The packet lists GNAS (chromosome 20) as the associated gene; it supplies no ClinGen validity classification for this association. According to GeneReviews, FD/MAS results from mosaic somatic activating pathogenic variants in GNAS, which encodes the G protein Gs alpha subunit. GeneReviews describes the variants as arising sporadically early in embryonic development, with manifestations depending on the time during embryogenesis at which the variant occurred, the tissue involved, and the role of Gs in that tissue. Earlier variants are described as leading to widespread disease and later ones to limited disease.

The packet's inheritance field lists a multifactorial pattern, whereas GeneReviews states that FD/MAS is not inherited. GeneReviews reports that verified vertical transmission has never been observed and that molecular data indicate all affected individuals are mosaic for an activating GNAS variant. It states that the risk to siblings and other family members is expected to be the same as in the general population and that there are no verified instances of transmission to offspring.

According to GeneReviews, FD/MAS is usually diagnosed from characteristic clinical, radiographic, and laboratory manifestations, although formal diagnostic criteria have not been published. It lists skin, skeletal, and endocrine features that raise suspicion. For skin, these are hyperpigmented macules with jagged, irregular borders, described as resembling the coast of Maine, that respect the body midline and follow the lines of Blaschko, in contrast to the smooth-bordered lesions seen in neurofibromatosis type 1. For the skeleton, fibrous dysplasia replaces normal bone and bone marrow with fibro-osseous tissue, and GeneReviews describes initial radiologic evaluation by bone scan (99Tc-MDP or 18F-NaF PET/CT) followed by radiographs and head CT of involved areas. Endocrine findings are those listed above.

GeneReviews states that the clinical diagnosis is established in individuals with two or more typical clinical features. When monostotic FD is the only finding, identification of a somatic activating GNAS pathogenic variant is required to confirm the diagnosis. Molecular approaches include targeted analysis of codons p.Arg201 and p.Gln227. GeneReviews reports a sensitivity of about 80% in lesional tissue and about 20% to 30% in peripheral blood leukocytes, and notes that detection depends on the level of mosaicism and on assay sensitivity, with detection highest in endocrine organs and lowest in affected skin. GeneReviews also states that prenatal testing for FD/MAS is not indicated because the condition results from a postzygotic somatic variant and is not inherited.

Treatment coverage is not certified in this packet. The packet lists no approved treatments and no foundational therapies. Its one orphan drug record, sermorelin acetate with status WITHDRAWN, carries an indication unrelated to this condition and is not a current option for it. The GeneReviews management text in the packet describes evaluations following initial diagnosis rather than therapies. It states that individuals with FD/MAS are evaluated to determine the extent of disease, and lists total body bone scintigraphy, radiographs or CT of identified lesions, and baseline ophthalmologic, otolaryngologic, and audiologic evaluations for craniofacial FD. For endocrine features, it lists biochemical screening for hyperthyroidism, growth hormone excess, and FGF23-mediated hypophosphatemia, and thyroid and testicular ultrasound. The GeneReviews surveillance section describes evaluations tailored to age and known affected organ systems, including routine orthopedic assessment of skeletal findings.

Prognosis is not certified in this packet as an overall estimate, because the packet contains no natural history field. The GeneReviews clinical description states that the course varies widely, from asymptomatic findings to neonatal lethality, and that outcome depends on when during embryogenesis the somatic variant arose and which tissues it affects. It describes progressive scoliosis as one of the few FD features that can lead to early morbidity, and reports that FD lesions typically become less active in adulthood.

The packet lists five ClinicalTrials.gov records matched to McCune-Albright syndrome, and a trial title does not establish what an intervention does. NCT05966064 is a Phase 4 trial whose title refers to denosumab for fibrous dysplasia/McCune-Albright syndrome in adults, sponsored by Natasha Appelman-Dijkstra (recruiting, start 2023-06-13). NCT00001727, sponsored by the National Institute of Dental and Craniofacial Research, is a screening and natural history study (recruiting, start 1998-12-13). NCT03231644 is a patient registry (recruiting, start 2016-10-31), and NCT07507942, from Hospices Civils de Lyon, concerns assessment of femoral failure load and fracture risk in fibrous dysplasia/McCune-Albright syndrome (active, not recruiting, start 2025-03-10). The packet lists the FD/MAS Alliance as a patient organization.