MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics

Abstract

Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1α regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.

MEN4 and CDKN1B mutations: the latest of the MEN syndromes

“…Mutations in CDKN1B in sporadic gigantism or acromegaly and among pediatric patients with pituitary adenomas appear to be very rare (Schernthaner-Reiter, et al 2016; Stratakis, et al 2010). Genetic alterations of CDKN1B in somatotropinoma, corticotropinoma, non-functioning pituitary adenomas and sporadic pNET are also very infrequent (Dahia, et al 1998; Ikeda, et al 1997; Lee and Pellegata 2013; Lindberg, et al 2007; Stratakis et al 2010; Takeuchi, et al 1998).…”

Recent advances in understanding corticotroph pituitary tumor initiation and progression

“…Patients with MEN1, which is caused by a mutation of the MEN1 gene encoding the tumor suppressor menin, mainly manifest prolactinomas and somatotropinomas and only about 5% of their totality is represented by corticotroph tumors 8, 9 . So far, a single case of CA has been described in MEN4, in which the cell cycle regulator p27 Kip1 is impaired by inactivating mutations of the CDKN1B gene 10 .…”

Pituitary adenoma: a literature review

“…Ávy kus mu ta ci jai, sutrin ka ðio pro duk to ga my ba ir vys to si prie sky di nës liaukos, ka sos neu ro en dok ri ni niai na vi kai ir hi po fi zës ade nomos (2,7 % vi sø HA at ve jø), taip pat ki ti en dok ri ni niai ir ne en dok ri ni niai na vi kai (vei do an gio fib ro mos ir kt.). Ge no raið ka yra di de lë, kli nið kai sin dro mas iki penk to gy ve ni mo de ðimt me èio pa si reið kia 80 % at ve jø: 73-75 % -pir mi niu hi per pa ra ti roi diz mu, 31-48 % -HA (daþ niau siai pro lak tino mo mis), 45-49 % -ka sos sa le liø na vi kais [17,18].…”

“…At li kus ty ri mus, bu vo nu sta ty ta, kad ðá sin dro mà su kelia CDKN1B ge no, esan èio 12 chro mo so mos trum po jo peties 13.1 re gio ne, mu ta ci ja. Jis ko duo ja nu ma no mà tu mo ro su pre so riø p27, ku ris da ly vau ja làs te lës cik lo re gu lia ci jo je, sà vei kau da mas su nuo cik li no pri klau so mo mis ki na zë mis [17][18][19]. Kol kas me di ci ni në je li te ra tû ro je ap ra ðy ta tik 19 at ve jø, kai bu vo nu sta ty tos CDKN1B ge no mu ta ci jos, tai gi kli ni ka në ra iki ga lo api bû din ta ir pa tvir tin ta.…”

“…Pas ta ra ja me yra ge nas, ko duo jan tis pro tein ki na zës A re gu lia ci ná subvie ne tà 1a (PRKAR1A). Jei ávyks ta jo mu ta ci ja, mRNR tam pa ne sta bi li, su ma þë ja ar ið nyks ta bal ty mø sin te zë [17,18,20]. CNC pa cien tams, ser gan tiems HA, ga li bû ti ste bima dau giau nei vie no hor mo no pro duk ci ja [20].…”