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Cushing’s Syndrome Secondary to Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia due to Activating Mutations of GNAS1 Gene

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM-42 (M.C.B.V.F., S.D., A.C.L., R.M.M., M.A.A.P., B.B.M.), Departamento de Anatomia Patológica (M.C.N.Z.), and Departamento de Urologia do Hospital das Clínicas (A.M.L.), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 01060-970

Address all correspondence and requests for reprints to: Maria Candida Barisson Villares Fragoso, M.D., Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, Caixa Postal: 3671, São Paulo 01060-970, Brazil. E-mail: mariafragoso{at}uol.com.br.

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an uncommon cause of Cushing’s syndrome characterized by bilateral nodular adrenocortical hyperfunction in the presence of suppressed ACTH levels. We investigated whether activating mutations in the ACTH receptor (MC2-R) or G_s (GNAS1) genes might be involved in AIMAH genesis. Five women with Cushing’s syndrome due to AIMAH, confirmed by histological studies, and no signs of McCune-Albright syndrome were selected for molecular analysis of these genes. The single exon of the MC2-R gene and exons 8 and 9 of the GNAS1 gene were amplified by PCR in genomic DNA from adrenal nodules and peripheral blood. Direct sequencing revealed only MC2-R wild-type sequences. GNAS1 PCR products at denaturing gradient gel electrophoresis revealed abnormal migration patterns in adrenal tissues of three patients. Automatic sequencing showed two different activating mutations at codon Arg²⁰¹ of GNAS1, a substitution by histidine in two cases and by serine in one case.

In conclusion, we found two different gsp mutations in three patients with Cushing’s syndrome due to AIMAH, and we speculate whether they belong to the spectrum of McCune-Albright syndrome or whether these are the first reported cases of AIMAH due to gsp mutations.

Fundação de Amparo à Pesquisa do Estado de São Paulo supported M.C.B.V.F. (00/00856-2) and B.B.M. (00/14338-3). Conselho Nacional de Amparo a Pesquisa provided a personal grant to A.C.L. (300151/96-9) and B.B.M. (301246/95-5).

Abbreviations: AIMAH, ACTH-independent macronodular adrenal hyperplasia; DGGE, denaturing gradient gel electrophoresis; MAS, McCune-Albright syndrome.

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