{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:20:39Z","timestamp":1788175239785,"version":"build-2803163510"},"reference-count":17,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Italian Ministery, ex 60%","award":["does not exist"],"award-info":[{"award-number":["does not exist"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Marfan syndrome (MFS) and Loeys\u2013Dietz syndrome type 4 (LDS4) are two hereditary connective tissue disorders. MFS displays ectopia lentis as a distinguishing, characterising feature, and thoracic aortic ectasia, aneurysm, dissection, and systemic features as manifestations overlapping with LDS4. LDS4 is characterised by the presence of hypertelorism, cleft palate and\/or bifid uvula, with possible ectasia or aneurysms in other arteries. The variable age of onset of clinical manifestations makes clinical diagnosis more difficult. In this study, we report the case of a patient with Marfan syndrome diagnosed at our centre at the age of 33 on the basis of typical clinical manifestations of this syndrome. At the age of 38, the appearance of ectasia of the left common iliac artery and tortuosity of the iliac arteries suggested the presence of LDS4. Next Generation Sequencing (NGS) analysis, followed by Array-CGH, allowed the detection of a novel chromosomal deletion including the entire TGFB2 gene, confirming not only the clinical suspicion of LDS4, but also the clinical phenotype associated with the haploinsufficiency mechanism, which is, in turn, associated with the deletion of the entire gene. The same mutation was detected in the two young sons. This emblematic case confirms that we must be very careful in the differential diagnosis of these two pathologies, especially before the age of 40, and that, in young subjects suspected to be affected by MFS in particular, we must verify the diagnosis, extending genetic analysis, when necessary, to the search for chromosomal alterations. Recently, ectopia lentis has been reported in a patient with LDS4, confirming the tight overlap between the two syndromes. An accurate revision of the clinical parameters both characterising and overlapping the two pathologies is highly desirable.<\/jats:p>","DOI":"10.3390\/genes12101462","type":"journal-article","created":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T22:24:13Z","timestamp":1632695053000},"page":"1462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Differential Diagnosis between Marfan Syndrome and Loeys\u2013Dietz Syndrome Type 4: A Novel Chromosomal Deletion Covering TGFB2"],"prefix":"10.3390","volume":"12","author":[{"given":"Stefano","family":"Nistri","sequence":"first","affiliation":[{"name":"CMSR Veneto Medica-Cardiology Service, 36077 Altavilla Vicentina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosina","family":"De Cario","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Sticchi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-6303","authenticated-orcid":false,"given":"Gaia","family":"Spaziani","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, Azienda Ospedaliera Universitaria Meyer, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Della Monica","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Cardarelli Hospital, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-326X","authenticated-orcid":false,"given":"Sabrina","family":"Giglio","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, 09024 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-6513","authenticated-orcid":false,"given":"Silvia","family":"Favilli","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, Azienda Ospedaliera Universitaria Meyer, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betti","family":"Giusti","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8338-3016","authenticated-orcid":false,"given":"Pierluigi","family":"Stefano","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Cardiac Surgery Unit, Careggi Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9825-6618","authenticated-orcid":false,"given":"Guglielmina","family":"Pepe","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Marfan Syndrome and Related Disorders Regional Referral Center, Careggi Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/ng1511","article-title":"A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2","volume":"37","author":"Loeys","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jmg.2009.072785","article-title":"The revised Ghent nosology for the Marfan syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. Med. Gene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1056\/NEJMoa055695","article-title":"Aneurysm syndromes caused by mutations in the TGF-beta receptor","volume":"355","author":"Loeys","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"582","DOI":"10.21037\/acs.2017.11.03","article-title":"Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome","volume":"6","author":"Meester","year":"2017","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/ng.744","article-title":"Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis","volume":"43","author":"Oldenburg","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/ng.2348","article-title":"TGFB2 mutations cause familial thoracic aortic aneurysms and acute aortic dissections associated with mild systemic features of the Marfan syndrome","volume":"44","author":"Boileau","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/ng.2349","article-title":"Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm","volume":"44","author":"Lindsay","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.jacc.2015.01.040","article-title":"Mutations in a TGF-ligand, TGFB3, cause syndromic aortic aneurysms and dissections","volume":"65","author":"Gillis","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_9","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (2008). Loeys-Dietz Syndrome. GeneReviews, University of Washington."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.gene.2014.01.017","article-title":"Loeys-Dietz syndrome type 4, caused by chromothripsis, involving the TGFB2 gene","volume":"538","author":"Fontana","year":"2014","journal-title":"Gene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1002\/ajmg.a.38286","article-title":"4.7\u2009Mb deletion encompassing TGFB2 associated with features of Loeys-Dietz syndrome and osteoporosis in adulthood","volume":"173","author":"Gaspar","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/humu.23407","article-title":"A mutation update on the LDS-associated genes TGFB2\/3 and SMAD2\/3","volume":"39","author":"Schepers","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/0002-9149(89)90430-X","article-title":"Two-dimensional echocardiographic aortic root dimensions in normal children and adults","volume":"64","author":"Roman","year":"1989","journal-title":"Am. J. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.amjcard.2009.11.040","article-title":"Nomograms for aortic root diameters in children using two-dimensional echocardiography","volume":"105","author":"Gautier","year":"2010","journal-title":"Am. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3389\/fphys.2017.00612","article-title":"Genetic Bases of Bicuspid Aortic Valve: The Contribution of Traditional and High-Throughput Sequencing Approaches on Research and Diagnosis","volume":"8","author":"Giusti","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_16","first-page":"293","article-title":"Genome-wide copy number analysis in pediatric glioblastoma multiforme","volume":"4","author":"Giunti","year":"2014","journal-title":"Am. J. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1002\/ajmg.a.61633","article-title":"Ectopia lentis in Loeys-Dietz syndrome type 4","volume":"182","author":"Braverman","year":"2020","journal-title":"Am. J. Med. Genet. 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