# The GNAS Gene: Fibrous Dysplasia, McCune–Albright Syndrome, and Skeletal Structure and Function

## TL;DR

This review explores the GNAS gene's role in McCune–Albright Syndrome and fibrous dysplasia, focusing on skeletal effects and treatment strategies.

## Contribution

The paper provides a comprehensive overview of the molecular and biomechanical aspects of FD/MAS, comparing them to other skeletal diseases.

## Key findings

- Gsα signaling from GNAS mutations causes fibrous dysplasia and diverse MAS symptoms.
- FD leads to skeletal deformities and increased fracture risk due to fibro-osseous tissue replacement.
- Biomechanical skeletal changes in FD/MAS differ from those in osteoporosis and Paget’s disease.

## Abstract

McCune–Albright Syndrome (MAS) is a rare mosaic disorder caused by somatic activating mutations of the GNAS gene, resulting in constitutive Gsα signaling and a broad spectrum of clinical phenotypes. The syndrome typically presents with fibrous dysplasia (FD) of bone, café-au-lait macules, and endocrinopathies such as gonadotropin-independent precocious puberty, hyperthyroidism, and/or growth hormone excess. FD, which characterizes the skeletal phenotype, results in the replacement of normal bone with disorganized fibro-osseous tissue, often leading to pain, deformities, and increased risk of fractures. This review discusses the following: 1. The molecular biology of the GNAS locus and its relation to the pathophysiology of FD/MAS; 2. The skeletal manifestations of FD/MAS; 3. Bone biomechanics and organizational skeletal aberrations observed in FD/MAS; and 4. Current and future therapeutic strategies for patients with FD/MAS. While there is much current literature available regarding FD/MAS, this review specifically aims to outline core understandings and summarize some of the latest investigations into the genotypic and phenotypic foundations of the disorders, while shedding new light on the biomechanical aberrations observed in skeletal structure within them and comparing them to those observed in related disease processes such as osteoporosis and Paget’s disease.