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Thyroid Carcinoma in the McCune-Albright Syndrome: Contributory Role of Activating G_s Mutations

Craniofacial and Skeletal Diseases Branch (M.T.C., P.G.R.), National Institute of Dental and Craniofacial Research, Division of Intramural Research (N.J.S., L.C.G.), National Institute of Diabetes Digestive and Kidney Diseases, Laboratory of Pathology (M.J.M.), National Cancer Institute, and Developmental Endocrinology Branch (S.B.), National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4320; Phoenix Epidemiology and Clinical Research Branch (J.A.K.), National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Phoenix, Arizona 85016; Department of Pediatrics (J.M., A.S.), Children’s Memorial Hospital, Chicago, Illinois 60614; and Department of Pathology (S.E.C.), Northwestern University, The Feinberg School of Medicine, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Michael T. Collins, M.D., Skeletal Clinical Studies Unit, CSDB, National Institute of Dental and Craniofacial Research/National Institutes of Health, Building #30, Room 228, MSC 4320, Bethesda, MD 20892-4320. E-mail: mc247k{at}nih.gov; or Nicholas J. Sarlis, M.D., Ph.D., Department of Endocrine Neoplasia and HD, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 435, Houston, Texas 77030-4009. E-mail: njsarlis{at}mdanderson.org.

McCune-Albright syndrome (MAS) is defined by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, such as precocious puberty, hyperthyroidism, GH excess, and Cushing’s syndrome. This disorder is caused by sporadic, postzygotic activating mutations in the GNAS1 gene, which codes for the G_s protein in the cAMP signaling cascade. Nodular and diffuse goiters (with and without hyperthyroidism), as well as benign thyroid nodules, have been reported in association with MAS. Herein we report two cases of thyroid carcinoma in patients with MAS. The first is a case of papillary thyroid cancer detected incidentally during a hemithyroidectomy for hyperthyroidism in a 14-yr-old girl. The second is one of a 41-yr-old woman with long-standing MAS and an enlarging thyroid nodule, which was diagnosed as a clear cell thyroid carcinoma, a rare variant of thyroid cancer. Molecular analysis revealed that foci of malignancy and adjacent areas of hyperplasia and some areas of normal thyroid harbored activating mutations of Arg²⁰¹ in the GNAS1 gene. These findings suggest that the infrequent development of thyroid carcinoma in MAS patients involves additional mutational or epigenetic events.

This paper was presented in part at the 81^st Annual Meeting of The Endocrine Society, San Diego, California, June 1999, and the 82^nd Annual Meeting of The Endocrine Society, Toronto, Ontario, Canada, June 2000.

M.T.C. and N.J.S. contributed equally to this work.

Current address for A.S.: Clinical Discovery, Bristol-Myers Squibb Co., P.O. Box 4000, Princeton, New Jersey 08543.

This work was supported in part by NIH Grant CA-78436. A.S. is the Crown Family Research Scholar in Developmental Systems Biology and a member of the Robert H. Lurie Comprehensive Cancer Center.

Abbreviations: LT4, Levothyroxine; MAS, McCune-Albright syndrome; PTC, papillary thyroid carcinoma; Tg, thyroglobulin; WBS, whole-body scan.

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