Faucz Fabio R, Zilbermint Mihail, Lodish Maya B, Szarek Eva, Trivellin Giampaolo, Sinaii Ninet, Berthon Annabel, Libé Rossella, Assié Guillaume, Espiard Stéphanie, Drougat Ludivine, Ragazzon Bruno, Bertherat Jerome, Stratakis Constantine A
Section on Endocrinology and Genetics (F.R.F., M.Z., M.B.L., E.S., G.T., A.B., C.A.S.), Program on Developmental Endocrinology and Genetics, Program on Reproductive and Adult Endocrinology (M.Z.), Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Group for Advanced Molecular Investigation (F.R.F.), Graduate Program in Health Science, Center for Biological and Sciences, Pontificia Universidade Catolica do Paraná, Curitiba Brazil 80215-901; Department of Endocrinology, Metabolism, and Cancer (R.L., G.A., S.E., L.D., B.R., J.B.), INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France.
J Clin Endocrinol Metab. 2014 Jun;99(6):E1113-9. doi: 10.1210/jc.2013-4280. Epub 2014 Mar 6.
Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH).
We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared.
Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed.
Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002).
ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.
最近已确定，可能的肿瘤抑制基因含犰狳重复序列5（ARMC5）的种系失活突变是大结节性肾上腺增生（MAH）的一个遗传病因。
我们在一大群MAH患者中寻找ARMC5突变。比较了有和没有ARMC5突变患者的临床表型。
采用桑格测序法对34例MAH患者的血液DNA进行基因分型。评估了昼夜血清皮质醇测量值、血浆促肾上腺皮质激素（ACTH）水平、尿类固醇、为期6天的利德尔试验、肾上腺计算机断层扫描以及肾上腺切除术中肾上腺的重量。
34例患者中有15例（44.1%）发现种系ARMC5突变。对这些突变的计算机分析表明，7个（20.6%）预测对基因功能有重大影响。与没有和/或有非致病性突变的患者相比，具有ARMC5破坏性突变的患者午夜皮质醇水平更高（14.5±5.6对6.7±4.3，P<.001）。所有携带致病性ARMC5突变的患者均有临床库欣综合征（7例中的7例，100%），而没有或有预测为良性突变的患者中，27例中有14例（52%）有临床库欣综合征（P = .029）。重复测量分析显示，在为期6天的利德尔试验中，具有ARMC5破坏性突变的患者尿17-羟皮质类固醇和游离皮质醇值总体上更高（P = .0002）。
ARMC5突变与伴有MAH的临床严重库欣综合征有关。了解患者的ARMC5状态对库欣综合征的诊断以及患者及其家属的遗传咨询具有重要的临床意义。
