McCune-Albright syndrome

McCune-Albright syndrome is a rare sporadic condition typically presenting in infancy or early childhood, classically with polyostotic fibrous dysplasia, café-au-lait skin macules with irregular borders, and endocrinopathies – most commonly precocious puberty in girls. Other endocrine features may include hyperthyroidism, growth hormone excess and hypercortisolism. The underlying genetic cause is a post-zygotic (non-inherited), somatic activating variant in the GNAS gene, resulting in mosaicism.

Clinical features of McCune-Albright syndrome include the following.

• Café-au-lait macules with an irregular (often described as ‘coast of Maine’) border. These may be isolated to one side of the midline, or follow ‘lines of Blaschko’, reflecting mosaicism. They are usually present at birth.
• Fibrous dysplasia: fibro-osseous tissue replaces normal bone, resulting in an increased risk of fractures, deformity, impaired function and/or pain. This can involve any part or combination of the craniofacial, axial and/or appendicular skeleton. Onset is usually early childhood.
• Precocious puberty is seen in around 50% of females and some males. This is gonadotropin independent and is caused by ovarian cysts in females and autonomous testosterone release in males. Onset is typically before five years of age and usually presents as vaginal bleeding in females.
• Variable endocrine dysfunction, which can be clinically diagnosed in the presence of two or more of the following features:
  • precocious puberty;
  • testicular lesions (with or without gonadotropin-independent precocious puberty);
  • thyroid lesions (with or without non-autoimmune hyperthyroidism);
  • growth hormone excess;
  • FGF23-mediated phosphate wasting with or without hypophosphataemia; and
  • neonatal hypercortisolaemia.

The causative gene in McCune-Albright syndrome, GNAS, provides an instruction for G protein signalling, which influences hormone regulation and many cell functions.

Individuals with McCune-Albright syndrome have activating (gain-of-function) pathogenic variants in GNAS, which increase activity of the G protein. The pathogenic variants arise in somatic cells in early embryonic development. This causes mosaicism, with some cells carrying a functioning copy of GNAS and others carrying the pathogenic GNAS variant. Disease severity is likely influenced by the extent of this mosaicism, rather than the individual variant.

The diagnosis ofMcCune-Albright syndrome is based on the finding of two or more typical clinical features, as mentioned above.

In individuals in which the only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating pathogenic variant in GNAS is required to establish the diagnosis.

Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the test method. The molecular diagnostic yield increases when testing an affected area (for example, analysis of a skin biopsy taken from an affected area).

For information about genomic testing, see Clinical suspicion of McCune-Albright syndrome.

McCune-Albright syndrome is sporadic. Vertical transmission has never been reported. The risk for siblings is the same as for the general population.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Managing McCune-Albright syndrome in children is complex and should be delivered via a multidisciplinary team, with detailed suggested approaches published by several authors (see the resources list below). Screening for all clinical manifestations of the condition is recommended, together with ongoing surveillance.

For clinicians

• GeneReviews: Fibrous dysplasia/McCune-Albright syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Javaid MK, Boyce A, Appelman-Dijkstra and others. ‘Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: A consensus statement from the FD/MAS international consortium‘. Orphanet Journal of Rare Diseases 2019: volume 14. DOI: 10.1186/s13023-019-1102-9

For patients

• Contact UK: McCune-Albright syndrome
• Fibrous Dysplasia Support Society