Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10#, Changjiang Zhilu, Yuzhong District, Chongqing, 400042, People's Republic of China.
Geneplus-Beijing Institute, Beijing, 102206, People's Republic of China.
BMC Med Genet. 2018 Mar 27;19(1):49. doi: 10.1186/s12881-018-0564-2.
Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS). BMAH is predominantly believed to be caused by two mutations, a germline and somatic one, respectively, as described in the two-hit hypothesis. In many familial cases of BMAH, mutations in armadillo repeat containing 5 (ARMC5), a putative tumor suppressor gene, are thought to induce the disorder. The objective of this study was to report a case in which the patient presented with BMAH induced by a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) alone rather than a two-hit mutation.
A 51-year-old woman was identified with masses in the bilateral adrenals. Serum cortisol levels were increased significantly both in the morning (08:00 AM) and late at night (24:00 AM), while plasma adrenocorticotropic hormone was normal. The patient underwent a left adrenalectomy and histopathology substantiated the BMAH diagnosis. WES of the germline DNA discovered a novel heterozygous germline ARMC5 mutation (c. 517C > T, p. Arg173*) and in silico analysis predicted that the mutation significantly impaired protein function, resulting in inactivated ARMC5. Subsequently, WES of the tumor specimen identified 79 somatic single nucleotide polymorphisms (SNPs)/insertion-deletion (indel) mutations, including 32 missense/nonsense/splice/stop-loss mutations. None of these mutations were CS-related.
A novel germline ARMC5 mutation (c. 517C > T, p. Arg173*) was identified that induced BMAH alone without a second mutation. ARMC5 sequencing may improve the identification of clinical forms of BMAH and allow earlier diagnosis of this disease.
双侧结节性肾上腺增生（Bilateral Macronodular Adrenal Hyperplasia，BMAH）是库欣综合征（Cushing's syndrome，CS）的罕见病因。BMAH 主要被认为是由两个突变引起的，分别是胚系突变和体细胞突变，正如双打击假说所描述的那样。在许多家族性 BMAH 病例中，认为携带假定肿瘤抑制基因 armadillo repeat containing 5（ARMC5）的突变会引发这种疾病。本研究的目的是报告一例由新型杂合胚系 ARMC5 突变（c.517C>T，p.Arg173*）引起的 BMAH 病例，而非双打击突变。
一名 51 岁女性被发现双侧肾上腺有肿块。清晨（08:00 AM）和深夜（24:00 PM）的血清皮质醇水平显著升高，而血浆促肾上腺皮质激素正常。患者接受了左侧肾上腺切除术，组织病理学证实了 BMAH 的诊断。对胚系 DNA 的 WES 发现了一种新型杂合胚系 ARMC5 突变（c.517C>T，p.Arg173*），并通过计算机模拟分析预测该突变显著损害了蛋白质功能，导致 ARMC5 失活。随后，对肿瘤标本的 WES 发现了 79 个体细胞单核苷酸多态性（Single Nucleotide Polymorphism，SNP）/插入缺失（Insertion-deletion，indel）突变，包括 32 个错义/无义/剪接/终止丢失突变。这些突变均与 CS 无关。
发现了一种新型的 ARMC5 胚系突变（c.517C>T，p.Arg173*），该突变单独引起 BMAH，而无第二次突变。ARMC5 测序可能会提高对 BMAH 临床形式的识别能力，并有助于更早地诊断该病。
