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Studying KS therefore requires a model that captures this complexity as accurately as possible while still permitting controlled experimental manipulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review integrates findings from clinical studies and experimental research using male mice carrying a supernumerary X chromosome that replicate key features of the syndrome, with particular emphasis on their translational relevance, experimental utility, and inherent limitations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Over the past decades, these mouse models have demonstrated their value by enabling the successful translation of experimental findings into clinical applications. Using these models, researchers have investigated multiple aspects of KS, including neurocognitive function, social behavior, metabolism, bone health, brain structure and function, endocrine dysregulation, testicular degeneration, germ cell fate, Sertoli and Leydig cell function, vascular abnormalities, chromosomal imbalance, and X\u2010chromosome dosage effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Although these models have some limitations, their availability allows the investigation of developmental timing and tissue\u2010specific mechanisms. They offer unique opportunities to dissect the genetic, hormonal, and systemic features of KS, thereby informing both basic research and clinical care. Given their demonstrated and ongoing value, we aim to encourage the scientific community to further adopt these models in future KS research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/andr.70247","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T07:05:43Z","timestamp":1777964743000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessing a Model for a Complex Systemic Disorder\u2014The Value of Male Mice With a Supernumerary X Chromosome for Klinefelter Syndrome Research"],"prefix":"10.1111","author":[{"given":"Fariba","family":"Saadati","sequence":"first","affiliation":[{"name":"Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology University Clinics M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9215-8582","authenticated-orcid":false,"given":"Joachim","family":"Wistuba","sequence":"additional","affiliation":[{"name":"Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology University Clinics M\u00fcnster  M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618\u2010016\u20100541\u20106"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem\u20102\u201011\u2010615"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(04)16678\u20106"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad205"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.84.10.3807"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/223643a0"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31787"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioae076"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.5694\/j.1326\u20105377.2011.tb04141.x"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/13685538.2025.2519035"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12909"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014\u20102780"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31792"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012\u20102382"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431\u2010021\u201004083\u20102"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaf261"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601\u2010183X.2011.00705.x"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/DBP.0000000000001201"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2017\u201000212"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2025.101230"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dead224"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12208"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ge.20.120186.001551"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000133152"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009\u20101396"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651\u20102227.2011.02149.x"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2008.08.007"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098\u20102795(199802)49:2<101::AID\u2010MRD1>3.0.CO;2\u2010T"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.142.4.8086"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651\u20102227.2010.02112.x"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaq024"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005\u20100278"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE\u201009\u20100768"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/183302a0"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03479"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.103200.109"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10577\u2010009\u20109063\u20109"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201031780\u20100"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2025.02.001"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.07.26.605328"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12249"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00085.2010"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1159\/000117387"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2015.07.008"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2047\u20102927.2014.00190.x"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020959818687"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201071377\u20100"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab605"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deaa132"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004\u20100777"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005\u20101077"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmi039"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE\u201012\u20100934"},{"ke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