Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors
Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors
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DOI：
10.1210/jc.2009-0516
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发表时间：
2009-08-01
影响因子：
5.8
通讯作者：
Stratakis, Constantine A.
中科院分区：
文献类型：
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作者：
Hsiao, Hui-Pin;Kirschner, Lawrence S.;Stratakis, Constantine A.
目的：ACTH非依赖性大结节肾上腺增生症(AIMAH)常与亚临床皮质醇分泌或不典型库欣综合征(CS)相关。设计和患者：我们收集了82例AIMAH患者，包括：1)AIMAH(n=16)；2)肾上腺皮质激素腺瘤伴CS(n=15)；3)醛固酮腺瘤(n=19)；以及4)单腺瘤(n=32)，临床无明显皮质醇分泌(n=32)。结果：AIMAH患者的17OHS排泄量最高，即使UFC在或接近正常范围。异常的受体表达非常普遍。组织学检查显示AIMAH至少有两种亚型。对于3例AIMAH患者，有CS家族史；在另外3例患者中发现脑膜素(1例)、富马酸水合酶(1例)和结肠腺瘤病(APC)(1例)基因的胚系突变；另1例发现PDE11A基因变异。1例患者仅肾上腺结节有GNAS突变。结论：AIMAH是一种临床和遗传异质性疾病，可能与多种遗传缺陷和激素受体异常有关。它经常与不典型的CS和17OHS增加有关；UFCs和其他肾上腺皮质活动的测量可能是误导性的正常。(临床内分泌代谢酶94：2930-2937,2009)
Objective: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often associated with subclinical cortisol secretion or atypical Cushing's syndrome (CS). We characterized a large series of patients of AIMAH and compared them with patients with other adrenocortical tumors.Design and Patients: We recruited 82 subjects with: 1) AIMAH (n = 16); 2) adrenocortical cortisol-producing adenoma with CS (n = 15); 3) aldosterone-producing adenoma (n = 19); and 4) single adenomas with clinically nonsignificant cortisol secretion (n = 32).Methods: Urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17OHS) were collected at baseline and during dexamethasone testing; aberrant receptor responses was also sought by clinical testing and confirmed molecularly. Peripheral and/or tumor DNA was sequenced for candidate genes.Results: AIMAH patients had the highest 17OHS excretion, even when UFCs were within or close to the normal range. Aberrant receptor expression was highly prevalent. Histology showed at least two subtypes of AIMAH. For three patients with AIMAH, there was family history of CS; germline mutations were identified in three other patients in the genes for menin (one), fumarate hydratase (one), and adenomatosis polyposis coli (APC) (one); a PDE11A gene variant was found in another. One patient had a GNAS mutation in adrenal nodules only. There were no mutations in any of the tested genes in the patients of the other groups.Conclusions: AIMAH is a clinically and genetically heterogeneous disorder that can be associated with various genetic defects and aberrant hormone receptors. It is frequently associated with atypical CS and increased 17OHS; UFCs and other measures of adrenocortical activity can be misleadingly normal. (J Clin Endocrinol Metab 94: 2930-2937, 2009)