocious puberty ✓ - Low phosphate + elevated FGF23 → hypophosphataemic rickets/osteomalacia ✓ - Borderline thyroid function → needs monitoring - Normal IGF-1 → no GH excess currently **Café-au-lait Comparison:** | Feature | McCune-Albright | Neurofibromatosis | |---------|-----------------|-------------------| | Borders | Coast of Maine (irregular, jagged) | Coast of California (smooth) | | Distribution | Often unilateral, follows dermatomes | Scattered bilaterally | | Number | Variable | ≥6 required | > **Consultant Tip:** McCune-Albright café-au-lait spots have "coast of Maine" (irregular) borders, while NF1 spots have "coast of California" (smooth) borders. **Shepherd's Crook Deformity:** **Definition:** Severe coxa vara with bowing of the proximal femur, resembling a shepherd's staff. **Pathophysiology:** - Abnormal fibrous tissue replaces normal bone - Weakened bone yields to load - Progressive deformity with weight-bearing - Neck-shaft angle can be <90° **Medical Optimisation:** | Treatment | Purpose | Evidence | |-----------|---------|----------| | **Bisphosphonates** | Reduce pain, improve bone density, decrease fractures | Pamidronate IV or zoledronic acid | | **Phosphate supplements** | Correct hypophosphataemia | If FGF23-mediated | | **Calcitriol** | Improve bone mineralisation | With phosphate | | **Burosumab** | Anti-FGF23 antibody | Emerging treatment | **Bisphosphonate Protocol:** | Agent | Dose | Frequency | |-------|------|-----------| | Pamidronate IV | 1mg/kg (max 60mg) | Every 3-4 months | | Zoledronic acid | 0.025-0.05mg/kg | Every 6 months | **Limitations of Medical Treatment:** - Does NOT prevent deformity progression - Does NOT correct existing deformity - Reduces pain and may decrease fracture rate - May improve radiographic appearance **Surgical Indications:** | Indication | Rationale | |------------|-----------| | **Progressive deformity** | Mechanical failure | | **Impending fracture** | Cortical thinning, pain | | **Pathological fracture** | Stabilisation | | **Significant LLD** | Function | | **Pain refractory to medical management** | Quality of life | **Surgical Technique - Valgus Osteotomy:** | Step | Detail | |------|--------| | **Approach** | Lateral | | **Osteotomy** | Closing wedge or dome to correct varus | | **Fixation** | Intramedullary nail preferred (avoid plates) | | **Multiple osteotomies** | May be needed for severe bowing | | **Target** | NSA 125-130° | **Why IM Fixation Over Plates?** - Plates create stress risers - Abnormal bone prone to fracture at plate ends - IM nail protects entire bone length - Better load sharing > **Consultant Tip:** Bisphosphonates help with pain but don't prevent deformity. Surgical correction uses IM nails, not plates - plates cause stress risers in abnormal bone. **Malignant Transformation in Fibrous Dysplasia:** **Overall Risk:** | Type | Risk | |------|------| | **Monostotic FD** | <1% | | **Polyostotic FD** | 4-6% | | **McCune-Albright syndrome** | Up to 4-6% | **Types of Malignancy:** | Malignancy | Frequency | |------------|-----------| | **Osteosarcoma** | Most common (60-70%) | | **Fibrosarcoma** | 20-25% | | **Chondrosarcoma** | 10-15% | | **Malignant fibrous histiocytoma** | Rare | **Risk Factors for Transformation:** | Factor | Increased Risk | |--------|----------------| | **Polyostotic disease** | Higher than monostotic | | **Previous radiation** | Significantly increased (historical treatment) | | **McCune-Albright syndrome** | Higher than isolated FD | | **Skull base involvement** | Slightly higher | | **Long duration** | Cumulative risk | **Warning Signs of Transformation:** | Sign | Significance | |------|--------------| | **New pain in stable lesion** | Red flag | | **Rapid growth** | Concerning | | **Cortical destruction** | Aggressive change | | **Soft tissue mass** | Extension beyond bone | | **Periosteal reaction** | New aggressive feature | | **Change in X-ray appearance** | Loss of ground-glass | **Investigation of Suspected Transformation:** | Step | Purpose | |------|---------| | **MRI with contrast** | Assess soft tissue, enhancement pattern | | **CT** | Cortical destruction, matrix | | **PET-CT** | Metabolic activity | | **Biopsy** | Definitive diagnosis | **Prognosis if Transformed:** - Generally poor - Often high-grade sarcomas - Treatment: wide resection ± chemotherapy - 5-year survival: 30-50% (worse than primary osteosarcoma) **Surveillance:** | Patient Type | Frequency | |--------------|-----------| | **Monostotic** | Clinical review annually | | **Polyostotic** | Clinical + imaging annually | | **Any new symptoms** | Urgent imaging | > **Consultant Tip:** New pain in a previously stable FD lesion is a red flag for malignant transformation. Radiation therapy is contraindicated in FD due to sarcoma risk. **Imaging Features of Fibrous Dysplasia:** **Plain Radiographs:** | Feature | Description | |---------|-------------| | **Ground-glass matrix** | Pathognomonic - homogeneous hazy density | | **Location** | Medullary, may extend to cortex | | **Margins** | Well-defined, often with rim of sclerosis | | **Expansion** | Smooth, may thin cortex | | **Deformity** | Shepherd's crook, bowing | | **Shape** | Often described as "long lesion in a long bone" | **Rind Sign:** - Thick rim of reactive bone surrounding lesion - More common in weight-bearing bones - Indicates attempted containment **CT Scan:** | Feature | Finding | |---------|---------| | **Matrix** | Ground-glass attenuation (70-130 HU) | | **Extent** | Defines lesion size accurately | | **Cortex** | Thinning, expansion, but usually intact | | **Enhancement** | Variable with contrast | **MRI:** | Sequence | Appearance | |----------|------------| | **T1** | Low to intermediate signal | | **T2** | Variable - low to high depending on composition | | **STIR** | Often intermediate signal | | **Enhancement** | Variable (can be marked) | **Caveats with MRI:** - Can look aggressive (high T2, enhancement) - May mimic malignancy - Correlate with X-ray and CT **Bone Scan:** | Finding | Description | |---------|-------------| | **Uptake** | Intense uptake in active lesions | | **Extent** | Useful for polyostotic disease staging | | **Limitations** | Cannot distinguish from malignancy | **Characteristic Radiological Patterns:** | Site | Pattern | |------|---------| | **Skull** | Expanded diploe, "leontiasis ossea" in severe cases | | **Proximal femur** | Shepherd's crook | | **Rib** | Expansile, lytic | | **Tibia** | Anterior bowing | **Cherubism (Differential):** - Bilateral mandible involvement - "Angel face" appearance - Autosomal dominant - Different from McCune-Albright > **Consultant Tip:** Ground-glass matrix on X-ray is pathognomonic for fibrous dysplasia. MRI can look worryingly aggressive - always correlate with plain films. **Histopathology of Fibrous Dysplasia:** **Classic Features:** | Feature | Description | |---------|-------------| | **Fibrous stroma** | Bland spindle cells in whorled pattern | | **Woven bone trabeculae** | "Chinese letter" or "alphabet soup" pattern | | **No osteoblastic rimming** | Key distinguishing feature | | **No inflammatory cells** | Unlike infection | | **Cystic change** | May occur (secondary ABC) | **"Chinese Letter" Pattern:** - Irregular curved trabeculae of woven bone - Randomly oriented - Surrounded by fibrous tissue - Pathognomonic appearance **Immunohistochemistry:** | Marker | Result | |--------|--------| | **GNAS mutation** | Positive in 70-80% | | **S100** | Negative (vs nerve sheath tumour) | | **CD68** | Negative (vs giant cell lesions) | **Differential Diagnosis on Histology:** | Lesion | Distinguishing Feature | |--------|----------------------| | **Low-grade osteosarcoma** | Osteoblastic rimming, permeative growth | | **Ossifying fibroma** | Osteoblastic rimming present | | **Non-ossifying fibroma** | Storiform pattern, foam cells, no bone | | **Osteofibrous dysplasia** | Osteoblastic rimming, zonal architecture | | **Adamantinoma** | Epithelial cells, cytokeratin positive | **Osteofibrous Dysplasia vs Fibrous Dysplasia:** | Feature | Fibrous Dysplasia | Osteofibrous Dysplasia | |---------|-------------------|------------------------| | **Age** | Any | Children | | **Location** | Any bone | Tibia (anterior cortex) | | **Osteoblast rimming** | Absent | Present | | **Zonal pattern** | No | Yes | | **Relation to adamantinoma** | None | Related lesion | **Molecular Testing:** - GNAS mutation testing increasingly available - Can be performed on tissue or blood (mosaic) - Helpful in ambiguous cases > **Consultant Tip:** The absence of osteoblastic rimming distinguishes fibrous dysplasia from ossifying fibroma and osteofibrous dysplasia. Look for "Chinese letter" woven bone pattern. **Skull Base Fibrous Dysplasia:** **Frequency:** - Present in 50-70% of polyostotic FD - Common in McCune-Albright syndrome - Sphenoid, ethmoid, frontal bones most affected **Clinical Concerns:** | Structure | Complication | |-----------|--------------| | **Optic canal** | Optic nerve compression → vision loss | | **Orbit** | Proptosis, diplopia | | **Auditory canal** | Conductive hearing loss | | **Paranasal sinuses** | Obstruction, mucocele | | **Foramen** | Cranial nerve compression | **Optic Nerve Involvement:** | Feature | Detail | |---------|--------| | **Incidence** | 20-30% of craniofacial FD | | **Vision loss** | 2-5% develop significant loss | | **Mechanism** | Canal narrowing, direct compression | | **Age at risk** | Usually during growth (childhood) | **Ophthalmological Monitoring:** | Assessment | Frequency | |------------|-----------| | **Visual acuity** | Every 6-12 months | | **Visual fields** | Every 6-12 months | | **Colour vision** | Annually | | **CT optic canals** | If symptoms or canal narrowing | | **VEP** | Visual evoked potentials if concern | **Management of Optic Canal Narrowing:** | Scenario | Management | |----------|------------| | **Asymptomatic narrowing** | Close observation | | **Progressive narrowing, good vision** | Controversial - prophylactic decompression vs observe | | **Vision deterioration** | Optic canal decompression | | **Acute vision loss** | Urgent decompression + steroids | **Optic Canal Decompression:** | Aspect | Detail | |--------|--------| | **Approach** | Transcranial, transnasal, or combined | | **Goal** | Unroof optic canal, decompress nerve | | **Risk** | Intraoperative nerve injury, CSF leak | | **Outcome** | Stabilises vision, rarely improves it | **Controversies:** - Prophylactic decompression not routinely recommended - Risk of surgery may exceed risk of observation - Individualised decision-making **Facial Deformity:** | Concern | Management | |---------|------------| | **Cosmetic** | Contouring surgery (shaving) | | **Functional** | Decompression of affected structures | | **Timing** | Often delay until growth complete | | **Recurrence** | Common after incomplete resection | **This Patient:** - CT shows skull base involvement - No optic canal encroachment currently - Needs regular ophthalmological surveillance - No indication for intervention currently > **Consultant Tip:** Vision loss from optic canal involvement is rare but devastating. Regular ophthalmological review is essential for any patient with craniofacial FD. --- ## Key Teaching Points ### Pattern Recognition **This pattern suggests McCune-Albright Syndrome:** - Polyostotic fibrous dysplasia - Café-au-lait spots with "coast of Maine" borders - Precocious puberty (especially in females) - Endocrine abnormalities - Ground-glass appearance on X-ray - Shepherd's crook deformity **Distinguish from Other Conditions:** | Feature | McCune-Albright | Neurofibromatosis | Monostotic FD | |---------|-----------------|-------------------|---------------| | Café-au-lait borders | Irregular (Maine) | Smooth (California) | None | | Bone lesions | Polyostotic | Rare osseous | Single | | Endocrine | Common | No | No | | Inheritance | Somatic mosaic | Autosomal dominant | Sporadic | ### Critical Management Points 1. **Coast of Maine (irregular) borders** - distinguishes from NF1 2. **Screen for multiple endocrinopathies** - thyroid, GH, adrenal 3. **Hypophosphataemia is FGF23-mediated** - treat with phosphate + calcitriol 4. **Bisphosphonates reduce pain** - but don't prevent deformity 5. **Use IM nails, not plates** - plates create stress risers 6. **Malignant transformation risk is 4-6%** - radiation is contraindicated 7. **Optic nerve surveillance** - essential in craniofacial involvement --- ## Common Examiner Follow-ups **Q: "What is the role of burosumab in McCune-Albright syndrome?"** Burosumab is an anti-FGF23 monoclonal antibody: - Approved for X-linked hypophosphataemia - Being studied in FD/MAS-related hypophosphataemia - Normalises phosphate without high-dose supplements - May improve bone mineralisation - Currently off-label for MAS - Emerging evidence is promising --- **Q: "What is the Mazabraud syndrome?"** Mazabraud syndrome is the association of: - Fibrous dysplasia (usually polyostotic) - Intramuscular myxomas (soft tissue masses) - Rare, <100 cases reported - Myxomas are benign but can be mistaken for malignancy - Same GNAS mutation as McCune-Albright - No endocrine abnormalities --- **Q: "When would you biopsy a fibrous dysplasia lesion?"** Biopsy indications: - Atypical imaging features - Suspicion of malignant transformation - Diagnostic uncertainty - New pain in established lesion - Aggressive periosteal reaction - Soft tissue mass Routine biopsy of classic-appearing FD is NOT required. --- ## Related Topics - Monostotic Fibrous Dysplasia - Bone Tumours in Children - Pathological Fractures - Hypophosphataemic Rickets - Paediatric Endocrinology - Craniofacial Surgery