It is a mosaic disease arising from somatic activating mutations in GNAS, which encodes the alpha-subunit of the Gs heterotrimeric G protein.

As such, the clinical presentation of patients with McCune Albright syndrome varies greatly depending on the disease features.

Genetically, there is a spontaneous postzygotic mutation of the gene GNAS, on the long (q) arm of chromosome 20 at position 13.3, which is involved in G-protein signaling.

[14] This mutation, which occurs only in the mosaic state, leads to constitutive receptor signaling and inappropriate production of excess cAMP.

For example, one child with McCune–Albright syndrome may be entirely healthy, with no outward evidence of bone or endocrine problems, enter puberty at close to the normal age, and have no unusual skin pigmentation.

[citation needed] All patients with known or suspected McCune–Albright syndrome should undergo a screening evaluation for fibrous dysplasia.

[citation needed] Patients with known or suspected McCune–Albright syndrome should undergo a screening evaluation for endocrine features.

[18] Cushing syndrome is very rare, and is typically diagnosed clinically in infants who present with signs of severe illness.

[20] Denosumab has been found successful in reducing bone pain and decreasing tumor growth, however there is limited safety data available in patients with fibrous dysplasia.

For example, untreated growth hormone excess increases the risk of craniofacial fibrous dysplasia expansion and may lead to vision loss.

Radiation therapy has been associated with malignant transformation of skull base fibrous dysplasia, and should be avoided in all but the most dire cases.