Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report

Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report Yi-kai Wang, Wei-bing Shuang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4320615/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of overt Cushing's syndrome (CS), which usually manifests as bilateral macronodular adrenal nodules and varying levels of cortisol secretion. Previous studies have shown that ARMC5 gene belongs to tumor suppressor gene, and its germline variants play a huge role in the occurrence of PBMAH, which may be inherited to family members and lead to more severe clinical symptoms. ARMC5 variants may be associated with meningiomas, which is also illustrated by our report. In addition, our discovery of a new mutation site in a family can also provide new targets and new directions for the study of PBMAH patients with ARMC5 mutations, and can also deepen clinicians' understanding of this disease. Primary bilateral macronodular adrenal hyperplasia Cushing's syndrome ARMC5 gene meningiomas Figures Figure 1 Figure 2 Figure 3 Introduction Patients with PBMAH have different levels of cortisol secretion, which can lead to asymptomatic, subclinical and overt CS. Patients with overt CS only account for about 2%-6.2% of all CS patients [ 1 , 2 ] . Therefore, the clinical manifestations of patients with PBMAH are not typical, and accurate diagnosis is difficult. Patients are often diagnosed because of the discovery of bilateral adrenal incidental tumors or the clinical manifestations of cortisol excess. The pathogenesis of PBMAH has not been well studied. Abnormal expression of membrane G protein-coupled receptors, abnormal activation of cAMP/PKA and wnt/ b-catenin signaling pathways, and inappropriat autonomous or paracrine secretion of ACTH are all possible mechanisms of nodule development and hormone dysregulation [ 3 ] . Pathogenic variants in ARMC5 are responsible for 20–25% of PBMAH [ 4 ] . ARMC5 (armadillo repeatcontaining 5) is a protein that contains an armadillo (ARM) domain that contains multiple ARM repeats at its middle end and a BTB domain at its c terminus. Studies have shown that ARMC5 is a part of RPB1-specific ubiquitin ligase, which is related to adrenal hyperplasia. Gene mutation of ARMC5 can lead to changes in degradation of ARMC5 by proteasome, thereby affecting the above mechanisms and causing PBMAH [ 3 , 5 ] . In addition to ARMC5 germline mutations, somatic mutations are frequently detected in patients with PBMAH, which supports ARMC5 as a "double-hit" model of tumor suppressor gene. A second somatic mutation or second hit may induce tumorigenesis or promote greater nodule progression [ 6 ] . PBMAH with ARMC5 mutation may have an autosomal dominant mode of inheritance, but the penetrance is incomplete [ 7 ] . Here, we report a PBMAH family with ARMC5 mutation, in which two family members had meningioma, and the inheritance pattern was also an autosomal dominant inheritance pattern. Case data A 41-year-old male patient was admitted to the hospital due to multiple bilateral adrenal nodules. He had a history of hypertension for more than 10 years, and was currently treated with irbesartan and hydrochlorothiazide tablets. Physical examination showed thin dry skin, central obesity, multiple ecchymosis, and facial redness and swelling. After admission, enhanced CT examination of the adrenal gland showed that the shape of bilateral adrenal glands was irregular, and multiple cyst-like low- density shadows with bed-like changes were seen locally, which was considered as multiple nodular hyperplasia. Laboratory tests showed that the patient had abnormal cortisol rhythm, increased cortisol secretion, and decreased adrenocorticotropic hormone secretion(Fig. 1 ). The patient's father had been diagnosed with adrenal hyperplasia and pituitary tumor, which was treated surgically, and his mother died of an accident. Based on the results of various examinations and clinical manifestations, we diagnosed the patient as PBMAH. Further examination was performed. Pituitary magnetic resonance imaging (MRI) showed a possible microadenoma and meningioma. Laboratory tests showed increased secretion of parathyroid hormone, progesterone and prolactin. After consideration, total adrenalectomy on the larger left side was performed. Pathology reported a left adrenal cortical adenoma, multifocal, 2cm to 3cm in diameter. Immunohistochemical results: CK (-), CgA (-), Syn (-), Vim (+), Melan-A (+), Ki67 (+ 1%), Inhibinα (+). Molecular analysis of DNA extracted from the patient's peripheral blood revealed a heterozygous mutation, NM_0011052472:c.943C > T (p.Arg315Trp), at chr16: 31473811, in the ARMC5 gene, which was classified as likely pathogenic. To our knowledge, this variant site has not been reported previously. Subsequently, we performed genetic testing on his father, brother and two daughters, and found that the father and one of the daughters had the same gene mutation(Fig. 2 ). The daughter was doing well, with no manifestations of disease, but required active monitoring(Fig. 3 ). Discussion PBMAH is a heterogeneous disease with a variety of clinical, hormonal, and imaging manifestations. Although sporadic cases are relatively common, it has also been linked to genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (FAP), or hereditary leiomyomatosis and renal cell carcinoma (HLRCC) [ 8 ] . Interestingly, the most common clinical manifestation of MEN1 is parathyroid hyperplasia/adenoma with an estimated penetrance of 90%, and the penetrance of pituitary adenoma is 30–40%. Patients can also present with meningioma, similar to the clinical presentation of the case reported here. Therefore, some scholars have found that 76 (68.4%) of 111 patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine tumors type 1 (MEN1) carry ARMC5 germline variants, and concluded that ARMC5 variants may play a role in the phenotype of spNETs or MEN1 patients [ 9 ] . The relationship between them needs to be further studied. ARMC5 germline mutations are responsible for the majority of familial cases of PBMAH, while the ARMC5 mutation rate is approximately 20%-25% in sporadic cases of PBMAH. ARMC5 variants are present in 55% of PBMAH patients with severe CS [ 10 ] . Through comparison and research, scholars have confirmed that the condition of most patients with ARMC5 mutations is more obvious than that of PBMAH patients without mutations, including cortisol secretion, adrenal morphology and metabolic complications [ 4 ] . Cavalcante et al. cultured ARMC5-silenced PBMAH cells and found that their steroidogenic enzyme gene expression was reduced and their proliferation ability was enhanced [ 11 ] . This suggests that ARMC5 inactivation leads to hyperplasia of adrenal tissue with a large increase in the total number of cells. Although the ability of the cells to produce steroids is reduced, the increase in the number of cells results in steroid overproduction. This may also explain why patients show no clinical signs in the early stages and are not detected until they are between the ages of 40 and 70 [ 12 ] . Conclusions In conclusion, screening of family members of PBMAH patients with ARMC5 germline mutations and active monitoring of family members carrying ARMC5 variants are recommended, and relevant examinations should include brain imaging for early detection and early treatment. The pattern of autosomal dominant inheritance is also supported by our report. Declarations Acknowledgements The authors thank doctors, nurses, and clinical staff who provided care for the patient. Authors’ contributions Conceptualization, WS; methodology, YK; investigation, YK; data curation, YK; writing—original draft preparation, WS and YK; writing—review and editing, YK; supervision, WS. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Written informed consent has been obtained from the patient to publish this paper. Consent for publication Written informed consent has been obtained from the patient to publish this paper. Competing interests The authors declare no competing interests. References Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet (London England). 2015;386(9996):913–27. 10.1016/s0140-6736(14)61375-1 . Zhou J, Zhang M, Bai X, Cui S, Pang C, Lu L et al. Demographic Characteristics, Etiology, and Comorbidities of Patients with Cushing's Syndrome: A 10-Year Retrospective Study at a Large General Hospital in China. International journal of endocrinology 2019, 2019:7159696. 10.1155/2019/7159696 . Bertherat J, Bourdeau I, Bouys L, Chasseloup F, Kamenický P, Lacroix A, Clinical. Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia. Endocr Rev. 2023;44(4):567–628. 10.1210/endrev/bnac034 . Bouys L, Vaczlavik A, Jouinot A, Vaduva P, Espiard S, Assié G, et al. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients. Eur J Endocrinol. 2022;187(1):123–34. 10.1530/eje-21-1032 . Lao L, Bourdeau I, Gagliardi L, He X, Shi W, Hao B, et al. ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia. Nucleic Acids Res. 2022;50(11):6343–67. 10.1093/nar/gkac483 . Correa R, Zilbermint M, Berthon A, Espiard S, Batsis M, Papadakis GZ, et al. The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia. Eur J Endocrinol. 2015;173(4):435–40. 10.1530/eje-15-0205 . Eghbali M, Cheraghi S, Samanian S, Rad I, Meghdadi J, Akbari H, et al. A Novel ARMC5 Germline Variant in Primary Macronodular Adrenal Hyperplasia Using Whole-Exome Sequencing. Diagnostics. 2022;12(12). 10.3390/diagnostics12123028 . Cavalcante IP, Berthon A, Fragoso MC, Reincke M, Stratakis CA, Ragazzon B, et al. Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease. Nat reviews Endocrinol. 2022;18(11):699–711. 10.1038/s41574-022-00718-y . Damjanovic SS, Antic JA, Elezovic-Kovacevic VI, Dundjerovic DM, Milicevic IT, Beleslin-Cokic BB, et al. ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2020;105(12). 10.1210/clinem/dgaa631 . Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N Engl J Med. 2013;369(22):2105–14. 10.1056/NEJMoa1304603 . Cavalcante IP, Nishi M, Zerbini MCN, Almeida MQ, Brondani VB, Botelho MLAA, et al. The role of ARMC5 in human cell cultures from nodules of primary macronodular adrenocortical hyperplasia (PMAH). Mol Cell Endocrinol. 2018;460:36–46. 10.1016/j.mce.2017.06.027 . Berthon A, Faucz FR, Espiard S, Drougat L, Bertherat J, Stratakis CA. Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function. Hum Mol Genet. 2017;26(18):3495–507. 10.1093/hmg/ddx235 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4320615","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":296160036,"identity":"629dc8a3-ebe9-43ef-b090-6960f654e85b","order_by":0,"name":"Yi-kai Wang","email":"","orcid":"","institution":"The First Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yi-kai","middleName":"","lastName":"Wang","suffix":""},{"id":296160038,"identity":"1c877f9e-2901-4b2a-b395-72ab68c06ba8","order_by":1,"name":"Wei-bing Shuang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYDACCSjNJsHYwMBQISHHT6KWMxbGkg3EagEzGNsqEjcQ0iI/u8fwc8Gvw3J80s1tD7/Ok2DcwMD88NENPFoM7pwxlp7Zd9iYTeZgu7HsNglmcwY2Y+McfFokcgykeXtuJ7ZJJLZJS26TYLNs4GGTxqdFfkaO8W+glnqIljkSPAYHCGhhuJFjJs3z43YCG1CL5McGCQmCWgxupJVZ8zb8N2yTOdgmzXBMwkCymYBf5Gckb77N8ydNXn52+zPJHzV19f3szQ8f43UYCDC2QWhmHjBJSDkY/IFq/UGU6lEwCkbBKBhpAADIvkiPgyLxrgAAAABJRU5ErkJggg==","orcid":"","institution":"The First Hospital of Shanxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Wei-bing","middleName":"","lastName":"Shuang","suffix":""}],"badges":[],"createdAt":"2024-04-25 00:09:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4320615/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4320615/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55760810,"identity":"086f2d5b-86eb-4f90-a8d9-c38714635aa8","added_by":"auto","created_at":"2024-05-02 18:57:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1910676,"visible":true,"origin":"","legend":"\u003cp\u003eCT examination revealed multiple adrenal nodules, many of which were larger than 1cm in diameter. Blue arrows point to bilateral adrenal multiple nodules.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4320615/v1/7c803b3f415c351e7f423b67.png"},{"id":55760809,"identity":"ad81fb61-ffb8-4698-ab9e-d15347234b05","added_by":"auto","created_at":"2024-05-02 18:57:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2446532,"visible":true,"origin":"","legend":"\u003cp\u003eGene sequencing results. Heterozygous represent AMRC5 mutation carriers. Wild type indicates no variation.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4320615/v1/a4502ff0dbdafe443c66f107.png"},{"id":55760811,"identity":"6150657b-f709-4c2f-bfd7-c3c82adfca25","added_by":"auto","created_at":"2024-05-02 18:57:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":949082,"visible":true,"origin":"","legend":"\u003cp\u003eFamily tree. The proband's wife and mother were not tested.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4320615/v1/b9e9d264bcf00c1b24f01b45.png"},{"id":61104264,"identity":"5a221f73-2d8b-45fd-9d2d-94e4ab3b612a","added_by":"auto","created_at":"2024-07-25 15:44:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8062934,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4320615/v1/3ab00806-782e-4a57-b8f6-391c6af836b5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePatients with PBMAH have different levels of cortisol secretion, which can lead to asymptomatic, subclinical and overt CS. Patients with overt CS only account for about 2%-6.2% of all CS patients\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Therefore, the clinical manifestations of patients with PBMAH are not typical, and accurate diagnosis is difficult. Patients are often diagnosed because of the discovery of bilateral adrenal incidental tumors or the clinical manifestations of cortisol excess.\u003c/p\u003e \u003cp\u003eThe pathogenesis of PBMAH has not been well studied. Abnormal expression of membrane G protein-coupled receptors, abnormal activation of cAMP/PKA and wnt/ b-catenin signaling pathways, and inappropriat autonomous or paracrine secretion of ACTH are all possible mechanisms of nodule development and hormone dysregulation\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Pathogenic variants in ARMC5 are responsible for 20–25% of PBMAH\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. ARMC5 (armadillo repeatcontaining 5) is a protein that contains an armadillo (ARM) domain that contains multiple ARM repeats at its middle end and a BTB domain at its c terminus. Studies have shown that ARMC5 is a part of RPB1-specific ubiquitin ligase, which is related to adrenal hyperplasia. Gene mutation of ARMC5 can lead to changes in degradation of ARMC5 by proteasome, thereby affecting the above mechanisms and causing PBMAH\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In addition to ARMC5 germline mutations, somatic mutations are frequently detected in patients with PBMAH, which supports ARMC5 as a \"double-hit\" model of tumor suppressor gene. A second somatic mutation or second hit may induce tumorigenesis or promote greater nodule progression\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePBMAH with ARMC5 mutation may have an autosomal dominant mode of inheritance, but the penetrance is incomplete\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Here, we report a PBMAH family with ARMC5 mutation, in which two family members had meningioma, and the inheritance pattern was also an autosomal dominant inheritance pattern.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Case data","content":"\u003cp\u003eA 41-year-old male patient was admitted to the hospital due to multiple bilateral adrenal nodules. He had a history of hypertension for more than 10 years, and was currently treated with irbesartan and hydrochlorothiazide tablets. Physical examination showed thin dry skin, central obesity, multiple ecchymosis, and facial redness and swelling. After admission, enhanced CT examination of the adrenal gland showed that the shape of bilateral adrenal glands was irregular, and multiple cyst-like low- density shadows with bed-like changes were seen locally, which was considered as multiple nodular hyperplasia. Laboratory tests showed that the patient had abnormal cortisol rhythm, increased cortisol secretion, and decreased adrenocorticotropic hormone secretion(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The patient's father had been diagnosed with adrenal hyperplasia and pituitary tumor, which was treated surgically, and his mother died of an accident. Based on the results of various examinations and clinical manifestations, we diagnosed the patient as PBMAH.\u003c/p\u003e\u003cp\u003e \u003c/p\u003e\u003cp\u003eFurther examination was performed. Pituitary magnetic resonance imaging (MRI) showed a possible microadenoma and meningioma. Laboratory tests showed increased secretion of parathyroid hormone, progesterone and prolactin. After consideration, total adrenalectomy on the larger left side was performed. Pathology reported a left adrenal cortical adenoma, multifocal, 2cm to 3cm in diameter. Immunohistochemical results: CK (-), CgA (-), Syn (-), Vim (+), Melan-A (+), Ki67 (+ 1%), Inhibinα (+).\u003c/p\u003e\u003cp\u003eMolecular analysis of DNA extracted from the patient's peripheral blood revealed a heterozygous mutation, NM_0011052472:c.943C \u0026gt; T (p.Arg315Trp), at chr16: 31473811, in the ARMC5 gene, which was classified as likely pathogenic. To our knowledge, this variant site has not been reported previously. Subsequently, we performed genetic testing on his father, brother and two daughters, and found that the father and one of the daughters had the same gene mutation(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The daughter was doing well, with no manifestations of disease, but required active monitoring(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePBMAH is a heterogeneous disease with a variety of clinical, hormonal, and imaging manifestations. Although sporadic cases are relatively common, it has also been linked to genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (FAP), or hereditary leiomyomatosis and renal cell carcinoma (HLRCC)\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Interestingly, the most common clinical manifestation of MEN1 is parathyroid hyperplasia/adenoma with an estimated penetrance of 90%, and the penetrance of pituitary adenoma is 30\u0026ndash;40%. Patients can also present with meningioma, similar to the clinical presentation of the case reported here. Therefore, some scholars have found that 76 (68.4%) of 111 patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine tumors type 1 (MEN1) carry ARMC5 germline variants, and concluded that ARMC5 variants may play a role in the phenotype of spNETs or MEN1 patients\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. The relationship between them needs to be further studied.\u003c/p\u003e \u003cp\u003eARMC5 germline mutations are responsible for the majority of familial cases of PBMAH, while the ARMC5 mutation rate is approximately 20%-25% in sporadic cases of PBMAH. ARMC5 variants are present in 55% of PBMAH patients with severe CS\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Through comparison and research, scholars have confirmed that the condition of most patients with ARMC5 mutations is more obvious than that of PBMAH patients without mutations, including cortisol secretion, adrenal morphology and metabolic complications\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCavalcante et al. cultured ARMC5-silenced PBMAH cells and found that their steroidogenic enzyme gene expression was reduced and their proliferation ability was enhanced\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. This suggests that ARMC5 inactivation leads to hyperplasia of adrenal tissue with a large increase in the total number of cells. Although the ability of the cells to produce steroids is reduced, the increase in the number of cells results in steroid overproduction. This may also explain why patients show no clinical signs in the early stages and are not detected until they are between the ages of 40 and 70\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, screening of family members of PBMAH patients with ARMC5 germline mutations and active monitoring of family members carrying ARMC5 variants are recommended, and relevant examinations should include brain imaging for early detection and early treatment. The pattern of autosomal dominant inheritance is also supported by our report.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank doctors, nurses, and clinical staff who provided care for the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, WS; methodology, YK; investigation, YK; data curation, YK; writing\u0026mdash;original draft preparation, WS and YK; writing\u0026mdash;review and editing, YK; supervision, WS. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. Written informed consent has been obtained from the patient to publish this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent has been obtained from the patient to publish this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet (London England). 2015;386(9996):913\u0026ndash;27. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0140-6736(14)61375-1\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(14)61375-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou J, Zhang M, Bai X, Cui S, Pang C, Lu L et al. 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Hum Mol Genet. 2017;26(18):3495\u0026ndash;507. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/hmg/ddx235\u003c/span\u003e\u003cspan address=\"10.1093/hmg/ddx235\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Primary bilateral macronodular adrenal hyperplasia, Cushing's syndrome, ARMC5 gene, meningiomas","lastPublishedDoi":"10.21203/rs.3.rs-4320615/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4320615/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePrimary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of overt Cushing's syndrome (CS), which usually manifests as bilateral macronodular adrenal nodules and varying levels of cortisol secretion. Previous studies have shown that ARMC5 gene belongs to tumor suppressor gene, and its germline variants play a huge role in the occurrence of PBMAH, which may be inherited to family members and lead to more severe clinical symptoms. ARMC5 variants may be associated with meningiomas, which is also illustrated by our report. In addition, our discovery of a new mutation site in a family can also provide new targets and new directions for the study of PBMAH patients with ARMC5 mutations, and can also deepen clinicians' understanding of this disease.\u003c/p\u003e","manuscriptTitle":"Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-02 18:57:12","doi":"10.21203/rs.3.rs-4320615/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"66420131-bfb8-4534-9b9d-12a35c1b3c77","owner":[],"postedDate":"May 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-25T15:36:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-02 18:57:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4320615","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4320615","identity":"rs-4320615","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}