{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:23:09Z","timestamp":1790752989174,"version":"4.1.0"},"reference-count":19,"publisher":"Bioscientifica","content-domain":{"domain":["edm.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,3,27]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in\n                    <jats:italic>armadillo repeat-containing 5<\/jats:italic>\n                    (\n                    <jats:italic>ARMC5<\/jats:italic>\n                    ) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH &lt;5\u2009pg\/mL; urinary free cortisol (UFC), 532\u2009\u00b5g\/24\u2009h (normal range: 20\u201390); failure to suppress the low-dose dexamethasone test (0.5\u2009mg every 6\u2009h for 48\u2009h): cortisol 21\u2009\u00b5g\/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55\u2009\u00d7\u200954\u2009\u00d7\u200930\u2009mm; left, 85\u2009\u00d7\u200953\u2009\u00d7\u200935\u2009mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient\u2019s 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15\u2009cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>Learning points:<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The asymmetric\/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>\n                          Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in\n                          <jats:italic>armadillo repeat-containing 5<\/jats:italic>\n                          (\n                          <jats:italic>ARMC5<\/jats:italic>\n                          ) gene.\n                        <\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>","DOI":"10.1530\/edm-16-0135","type":"journal-article","created":{"date-parts":[[2017,3,27]],"date-time":"2017-03-27T03:09:47Z","timestamp":1490584187000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-2","source":"Crossref","is-referenced-by-count":10,"title":["ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH)"],"prefix":"10.1530","volume":"2017","author":[{"given":"Teresa","family":"Rego","sequence":"first","affiliation":[{"name":"1Endocrinology Department, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Fonseca","sequence":"additional","affiliation":[{"name":"1Endocrinology Department, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Espiard","sequence":"additional","affiliation":[{"name":"2Endocrinology Department, INSERM U1016, Institut Cochin, Paris Descartes University, & Center for Rare Adrenal Diseases, H\u00f4pital Cochin, APHP-Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Perlemoine","sequence":"additional","affiliation":[{"name":"2Endocrinology Department, INSERM U1016, Institut Cochin, Paris Descartes University, & Center for Rare Adrenal Diseases, H\u00f4pital Cochin, APHP-Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Bertherat","sequence":"additional","affiliation":[{"name":"2Endocrinology Department, INSERM U1016, Institut Cochin, Paris Descartes University, & Center for Rare Adrenal Diseases, H\u00f4pital Cochin, APHP-Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Agapito","sequence":"additional","affiliation":[{"name":"1Endocrinology Department, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"key20170421170318562_bib1","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1210\/jcem-24-10-947","article-title":"Cushing\u2019s syndrome: nodular cortical hyperplasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor","volume":"24","author":"Kirschner","year":"1964","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib2","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.beem.2008.10.011","article-title":"ACTH-independent macronodular adrenal hyperplasia","volume":"23","author":"Lacroix","year":"2009","journal-title":"Best Practice and Research Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib3","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1210\/jc.2013-4237","article-title":"ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia","volume":"99","author":"Alencar","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib4","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1001\/archsurg.133.5.541","article-title":"Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation","volume":"133","author":"Swain","year":"1998","journal-title":"Archives of Surgery"},{"key":"key20170421170318562_bib5","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1097\/MED.0000000000000061","article-title":"Primary bilateral macronodular adrenal hyperplasia","volume":"21","author":"De Venanzi","year":"2014","journal-title":"Current Opinion in Endocrinology, Diabetes and Obesity"},{"key":"key20170421170318562_bib6","doi-asserted-by":"publisher","first-page":"R31","DOI":"10.1530\/JOE-14-0568","article-title":"Genetics of primary macronodular hyperplasia","volume":"224","author":"Fragoso","year":"2015","journal-title":"Journal of Endocrinology"},{"key":"key20170421170318562_bib7","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.mce.2003.10.052","article-title":"Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene","volume":"213","author":"Swords","year":"2004","journal-title":"Molecular and Cellular of Endocrinology"},{"key":"key20170421170318562_bib8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2265.2009.03689.x","article-title":"Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction","volume":"73","author":"Lacroix","year":"2010","journal-title":"Clinical Endocrinology"},{"key":"key20170421170318562_bib9","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1530\/EJE-10-0195","article-title":"Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing\u2019s syndrome","volume":"163","author":"Lib\u00e9","year":"2010","journal-title":"European Journal of Endocrinology"},{"key":"key20170421170318562_bib10","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1210\/jc.2002-030014","article-title":"Intraadrenal adrenoccorticotropin production in a case of bilateral macronodular adrenal hyperplasia causing Cushing\u2019s syndrome","volume":"88","author":"Lefebvre","year":"2003","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib11","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.1056\/NEJMoa1215245","article-title":"Intradrenal corticotropin in bilateral macronodular adrenal hyperplasia","volume":"369","author":"Louiset","year":"2013","journal-title":"New England Journal of Medicine"},{"key":"key20170421170318562_bib12","first-page":"189","article-title":"Familial adrenocorticotropin-independent Cushing syndrome with bilateral macronodular adrenal hyperplasia","volume":"76","author":"Findlay","year":"1993","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib13","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1046\/j.1365-2265.1996.682504.x","article-title":"ACTH independent Cushing syndrome occurring in siblings","volume":"44","author":"Minami","year":"1996","journal-title":"Clinical Endocrinology"},{"key":"key20170421170318562_bib14","doi-asserted-by":"publisher","first-page":"M121","DOI":"10.1530\/EJE-15-0532","article-title":"Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing\u2019s syndrome?","volume":"173","author":"Drougat","year":"2015","journal-title":"European Journal of Endocrinology"},{"key":"key20170421170318562_bib15","doi-asserted-by":"publisher","first-page":"2105","DOI":"10.1056\/NEJMoa1304603","article-title":"ARMC5 mutations in macronodular adrenal hyperplasia with Cushing\u2019s syndrome","volume":"369","author":"Assie","year":"2013","journal-title":"New England Journal of Medicine"},{"key":"key20170421170318562_bib16","doi-asserted-by":"publisher","first-page":"E1113","DOI":"10.1210\/jc.2013-4280","article-title":"Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation","volume":"99","author":"Faucz","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib17","doi-asserted-by":"publisher","first-page":"E1784","DOI":"10.1210\/jc.2014-1265","article-title":"ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia","volume":"99","author":"Gagliard","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib18","doi-asserted-by":"publisher","first-page":"E119","DOI":"10.1210\/jc.2014-2648","article-title":"Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma","volume":"100","author":"Elbelt","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"key20170421170318562_bib19","doi-asserted-by":"publisher","first-page":"E926","DOI":"10.1210\/jc.2014-4204","article-title":"ARMC5 mutations in a large cohort of primary macronodular adrenal hyperplasia: clinical and functional consequences","volume":"100","author":"Espiard","year":"2015","journal-title":"Journal of Clinical Endocrinology and Metabolism"}],"container-title":["Endocrinology, Diabetes &amp; Metabolism Case Reports"],"original-title":[],"link":[{"URL":"https:\/\/edm.bioscientifica.com\/view\/journals\/edm\/2017\/1\/EDM16-0135.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/edm.bioscientifica.com\/downloadpdf\/journals\/edm\/2017\/1\/EDM16-0135.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:46:28Z","timestamp":1784555188000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/edm\/article\/3411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,27]]},"references-count":19,"URL":"https:\/\/doi.org\/10.1530\/edm-16-0135","relation":{},"ISSN":["2052-0573"],"issn-type":[{"value":"2052-0573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,27]]}}}