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Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome

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Abstract

Purpose

Multiple endocrine neoplasia type 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome, associated with a wide tumor spectrum but hallmarked by primary hyperparathyroidism, which represents the most common clinical feature, followed by pituitary (functional and non-functional) adenomas, and neuroendocrine tumors. MEN4 clinically overlaps MEN type 1 (MEN1) but differs from it for milder clinical features and an older patient’s age at onset. The underlying mutated gene, CDKN1B, encodes the cell cycle regulator p27, implicated in cellular proliferation, motility and apoptosis. Given the paucity of MEN4 cases described in the literature, possible genotype–phenotype correlations have not been thoroughly assessed, and specific clinical recommendations are lacking. The present review provides an extensive overview of molecular genetics and clinical features of MEN4, with the aim of contributing to delineate peculiar strategies for clinical management, screening and follow-up of the last and least known MEN syndrome.

Methods

A literature search was performed through online databases like MEDLINE and Scopus.

Conclusions

MEN4 is much less common that MEN1, tend to present later in life with a more indolent course, although involving the same primary organs as MEN1. As a consequence, MEN4 patients might need specific diagnostic and therapeutic approaches and a different strategy for screening and follow-up. Further studies are needed to assess the real oncological risk of MEN4 carriers, and to establish a standardized screening protocol. Furthermore, a deeper understanding of molecular genetics of MEN4 is needed in order to explore p27 as a novel therapeutic target.

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References

  1. M.L. Brandi, S.K. Agarwal, N.D. Perrier, K.E. Lines, G.D. Valk, R.V. Thakker, Multiple Endocrine Neoplasia Type 1: latest insights. Endocr. Rev. 42(2), 133–70. (2021)

    Article  PubMed  Google Scholar 

  2. M.L. Brandi, R.F. Gagel, A. Angeli, J.P. Bilezikian, P. Beck-Peccoz, C. Bordi et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 86(12), 5658–5671 (2001)

    Article  CAS  PubMed  Google Scholar 

  3. A. Fritz, A. Walch, K. Piotrowska, M. Rosemann, E. Schaffer, K. Weber et al. Recessive transmission of a multiple endocrine neoplasia syndrome in the rat. Cancer Res. 62(11), 3048–3051 (2002)

    CAS  PubMed  Google Scholar 

  4. N.S. Pellegata, L. Quintanilla-Martinez, H. Siggelkow, E. Samson, K. Bink, H. Hofler et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl. Acad. Sci. USA 103(42), 15558–15563 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. M. Georgitsi, A. Raitila, A. Karhu, R.B. van der Luijt, C.M. Aalfs, T. Sane et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J. Clin. Endocrinol. Metab. 92(8), 3321–3325 (2007)

    Article  CAS  PubMed  Google Scholar 

  6. R. Halperin, L. Arnon, S. Nasirov, L. Friedensohn, M. Gershinsky, A. Telerman, Germline CDKN1B variant type and site are associated with phenotype in MEN4. Endocr. Relat. Cancer 30(1), e220174 (2022)

    PubMed  Google Scholar 

  7. H. Singeisen, M.M. Renzulli, V. Pavlicek, P. Probst, F. Hauswirth, M.K. Muller, Multiple endocrine neoplasia type 4: a new member of the MEN family. Endocr. Connect. 12(2), e220411 (2023)

    Article  CAS  PubMed  Google Scholar 

  8. S.F. Razavipour, K.B. Harikumar, J.M. Slingerland, p27 as a transcriptional regulator: new roles in development and cancer. Cancer Res. 80(17), 3451–3458 (2020)

    Article  CAS  PubMed  Google Scholar 

  9. D. Bencivenga, I. Caldarelli, E. Stampone, F.P. Mancini, M.L. Balestrieri, F. Della Ragione et al. p27(Kip1) and human cancers: a reappraisal of a still enigmatic protein. Cancer Lett. 403, 354–65. (2017)

    Article  CAS  PubMed  Google Scholar 

  10. H. Li, M. Collado, A. Villasante, A. Matheu, C.J. Lynch, M. Canamero et al. p27(Kip1) directly represses Sox2 during embryonic stem cell differentiation. Cell Stem Cell 11, 845–852 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. G. Baldassarre, B. Belletti, M.S. Nicoloso, M. Schiappacassi, A. Vecchione, P. Spessotto et al. p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell 7, 51–63 (2005)

    Article  CAS  PubMed  Google Scholar 

  12. C.I. Rubin, G.F. Atweh, The role of stathmin in the regulation of the cell cycle. J. Cell Biochem. 93, 242–250 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. R.T. Perchey, M.P. Serres, A. Nowosad, J. Creff, C. Callot, A. Gay et al. p27(Kip1) regulates the microtubule bundling activity of PRC1. Biochim. Biophys. Acta Mol. Cell Res. 1865, 1630–1639 (2018)

    Article  CAS  PubMed  Google Scholar 

  14. M.M. Babu, The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease. Biochem. Soc. Trans. 44(5), 1185–200. (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. A. Nowosad, A. Besson, CDKN1B/p27 regulates autophagy via the control of Ragulator and MTOR activity in amino acid-deprived cells. Autophagy 16(12), 2297–2298 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. O.V. Bochis, A. Irimie, M. Pichler, I. Berindan-Neagoe, The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer. J. Gastrointestin Liver Dis. 24(2), 225–234 (2015)

    Article  PubMed  Google Scholar 

  17. S. Dietrich, J. Hullein, S.C. Lee, B. Hutter, D. Gonzalez, S. Jayne et al. Recurrent CDKN1B (p27) mutations in hairy cell leukemia. Blood 126(8), 1005–1008 (2015)

    Article  CAS  PubMed  Google Scholar 

  18. D. Viotto, F. Russo, I. Anania, I. Segatto, G.L. Rampioni Vinciguerra, A. Dall’Acqua et al. CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer. J. Pathol. 253(2), 234–45. (2021)

    Article  CAS  PubMed  Google Scholar 

  19. C.E. Barbieri, S.C. Baca, M.S. Lawrence, F. Demichelis, M. Blattner, J.P. Theurillat et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44(6), 685–689 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. J.M. Francis, A. Kiezun, A.H. Ramos, S. Serra, C.S. Pedamallu, Z.R. Qian et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat. Genet. 45(12), 1483–1486 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. C.S. Martins, R.C. Camargo, F.P. Saggioro, L. Neder, H.R. Machado, A.C. Moreira et al. P27/CDKN1B translational regulators in pituitary tumorigenesis. Horm. Metab. Res. 48(12), 840–846 (2016)

    Article  CAS  PubMed  Google Scholar 

  22. B. Belletti, G. Baldassarre, Roles of CDKN1B in cancer? Aging (Albany NY) 7(8), 529–530 (2015)

    Article  CAS  PubMed  Google Scholar 

  23. R.V. Thakker, Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell Endocrinol. 386(1-2), 2–15 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. S.K. Karnik, C.M. Hughes, X. Gu, O. Rozenblatt-Rosen, G.W. McLean, Y. Xiong et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc. Natl. Acad. Sci. USA 102(41), 14659–14664 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. J. Huang, B. Gurung, B. Wan, S. Matkar, N.A. Veniaminova, K. Wan et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482(7386), 542–546 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. S. Borsari, E. Pardi, N.S. Pellegata, M. Lee, F. Saponaro, L. Torregrossa et al. Loss of p27 expression is associated with MEN1 gene mutations in sporadic parathyroid adenomas. Endocrine 55(2), 386–97. (2017)

    Article  CAS  PubMed  Google Scholar 

  27. R. Alrezk, F. Hannah-Shmouni, C.A. Stratakis, MEN4 and CDKN1B mutations: the latest of the MEN syndromes. Endocr. Relat. Cancer 24(10), T195–T208 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. T.A. Milne, C.M. Hughes, R. Lloyd, Z. Yang, O. Rozenblatt-Rosen, Y. Dou et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl. Acad. Sci. USA 102(3), 749–754 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. S.K. Agarwal, C.M. Mateo, S.J. Marx, Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J. Clin. Endocrinol. Metab. 94(5), 1826–1834 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. S. Molatore, I. Marinoni, M. Lee, E. Pulz, M.R. Ambrosio, E.C. degli Uberti et al. A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum. Mutat. 31(11), E1825–E1835 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. M.C. Lemos, R.V. Thakker, Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum. Mutat. 29(1), 22–32 (2008)

    Article  CAS  PubMed  Google Scholar 

  32. P. Concolino, A. Costella, E. Capoluongo, Multiple endocrine neoplasia type 1 (MEN1): an update of 208 new germline variants reported in the last nine years. Cancer Genet. 209(1-2), 36–41 (2016)

    Article  PubMed  Google Scholar 

  33. S.A. Wells Jr., S.L. Asa, H. Dralle, R. Elisei, D.B. Evans, R.F. Gagel et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25(6), 567–610 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  34. I. Christakis, W. Qiu, S.M. Hyde, G.J. Cote, E.G. Grubbs, N.D. Perrier et al. Genotype-phenotype pancreatic neuroendocrine tumor relationship in multiple endocrine neoplasia type 1 patients: a 23-year experience at a single institution. Surgery 163(1), 212–217 (2018)

    Article  PubMed  Google Scholar 

  35. S.Y. Li, Y.Q. Ding, Y.L. Si, M.J. Ye, C.M. Xu, X.P. Qi, 5P strategies for management of multiple endocrine neoplasia Type 2: a paradigm of precision medicine. Front. Endocrinol. (Lausanne) 11, 543246 (2020)

    Article  PubMed  Google Scholar 

  36. D. Muller, K. Thieke, A. Burgin, A. Dickmanns, M. Eilers, Cyclin E-mediated elimination of p27 requires its interaction with the nuclear pore-associated protein mNPAP60. EMBO J. 19(10), 2168–2180 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. A. Sakurai, S. Suzuki, S. Kosugi, T. Okamoto, S. Uchino, A. Miya et al. Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database. Clin. Endocrinol. (Oxf.) 76(4), 533–539 (2012)

    Article  PubMed  Google Scholar 

  38. E. Tham, U. Grandell, E. Lindgren, G. Toss, B. Skogseid, M. Nordenskjold, Clinical testing for mutations in the MEN1 gene in Sweden: a report on 200 unrelated cases. J. Clin. Endocrinol. Metab. 92(9), 3389–3395 (2007)

    Article  CAS  PubMed  Google Scholar 

  39. R.A. Carvalho, B. Urtremari, A.A.L. Jorge, L.S. Santana, E.P.S. Quedas, T. Sekiya et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. Eur. J. Endocrinol. 179(6), 391–407 (2018)

    Article  CAS  PubMed  Google Scholar 

  40. S.K. Agarwal, The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocr. Relat. Cancer 24(10), T119–T34. (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. J.J. Turner, P.T. Christie, S.H. Pearce, P.D. Turnpenny, R.V. Thakker, Diagnostic challenges due to phenocopies: lessons from multiple Endocrine Neoplasia type1 (MEN1). Hum. Mutat. 31(1), E1089–E1101 (2010)

    Article  PubMed  Google Scholar 

  42. L.B. Nachtigall, F.J. Guarda, K.E. Lines, A. Ghajar, L. Dichtel, G. Mumbach et al. Clinical MEN-1 Among a Large Cohort of Patients With Acromegaly. J. Clin. Endocrinol. Metab. 105(6), e2271–e2281 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  43. J.R. Burgess, B. Nord, R. David, T.M. Greenaway, V. Parameswaran, C. Larsson et al. Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1). Clin. Endocrinol. (Oxf.) 53(2), 205–211 (2000)

    Article  CAS  PubMed  Google Scholar 

  44. P.J. Newey, R.V. Thakker, Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr. Pract. 17(Suppl 3), 8–17 (2011)

    Article  PubMed  Google Scholar 

  45. R.W. Carroll, Multiple endocrine neoplasia type 1 (MEN1). Asia Pac. J. Clin. Oncol. 9(4), 297–309 (2013)

    Article  PubMed  Google Scholar 

  46. E.O. Mamedova, D.A. Dimitrova, Z.E. Belaya, G.A. Melnichenko,, The role of non-coding RNAs in the pathogenesis of multiple endocrine neoplasia syndrome type 1. Probl. Endokrinol. 66(2), 4–12 (2020).

    Article  Google Scholar 

  47. E. Luzi, S. Ciuffi, F. Marini, C. Mavilia, G. Galli, M.L. Brandi, Analysis of differentially expressed microRNAs in MEN1 parathyroid adenomas. Am. J. Transl. Res. 9(4), 1743–53. (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. L.R. Yates, S. Knappskog, D. Wedge, J.H.R. Farmery, S. Gonzalez, I. Martincorena et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32(2), 169–184 e7 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. C.E. Barbieri, C.H. Bangma, A. Bjartell, J.W. Catto, Z. Culig, H. Gronberg et al. The mutational landscape of prostate cancer. Eur. Urol. 64(4), 567–576 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. E. Lavezzi, A. Brunetti, V. Smiroldo, G. Nappo, V. Pedicini, E. Vitali et al. Case report: new CDKN1B mutation in multiple Endocrine Neoplasia Type 4 and brief literature review on clinical management. Front. Endocrinol. 13, 773143 (2022)

    Article  Google Scholar 

  51. P. Goudet, P. Cougard, B. Verges, A. Murat, B. Carnaille, A. Calender et al. Hyperparathyroidism in multiple endocrine neoplasia type I: surgical trends and results of a 256-patient series from Groupe D’etude des Neoplasies Endocriniennes Multiples Study Group. World J. Surg. 25(7), 886–890 (2001)

    Article  CAS  PubMed  Google Scholar 

  52. M.S. Elston, G.Y. Meyer-Rochow, M. Dray, M. Swarbrick, J.V. Conaglen, Early onset primary Hyperparathyroidism Associated with a Novel Germline Mutation in CDKN1B. Case Rep. Endocrinol. 2015, 510985 (2015)

    PubMed  PubMed Central  Google Scholar 

  53. P. Goudet, A. Dalac, M. Le Bras, C. Cardot-Bauters, P. Niccoli, N. Levy-Bohbot et al. MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d’etude des Tumeurs Endocrines. J. Clin. Endocrinol. Metab. 100(4), 1568–1577 (2015)

    Article  CAS  PubMed  Google Scholar 

  54. B. Verges, F. Boureille, P. Goudet, A. Murat, A. Beckers, G. Sassolas et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 87(2), 457–465 (2002)

    Article  CAS  PubMed  Google Scholar 

  55. J.M. de Laat, O.M. Dekkers, C.R. Pieterman, W.P. Kluijfhout, A.R. Hermus, A.M. Pereira et al. Long-term natural course of pituitary tumors in patients with MEN1: results From the DutchMEN1 Study Group (DMSG). J. Clin. Endocrinol. Metab. 100(9), 3288–3296 (2015)

    Article  PubMed  Google Scholar 

  56. M.A. Tichomirowa, M. Lee, A. Barlier, A.F. Daly, I. Marinoni, M.L. Jaffrain-Rea et al. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocr. Relat. Cancer 19(3), 233–241 (2012)

    Article  CAS  PubMed  Google Scholar 

  57. D. Donegan, N. Singh Ospina, R. Rodriguez-Gutierrez, Z. Al-Hilli, G.B. Thompson, B.L. Clarke et al. Long-term outcomes in patients with multiple endocrine neoplasia type 1 and pancreaticoduodenal neuroendocrine tumours. Clin. Endocrinol. 86(2), 199–206 (2017)

    Article  CAS  Google Scholar 

  58. A. Frederiksen, M. Rossing, P. Hermann, C. Ejersted, R.V. Thakker, M. Frost, Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel pathogenic variant and review of published cases. J. Clin. Endocrinol. Metab. 104(9), 3637–46. (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  59. R.V. Thakker, P.J. Newey, G.V. Walls, J. Bilezikian, H. Dralle, P.R. Ebeling et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 97(9), 2990–3011 (2012)

    Article  CAS  PubMed  Google Scholar 

  60. H.R. Choi, S.H. Choi, S.M. Choi, J.K. Kim, C.R. Lee, S.W. Kang et al. Benefit of diverse surgical approach on short-term outcomes of MEN1-related hyperparathyroidism. Sci. Rep. 10(1), 10634 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. F. Giusti, F. Tonelli, M.L. Brandi, Primary hyperparathyroidism in multiple endocrine neoplasia type 1: when to perform surgery. Clinics 67(Suppl 1), 141–144 (2012). Suppl 1

    Article  PubMed  PubMed Central  Google Scholar 

  62. N. Aygun, M. Uludag, Surgical treatment of primary hyperparathyroidism: which therapy to whom? Sisli Etfal Hastan. Tip. Bul. 53(3), 201–14. (2019)

    PubMed  PubMed Central  Google Scholar 

  63. M.E. Molitch, Diagnosis and treatment of pituitary adenomas: a review. JAMA 317(5), 516–524 (2017)

    Article  PubMed  Google Scholar 

  64. S. Sambugaro, M. Di Ruvo, M.R. Ambrosio, N.S. Pellegata, M. Bellio, A. Guerra et al. Early onset acromegaly associated with a novel deletion in CDKN1B 5’UTR region. Endocrine 49(1), 58–64 (2015)

    Article  CAS  PubMed  Google Scholar 

  65. V. Andreasi, C. Ricci, S. Partelli, G. Guarneri, C. Ingaldi, F. Muffatti et al. Predictors of disease recurrence after curative surgery for nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNENs): a systematic review and meta-analysis. J. Endocrinol. Investig. 45(4), 705–18. (2022)

    Article  CAS  Google Scholar 

  66. J.Y. Zhang, P.L. Kunz, Making sense of a complex disease: a practical approach to managing Neuroendocrine Tumors. JCO Oncol. Pract. 18(4), 258–64. (2022)

    Article  PubMed  Google Scholar 

  67. I.M. Chu, L. Hengst, J.M. Slingerland, The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat. Rev. Cancer 8(4), 253–267 (2008)

    Article  CAS  PubMed  Google Scholar 

  68. D. Busse, R.S. Doughty, T.T. Ramsey, W.E. Russell, J.O. Price, W.M. Flanagan et al. Reversible G(1) arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27(KIP1) independent of MAPK activity. J. Biol. Chem. 275(10), 6987–6995 (2000)

    Article  CAS  PubMed  Google Scholar 

  69. J. Liang, J.M. Slingerland, Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2(4), 339–345 (2003)

    Article  CAS  PubMed  Google Scholar 

  70. K. Szymonowicz, S. Oeck, N.M. Malewicz, V. Jendrossek, New Insights into Protein Kinase B/Akt Signaling: role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response. Cancers (Basel) 10(3), 78 (2018)

    Article  PubMed  Google Scholar 

  71. K. Shanmugasundaram, K. Block, B.K. Nayak, C.B. Livi, M.A. Venkatachalam, S. Sudarshan, PI3K regulation of the SKP-2/p27 axis through mTORC2. Oncogene 32(16), 2027–2036 (2013)

    Article  CAS  PubMed  Google Scholar 

  72. Z. Hao, S. Huang, E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy. Front. Biosci. (Landmark Ed.) 20(3), 474–490 (2015)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study is part of the ‘Neuroendocrine Tumors Innovation Knowledge and Education’ project led by Prof. A.M.I, Prof. A.C and Prof. A.F which aims at increasing the knowledge on neuroendocrine tumors. We would like to acknowledge all the Collaborators of the “NIKE” project.

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Each Author gave a substantial contribute to the paper and approved the final version to be published.

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Authors and Affiliations

  1. Endocrinology Unit, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, 98125, Messina, Italy

    Rosaria M. Ruggeri

  2. Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy

    Elio Benevento & Annamaria Colao

  3. SSD Endocrine Disease and Diabetology, ASL TO3, Pinerolo, TO, Italy

    Federica De Cicco

  4. Endocrine Unit, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy

    Erika Maria Grossrubatscher

  5. Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Genova, Italy

    Iderina Hasballa

  6. Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy

    Maria Grazia Tarsitano

  7. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Roberta Centello & Andrea M. Isidori

  8. UNESCO Chair “Education for Health and Sustainable Development”, Federico II University, Naples, Italy

    Annamaria Colao

  9. Department of Biology and Biotechnology, University of Pavia, Pavia, Italy

    Natalia S. Pellegata

  10. Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ENETS Center of excellence, Sapienza University of Rome, Rome, Italy

    Antongiulio Faggiano

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  1. Rosaria M. Ruggeri
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Ruggeri, R.M., Benevento, E., De Cicco, F. et al. Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome. Endocrine 82, 480–490 (2023). https://doi.org/10.1007/s12020-023-03497-2

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