McCune-Albright syndrome results from mosaic somatic activating pathogenic variants in the GNAS gene, located on chromosome 20. GNAS encodes the alpha subunit of the cAMP-pathway-associated G protein (Gs), a signaling molecule present in virtually every tissue. The pathogenic variant arises post-zygotically during early embryonic development and is confined to a subset of cells. This somatic nature means the condition is not inherited from parents and does not run in families; verified vertical transmission has never been documented. The timing of the somatic event during embryogenesis determines which organ systems are affected and the degree of disease severity. Variants arising earlier in development tend to produce more widespread involvement, while those arising later lead to more limited manifestations. Because Gs signaling is present throughout the body, sites beyond skin, bone, and classical endocrine organs can potentially be involved.

Diagnosis of McCune-Albright syndrome is generally established in individuals with two or more characteristic clinical features, as formal diagnostic criteria have not been published. Skeletal evaluation typically includes total-body bone scintigraphy to characterize the extent of fibrous dysplasia, followed by targeted radiographic or CT imaging of affected areas. In individuals with only monostotic FD, molecular identification of a somatic activating GNAS pathogenic variant in affected tissue may be required; sensitivity is approximately 80% in lesional tissue and approximately 20-30% in peripheral blood. Endocrine evaluation involves biochemical screening for hyperthyroidism, growth hormone excess, and FGF23-mediated phosphate wasting. Imaging of relevant organs, including thyroid and gonadal ultrasound, characterizes the extent of endocrine involvement. The differential diagnosis includes neurofibromatosis type 1, which produces cafe-au-lait macules with smooth rather than irregular borders, and other fibro-osseous skeletal lesion entities.

No FDA-approved treatments are specifically indicated for McCune-Albright syndrome. Management targets specific manifestations present in each individual and is delivered by a multidisciplinary team that may include endocrinology, orthopedic surgery, ophthalmology, and other relevant specialties depending on affected organ systems. Long-term management incorporates regular surveillance for potential complications. Skeletal surveillance includes assessment for fibrous dysplasia progression, scoliosis, and fracture risk through periodic imaging and ongoing orthopedic evaluation. Craniofacial FD is assessed by CT imaging at regular intervals, with ophthalmologic and audiologic evaluations for those with craniofacial involvement. Endocrine surveillance encompasses thyroid function testing, assessment for pubertal progression, growth hormone evaluation using IGF-1 levels, and screening for FGF23-mediated hypophosphatemia. Surveillance schedules are tailored to each individual's age and known pattern of organ system involvement. Interventions for active manifestations, including orthopedic management of fractures and skeletal deformity and endocrine-directed approaches for specific endocrinopathies, are individualized to the clinical situation. Several clinical trials are currently evaluating pharmacological agents for FD/MAS management.

The prognosis of McCune-Albright syndrome is highly variable, spanning a spectrum from incidentally discovered monostotic FD to severe, multisystem disease. Skeletal lesions typically stabilize and become less active in adulthood, likely related to apoptosis of cells bearing the somatic GNAS variant. Serious complications, including significant skeletal deformity, loss of vision or hearing from craniofacial lesions, severe progressive scoliosis, and rare malignant transformation of FD lesions, may occur in a subset of individuals. Long-term multidisciplinary follow-up is central to the management of this condition.

McCune-Albright syndrome is an area of active clinical investigation, with several ongoing trials examining natural history characterization, fracture risk assessment tools, pain characterization, and pharmacological approaches targeting bone metabolism. The published literature encompasses case reports, reviews, and biomarker research. Information on active trials, including a Phase 4 study evaluating denosumab for FD/MAS in adults, is available at ClinicalTrials.gov.