Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene.
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 alpha) (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 Arg(201) 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.
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM-42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 01060-970. mariofragoso@uol.com.br
Maria Candida Barisson Villares
MC
Fragoso
Sorahia
S
Domenice
Ana Claudia
AC
Latronico
Regina Matsunaga
RM
Martin
Maria Adelaide Albergaria
MA
Pereira
Maria Claudia Nogueira
MC
Zerbini
Antonio Marmo
AM
Lucon
Berenice Bilharinho
BB
Mendonca
D000308:Adrenocortical Hyperfunction / Q000235:genetics*; D000324:Adrenocorticotropic Hormone; D000328:Adult; D003480:Cushing Syndrome / Q000209:etiology*; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D000324:Adrenocorticotropic Hormone; D019205:GTP-Binding Protein alpha Subunits, Gs