Editorial
The importance of the genetic study in primary bilateral macronodular adrenal hyperplasia
Importancia del estudio genético en la hiperplasia suprarrenal macronodular bilateral primaria
Marta Araujo-Castroa,b,
, Martín Reinckec
Corresponding author
marta.araujo@salud.madrid.org
Corresponding author. Department of endocrinology and Nutrition. Hospital Ramón y Cajal. Ctra. de Colmenar Viejo km. 9,100 28034 Madrid, Spain.
Corresponding author. Department of endocrinology and Nutrition. Hospital Ramón y Cajal. Ctra. de Colmenar Viejo km. 9,100 28034 Madrid, Spain.
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Ortiz-Zúñiga, María Clemente León, Lía Nattero-Chávez, Andrés Mingorance, Ana Prado, Laura Galiana, Amparo Oliver, Olga Simó-Servat" "autores" => array:10 [ 0 => array:2 [ "nombre" => "David" "apellidos" => "Rudilla" ] 1 => array:2 [ "nombre" => "Elena" "apellidos" => "García" ] 2 => array:2 [ "nombre" => "Ángel M." "apellidos" => "Ortiz-Zúñiga" ] 3 => array:2 [ "nombre" => "María Clemente" "apellidos" => "León" ] 4 => array:2 [ "nombre" => "Lía" "apellidos" => "Nattero-Chávez" ] 5 => array:2 [ "nombre" => "Andrés" "apellidos" => "Mingorance" ] 6 => array:2 [ "nombre" => "Ana" "apellidos" => "Prado" ] 7 => array:2 [ "nombre" => "Laura" "apellidos" => "Galiana" ] 8 => array:2 [ "nombre" => "Amparo" "apellidos" => "Oliver" ] 9 => array:2 [ "nombre" => "Olga" "apellidos" => "Simó-Servat" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018023000148?idApp=UINPBA00004N" "url" => "/25300180/0000007000000001/v1_202302101139/S2530018023000148/v1_202302101139/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "The importance of the genetic study in primary bilateral macronodular adrenal hyperplasia" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "3" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Marta Araujo-Castro, Martín Reincke" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Marta" "apellidos" => "Araujo-Castro" "email" => array:1 [ 0 => "marta.araujo@salud.madrid.org" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Martín" "apellidos" => "Reincke" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Endocrinology and Nutrition. Hospital Ramón y Cajal. Instituto de Investigación Ramón y Cajal (IRYCIS), Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidad de Alcalá, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author. Department of endocrinology and Nutrition. Hospital Ramón y Cajal. Ctra. de Colmenar Viejo km. 9,100 28034 Madrid, Spain." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Importancia del estudio genético en la hiperplasia suprarrenal macronodular bilateral primaria" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1184 "Ancho" => 3167 "Tamanyo" => 346341 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genetic background of primary bilateral macronodular adrenal hyperplasia (PBMAH)</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">ARMC5</span>: armadillo repeat containing 5; CS: Cushing's syndrome; FAP: familial adenomatosous poliposis; MEN1: multiple endocrine neoplasia type 1, <span class="elsevierStyleItalic">MCR2</span>: adrenocorticotropic hormone receptor; <span class="elsevierStyleItalic">PRKACA</span>: protein regulatory subunit Kinase A; <span class="elsevierStyleItalic">PDE11A</span>: phosphodiesterase 11A; <span class="elsevierStyleItalic">PDE8B</span>: phosphodiesterase 8B; <span class="elsevierStyleItalic">KDM1A:</span> lysine (K)-specific demethylase 1 A; PBMAH: primary bilateral macronodular adrenal hyperplasia.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Primary bilateral macronodular adrenal hyperplasia (PBMAH) accounts for less than 1% of all cases of endogenous Cushing's syndrome <a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. It is morphologically characterized by bilaterally enlarged adrenal glands containing two or more adrenal nodules larger than 10<span class="elsevierStyleHsp" style=""></span>mm. Although cases of hyperandrogenism and increased aldosterone secretion have been described, increased cortisol production is the most frequent biochemical phenotype. Generally, the disease progresses slowly over time, and often manifests as autonomous cortisol secretion (ACS) with mild hypercortisolism, whereas its presentation as overt Cushing's syndrome is infrequent <a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. The bilateral appearance of nodules has put forward the hypothesis of potential germline genetic predisposition to the disease. In fact, the new World Health Organization classification (WHO 2022) of adrenal cortical proliferations highlights the importance of the frequent genetic origin of PBMAH and suggests that the term hyperplasia is not appropriate due to the characteristic clonal and/or neoplastic pattern of the disease. The new term <span class="elsevierStyleItalic">bilateral macronodular adrenal cortical disease</span> is suggested as more appropriate instead of PBMAH <a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>, but currently lacks endorsement by other scientific organizations.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In many familial cases of PBMAH, the variants in the <span class="elsevierStyleItalic">armadillo repeat containing 5</span> (<span class="elsevierStyleItalic">ARMC5</span>) gene are closely associated with the disease. The inactivating variants in <span class="elsevierStyleItalic">ARMC5,</span> located on chromosome 16p11.2, are the most common underlying genetic cause of PBMAH <a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>. Germline pathogenic variants are found in 15% of patients with apparently sporadic PBMAH, 50% of operated patients, and 80% of patients with evident familial presentation <a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a>. Several differential features have been described in patients with <span class="elsevierStyleItalic">ARMC5</span> pathogenic variants compared to those patients harboring wild-type <span class="elsevierStyleItalic">ARMC5</span>, including: i) a more advanced Cushing's syndrome; ii) lower mean age at diagnosis (45-50 vs. 50-55 years); iii) higher adrenal weight and number of adrenal nodules, and iv) a higher prevalence of hypertension <a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>. Early detection of <span class="elsevierStyleItalic">ARMC5</span> variant status and familial screening might have important clinical implications leading to an earlier diagnosis of PBMAH. The latter would allow to detect the disease when hypercortisolism is still mild and has not yet generated negative effects on the cardiometabolic system. In addition, pathogenic <span class="elsevierStyleItalic">ARMC5</span> variants have been associated with a higher risk of intracranial meningiomas <a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> (<a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a>). Thus, if <span class="elsevierStyleItalic">ARMC5</span> pathogenic variants are detected, a cerebral MRI should be performed at least at the diagnosis of PBMAH. However, the prevalence of meningioma also seems to be higher in benign adrenocortical adenomas than in age- and sex-matched controls (18% vs. 6%) according to a recent study <a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>. Nevertheless, the role of <span class="elsevierStyleItalic">ARMC5</span> in the pathogenesis of sporadic unilateral adrenal adenomas has been poorly investigated, with only non-pathogenetic allelic variants or variants of uncertain significance detected <a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>.</p><p id="par0015" class="elsevierStylePara elsevierViewall">One of the most important recent discoveries in the field of PBMAH is the role of <span class="elsevierStyleItalic">lysine (K)-specific demethylase 1 A</span> (<span class="elsevierStyleItalic">KDM1A</span>) pathogenic variants in patients with food-dependent Cushing's syndrome <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>. <span class="elsevierStyleItalic">KDM1A</span> inactivation appears to be an exclusive genetic mechanism of this phenotype explaining about 90% of cases <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>, or even 100%, according to another series <a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>. Thus, overall, <span class="elsevierStyleItalic">KMD1A</span> pathogenic variants could be present in 10 to 30% of the cases with PBMAH <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>. In patients with these pathogenic variants, cortisol secretion is stimulated by food ingestion and diagnosis can be done by analysis of the circadian rhythm of cortisol levels. Moreover, patients with the pathogenic variant are mostly female <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>. One important point to consider is that, according to one study, carriers of <span class="elsevierStyleItalic">KDM1A</span> pathogenic variants had a higher risk of developing monoclonal gammopathies. Thus, serum protein electrophoresis should be performed these patients <a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> (<a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">All the genes associated with PBMAH that have been identified are transmitted in an autosomal dominant mode. Moreover, for constitutive <span class="elsevierStyleItalic">ARMC5</span> variants, the penetrance of the disease is quite high, probably above 80–85% in adults above 45 years, but with variable severity of cortisol dysregulation between relatives <a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>. Hence, genetic screening for <span class="elsevierStyleItalic">ARMC5</span> and <span class="elsevierStyleItalic">KDM1A</span> pathogenic variants can now be offered to most PBMAH patients and their families, opening the way to an earlier diagnosis of hypercortisolism and potentially associated comorbidities and extraadrenal malignancies. This could lead to an optimization in their management. Nevertheless, pathogenic variants in <span class="elsevierStyleItalic">ARMC5</span> have not been reported in patients with food dependent Cushing's syndrome, making <span class="elsevierStyleItalic">ARMC5</span> and <span class="elsevierStyleItalic">KDM1A</span> pathogenic variants mutually exclusive. Therefore, investigating <span class="elsevierStyleItalic">ARMC5</span> might not be necessary in these patients <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>. Moreover, a recent study suggests that genotyping of <span class="elsevierStyleItalic">ARMC5</span> should be limited to patients with clear bilateral adrenal involvement and ACS since this combination holding a 100% sensitivity for detecting ARMC5 pathogenic variants <a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>. Beyond <span class="elsevierStyleItalic">ARMC5</span> and <span class="elsevierStyleItalic">KDM1A</span> pathogenic variants, patients with PBMAH may occasionally - approximately 5% of the cases- present alterations in genes responsible for a multiple tumor syndromes, including <span class="elsevierStyleItalic">multiple endocrine neoplasia type 1 (MEN1), adenomatous polyposis coli (APC), and fumarate hydratase (FH)</span> genes <a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. In addition, pathogenic variants in the <span class="elsevierStyleItalic">adrenocorticotropic hormone receptor (MCR2)</span><a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>, <span class="elsevierStyleItalic">protein regulatory subunit Kinase A</span> (<span class="elsevierStyleItalic">PRKACA</span> gene) <a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>, <span class="elsevierStyleItalic">phosphodiesterase 11A</span> (<span class="elsevierStyleItalic">PDE11A</span> gene) <a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and <span class="elsevierStyleItalic">8B</span> (<span class="elsevierStyleItalic">PDE8B</span> gene) <a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>, have been anecdotally described as a cause of PBMAH (see figure).</p><p id="par0025" class="elsevierStylePara elsevierViewall">In conclusion, the identification of frequent pathogenic variants in <span class="elsevierStyleItalic">ARMC5</span> and <span class="elsevierStyleItalic">KDM1A</span> genes in patients with PBMAH, including familial and apparently sporadic cases, indicates that it is a disorder with a very common genetic origin. Thus, genetic studies should be considered in all patients with PBMAH with the aim to achieve an earlier diagnosis of hypercortisolism and optimize its management. Testing for <span class="elsevierStyleItalic">ARMC5</span> is not indicated in patients with food dependent Cushing's syndrome, while <span class="elsevierStyleItalic">KDM1A</span> should be the first gene to study in these patients.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical approval</span><p id="par0030" class="elsevierStylePara elsevierViewall">Not applicable</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Financial Support</span><p id="par0035" class="elsevierStylePara elsevierViewall">Not applicable</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015"><span class="elsevierStyleBold">Conflict of</span> interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical approval" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Financial Support" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-11-22" "fechaAceptado" => "2022-11-24" "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1184 "Ancho" => 3167 "Tamanyo" => 346341 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Genetic background of primary bilateral macronodular adrenal hyperplasia (PBMAH)</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">ARMC5</span>: armadillo repeat containing 5; CS: Cushing's syndrome; FAP: familial adenomatosous poliposis; MEN1: multiple endocrine neoplasia type 1, <span class="elsevierStyleItalic">MCR2</span>: adrenocorticotropic hormone receptor; <span class="elsevierStyleItalic">PRKACA</span>: protein regulatory subunit Kinase A; <span class="elsevierStyleItalic">PDE11A</span>: phosphodiesterase 11A; <span class="elsevierStyleItalic">PDE8B</span>: phosphodiesterase 8B; <span class="elsevierStyleItalic">KDM1A:</span> lysine (K)-specific demethylase 1 A; PBMAH: primary bilateral macronodular adrenal hyperplasia.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cushing's syndrome due to bilateral adrenal cortical disease: Bilateral macronodular adrenal cortical disease and bilateral micronodular adrenal cortical disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 36 | 3 | 39 |
| 2024 September | 41 | 3 | 44 |
| 2024 August | 32 | 8 | 40 |
| 2024 July | 36 | 5 | 41 |
| 2024 June | 37 | 2 | 39 |
| 2024 May | 30 | 5 | 35 |
| 2024 April | 31 | 3 | 34 |
| 2024 March | 42 | 4 | 46 |
| 2024 February | 36 | 3 | 39 |
| 2024 January | 24 | 2 | 26 |
| 2023 December | 31 | 1 | 32 |
| 2023 November | 30 | 1 | 31 |
| 2023 October | 46 | 4 | 50 |
| 2023 September | 12 | 7 | 19 |
| 2023 August | 7 | 0 | 7 |
| 2023 March | 1 | 1 | 2 |
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