McCune-Albright Syndrome
McCune-Albright syndrome (MAS) is a rare genetic disorder caused by somatic activating mutations in the GNAS gene, classically characterized by the triad of fibrous dysplasia of bone, café-au-lait skin macules, and peripheral precocious puberty, though the clinical presentation varies widely depending on which tissues harbor the mutation. 1, 2
Pathophysiology and Genetic Basis
- MAS results from post-zygotic somatic mutations in the GNAS gene, specifically affecting the cAMP-regulating protein Gsα, leading to constitutive activation of adenylyl cyclase and ligand-independent signaling 1, 3
- The mutation is almost always a substitution of arginine at position 201, most commonly to histidine or cysteine 3
- Because the mutation occurs during embryonic development, the disease manifests as a mosaic pattern—the extent and severity depend on when the mutation occurs and which cell populations are affected 1, 3
- Earlier mutations during development result in more widespread tissue involvement and more severe disease expression 3
Clinical Features
The Classic Triad
Fibrous Dysplasia of Bone (FD):
- Can involve single or multiple skeletal sites (polyostotic) 1
- Presents with limping, bone pain, pathologic fractures, and skeletal deformities 1, 2
- Scoliosis is common and may be progressive 1
- Craniofacial bone involvement is typical, particularly in patients with growth hormone excess 4
- Plain radiographs show characteristic "ground-glass" lesions 5
Café-au-Lait Skin Macules:
- Usually appear in the neonatal period 1
- Multiple pigmented skin lesions with irregular borders 1, 6
- Distribution pattern follows the lines of Blaschko, reflecting the mosaic nature of the disease 2
Peripheral Precocious Puberty:
- Most common endocrinopathy, particularly in girls 1, 6
- In girls: vaginal bleeding or spotting and breast development, typically caused by autonomous ovarian cysts 1, 6
- In boys: testicular and penile enlargement with precocious sexual behavior 1
- Age at presentation is typically early (mean 2.6 ± 1.3 years) 6
- Gonadotropin levels are suppressed or in prepubertal range despite elevated estradiol 6
Additional Endocrinopathies
- Growth hormone excess: Occurs in approximately 5% of pediatric patients with gigantism, with almost half (46%) being children and young people at diagnosis 4
- Hyperthyroidism: Autonomous thyroid hyperfunction 1, 2
- Cushing syndrome: Due to adrenal hyperplasia 1, 3
- Renal phosphate wasting: Leading to hypophosphatemic rickets 1
Other Manifestations
- Renal involvement occurs in approximately 50% of patients 1
- Elevated alkaline phosphatase due to increased bone turnover from fibrous dysplasia 5
Diagnosis
Clinical diagnosis is typically established based on the presence of characteristic features from the classic triad. 1
Diagnostic Workup
- Plain radiographs are often sufficient to diagnose fibrous dysplasia, showing ground-glass lesions 5, 1
- Bone biopsy can confirm fibrous dysplasia diagnosis when imaging is inconclusive 5, 1
- Laboratory evaluation should include bone-specific alkaline phosphatase, calcium, phosphate, and PTH levels to assess bone turnover and exclude other metabolic bone disorders 5
- Screening for all potential endocrinopathies should be performed based on clinical suspicion, including thyroid function, growth hormone/IGF-1 levels, cortisol, and gonadal hormones 1, 2
- Genetic testing for GNAS mutations is possible but not routinely available or necessary for diagnosis 1
Differential Diagnosis
- Neurofibromatosis (multiple café-au-lait spots but different bone pathology) 1
- Osteofibrous dysplasia and non-ossifying fibromas (isolated bone lesions without endocrine features) 1
- Idiopathic central precocious puberty (gonadotropin-dependent vs. peripheral in MAS) 1
- Paget's disease (affects older adults with different radiographic findings) 5
Management Approach
Skeletal Management
- Surgical intervention is generally recommended for symptomatic fibrous dysplasia lesions causing fractures, deformity, or functional impairment 1, 2
- Bisphosphonates are frequently used to treat fibrous dysplasia, though they do not alter the underlying disease course 1, 2
- Strengthening exercises are recommended to maintain musculature around affected bones and minimize fracture risk 1
- Avoid corrective surgery for jaw, spine, and joint abnormalities until growth hormone and IGF-1 are controlled in patients with concurrent GH excess 4
Endocrine Management
- All endocrinopathies require specific treatment tailored to the affected gland 1
- For peripheral precocious puberty, various treatments have been used with variable effectiveness to reduce ovarian cyst recurrence and hyperestrogenism effects 6
- For growth hormone excess, alternative medical and surgical treatments are preferred over radiotherapy due to concerns about sarcomatous transformation of dysplastic bone 4
Critical Management Consideration for GH Excess
In patients with MAS and growth hormone excess, radiotherapy should be avoided or used with extreme caution due to increased risk of sarcomatous transformation of craniofacial fibrous dysplasia. 4
- In one study, 6 of 112 MAS patients developed skull base sarcoma, with 3 having prior pituitary irradiation 4
- The risk of sarcomatous transformation is higher in MAS than in isolated fibrous dysplasia 4
- Medical and surgical treatments are preferred to control GH excess and preserve vision 4
Prognosis and Complications
- Malignancies associated with MAS are rare, occurring in probably less than 1% of cases 1
- Malignant transformation of fibrous dysplasia lesions is distinctly uncommon 1
- The course of disease typically shows persistent gonadal hyperfunction and progressive worsening of bone lesions 6
- Genetic counseling should be offered, though the sporadic somatic nature means there is no risk of transmission to offspring 1