Description
McCune-Albright Syndrome (MAS) is a sporadic, postzygotic, mosaic disorder characterised by the clinical triad of fibrous dysplasia of bone (polyostotic or monostotic), café-au-lait skin pigmentation, and peripheral precocious puberty. Other endocrinopathies, including hyperthyroidism, growth hormone excess, renal phosphate wasting with or without rickets/osteomalacia, and Cushing syndrome, may also be associated with MAS.
Pathogenesis
MAS results from postzygotic activating mutations in the GNAS gene, leading to mosaicism. The GNAS gene encodes the α-subunit of the stimulatory G protein (Gsα), which regulates the production of cyclic AMP in response to hormone stimulation. Constitutive activation of Gsα leads to increased intracellular cyclic AMP, which leads to cellular proliferation and tissue-specific endocrine dysfunction.
Subtype
There are no specific subtypes of MAS, but the clinical presentation can vary significantly between patients due to the mosaic nature of the disease.
Epidemiology, Risk Factors & Associations
- Incidence is estimated at 1 in 100,000 to 1 in 1,000,000 births
- Females are more frequently affected than males
Clinical Features
- Café-au-lait skin pigmentation, often ipsilateral to the bone lesions with irregular borders (termed coast of Maine borders), typically occuring along the midline.
- Polyostotic unilateral fibrous dysplasia, typically presenting as bone pain, pathological fractures or deformities
- Precocious puberty, often presents as early menarche in infants or young girls. Testicular and thyroid involvement may also occur.
Complications
- Skeletal deformity and fractures due to fibrous dysplasia of bone
- Endocrine overactivity leading to various conditions such as Cushing syndrome, hyperthyroidism, and precocious puberty
- Rare potential risk of fibrous dysplasia malignant transformation into osteosarcoma.
Pathological Features
Histopathology
- Macroscopic: Bones may be deformed with a ‘ground glass’ appearance on cut sections
- Microscopic: Replacement of normal bone architecture by fibrous tissue and immature, woven bone trabeculae (Chinese character appearance) with no osteoblastic rimming
Serology
- Hormonal Imbalances: Elevated levels of hormones due to autonomous endocrine hyperactivity, such as increased levels of thyroid hormones, cortisol, growth hormone, or sex steroids.
- Thyroid Function Tests: Elevated T3 and T4, suppressed TSH.
- Adrenal Function Tests: Elevated cortisol and ACTH levels.
- Growth Hormone Levels: Elevated due to pituitary adenomas.
Biochemistry
- Increased Alkaline Phosphatase: Often elevated due to high bone turnover associated with fibrous dysplasia.
- Hypercalcaemia: Occasionally seen in patients with hyperparathyroidism or other endocrine abnormalities.
Immunohistochemistry
- GNAS Gene Mutation: Immunohistochemical staining may demonstrate the presence of the Gs alpha protein, indicative of activating mutations in the GNAS gene, which causes constitutive activation of adenylate cyclase.
- Markers of Bone Formation: Increased expression of osteocalcin and bone sialoprotein within fibrous dysplasia lesions.
Molecular
- GNAS Gene Mutation: Activating mutations in the GNAS gene, which encodes the Gs alpha subunit of the stimulatory G protein, leading to constitutive activation of adenylate cyclase and increased cyclic AMP (cAMP) production.
- Somatic Mosaicism: The mutation is post-zygotic, leading to a mosaic distribution of affected and unaffected tissues.
Genetics
- Somatic Mosaicism: The disorder arises from post-zygotic mutations in the GNAS gene, resulting in a mosaic pattern of affected tissues. This explains the variability in clinical presentation and the asymmetric distribution of lesions.
Radiological Features
General Features
- Characteristically demonstrates polyostotic fibrous dysplasia, often unilateral, with a ground glass appearance and cortical thinning on plain radiographs and CT
- Fibrous dysplasia classically occurs in long bones as a central diaphyseal lesion, mildly expanded with dense and amorphous ground-glass matrix.
- Café-au-lait spots are not visualised on imaging
CT
MRI
- T1WI: Uniform low to intermediate signal intensity.
- T2WI: Variable signal intensity, depending on how much calcification is present in the ground-glass matrix.
- T1 C+: No significant enhancement.
- DWI/ADC: No significant diffusion restriction.
Grading and Staging
There is no specific grading or staging system for MAS.
Diagnosis
Diagnosis is clinical, based on the characteristic triad of symptoms. Genetic testing can be done to identify the GNAS mutation, but a negative result does not rule out the condition due to the mosaic pattern of this disease. A bone age examination should be performed to evaluation for skeletal maturation.
Differential Diagnosis
- Mazabraud syndrome: Rare syndrome which is also linked with mutation of GNAS1 gene, characterised by skeletal fibrous dysplasia and intramuscular myxomas.
- Neurofibromatosis type 1: may also present with café-au-lait spots, but also has neurofibromas and Lisch nodules.
- Polyostotic fibrous dysplasia without endocrine involvement or skin changes
- Osteofibrous dysplasia, adamantinoma, fibrous cortical defect/non-ossifying fibroma for bone lesions
Management
Management of MAS is symptomatic and multidisciplinary. This often involves paediatricians, endocrinologists, orthopaedic surgeons, and sometimes neurosurgeons and maxillofacial surgeons. Bisphosphonates can be used to increase bone density and decrease pain from fibrous dysplasia. Precocious puberty and other endocrine issues are typically managed medically with various hormone antagonists. Surgical intervention may be required for significant bone deformities.