Pathophysiology[edit]

Fibrous dysplasia is a mosaic disease resulting from post-zygotic activating mutations of the
GNAS locus at 20q13.2-q13.3, which codes for the subunit of the Gs G-coupled protein
receptor.[3] In bone, constitutive Gs signaling results in impaired differentiation and proliferation
of bone marrow stromal cells.[4] Proliferation of these cells causes replacement of normal bone
and marrow with fibrous tissue. The bony trabeculae are abnormally thin and irregular, and often
likened to Chinese characters (bony spicules on biopsy).
Fibrous dysplasia is not hereditary, and there has never been a case of transmission from parent
to child.
Molecular/Genetics

Fibrous dysplasia is caused by a somatic mutation in the GNAS1 gene located on chromosome
20q13.2-13.3, which encodes the alpha subunit of the stimulatory G protein, Gs.[13] As a
consequence of this mutation, there is a substitution of amino acid arginine in position 201
(R201) of the genomic DNA in the osteoblastic cells, by amino acid cysteine (R201C) or
histidine (R201H).
The abnormal G1 protein stimulates cyclic adenosine monophosphate (AMP), and the
osteoblastic cells expressing this mutation have a higher rate of DNA synthesis than normal cells.
[13]
This abnormal growth leads to the formation of a disorganized fibrotic bone matrix with
primitive bone formation, and lack of maturation to lamellar bone. Mineralization is also
abnormal. There is a failure of the bone to align in response to mechanical stress. This defect is
seen in the monostotic as well as the polyostotic forms of fibrous dysplasia. The extent of disease
is related to the stage at which the postzygotic mutation in Gs has occurred, whether during
embryonic development or postnatally.
A meta-analysis found an overall positive rate of GNAS mutation in 71.9% of fibrous dysplasia
cases. The major types of mutations were the missense mutations of R201H and R201C,
although at least one new site of mutation was revealed at codon 224 (V224A). Mutation was
more commonly seen in tubular bone lesions than in flat bone lesions.[14]
Tabareau-Delalande et al evaluate the sensitivity and specificity of GNAS mutations in fibrous
dysplasia, to assess the value of investigating this mutation in the diagnosis of fibro-osseous
lesions. They studied 91 cases of fibrous dysplasia. Twenty-three cases of fibrous dysplasia
(45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found
on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the
same proportion (47%) as in the other histological subtypes (47%, P=0.96), regardless of sex,
age and location. GNAS mutations were not detected in any other fibro-osseous lesions. The
GNAS mutation was found to be specific to fibrous dysplasia. The particular mosaicism of

mutant and non-mutant cells within the lesion or the existence of other mutations not already
described could explain the lack of GNAS mutation in cases of fibrous dysplasia. The authors
concluded that investigating this mutation may constitute a valuable
complementarydiagnostictool, despite its low sensitivity, particularly in unconventional
morphologically different subtypes of fibrous dysplasia.[15]