{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:35:07Z","timestamp":1760060107710,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T00:00:00Z","timestamp":1754092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EMEKNNOK, KIDS-CRETE (Kidney Inherited Diseases reSearch in Crete)","award":["13\/20-12-23"],"award-info":[{"award-number":["13\/20-12-23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background and Clinical Significance: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant disorder caused by mutations in the MEN1 gene. Although primarily characterized by endocrine tumors, renal manifestations remain underreported. Case Presentation: We report a three-generation family carrying a pathogenic MEN1 mutation (c.1351-3_1359del) with a co-occurring Claudin 16 (CLDN16) variant (c.324+13C&gt;G). Genetic testing included MLPA and whole-exome sequencing (WES), with bioinformatics analysis validating variant pathogenicity. All three patients exhibited primary hyperparathyroidism, hypercalcemia, hypercalciuria, early nephrocalcinosis, and renal hypomagnesemia. The CLDN16 variant, previously considered benign, co-segregated with hypomagnesemia and renal involvement, suggesting a potential modifying role. Conclusions: These findings support the need for comprehensive genetic screening in MEN1 patients with atypical renal presentations. Concomitant genetic variations can alter the principal phenotype.<\/jats:p>","DOI":"10.3390\/jcm14155447","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T08:46:55Z","timestamp":1754383615000},"page":"5447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial MEN1 Syndrome with Atypical Renal Features and a Coexisting CLDN16 Variant: A Case Series"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0095-9823","authenticated-orcid":false,"given":"Ioannis","family":"Petrakis","sequence":"first","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni","family":"Drosataki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitra","family":"Lygerou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Antonakis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantina","family":"Kydonaki","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marinos","family":"Mitrakos","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8123-771X","authenticated-orcid":false,"given":"Christos","family":"Pleros","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Sfakiotaki","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paraskevi","family":"Xekouki","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3678-9421","authenticated-orcid":false,"given":"Kostas","family":"Stylianou","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University of Crete, Voutes, 70500 Heraklion, Crete, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yalcin, S., and \u00d6berg, K. (2015). The Multiple Endocrine Neoplasia Syndromes. Neuroendocrine Tumours, Springer.","DOI":"10.1007\/978-3-662-45215-8"},{"key":"ref_2","first-page":"MJ01","article-title":"An unusual presentation of a patient with multiple endocrine neoplasia-1","volume":"8","author":"Kapoor","year":"2014","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"69","DOI":"10.6061\/clinics\/2012(Sup01)13","article-title":"Genotype-phenotype correlation in multiple endocrine neoplasia type 2","volume":"67","author":"Raue","year":"2012","journal-title":"Clinics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"49","DOI":"10.6061\/clinics\/2012(Sup01)10","article-title":"Variable clinical expression in patients with a germline MEN1 disease gene mutation: Clues to a genotype-phenotype correlation","volume":"67","author":"Lips","year":"2012","journal-title":"Clinics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.6061\/clinics\/2012(Sup01)15","article-title":"Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome","volume":"67","author":"Lendvai","year":"2012","journal-title":"Clinics"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.tibs.2013.05.005","article-title":"Menin: A scaffold protein that controls gene expression and cell signaling","volume":"38","author":"Matkar","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.omtn.2019.08.013","article-title":"Menin Coordinates C\/EBPbeta-Mediated TGF-beta Signaling for Epithelial-Mesenchymal Transition and Growth Inhibition in Pancreatic Cancer","volume":"18","author":"Cheng","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1210\/en.2019-00274","article-title":"Menin Associates with the Mitotic Spindle and Is Important for Cell Division","volume":"160","author":"Sawicki","year":"2019","journal-title":"Endocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Papaconstantinou, M., Pepper, A.N., Wu, Y., Kasimer, D., Westwood, T., Campos, A.R., B\u00e9dard, P.-A., and Bergmann, A. (2010). Menin links the stress response to genome stability in Drosophila melanogaster. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0014049"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5477","DOI":"10.1128\/MCB.00335-09","article-title":"Nuclear-cytoplasmic shuttling of menin regulates nuclear translocation of beta-catenin","volume":"29","author":"Cao","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1097\/MPA.0b013e31827591e9","article-title":"Pancreatic adenocarcinoma in a patient with multiple endocrine neoplasia 1 syndrome","volume":"42","author":"Karpathakis","year":"2013","journal-title":"Pancreas"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1111\/1759-7714.14863","article-title":"Thymic atypical carcinoid tumors with elevated mitotic counts in a patient with multiple endocrine neoplasia: A case report","volume":"14","author":"Hiro","year":"2023","journal-title":"Thorac. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41574-021-00468-3","article-title":"Clinical aspects of multiple endocrine neoplasia type 1","volume":"17","author":"Cadiot","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"99","DOI":"10.6061\/clinics\/2012(Sup01)17","article-title":"Biochemical, bone and renal patterns in hyperparathyroidism associated with multiple endocrine neoplasia type 1","volume":"67","author":"Lourenco","year":"2012","journal-title":"Clinics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33549\/physiolres.933059","article-title":"Hypercalcemia. Pathophysiological aspects","volume":"65","author":"Zofkova","year":"2016","journal-title":"Physiol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.kint.2017.08.029","article-title":"Deletion of claudin-10 rescues claudin-16-deficient mice from hypomagnesemia and hypercalciuria","volume":"93","author":"Breiderhoff","year":"2018","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2215\/CJN.12841211","article-title":"Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: Phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations","volume":"7","author":"Godron","year":"2012","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bennati, G., Cirino, M., Benericetti, G., Maximova, N., Zanier, M., Pigato, F., Parzianello, A., Maestro, A., Barbi, E., and Zanon, D. (2023). Compounded Effervescent Magnesium for Familial Hypomagnesemia: A Case Report. Pharmaceuticals, 16.","DOI":"10.3390\/ph16060785"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zeng, T., and Li, Y.I. (2022). Predicting RNA splicing from DNA sequence using Pangolin. Genome Biol., 23.","DOI":"10.1186\/s13059-022-02664-4"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/01.GIM.0000153663.62300.F8","article-title":"Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory","volume":"7","author":"Klein","year":"2005","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1136\/jmg.2003.017319","article-title":"A report of a national mutation testing service for the MEN1 gene: Clinical presentations and implications for mutation testing","volume":"42","author":"Cardinal","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.mce.2006.02.008","article-title":"Characteristics of the Danish families with multiple endocrine neoplasia type 1","volume":"249","author":"Hansen","year":"2006","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ding, N., Guo, T., Liu, S.-Y., Wang, Q.-Y., Qu, X.-L., Li, Y.-F., Ou Yang, N., Sheng, Z.-F., and Yang, Y.-Y. (2021). Association between hypomagnesemia and severity of primary hyperparathyroidism: A retrospective study. BMC Endocr. Disord., 21.","DOI":"10.1186\/s12902-021-00838-y"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1349-7006.2008.01034.x","article-title":"MEN1 gene and its mutations: Basic and clinical implications","volume":"100","author":"Tsukada","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/humu.20605","article-title":"Multiple endocrine neoplasia type 1 (MEN1): Analysis of 1336 mutations reported in the first decade following identification of the gene","volume":"29","author":"Lemos","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"L1","DOI":"10.1530\/ERC-16-0446","article-title":"De novo mutation in MEN1 is not associated with parental somatic mosaicism","volume":"24","author":"Laitman","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1073\/pnas.0408836102","article-title":"Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors","volume":"102","author":"Milne","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6569","DOI":"10.1128\/MCB.24.15.6569-6580.2004","article-title":"Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway","volume":"24","author":"Yaguchi","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"de Laat, J.M., van der Luijt, R.B., Pieterman, C.R.C., Oostveen, M.P., Hermus, A.R., Dekkers, O.M., de Herder, W.W., van der Horst-Schrivers, A.N., Drent, M.L., and Bisschop, P.H. (2016). MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med., 14.","DOI":"10.1186\/s12916-016-0708-1"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mele, C., Mencarelli, M., Caputo, M., Mai, S., Pagano, L., Aimaretti, G., Scacchi, M., Falchetti, A., and Marzullo, P. (2020). Phenotypes Associated with MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.591501"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s12020-019-01932-x","article-title":"True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome","volume":"65","author":"Butz","year":"2019","journal-title":"Endocrine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1054\/bjoc.2000.1380","article-title":"Identification of MEN1 gene mutations in families with MEN 1 and related disorders","volume":"83","author":"Bergman","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/hmg\/6.7.1169","article-title":"Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states","volume":"6","author":"Agarwal","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1067\/msy.2000.109727","article-title":"Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: Surgery or surveillance?","volume":"128","author":"Bartsch","year":"2000","journal-title":"Surgery"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/cgt.2010.39","article-title":"Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients","volume":"17","author":"Luzi","year":"2010","journal-title":"Cancer Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Luzi, E., Marini, F., Giusti, F., Galli, G., Cavalli, L., and Brandi, M.L. (2012). The negative feedback-loop between the oncomir Mir-24-1 and menin modulates the Men1 tumorigenesis by mimicking the \u201cKnudson\u2019s second hit\u201d. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039767"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1093\/hmg\/ddt039","article-title":"Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: A Groupe d\u2019etude des Tumeurs Endocrines (GTE) cohort study","volume":"22","author":"Thevenon","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"R13","DOI":"10.1530\/JME-18-0050","article-title":"Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types","volume":"61","author":"Iyer","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.surg.2018.04.064","article-title":"High prevalence of chronic kidney disease in patients with multiple endocrine neoplasia type 1 and improved kidney function after parathyroidectomy","volume":"165","author":"Green","year":"2019","journal-title":"Surgery"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s12020-018-1566-8","article-title":"Multiple endocrine neoplasia type 1: Analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database","volume":"62","author":"Marini","year":"2018","journal-title":"Endocrine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1038\/s41388-020-01614-3","article-title":"Comprehensive characterisation of intronic mis-splicing mutations in human cancers","volume":"40","author":"Jung","year":"2021","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"F74","DOI":"10.1152\/ajprenal.00397.2020","article-title":"Localization and regulation of claudin-14 in experimental models of hypercalcemia","volume":"320","author":"Frische","year":"2021","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1038\/emboj.2012.49","article-title":"Claudin-14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway","volume":"31","author":"Gong","year":"2012","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1210\/jc.2011-0569","article-title":"Nephrolithiasis and renal calcifications in primary hyperparathyroidism","volume":"96","author":"Rejnmark","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1001\/archinte.1978.03630290069022","article-title":"Hypercalcemic nephropathy","volume":"138","author":"Benabe","year":"1978","journal-title":"Arch. Intern. Med."},{"key":"ref_50","first-page":"117","article-title":"Acute renal failure as an initial manifestation of multiple endocrine neoplasia (MEN) type 1","volume":"23","author":"Afshar","year":"2012","journal-title":"Saudi. J. Kidney Dis. Transpl."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1359\/jbmr.090304","article-title":"Sporadic and MEN1-related primary hyperparathyroidism: Differences in clinical expression and severity","volume":"24","author":"Chiodini","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1002\/jbmr.125","article-title":"Early-onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism","volume":"25","author":"Lourenco","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s10157-004-0318-7","article-title":"Multiple endocrine neoplasia type 1 in end-stage renal failure","volume":"8","author":"Suzuki","year":"2004","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e982","DOI":"10.1002\/ctm2.982","article-title":"Loss of MEN1 leads to renal fibrosis and decreases HGF-Adamts5 pathway activity via an epigenetic mechanism","volume":"12","author":"Jin","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e22712","DOI":"10.1096\/fj.202100634RRR","article-title":"Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy","volume":"37","author":"Zou","year":"2023","journal-title":"FASEB J."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/15\/5447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:50Z","timestamp":1760034110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/15\/5447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,2]]},"references-count":55,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["jcm14155447"],"URL":"https:\/\/doi.org\/10.3390\/jcm14155447","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2025,8,2]]}}}