title: Genetics of primary macronodular adrenal hyperplasia.
abstract: ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term 'ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression.
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada maria.villares@hc.fm.usp.br.
authors.forename: Maria Candida Barisson Villares
authors.initials: MC
authors.lastname: Fragoso
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Guilherme Asmar
authors.initials: GA
authors.lastname: Alencar
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Antonio Marcondes
authors.initials: AM
authors.lastname: Lerario
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourdeau
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Madson Queiroz
authors.initials: MQ
authors.lastname: Almeida
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Berenice Bilharinho
authors.initials: BB
authors.lastname: Mendonca
authors.affiliation: Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Lacroix
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000235:genetics; D000302:Adrenal Cortex / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002864:Chromogranins; D003480:Cushing Syndrome / Q000150:complications / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018761:Multiple Endocrine Neoplasia Type 1 / Q000150:complications / Q000235:genetics; D009154:Mutation; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D002864:Chromogranins; D044103:Receptor, Melanocortin, Type 2; D000324:Adrenocorticotropic Hormone; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: adrenal cortex; adrenal hormones; gene expression; molecular genetics; mutations