McCune–Albright syndrome (MAS) is a nonheritable disorder classically characterized by the triad of polyostotic fibrous dysplasia (POFD), café-au- lait spots, and sexual precocity. Somatic gain-of-function mutations in the GNAS1 locus on 20q13.2-q13.3 have been described in affected tissues. Since these mutations arise post-zygotically, affected individuals are considered somatic mosaics.
POFD is characterized by fibrous tissue proliferation with the destruction of bone, leading to pathological fractures and pseudoarthroses. The diagnosis of McCune–Albright syndrome is usually clinically obvious and is confirmed by excess circulating levels of one or more hormones (thyroid hormone, cortisol, growth hormone, or estrogen) in the absence of the respective stimulating hormones. Fibrous dysplasia is usually diagnosed by its characteristic ground-glass (but occasionally sclerotic) appearance on X-ray, although it can be confused with osteofibrous dysplasia or hyperparathyroidism–jaw Tumours syndrome (Hammami et al. 1997; Weinstein et al. 2002). Deafness and blindness may result from pressure within the cranial foramina. In addition, café-au-lait patches, with irregular borders, and multiple endocrinopathies occur. The most frequent endocrine disturbances are precocious puberty, especially in females, but thyroid dysfunction, hyperparathyroidism, acromegaly, Cushing syndrome, or hyperprolactinemia may occur.
Osteosarcomatous transformation in areas of fibrous dysplasia has been described as a complication of this condition (Taconis 1988). Recently, four patients with severe McCune–Albright syndrome (two of whom had perioral freckling reminiscent of Peutz–Jeghers syndrome and three of whom had a detectable GNAS1 mutation in peripheral blood) were found to harbor multiple hamartomatous gastrointestinal polyps in the stomach and/or duodenum. The authors suggested that gastrointestinal polyps may be frequent in patients with McCune–Albright syndrome (Zacharin et al. 2011).
It had been suggested that this disorder might be caused by somatic mutations in an autosomal dominant lethal gene, which would only be compatible with survival if present in mosaic form (Happle 1989). Subsequently, mutations in the GNAS1 gene that encodes a subunit of the stimulatory G protein GS alpha were identified (Weinstein et al. 1991). It has been postulated that somatic mutations of this type occur early in embryogenesis and result in a mosaic population of cells, which would explain the sporadic occurrence and variable abnormalities in this syndrome (Marie et al. 1997). Subsequent to the initial description of somatic mosaic GNAS1 mutations in this syndrome, alternative exons with multiple transcripts and imprinting were described (Weinstein et al. 2002; Rickard and Wilson 2003). Loss of exon 1A imprinting causes pseudohypoparathyroidism type Ib (Weinstein et al. 2002). GNAS1 is biallelically expressed in most human tissues, but shows exclusive or preferential expression from the maternal allele in some tissues, including pituitary, thyroid, and ovary (Weinstein et al. 2002). In pituitary Tumours that harbor an activating GNAS1 mutation, the mutation almost always occurs on the maternal allele (Weinstein et al. 2002). Therefore the clinical manifestations observed in each McCune–Albright syndrome patient might be affected by which parental allele harbors the GNAS1 gene mutation.
Since McCune–Albright syndrome and POFD result from somatic mosaic mutations, and not germline mutations, in GNAS1, these syndromes are virtually never inherited. Patients with fibrous dysplasia should not be treated with radiation, as it is ineffective and may increase the risk for malignant transformation. It would be prudent for all POFD patients to be screened for endocrine manifestations of McCune–Albright syndrome.