McCune-Albright Syndrome and Disorders Due to Activating Mutations of GNAS1

Abstract

It has been more than seven decades since Drs. Fuller Albright and Donovan McCune published the first reports on individuals with McCune-Albright syndrome (MAS). Since then, the classic triad of precocious puberty, café-aulait spots, and polyostotic bone dysplasia continues to define the syndrome. However, having gathered a better picture of the pathophysiology of MAS, the way this condition is understood has changed. Isolated activating mutations of the alpha subunit of the G protein (GNAS1) have been found in different tissues, including pituitary adenomas, thyroid adenomas, ovarian cysts, monostotic bone dysplasia, and the adrenal glands, to name a few. For this reason, we have added 'and disorders due to activating mutations of GNAS1' to the title of this review. We discuss here the clinical consequences of GNAS1 activating mutations in different body systems and organs, the diagnostic approach to MAS, and the current therapeutic recommendations.

A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex

“…7 -11 Adrenocortical hyperplasia in the presence of a partially inactivated PDE is likely to be caused by high cellular cAMP levels in a manner analogous to endocrine tumor formation in McCune -Albright syndrome. 7,12 The GWA study identified a number of other chromosomal loci as potentially linked to the development of iMAD. Among them, the chromosomal locus 5q13 containing the gene for a cAMP-specific PDE, PDE8B, was the second most favored by all analyses, including loss of heterozygosity and transmission disequilibrium testing 7 , supplementary data available at http://www.…”

Fibrous Dysplasia

“…The gene is located on band 20q13, an area that codes for the a subunit on G-protein receptors. 1,[10][11][12][13][14][15][16] This mutation is also present in various endocrine tumors as well as FD. The G-proteins begin a cascade that ultimately leads to activation of the enzyme adenylyl cyclase that produces cAMP.…”

“…In MAS, there is a missense mutation that causes the substitution of arginine in position 201 of the Gs-a gene. [11][12][13] Normally, there is an almost immediate deactivation of adenylyl cyclase and a break down of the cAMP. In MAS, that does not occur.…”

“…Similarly, most of the endocrine problems associated with MAS can be related to Gs-a activation. 11 In addition, activating Gs-a mutations have been shown to potentiate WNT/b-catenin signaling, and removal of Gs-a leads to reduced WNT/b-catenin signaling and decreased bone formation ( Figure 2). Activation of WNT/b-catenin signaling in osteoblast progenitors causes an FD-like phenotype and reduction of b-catenin levels rescued differentiation defects of stromal cells derived from patients with FD.…”

The Use of Real Time PCR Genotyping to Detect Activating GNAS Mutations in McCune-Albright Syndrome

“…However only patient's affected organs carry a significant percentage of mutant cells and these tissues are not always available (4). A low percentage of mutated cells may be present in peripheral blood and could be used in the identification of GNAS-activating mutations leading to earlier diagnosis in patients with partial forms of MAS [8][9][10]. Nevertheless, this is only realistic if an accurate and sensitive assay for mosaic mutations detection is available.…”