McCune-Albright syndrome is a rare genetic disorder caused by a sporadic, somatic activating missense mutation in the GNAS gene.
This gene encodes the alpha subunit of the stimulatory G protein (Gsα), which couples transmembrane receptors to adenylate cyclase.
The mutation results in constitutive, autonomous activation of cAMP-dependent receptors, including those for luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone.
Because the mutation occurs postzygotically during embryogenesis, the disease exhibits somatic mosaicism, meaning the mutation is distributed variably across different tissues, leading to a highly heterogeneous clinical presentation.
Clinical Features
The syndrome is classically defined by a clinical triad:
polyostotic fibrous dysplasia of bone,
café-au-lait skin pigmentation, and
gonadotropin-independent precocious puberty.
The café-au-lait macules characteristically have irregular, jagged margins described as a “coast of Maine” appearance and frequently demonstrate an association with the midline of the body.
Fibrous dysplasia typically occurs at multiple sites (polyostotic) and commonly presents with bone pain, deformities, pathological fractures, and characteristic expansile lesions with a “ground-glass” appearance on radiographs.
Gonadotropin-independent precocious puberty occurs predominantly in females, presenting with recurrent autonomous ovarian cysts, widely fluctuating estradiol levels, and episodes of early vaginal bleeding.
In males, precocious puberty is less common but presents with symmetric testicular enlargement driven by Leydig cell hyperplasia.
Other associated endocrinopathies include hyperthyroidism, growth hormone excess (pituitary gigantism), FGF23-mediated renal phosphate wasting (hypophosphatemia), and infantile Cushing syndrome secondary to bilateral macronodular adrenal hyperplasia.
Significant non-endocrine manifestations can include severe neonatal cholestasis, cardiomyopathy, optic neuropathy, and sudden death.
Diagnosis and Management
Diagnosis is primarily clinical, as genetic testing of peripheral blood leukocytes has limited sensitivity (detecting the mutation in only about 50% of cases) due to somatic mosaicism.
Precocious puberty in females is managed medically with aromatase inhibitors (such as letrozole or anastrozole) or estrogen receptor antagonists (such as tamoxifen or fulvestrant).
Routine surgical resection or cystectomy for ovarian cysts should be avoided because of high recurrence rates; intervention is reserved for specific risks like ovarian torsion.
If the patient’s bone age advances to a pubertal level, central (gonadotropin-dependent) precocious puberty may become superimposed, necessitating the addition of gonadotropin-releasing hormone (GnRH) agonist therapy.
Bisphosphonates are frequently utilized to effectively relieve the bone pain associated with fibrous dysplasia, though they do not alter the long-term course of the skeletal lesions.