Charchar Helaine Laiz Silva, Fragoso Maria Candida Barisson Villares
Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular (LIM/42), Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil.
J Endocr Soc. 2022 Mar 17;6(5):bvac041. doi: 10.1210/jendso/bvac041. eCollection 2022 May 1.
Primary macronodular adrenal hyperplasia (PMAH) is considered a rare cause of adrenal Cushing syndrome, is pituitary ACTH-independent, generally results from bilateral adrenal macronodules (>1 cm), and is often associated with variable cortisol secretion, resulting in a heterogeneous clinical presentation. Recent advances in the molecular pathogenesis of PMAH have offered new insights into the comprehension of this heterogeneous and complex adrenal disorder. Different molecular mechanisms involving the actors of the cAMP/protein kinase A pathway have been implicated in the development of PMAH, including germline and/or somatic molecular defects such as hyperexpression of the G-protein aberrant receptors and pathogenic variants of , , , and . Nevertheless, since 2013, the gene is believed to be a major genetic cause of PMAH, accounting for more than 80% of the familial forms of PMAH and 30% of apparently sporadic cases, except in food-dependent Cushing syndrome in which is not involved. Recently, 2 independent groups have identified that the tumor suppressor gene is responsible for PMAH associated specifically with food-dependent Cushing syndrome. Consequently, PMAH has been more frequently genetically associated than previously assumed. This review summarizes the most important aspects, including hormone secretion, clinical presentation, radiological imaging, and molecular mechanisms, involved in familial Cushing syndrome associated with PMAH.
原发性大结节性肾上腺增生（PMAH）被认为是肾上腺库欣综合征的罕见病因，不依赖垂体促肾上腺皮质激素（ACTH），通常由双侧肾上腺大结节（>1cm）引起，且常伴有皮质醇分泌变化，导致临床表现异质性。PMAH分子发病机制的最新进展为理解这种异质性和复杂性肾上腺疾病提供了新的见解。涉及环磷酸腺苷/蛋白激酶A途径相关因子的不同分子机制与PMAH的发生有关，包括种系和/或体细胞分子缺陷，如G蛋白异常受体的过度表达以及、、和的致病变异。然而，自2013年以来，基因被认为是PMAH的主要遗传原因，除了与食物依赖型库欣综合征无关外，它占PMAH家族形式的80%以上以及明显散发病例的30%。最近，两个独立的研究小组发现肿瘤抑制基因与特定的食物依赖型库欣综合征相关的PMAH有关。因此，PMAH在遗传上的相关性比以前认为的更为常见。本综述总结了与PMAH相关的家族性库欣综合征所涉及的最重要方面，包括激素分泌、临床表现、放射影像学和分子机制。
