Cushing’s Syndrome Secondary to Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia due to Activating Mutations of GNAS1 Gene
Maria Candida Barisson Villares Fragoso,
Sorahia Domenice,
Ana Claudia Latronico,
Regina Matsunaga Martin,
Maria Adelaide Albergaria Pereira,
Maria Claudia Nogueira Zerbini,
Antonio Marmo Lucon and
Berenice Bilharinho Mendonca
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) isan uncommon cause of Cushing’s syndrome characterizedby bilateral nodular adrenocortical hyperfunction in the presenceof suppressed ACTH levels. We investigated whether activatingmutations in the ACTH receptor (MC2-R) or Gs (GNAS1) genes mightbe involved in AIMAH genesis. Five women with Cushing’ssyndrome due to AIMAH, confirmed by histological studies, andno signs of McCune-Albright syndrome were selected for molecularanalysis of these genes. The single exon of the MC2-R gene andexons 8 and 9 of the GNAS1 gene were amplified by PCR in genomicDNA from adrenal nodules and peripheral blood. Direct sequencingrevealed only MC2-R wild-type sequences. GNAS1 PCR productsat denaturing gradient gel electrophoresis revealed abnormalmigration patterns in adrenal tissues of three patients. Automaticsequencing showed two different activating mutations at codonArg201 of GNAS1, a substitution by histidine in two cases andby serine in one case.
In conclusion, we found two different gsp mutations in threepatients with Cushing’s syndrome due to AIMAH, and wespeculate whether they belong to the spectrum of McCune-Albrightsyndrome or whether these are the first reported cases of AIMAHdue to gsp mutations.
Fundação de Amparo à Pesquisa do Estadode São Paulo supported M.C.B.V.F. (00/00856-2) and B.B.M.(00/14338-3). Conselho Nacional de Amparo a Pesquisa provideda personal grant to A.C.L. (300151/96-9) and B.B.M. (301246/95-5).
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(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. 
