SEVERE ENDOCRINE AND NONENDOCRINE MANIFESTATIONS OF THE MCCUNE-ALBRIGHT SYNDROME-ASSOCIATED WITH ACTIVATING MUTATIONS OF STIMULATORY G-PROTEIN G(S)

McCune-Albright syndrome (MCAS) is a sporadic disease classically incl uding polyostotic fibrous dysplasia, cafe au lait spots, sexual precoc ity, and other hyperfunctional endocrinopathies. An activating missens e mutation in the gene for the alpha subunit of G(s), the G protein th at stimulates cyclic adenosine monophosphate formation, has been repor ted to be present in these patients. The mutation is found in variable abundance in different affected endocrine and nonendocrine tissues, c onsistent with the mosaic distribution of abnormal cells generated by a somatic cell mutation early in embryogenesis. We describe three pati ents with MCAS who had profound endocrine and nonendocrine-disease and who died in childhood. Two of the patients were severely ill neonates whose complex symptoms did not immediately suggest MCAS. A mutation o f residue Arg201 of G(s)alpha was found in affected tissues from all t hree children. A review of the literature and unpublished case histori es emphasizes the existence of other patients with severe and unusual clinical manifestations. We conclude that the manifestations of MCAS a re more extensive than is generally appreciated, and may include hepat obiliary disease, cardiac disease, other nonendocrine abnormalities, a nd sudden or premature death.