McCune-Albright syndrome

McCune-Albright syndrome is a rare genetic disorder that manifests with skeletal, dermatologic, and endocrine abnormalities. It is caused by a G-protein activating mutation that leads to excess production of cAMP. Clinical features include bone pain and/or fractures due to fibrous dysplasia, café-au-lait macules, and peripheral precocious puberty. Other endocrinopathies, such as hyperthyroidism, growth hormone excess, and hypercortisolism, can also occur. Diagnosis is primarily clinical. X-rays showing fibrous dysplasia, abnormal hormone levels on laboratory testing, and genetic testing of affected tissue can help confirm the diagnosis. Management is multidisciplinary and tailored to the specific manifestations of the disease.

• Accounts for 5% of cases of precocious puberty (more common in females) ^[1]
• Affects 1 in 100,000 to 1 in 1,000,000 individuals in the general population ^[1]
• Peak incidence: early childhood

Epidemiological data refers to the US, unless otherwise specified.

• Mosaic mutation in the GNAS1 gene on chromosome 20 (autosomal recessive inheritance)
  • Some cells have a normal version of the GNAS1 gene, while other cells have the mutated version.
  • Embryos only survive if mosaicism occurs.
• If the mutation occurs before fertilization, it affects all cells → incompatible with life.

Activating mutation in GNAS gene → impaired G_s-protein signaling → constitutively activated adenylate cyclase → excess production of cAMP ^[2]

• Unilateral café-au-lait spots with unilateral, ragged edges
• Polyostotic fibrous dysplasia
• Endocrinopathies
  • Peripheral precocious puberty (most common)
  • Cushing syndrome
  • Acromegaly
  • Hyperthyroidism

The 3 P's of McCune-Albright syndrome are Polyostotic fibrous dysplasia, Pigmentation (café-au-lait spots), and Precocious puberty.

• Clinical features: See above.
• Laboratory tests
  • Increased hormone levels (e.g., estradiol, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C)
  • Increased alkaline phosphatase (see “Diagnostics” in “Fibrous dysplasia”)
  • Molecular testing: GNAS1 analysis
• Imaging
  • X-rays of long bones: well-defined, lobulated lesions with a thin cortex and a radiolucent, ground-glass appearance
  • CT/MRI: identify fibrodysplastic lesions
  • Bone scan: determine the extent of bone disease

• Symptomatic: treat underlying endocrinopathies
• Estrogen synthesis inhibitors: letrozole ^[5]
• Selective estrogen receptor modulators (e.g., tamoxifen)

• Neurofibromatosis type 1
• Fibrous dysplasia

The differential diagnoses listed here are not exhaustive.

The condition is lethal when the mutation affects all cells (i.e., occurs before fertilization), but survivable in patients affected by mosaicism.