{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:16:47Z","timestamp":1784557007828,"version":"3.55.0"},"reference-count":24,"publisher":"Bioscientifica","license":[{"start":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T00:00:00Z","timestamp":1534982400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/deed.en_GB"}],"content-domain":{"domain":["edm.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,8,23]]},"abstract":"Summary<\/jats:title>\n \n Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem hereditary cutaneous condition, characterized by multiple hamartomas. In rare cases, pituitary neuroendocrine tumors (PitNETs) have been described in patients with TSC, but the causal relationship between these two diseases is still under debate. TSC is mostly caused by mutations of two tumor suppressor genes, encoding for hamartin (TSC1) and tuberin (TSC2), controlling cell growth and proliferation. Here, we present the case of a 62-year-old Caucasian woman with TSC and a silent gonadotroph PitNET with suprasellar extension, treated with transsphenoidal endoscopic neurosurgery with complete resection. Therapeutic approaches based on mTOR signaling (i.e. everolimus) have been successfully used in patients with TSC and tested in non-functioning PitNET cellular models with promising results. Here, we observed a reduction of cell viability after an\n in vitro<\/jats:italic>\n treatment of PitNET\u2019s derived primary cells with everolimus. TSC analysis retrieved no disease-associated variants with the exception of the heterozygous intronic variant c.4006-71C>T found in\n TSC2<\/jats:italic>\n : the computational tools predicted a gain of a new splice site with consequent intron retention, not confirmed by an\n in vitro<\/jats:italic>\n analysis of patient\u2019s lymphocyte-derived RNA. Further analyses are therefore needed to provide insights on the possible mechanisms involving the hamartin-tuberin complex in the pathogenesis of pituitary adenomas. However, our data further support previous observations of an antiproliferative effect of everolimus on PitNET.\n <\/jats:p>\n \n Learning points:<\/jats:title>\n \n \n Pituitary neuroendocrine tumors (PitNET) in patients with tuberous sclerosis complex (TSC) are rare: only few cases have been reported in literature.<\/jats:p>\n <\/jats:list-item>\n \n Therapeutic approach related to mTOR signaling, such as everolimus, may be used in some patients with PitNETs as well as those with TSC.<\/jats:p>\n <\/jats:list-item>\n \n We reported a woman with both non-secreting PitNET and TSC; PitNET was surgically removed and classified as a silent gonadotroph tumor.<\/jats:p>\n <\/jats:list-item>\n \n Everolimus treatment in PitNET\u2019s-derived primary cells revealed a significant decrease in cell viability.<\/jats:p>\n <\/jats:list-item>\n \n Considering our case and available evidence, it is still unclear whether a PitNET is a part of TSC or just a coincidental tumor.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>","DOI":"10.1530\/edm-18-0086","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T09:28:17Z","timestamp":1535016497000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-2","source":"Crossref","is-referenced-by-count":8,"title":["Silent gonadotroph pituitary neuroendocrine tumor in a patient with tuberous sclerosis complex: evaluation of a possible molecular link"],"prefix":"10.1530","volume":"2018","author":[{"given":"Daniela","family":"Regazzo","sequence":"first","affiliation":[{"name":"1Department of Medicine DIMED, Endocrinology Unit, University Hospital of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Paola","family":"Gardiman","sequence":"additional","affiliation":[{"name":"2Department of Medicine DIMED, Surgical Pathology & Cytopathology Unit, University Hospital of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marily","family":"Theodoropoulou","sequence":"additional","affiliation":[{"name":"3Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t M\u00fcnchen, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Scaroni","sequence":"additional","affiliation":[{"name":"1Department of Medicine DIMED, Endocrinology Unit, University Hospital of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Occhi","sequence":"additional","affiliation":[{"name":"4Department of Biology, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Ceccato","sequence":"additional","affiliation":[{"name":"1Department of Medicine DIMED, Endocrinology Unit, University Hospital of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref111","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2217\/cns-2016-0011","article-title":"Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy","volume":"5","year":"2016","journal-title":"CNS Oncology"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ando.2015.04.002","article-title":"Management of clinically non-functioning pituitary adenoma","volume":"76","year":"2015","journal-title":"Annales d\u2019Endocrinologie"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ando.2015.04.002","article-title":"Management of clinically non-functioning pituitary adenoma","volume":"76","year":"2015","journal-title":"Annales d\u2019Endocrinologie"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1210\/jc.2009-1641","article-title":"Effect of everolimus on cell viability in nonfunctioning pituitary adenomas","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s12020-017-1432-0","article-title":"PI3K\/Akt\/mTOR pathway involvement in regulating growth hormone secretion in a rat pituitary adenoma cell line","volume":"60","year":"2018","journal-title":"Endocrine"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0140-6736(08)61279-9","article-title":"Tuberous sclerosis","volume":"372","year":"2008","journal-title":"Lancet"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1210\/jc.2006-1668","article-title":"High prevalence of pituitary adenomas: a cross-sectional study in the province of Li\u00e8ge, Belgium","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1210\/jc.2009-1641","article-title":"Effect of everolimus on cell viability in nonfunctioning pituitary adenomas","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11102-011-0341-0","article-title":"New targeted therapies in pituitary carcinoma resistant to temozolomide","volume":"15","year":"2012","journal-title":"Pituitary"},{"key":"ref191","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1210\/jc.2006-1668","article-title":"High prevalence of pituitary adenomas: a cross-sectional study in the province of Li\u00e8ge, Belgium","volume":"91","year":"2006","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0140-6736(08)61279-9","article-title":"Tuberous sclerosis","volume":"372","year":"2008","journal-title":"Lancet"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1749-6632.2009.05117.x","article-title":"The tuberous sclerosis complex","volume":"1184","year":"2010","journal-title":"Annals of the New York Academy of Sciences"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1749-6632.2009.05117.x","article-title":"The tuberous sclerosis complex","volume":"1184","year":"2010","journal-title":"Annals of the New York Academy of Sciences"},{"key":"ref41","first-page":"1477","article-title":"Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis","volume":"151","year":"1997","journal-title":"American Journal of Pathology"},{"key":"ref151","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1677\/ERC-08-0142","article-title":"Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review","volume":"16","year":"2009","journal-title":"Endocrine-Related Cancer"},{"key":"ref161","first-page":"1477","article-title":"Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis","volume":"151","year":"1997","journal-title":"American Journal of Pathology"},{"key":"ref21","first-page":"1","article-title":"Mosaic and intronic mutations in TSC1\/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing","volume":"11","year":"2015","journal-title":"PLoS Genetics"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11102-011-0341-0","article-title":"New targeted therapies in pituitary carcinoma resistant to temozolomide","volume":"15","year":"2012","journal-title":"Pituitary"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s12020-017-1432-0","article-title":"PI3K\/Akt\/mTOR pathway involvement in regulating growth hormone secretion in a rat pituitary adenoma cell line","volume":"60","year":"2018","journal-title":"Endocrine"},{"key":"ref231","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2217\/cns-2016-0011","article-title":"Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy","volume":"5","year":"2016","journal-title":"CNS Oncology"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.1210\/en.2016-1028","article-title":"Role of mTOR inhibitors in growth hormone-producing pituitary adenomas harboring different FGFR4 genotypes","volume":"157","year":"2016","journal-title":"Endocrinology"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1677\/ERC-08-0142","article-title":"Are neuroendocrine tumours a feature of tuberous sclerosis? 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