McCune-Albright Syndrome

GNAS1 and Gs-alpha Signaling

Normal Physiology:

1. Hormone binds to G protein-coupled receptor (GPCR)
2. Gs-alpha exchanges GDP for GTP → becomes active
3. Gs-alpha stimulates adenylyl cyclase → cAMP production
4. cAMP activates protein kinase A (PKA) → cellular effects
5. Gs-alpha has intrinsic GTPase activity → hydrolyzes GTP to GDP → returns to inactive state

McCune-Albright Syndrome:

1. Arginine to histidine/cysteine mutation at codon 201
2. Loss of GTPase activity → cannot hydrolyze GTP
3. Gs-alpha remains constitutively active
4. Continuous cAMP production independent of hormone binding
5. Unregulated downstream signaling in affected tissues

Tissue-Specific Effects

Fibrous Dysplasia Mechanism

Normal Bone Formation:

• Mesenchymal stem cells differentiate into mature osteoblasts
• Osteoblasts produce osteoid matrix
• Matrix mineralizes to form normal lamellar bone

Fibrous Dysplasia Pathology:

1. GNAS1 mutation in bone marrow stromal cells
2. Arrested osteoblast differentiation at immature stage
3. Cells produce fibrous connite tissue instead of normal bone
4. Woven bone trabeculae formed (Chinese letter pattern)
5. No lamellar bone maturation occurs
6. Fibrous tissue expands → bone weakening → deformity

Histological Features

• Fibrous stroma with spindle cells
• Immature woven bone trabeculae (curvilinear "Chinese character" pattern)
• No osteoblastic rimming of trabeculae (key diagnostic feature)
• Variable amounts of cartilage may be present
• Cystic degeneration in some lesions

Biomechanical Consequences

The replacement of normal bone with fibrous tissue results in:

• Reduced bone strength (bending and torsional weakness)
• Pathologic fractures with minimal trauma
• Progressive deformity under physiological loading
• Shepherd's crook deformity in proximal femur (classic)
• Limb length discrepancy from growth disturbance

Fibrous Dysplasia Distribution

Common Sites (in order of frequency):

1. Femur - most commonly affected (shepherd's crook deformity)
2. Tibia - anterior bowing, saber shin
3. Pelvis - may cause acetabular protrusion
4. Skull/facial bones - craniofacial fibrous dysplasia
5. Ribs - painless swelling, rare fractures
6. Humerus - less common than lower limb

Characteristic Features:

• Unilateral predominance - lesions often on same side
• Asymmetric distribution - reflects mosaic pattern
• Progressive during growth - may stabilize after skeletal maturity

Shepherd's Crook Deformity

Definition: Severe coxa vara and anterolateral bowing of the proximal femur resembling a shepherd's walking stick.

Pathogenesis:

1. Fibrous dysplasia weakens proximal femur
2. Weight-bearing forces cause progressive varus
3. Repeated microfractures and healing
4. Progressive deformity with growth
5. May result in significant limb length discrepancy

Clinical Features:

• Limp and Trendelenburg gait
• Shortened limb
• External rotation of affected leg
• Hip and thigh pain
• Limited hip abduction

Pathologic Fractures

• Most common complication of fibrous dysplasia
• May be presenting feature
• Often heal with conservative treatment
• Progressive deformity with each fracture
• Increased risk during growth spurts

Cafe-au-Lait Spots

Characteristics (Coast of Maine pattern):

• Irregular, jagged borders (unlike smooth NF1 spots)
• Large size - may cover large body areas
• Unilateral distribution - respect the midline
• Same side as bone lesions - reflects embryonic derivation
• Color: light brown ("coffee with milk")
• Present at birth or early infancy

Comparison with Neurofibromatosis Type 1:

Precocious Puberty

Most common endocrine manifestation (50-80% of MAS patients)

Features:

• GnRH-independent (peripheral/gonadotropin-independent)
• Occurs due to autonomous gonadal hormone production
• More common and earlier in girls (2-4 years)
• Boys may have testicular macroorchidism

In Girls:

• Vaginal bleeding (may be first sign)
• Breast development before age 8
• Advanced bone age
• Accelerated growth initially, reduced final height

Treatment:

• GnRH agonists do NOT work (peripheral mechanism)
• Aromatase inhibitors (anastrozole, letrozole) - girls
• Antiandrogens + aromatase inhibitors - boys

Other Endocrine Features

Hyperthyroidism (30-50%):

• TSH-independent thyroid hormone production
• May require thyroidectomy if severe

Growth Hormone Excess (10-20%):

• Acromegaly or gigantism
• May require somatostatin analogs or surgery

Cushing Syndrome (rare):

• ACTH-independent cortisol production
• Usually presents in infancy

Phosphate Wasting (renal):

• FGF23 overproduction from FD lesions
• Hypophosphatemia, rickets-like features
• Requires phosphate supplementation

Craniofacial Fibrous Dysplasia

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Sites: Skull base, facial bones, orbit, mandible

Complications:

• Facial asymmetry and cosmetic concerns
• Optic nerve compression → vision loss (urgent)
• Hearing loss (temporal bone involvement)
• Nasal obstruction
• Dental malocclusion

Management:

• Observation for stable lesions
• Decompression for nerve compression
• Contouring surgery for cosmesis (controversial timing)

Hepatobiliary Disease

• Neonatal cholestasis
• Hepatic involvement rare but recognized

Cardiac Manifestations

• Cardiac rhythm abnormalities (rare)
• Related to phosphate wasting and electrolyte disturbances

Pain

Common and debilitating feature:

• Bone pain from FD lesions
• Pain with activity
• May limit mobility significantly
• Responds to bisphosphonates

Radiographic Features

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Classic Findings:

• Ground-glass appearance - hazy, smoky bone density (pathognomonic)
• Well-defined margins with thin sclerotic rim (rind sign)
• Endosteal scalloping - expansion from within
• Bone expansion with intact but thinned cortex
• No periosteal reaction (unless fractured)

Deformity Patterns:

• Shepherd's crook (proximal femur)
• Saber shin (tibia)
• Coxa vara with limb shortening
• Acetabular protrusion (pelvis)

CT Scan

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Indications:

• Craniofacial involvement assessment
• Preoperative planning
• Evaluating extent of lesions

Findings:

• Ground-glass matrix clearly visible
• Cortical thinning and expansion
• Nerve canal encroachment (skull base)

MRI

Indications:

• Soft tissue assessment
• Nerve compression evaluation
• Ruling out malignant transformation

Typical Findings:

• T1: Low to intermediate signal
• T2: Variable, often high signal
• Enhancement with gadolinium
• Cystic areas may be present

Bone Scan (Tc-99m)

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• Increased uptake in FD lesions
• Useful for mapping polyostotic disease
• Identifies all skeletal involvement
• Consider for baseline assessment

Routine Tests

Biochemistry:

• Alkaline phosphatase (ALP) - often elevated (bone turnover marker)
• Calcium - usually normal
• Phosphate - may be LOW (FGF23-mediated wasting)
• 25-OH Vitamin D - check and optimize
• PTH - usually normal

Endocrine Workup

Essential for all MAS patients:

Genetic Testing

GNAS1 Mutation Analysis:

• Confirms diagnosis when clinical features unclear
• Tissue-specific testing may be needed (blood may be negative)
• Biopsy of affected tissue (bone, skin) more reliable
• Identifies R201H, R201C, or codon 227 mutations

Bone Biopsy

Indications:

• Atypical radiographic features
• Concern for malignant transformation
• Genetic confirmation needed

Histology:

• Fibrous stroma with woven bone trabeculae
• "Chinese letter" pattern of trabeculae
• No osteoblastic rimming (diagnostic)
• Excludes osteosarcoma if concerning features

Multidisciplinary Team

Essential Team Members:

• Orthopaedic surgeon (skeletal management)
• Pediatric endocrinologist (hormonal disorders)
• Craniofacial surgeon (facial involvement)
• Ophthalmologist (optic nerve monitoring)
• Audiologist (hearing assessment)
• Geneticist (diagnosis, counseling)
• Pain specialist (chronic pain management)

Bisphosphonate Therapy

Role in MAS:

• Primary indication: bone pain (often significant)
• May reduce lesion activity (controversial)
• Does NOT prevent fractures or deformity progression
• Does NOT change natural history of FD

Commonly Used:

• Pamidronate IV (pediatric): 1 mg/kg/day for 3 days, every 3-6 months
• Zoledronic acid IV: 0.025-0.05 mg/kg, every 6 months
• Oral bisphosphonates less commonly used in children

Monitoring:

• Calcium, phosphate, vitamin D before each cycle
• Renal function
• Bone turnover markers (ALP, CTX)
• Clinical pain assessment

Precautions:

• Ensure adequate vitamin D and calcium
• Atypical fractures with long-term use (controversial in FD)
• Osteonecrosis of jaw (rare in pediatric population)

Phosphate Wasting Management

If FGF23-mediated hypophosphatemia present:

• Oral phosphate supplementation (like XLH treatment)
• Calcitriol to enhance absorption
• Monitor for nephrocalcinosis
• Consider burosumab (anti-FGF23) - emerging data

Vitamin D Optimization

• Maintain 25-OH vitamin D greater than 75 nmol/L
• Essential for bone health
• May help reduce fracture risk

Precocious Puberty

Key Principle: GnRH-independent, so standard puberty blockers do NOT work.

Treatment Options:

Girls:

• Aromatase inhibitors (anastrozole 1mg daily, letrozole)
• Blocks conversion of androgens to estrogens
• Reduces breast development and vaginal bleeding
• May be combined with GnRH agonist if central puberty also triggered

Boys:

• Antiandrogens (spironolactone, bicalutamide)
• Aromatase inhibitors
• Ketoconazole (rarely used)

Goals:

• Prevent premature epiphyseal closure
• Maximize final adult height
• Psychological support for early development

Hyperthyroidism

• Antithyroid medications (methimazole)
• May require thyroidectomy if refractory
• Radioactive iodine NOT recommended (radiation concerns)

Growth Hormone Excess

• Somatostatin analogs (octreotide, lanreotide)
• Pegvisomant (GH receptor antagonist)
• Pituitary surgery if adenoma identified

Cushing Syndrome

• Usually presents in infancy
• Adrenalectomy may be required
• Medical management (metyrapone) as bridge

Skeletal Monitoring

Frequency: Every 6-12 months during growth

Assessments:

• Clinical examination (deformity, pain, function)
• Radiographs of affected bones
• Limb length measurement
• Gait analysis if lower limb involved

Endocrine Surveillance

Annual screening:

• Thyroid function (TSH, free T4)
• Growth assessment (height velocity, bone age)
• Pubertal staging
• IGF-1 if GH excess suspected
• Phosphate level

Craniofacial Monitoring

If skull/facial involvement:

• Annual ophthalmology review (visual acuity, visual fields)
• Audiology assessment
• CT/MRI if symptoms change
• Urgent referral for vision changes

Malignant Transformation Surveillance

Risk Factors:

• Prior radiation therapy (AVOID in FD)
• Large lesions
• Older age

Warning Signs:

• Rapid lesion growth
• Increasing pain
• Soft tissue mass
• Cortical destruction on imaging

Action:

• Urgent MRI
• Biopsy if concerning
• Osteosarcoma is most common malignancy

Acute Pathologic Fractures

Initial Management:

• Standard fracture care principles apply
• Healing usually occurs (fibrous tissue produces callus)
• May require longer immobilization
• Assess for underlying deformity

Operative Indications:

• Unstable fractures
• Significant displacement
• Pre-existing deformity requiring correction
• Impending fracture (prophylactic fixation)

Fixation Principles:

• Intramedullary devices preferred over plates
• Load-sharing rather than load-bearing
• Span entire lesion if possible
• Consider locking nails for femur/tibia

Why Intramedullary Fixation?

1. Load sharing - distributes stress along bone
2. Spans entire lesion - protects from refracture
3. Allows fracture healing without stress concentration
4. Less stress shielding than plate fixation
5. Accommodates growing bone (with appropriate nail choice)

Healing Considerations

• Fractures in FD do heal but may take longer
• Callus may be fibrous rather than normal bone
• Recurrent fracture risk remains high
• Progressive deformity expected without stabilization

Indications for Surgery

Absolute:

• Significant functional impairment
• Progressive deformity
• Recurrent fractures
• Impending fracture (thin cortex, stress risers)

Relative:

• Pain not controlled with bisphosphonates
• Limb length discrepancy greater than 2 cm
• Cosmetic concerns

Shepherd's Crook Deformity Correction

Surgical Options:

1. Valgus Osteotomy:

   • Single or multiple level
   • Correct mechanical axis
   • Combined with intramedullary fixation

2. Multiple Osteotomies:

   • For severe, multiapical deformity
   • "Shish kebab" technique with IM nail
   • Gradual correction possible with external fixator

Technical Considerations:

• Osteotomy through NORMAL bone if possible
• If through FD lesion, healing may be delayed
• Use locked IM nail spanning entire lesion
• May need to ream through fibrous tissue

Femoral Deformity Algorithm

Shepherd's Crook Deformity
├── Mild (neck-shaft angle greater than 100°)
│   └── Observation + bisphosphonates
│       └── Prophylactic IM nail if progressing
├── Moderate (90-100°)
│   └── Valgus osteotomy + IM nail
└── Severe (less than 90°)
    └── Multiple osteotomies + locked IM nail
        └── Consider external fixator for gradual correction

Tibial Deformity

Anterior bowing (saber shin):

• Corrective osteotomy if symptomatic
• IM nail fixation
• May require multiple osteotomies

Growing Child Considerations

• Flexible IM devices in young children
• Plan for nail exchange with growth
• Limb length monitoring essential
• Consider growth modulation for mild discrepancy

Indications

Urgent:

• Optic nerve compression (vision threatened)
• Severe nasal obstruction
• Significant hearing loss from temporal bone involvement

Elective:

• Facial asymmetry/cosmesis
• Dental/occlusal problems
• Stable lesions at skeletal maturity

Optic Nerve Decompression

• Indicated for progressive vision loss
• Controversial for prophylactic decompression
• Endoscopic or open approach
• Collaboration with neurosurgery/ENT

Facial Contouring

• Generally deferred until skeletal maturity
• Lesions may continue to expand during growth
• Shaving/burring of prominent areas
• Risk of recurrence if lesion active

Principles

• Conservative resection - FD lesions may regrow
• Preserve function over cosmesis
• Staged procedures often needed
• Long-term follow-up essential