What causes the classic triad of features in McCune-Albright syndrome?

Updated: Jan 17, 2019
  • Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD  more...
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Answer

The classic triad of features in MAS—PFD, autonomous endocrine hyperfunction, and café-au-lait skin pigmentation—can all be explained by activation of the Gs alpha subunit and increased intracellular cAMP levels.

Eumelanogenesis (formation of brown/black pigment) is normally stimulated by melanocyte-stimulating hormone (MSH) binding to the MSH receptor, a classic G protein receptor coupled to Gs alpha. Constitutive activation of the Gs alpha subunit in melanocytes results in the increase in brown pigmentation characteristic of the café-au-lait spots seen in the syndrome. Likewise, both the luteinizing hormone (LH) and the follicle-stimulating hormone (FSH) receptors are Gs alpha−coupled receptors.

Constitutive activation of the postreceptor cAMP signaling cascade in ovarian follicular cells results in cyst formation, estrogen production, and gonadotropin-independent precocious puberty. Similar mechanisms of increased intracellular cAMP likely explain essentially all of the other endocrine and nonendocrine features of MAS.

Because MAS results from a postzygotic somatic mutation, all the daughter cells of the embryonic cell in which the initial mutation occurred also contain the mutation. The earlier the mutation occurs in embryogenesis, the more widespread the tissue involvement.

Mutations late in embryogenesis are more focused and account for those mild cases in which only 2 or 3 of the classic phenotypic features of the syndrome are present. If the mutation occurs very late in tissue development after differentiation into a specific cell line, then a single adenoma may result. Gs alpha−activating mutations have been reported in isolated hyperfunctioning thyroid nodules and in somatotroph adenomas.

Although GNAS1 mutations could occur in germ cells (either oocytes or spermatocytes), the resulting zygote and all daughter cells then would contain the mutation. Activating GNAS1 mutations are likely lethal if they occur very early in embryogenesis. This accounts for the lack of autosomal dominant transmission of this syndrome.


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