McCune-Albright syndrome

McCune-Albright syndrome is a rare, mosaic genetic condition that can affect the skin, skeleton and endocrine system.

• 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.
• 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.
• Variable endocrine dysfunction, which can be clinically diagnosed in the presence of two or more of the following features:
  • precocious puberty (found 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;
  • 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.

For information about testing, see Presentation: 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.

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 Disease 2019: volume 14. DOI: 10.1186/s13023-019-1102-9

For patients

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