{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:20:56Z","timestamp":1784557256619,"version":"3.55.0"},"reference-count":55,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1,1]]},"abstract":"<jats:p>\n                    Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene \u2013\n                    <jats:italic>CDKN1B<\/jats:italic>\n                    , encodes for the cell-cycle regulator p27. Possible genotype\u2013phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4\/\n                    <jats:italic>CDKN1B<\/jats:italic>\n                    cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 \u00b1 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 \u00b1 21.4 and 52.9 \u00b1 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4\/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.029). Variants in codons 94\u201396 were associated with higher risk for PHPT (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001) and PitAd (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent\n                    <jats:italic>CDKN1B<\/jats:italic>\n                    frameshift variants and possible genotype\u2013phenotype correlations.\n                  <\/jats:p>","DOI":"10.1530\/erc-22-0174","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T14:40:18Z","timestamp":1666104018000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":18,"title":["Germline CDKN1B variant type and site are associated with phenotype in MEN4"],"prefix":"10.1530","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-667X","authenticated-orcid":true,"given":"Reut","family":"Halperin","sequence":"first","affiliation":[{"name":"ENTIRE Endocrine Neoplasia Translational Research Center, Sheba Medical Center, Tel Hashomer, Israel"},{"name":"Tel Aviv University Faculty of Medicine, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liat","family":"Arnon","sequence":"additional","affiliation":[{"name":"ENTIRE Endocrine Neoplasia Translational Research Center, Sheba Medical Center, Tel Hashomer, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapir","family":"Nasirov","sequence":"additional","affiliation":[{"name":"ENTIRE Endocrine Neoplasia Translational Research Center, Sheba Medical Center, Tel Hashomer, Israel"},{"name":"Tel Aviv University Faculty of Medicine, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limor","family":"Friedensohn","sequence":"additional","affiliation":[{"name":"ENTIRE Endocrine Neoplasia Translational Research Center, Sheba Medical Center, Tel Hashomer, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Gershinsky","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Lady Davis Carmel Medical Center and Linn Medical Center and Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alona","family":"Telerman","sequence":"additional","affiliation":[{"name":"ENTIRE Endocrine Neoplasia Translational Research Center, Sheba Medical Center, Tel Hashomer, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan","family":"Friedman","sequence":"additional","affiliation":[{"name":"Tel Aviv University Faculty of Medicine, Tel Aviv, Israel"},{"name":"Personalized Preventive Genetics Center, Assuta Medical Center, Tel-Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinat","family":"Bernstein-Molho","sequence":"additional","affiliation":[{"name":"Tel Aviv University Faculty of Medicine, Tel Aviv, Israel"},{"name":"The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-9634","authenticated-orcid":true,"given":"Amit","family":"Tirosh","sequence":"additional","affiliation":[{"name":"ENTIRE Endocrine Neoplasia Translational Research Center, Sheba Medical Center, Tel Hashomer, Israel"},{"name":"Tel Aviv University Faculty of Medicine, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"DNA Repair","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.dnarep.2018.07.008","article-title":"Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: a double-edged sword protein","volume":"69","author":"Abbastabar","year":"2018","unstructured":"Abbastabar MKheyrollah MAzizian KBagherlou NTehrani SSManiati MKarimian A2018Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: a double-edged sword protein. 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