{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:58Z","timestamp":1787028478723,"version":"build-2736575974"},"reference-count":112,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T00:00:00Z","timestamp":1655596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cushing\u2019s disease represents 60\u201370% of all cases of Cushing\u2019s syndrome, presenting with a constellation of clinical features associated with sustained hypercortisolism. Molecular alterations in corticotrope cells lead to the formation of ACTH-secreting adenomas, with subsequent excessive production of endogenous glucocorticoids. In the last few years, many authors have contributed to analyzing the etiopathogenesis and pathophysiology of corticotrope adenomas, which still need to be fully clarified. New molecular modifications such as somatic mutations of USP8 and other genes have been identified, and several case series and case reports have been published, highlighting new molecular alterations that need to be explored. To investigate the current knowledge of the genetics of ACTH-secreting adenomas, we performed a bibliographic search of the recent scientific literature to identify all pertinent articles. This review presents the most recent updates on somatic and germline mutations underlying Cushing\u2019s disease. The prognostic implications of these mutations, in terms of clinical outcomes and therapeutic scenarios, are still debated. Further research is needed to define the clinical features associated with the different genotypes and potential pharmacological targets.<\/jats:p>","DOI":"10.3390\/ijms23126824","type":"journal-article","created":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T10:14:52Z","timestamp":1655633692000},"page":"6824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genetic Basis of ACTH-Secreting Adenomas"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4772-1417","authenticated-orcid":false,"given":"Pietro","family":"Locantore","sequence":"first","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Maria","family":"Paragliola","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6857-2660","authenticated-orcid":false,"given":"Gianluca","family":"Cera","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-6847","authenticated-orcid":false,"given":"Roberto","family":"Novizio","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Maggio","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Ramunno","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8167-4338","authenticated-orcid":false,"given":"Andrea","family":"Corsello","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore Maria","family":"Corsello","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Translational Medicine and Surgery, Universit\u00e0 Cattolica del Sacro Cuore\u2014Fondazione Policlinico \u201cGemelli\u201d IRCCS, Largo Gemelli 8, I-00168 Rome, Italy"},{"name":"Unicamillus, Saint Camillus International University of Medical Sciences, via di S. Alessandro 10, I-00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104091","DOI":"10.1016\/j.lpm.2021.104091","article-title":"Cushing\u2019s Disease","volume":"50","author":"Ferriere","year":"2021","journal-title":"Presse Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1210\/jc.2005-0070","article-title":"Clinical and Biochemical Characteristics of Adrenocorticotropin-Secreting Macroadenomas","volume":"90","author":"Woo","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s12020-021-02621-4","article-title":"Cortisol Circadian Rhythm and Jet-Lag Syndrome: Evaluation of Salivary Cortisol Rhythm in a Group of Eastward Travelers","volume":"73","author":"Paragliola","year":"2021","journal-title":"Endocrine"},{"key":"ref_4","first-page":"851942","article-title":"Pediatric Cushing\u2019s Disease and Pituitary Incidentaloma: Is This a Real Challenge?","volume":"2014","author":"Paragliola","year":"2014","journal-title":"Case Rep. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Paragliola, R.M., Corsello, A., Locantore, P., Papi, G., Pontecorvi, A., and Corsello, S.M. (2020). Medical Approaches in Adrenocortical Carcinoma. Biomedicines, 8.","DOI":"10.3390\/biomedicines8120551"},{"key":"ref_6","first-page":"62","article-title":"Role of Mitotane in Adrenocortical Carcinoma\u2014Review and State of the Art","volume":"14","author":"Paragliola","year":"2018","journal-title":"Eur. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1038\/s42003-021-02802-x","article-title":"Molecular Basis of Ubiquitin-Specific Protease 8 Autoinhibition by the WW-like Domain","volume":"4","author":"Kakihara","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/cr.2015.20","article-title":"Recurrent Gain-of-Function USP8 Mutations in Cushing\u2019s Disease","volume":"25","author":"Ma","year":"2015","journal-title":"Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/ng.3166","article-title":"Mutations in the Deubiquitinase Gene USP8 Cause Cushing\u2019s Disease","volume":"47","author":"Reincke","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Treppiedi, D., Barbieri, A.M., Di Muro, G., Marra, G., Mangili, F., Catalano, R., Esposito, E., Ferrante, E., Serban, A.L., and Locatelli, M. (2021). Genetic Profiling of a Cohort of Italian Patients with ACTH-Secreting Pituitary Tumors and Characterization of a Novel USP8 Gene Variant. Cancers, 13.","DOI":"10.1530\/endoabs.73.PEP3.1"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fukuoka, H., Shichi, H., Yamamoto, M., and Takahashi, Y. (2020). The Mechanisms Underlying Autonomous Adrenocorticotropic Hormone Secretion in Cushing\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239132"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E997","DOI":"10.1210\/jc.2015-1453","article-title":"The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing\u2019s Disease","volume":"100","author":"Theodoropoulou","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"D\u2019Angelo, D., De Martino, M., Arra, C., and Fusco, A. (2019). Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis. Cancers, 11.","DOI":"10.3390\/cancers11091302"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s12020-015-0682-y","article-title":"USP8: A Novel Therapeutic Target for Cushing\u2019s Disease","volume":"50","author":"Jian","year":"2015","journal-title":"Endocrine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000500688","article-title":"Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing","volume":"110","author":"Sesta","year":"2020","journal-title":"Neuroendocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1055\/a-1089-7806","article-title":"USP8 Mutations and Cell Cycle Regulation in Corticotroph Adenomas","volume":"52","author":"Martins","year":"2020","journal-title":"Horm. Metab. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.tem.2015.08.003","article-title":"The New Molecular Landscape of Cushing\u2019s Disease","volume":"26","author":"Sbiera","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s11102-019-00973-9","article-title":"Cushing\u2019s Disease Due to Somatic USP8 Mutations: A Systematic Review and Meta-Analysis","volume":"22","author":"Wanichi","year":"2019","journal-title":"Pituitary"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1677\/joe.1.05616","article-title":"Expression of Epidermal Growth Factor Receptor in Neoplastic Pituitary Cells: Evidence for a Role in Corticotropinoma Cells","volume":"183","author":"Theodoropoulou","year":"2004","journal-title":"J. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4712","DOI":"10.1172\/JCI60417","article-title":"EGFR as a Therapeutic Target for Human, Canine, and Mouse ACTH-Secreting Pituitary Adenomas","volume":"121","author":"Fukuoka","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1210\/js.2016-1053","article-title":"EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis","volume":"1","author":"Araki","year":"2017","journal-title":"J. Endocr. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41392-020-00284-7","article-title":"Bexarotene Combined with Lapatinib for the Treatment of Cushing\u2019s Disease: Evidence Based on Drug Repositioning and Experimental Confirmation","volume":"5","author":"Yu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a001602","DOI":"10.1101\/mcs.a001602","article-title":"Identification of a Novel RASD1 Somatic Mutation in a USP8-Mutated Corticotroph Adenoma","volume":"3","author":"Uzilov","year":"2017","journal-title":"Mol. Case Stud."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1080\/10253890.2021.1907340","article-title":"Expression of Rasd1 in Mouse Endocrine Pituitary Cells and Its Response to Dexamethasone","volume":"24","author":"Foradori","year":"2021","journal-title":"Stress"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1210\/jc.2018-02564","article-title":"Impact of USP8 Gene Mutations on Protein Deregulation in Cushing Disease","volume":"104","author":"Weigand","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ccell.2019.11.002","article-title":"Pangenomic Classification of Pituitary Neuroendocrine Tumors","volume":"37","author":"Neou","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xia, R., Jia, H., Fan, J., Liu, Y., and Jia, J. (2012). USP8 Promotes Smoothened Signaling by Preventing Its Ubiquitination and Changing Its Subcellular Localization. PLoS Biol., 10.","DOI":"10.1371\/journal.pbio.1001238"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bujko, M., Kober, P., Boresowicz, J., Rusetska, N., Zeber-Lubecka, N., Paziewska, A., Pekul, M., Zielinski, G., Styk, A., and Kunicki, J. (2021). Differential MicroRNA Expression in USP8-Mutated and Wild-Type Corticotroph Pituitary Tumors Reflect the Difference in Protein Ubiquitination Processes. J. Clin. Med., 10.","DOI":"10.3390\/jcm10030375"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1210\/clinem\/dgaa853","article-title":"USP8 and TP53 Drivers Are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors","volume":"106","author":"Uzilov","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/cr.2016.114","article-title":"The Genome-Wide Mutational Landscape of Pituitary Adenomas","volume":"26","author":"Song","year":"2016","journal-title":"Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1530\/EJE-15-0689","article-title":"The USP8 Mutational Status May Predict Drug Susceptibility in Corticotroph Adenomas of Cushing\u2019s Disease","volume":"174","author":"Hayashi","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1210\/jc.2017-00161","article-title":"Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease","volume":"102","author":"Faucz","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/cen.13802","article-title":"The USP8 Mutational Status May Predict Long-Term Remission in Patients with Cushing\u2019s Disease","volume":"89","author":"Albani","year":"2018","journal-title":"Clin. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s12020-018-1776-0","article-title":"Clinical Characteristics and Surgical Outcome in USP8-Mutated Human Adrenocorticotropic Hormone-Secreting Pituitary Adenomas","volume":"63","author":"Losa","year":"2019","journal-title":"Endocrine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1001\/jamaoto.2020.1471","article-title":"Molecular Diagnosis and Extracranial Extension in Cushing Disease","volume":"146","author":"Hong","year":"2020","journal-title":"JAMA Otolaryngol. Neck Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104","DOI":"10.5603\/EP.a2020.0073","article-title":"Is There a Common Cause for Paediatric Cushing\u2019s Disease?","volume":"72","author":"Faucz","year":"2021","journal-title":"Endokrynol. Pol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4676","DOI":"10.1210\/jc.2019-00697","article-title":"Germline USP8 Mutation Associated with Pediatric Cushing Disease and Other Clinical Features: A New Syndrome","volume":"104","author":"Cohen","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sbiera, S., Kunz, M., Weigand, I., Deutschbein, T., Dandekar, T., and Fassnacht, M. (2019). The New Genetic Landscape of Cushing\u2019s Disease: Deubiquitinases in the Spotlight. Cancers, 11.","DOI":"10.3390\/cancers11111761"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s12020-021-02903-x","article-title":"USP8, USP48, and BRAF Mutations Differ in Their Genotype-Phenotype Correlation in Asian Indian Patients with Cushing\u2019s Disease","volume":"75","author":"Abraham","year":"2022","journal-title":"Endocrine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nrm2731","article-title":"Breaking the Chains: Structure and Function of the Deubiquitinases","volume":"10","author":"Komander","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1093\/neuonc\/noz109","article-title":"Driver Mutations in USP8 Wild-Type Cushing\u2019s Disease","volume":"21","author":"Sbiera","year":"2019","journal-title":"Neuro-Oncology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1038\/s41467-018-05275-5","article-title":"Identification of Recurrent USP48 and BRAF Mutations in Cushing\u2019s Disease","volume":"9","author":"Chen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_43","first-page":"1934","article-title":"Decreased Expression of SFRP2 Promotes Development of the Pituitary Corticotroph Adenoma by Upregulating Wnt Signaling","volume":"52","author":"Ren","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s11033-019-04587-z","article-title":"Catalytic Domain of Deubiquitinylase USP48 Directs Interaction with Rel Homology Domain of Nuclear Factor KappaB Transcription Factor RelA","volume":"46","author":"Ghanem","year":"2019","journal-title":"Mol. Biol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s12022-007-9006-y","article-title":"P53 Gene Mutations in Pituitary Carcinomas","volume":"18","author":"Tanizaki","year":"2007","journal-title":"Endocr. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/j.1365-2265.2008.03404.x","article-title":"P53 Gene Mutation in an Atypical Corticotroph Adenoma with Cushing\u2019s Disease","volume":"70","author":"Kawashima","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1210\/jc.2016-1379","article-title":"Testicular Receptor-4: Novel Regulator of Glucocorticoid Resistance","volume":"101","author":"Zhang","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1101\/gad.1444606","article-title":"Role of Brg1 and HDAC2 in GR Trans-Repression of the Pituitary POMC Gene and Misexpression in Cushing Disease","volume":"20","author":"Bilodeau","year":"2006","journal-title":"Genes Dev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s40291-020-00480-9","article-title":"A Novel Pathogenic Variant in the N-Terminal Domain of the Glucocorticoid Receptor, Causing Glucocorticoid Resistance","volume":"24","author":"Paragliola","year":"2020","journal-title":"Mol. Diagn. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"bqab167","DOI":"10.1210\/endocr\/bqab167","article-title":"Effect of 3 NR3C1 Mutations in the Pathogenesis of Pituitary ACTH Adenoma","volume":"162","author":"Miao","year":"2021","journal-title":"Endocrinology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jmgm.2019.07.020","article-title":"Deciphering the Structural Basis for Glucocorticoid Resistance Caused by Missense Mutations in the Ligand Binding Domain of Glucocorticoid Receptor","volume":"92","author":"Monteiro","year":"2019","journal-title":"J. Mol. Graph. Model."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"bqab257","DOI":"10.1210\/endocr\/bqab257","article-title":"Glucocorticoid Receptors Are Making a Comeback in Corticotroph Tumorigenesis","volume":"163","author":"Theodoropoulou","year":"2022","journal-title":"Endocrinology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1210\/jc.2015-3324","article-title":"The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease","volume":"101","author":"Couture","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1158\/0008-5472.CAN-14-0036","article-title":"Cables1 Complex Couples Survival Signaling to the Cell Death Machinery","volume":"75","author":"Shi","year":"2015","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1507\/endocrj.EJ19-0239","article-title":"Ubiquitin-Specific Protease 8 Inhibitor Suppresses Adrenocorticotropic Hormone Production and Corticotroph Tumor Cell Proliferation","volume":"67","author":"Kageyama","year":"2020","journal-title":"Endocr. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1530\/ERC-17-0131","article-title":"Loss-of-Function Mutations in the CABLES1 Gene Are a Novel Cause of Cushing\u2019s Disease","volume":"24","author":"Gam","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.mce.2013.08.022","article-title":"Carney Complex and McCune Albright Syndrome: An Overview of Clinical Manifestations and Human Molecular Genetics","volume":"386","author":"Salpea","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1097\/PAS.0b013e31821ec4ce","article-title":"Primary Bimorphic Adrenocortical Disease","volume":"35","author":"Carney","year":"2011","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1365-2362.1995.tb01537.x","article-title":"G-Protein Mutations in Human Pituitary Adrenocorticotrophic Hormone-Secreting Adenomas","volume":"25","author":"WILLIAMSON","year":"1995","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1136\/mp.55.1.58","article-title":"An R201H Activating Mutation of the GNAS1 (Gsalpha) Gene in a Corticotroph Pituitary Adenoma","volume":"55","author":"Riminucci","year":"2002","journal-title":"Mol. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"650791","DOI":"10.3389\/fendo.2021.650791","article-title":"Aggressive Cushing\u2019s Disease: Molecular Pathology and Its Therapeutic Approach","volume":"12","author":"Yamamoto","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e1183","DOI":"10.1210\/clinem\/dgaa749","article-title":"Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations","volume":"106","author":"Boldt","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.1210\/jc.2017-01401","article-title":"Corticotroph Pituitary Carcinoma in a Patient with Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort","volume":"102","author":"Bengtsson","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1210\/jc.2018-01347","article-title":"Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab","volume":"103","author":"Lin","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_65","first-page":"124","article-title":"Nelson\u2019s Syndrome Associated with a Somatic Frame Shift Mutation in the Glucocorticoid Receptor Gene","volume":"81","author":"Karl","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1530\/EJE-17-0634","article-title":"Somatic USP8 Mutations Are Frequent Events in Corticotroph Tumor Progression Causing Nelson\u2019s Tumor","volume":"178","author":"Theodoropoulou","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_67","first-page":"1039","article-title":"Recurrence in Silent Corticotroph Adenomas after Primary Treatment: A Systematic Review and Meta-Analysis","volume":"104","author":"Fountas","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s11102-018-0864-8","article-title":"Silent Corticotroph Adenomas","volume":"21","author":"Cooper","year":"2018","journal-title":"Pituitary"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Eieland, A.K., Normann, K.R., Sundaram, A.Y.M., Nyman, T.A., \u00d8ystese, K.A.B., Lekva, T., Berg, J.P., Bollerslev, J., and Olarescu, N.C. (2020). Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas. Cancers, 12.","DOI":"10.3390\/cancers12102980"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/BF02738816","article-title":"Pars Intermedia of the Human Pituitary Revisited: Morphologic Aspects and Frequency of Hyperplasia of POMC-Peptide Immunoreactive Cells","volume":"10","author":"Horvath","year":"1999","journal-title":"Endocr. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1530\/EJE-10-0245","article-title":"Upregulation of CDKN2A and Suppression of Cyclin D1 Gene Expressions in ACTH-Secreting Pituitary Adenomas","volume":"163","author":"Tani","year":"2010","journal-title":"Eur. J. Endocrinol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1530\/EJE-19-0194","article-title":"USP8 Mutations in Corticotroph Adenomas Determine a Distinct Gene Expression Profile Irrespective of Functional Tumour Status","volume":"181","author":"Bujko","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1530\/EJE-10-0076","article-title":"Clinical, Hormonal and Molecular Characterization of Pituitary ACTH Adenomas without (Silent Corticotroph Adenomas) and with Cushing\u2019s Disease","volume":"163","author":"Raverot","year":"2010","journal-title":"Eur. J. Endocrinol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/j.1365-2362.2011.02621.x","article-title":"The Molecular Pathogenesis of Corticotroph Tumours","volume":"42","author":"Dworakowska","year":"2012","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1365-2559.2010.03495.x","article-title":"Increased Expression of HMGA1 Correlates with Tumour Invasiveness and Proliferation in Human Pituitary Adenomas","volume":"56","author":"Wang","year":"2010","journal-title":"Histopathology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e754","DOI":"10.1016\/j.wneu.2021.11.049","article-title":"Functioning Crooke Cell Adenomas: Case Series and Literature Review","volume":"158","author":"Giraldi","year":"2022","journal-title":"World Neurosurg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"bvac001","DOI":"10.1210\/jendso\/bvac001","article-title":"MEN1 Surveillance Guidelines: Time to (Re)Think?","volume":"6","author":"Newey","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1210\/jc.2012-1230","article-title":"Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1)","volume":"97","author":"Thakker","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s12020-017-1234-4","article-title":"Multiple Endocrine Neoplasia Syndrome Type 1: Institution, Management, and Data Analysis of a Nationwide Multicenter Patient Database","volume":"58","author":"Giusti","year":"2017","journal-title":"Endocrine"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1210\/jcem.87.2.8145","article-title":"Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study","volume":"87","author":"Boureille","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1111\/cen.13796","article-title":"Children with MEN1 Gene Mutations May Present First (and at a Young Age) with Cushing Disease","volume":"89","author":"Makri","year":"2018","journal-title":"Clin. Endocrinol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e46","DOI":"10.1016\/j.amjmed.2019.07.043","article-title":"Cushing\u2019s Disease in a Patient with MEN 2B Syndrome","volume":"133","author":"Kruljac","year":"2020","journal-title":"Am. J. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1111\/cen.12072","article-title":"Confusing Genes: A Patient with MEN2A and Cushing\u2019s Disease","volume":"78","author":"Naziat","year":"2013","journal-title":"Clin. Endocrinol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1308\/003588412X13171221590818","article-title":"MEN 2 Syndrome Masquerading as MEN 1","volume":"94","author":"Ezzat","year":"2012","journal-title":"Ann. R. Coll. Surg. Engl."},{"key":"ref_85","first-page":"1","article-title":"Cushing Disease in a Patient with Multiple Endocrine Neoplasia Type 2B","volume":"4","author":"Kasturi","year":"2017","journal-title":"J. Clin. Transl. Endocrinol. Case Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1111\/imj.14394","article-title":"Multiple Endocrine Neoplasia: An Update","volume":"49","author":"McDonnell","year":"2019","journal-title":"Intern. Med. J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1210\/endrev\/bnaa006","article-title":"Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms","volume":"41","author":"Korbonits","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"15558","DOI":"10.1073\/pnas.0603877103","article-title":"Germ-Line Mutations in P27 Kip1 Cause a Multiple Endocrine Neoplasia Syndrome in Rats and Humans","volume":"103","author":"Pellegata","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1210\/jc.2006-2843","article-title":"Germline CDKN1B\/P27Kip1 Mutation in Multiple Endocrine Neoplasia","volume":"92","author":"Georgitsi","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1365-2265.2008.03379.x","article-title":"Assessment of P27 (Cyclin-Dependent Kinase Inhibitor 1B) and Aryl Hydrocarbon Receptor-Interacting Protein (AIP) Genes in Multiple Endocrine Neoplasia (MEN1) Syndrome Patients without Any Detectable MEN1 Gene Mutations","volume":"70","author":"Igreja","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.1399-0004.2010.01406.x","article-title":"The Role of Germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C Mutations in Causing Pituitary Adenomas in a Large Cohort of Children, Adolescents, and Patients with Genetic Syndromes","volume":"78","author":"Stratakis","year":"2010","journal-title":"Clin. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1210\/jc.2008-2083","article-title":"Rare Germline Mutations in Cyclin-Dependent Kinase Inhibitor Genes in Multiple Endocrine Neoplasia Type 1 and Related States","volume":"94","author":"Agarwal","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1210\/jc.2009-0494","article-title":"Multiple Endocrine Neoplasia Type I Variants and Phenocopies: More than a Nosological Issue?","volume":"94","author":"Falchetti","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1210\/clinem\/dgaa160","article-title":"Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing\u2019s Disease with or without an MEN4 Phenotype","volume":"105","author":"Chasseloup","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1530\/EJE-20-1120","article-title":"MANAGEMENT Of ENDOCRINE DISEASE: Carney complex: Clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) Gene","volume":"184","author":"Bouys","year":"2021","journal-title":"Eur. J. Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1210\/js.2017-00231","article-title":"Corticotropinoma as a Component of Carney Complex","volume":"1","author":"Tatsi","year":"2017","journal-title":"J. Endocr. Soc."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"K7","DOI":"10.1530\/EJE-17-0227","article-title":"PRKAR1A Mutation Causing Pituitary-Dependent Cushing Disease in a Patient with Carney Complex","volume":"177","author":"Kiefer","year":"2017","journal-title":"Eur. J. Endocrinol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"E710","DOI":"10.1210\/jc.2014-4297","article-title":"Pituitary Adenoma with Paraganglioma\/Pheochromocytoma (3PAs) and Succinate Dehydrogenase Defects in Humans and Mice","volume":"100","author":"Xekouki","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"R197","DOI":"10.1530\/ERC-17-0509","article-title":"DICER1 Gene Mutations in Endocrine Tumors","volume":"25","author":"Solarski","year":"2018","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00401-014-1285-z","article-title":"Pituitary Blastoma: A Pathognomonic Feature of Germ-Line DICER1 Mutations","volume":"128","author":"Sabbaghian","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"E1487","DOI":"10.1210\/jc.2014-1016","article-title":"Germline and Somatic DICER1 Mutations in a Pituitary Blastoma Causing Infantile-Onset Cushing\u2019s Disease","volume":"99","author":"Sahakitrungruang","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3389\/fendo.2020.00433","article-title":"Rare Germline DICER1 Variants in Pediatric Patients with Cushing\u2019s Disease: What Is Their Role?","volume":"11","author":"Portillo","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1507\/endocrj.EJ17-0036","article-title":"Atypical Pituitary Adenoma with MEN1 Somatic Mutation Associated with Abnormalities of DNA Mismatch Repair Genes; MLH1 Germline Mutation and MSH6 Somatic Mutation","volume":"64","author":"Uraki","year":"2017","journal-title":"Endocr. J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1159\/000446435","article-title":"Hypercortisolism Due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome","volume":"86","author":"Brioude","year":"2016","journal-title":"Horm. Res. Paediatr."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"101418","DOI":"10.1016\/j.beem.2020.101418","article-title":"Cushing Syndrome: Old and New Genes","volume":"34","author":"Tatsi","year":"2020","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1111\/j.1365-2265.2005.02374.x","article-title":"Simultaneous Cushing\u2019s Disease and Tuberous Sclerosis; a Potential Role for TSC in Pituitary Ontogeny","volume":"63","author":"Tigas","year":"2005","journal-title":"Clin. Endocrinol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/j.1365-2265.2007.02941.x","article-title":"Cushing\u2019s Syndrome Due to a Pituitary Corticotropinoma in a Child with Tuberous Sclerosis: An Association or a Coincidence?","volume":"67","author":"Nandagopal","year":"2007","journal-title":"Clin. Endocrinol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"907","DOI":"10.4158\/EP-2018-0111","article-title":"Pathogenesis of Cushing Disease: An Update on the Genetics of Corticotropinomas","volume":"24","author":"Albani","year":"2018","journal-title":"Endocr. Pract."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"E663","DOI":"10.1210\/jc.2011-2291","article-title":"Germline AIP Mutations in Apparently Sporadic Pituitary Adenomas: Prevalence in a Prospective Single-Center Cohort of 443 Patients","volume":"97","author":"Cazabat","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_110","first-page":"140105","article-title":"An Unusual Case of an ACTH-Secreting Macroadenoma with a Germline Variant in the Aryl Hydrocarbon Receptor-Interacting Protein (AIP) Gene","volume":"2015","author":"Dinesen","year":"2015","journal-title":"Endocrinol. Diabetes Metab. Case Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1159\/000495252","article-title":"Three Novel MEN1 Variants in AIP-Negative Familial Isolated Pituitary Adenoma Patients","volume":"86","author":"Yarman","year":"2019","journal-title":"Pathobiology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.ajhg.2017.03.011","article-title":"Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas","volume":"100","author":"Zhang","year":"2017","journal-title":"Am. J. Hum. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6824\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:35:12Z","timestamp":1760139312000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,19]]},"references-count":112,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23126824"],"URL":"https:\/\/doi.org\/10.3390\/ijms23126824","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,19]]}}}