{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:17:46Z","timestamp":1790677066748,"version":"4.1.0"},"reference-count":17,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Chinese National Science Foundation","doi-asserted-by":"publisher","award":["81272146"],"award-info":[{"award-number":["81272146"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>This study explored mutations in the Fms-related tyrosine kinase 4\/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.<\/jats:p>","DOI":"10.3390\/genes12101611","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:36:15Z","timestamp":1634160975000},"page":"1611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Ningfei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Plastic & Reconstructive Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minzhe","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Plastic & Reconstructive Surgery, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1093\/hmg\/7.13.2073","article-title":"Hereditary lymphedema: Evidence for linkage and genetic heterogeneity","volume":"7","author":"Ferrell","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1136\/jmg.2004.024802","article-title":"Milroy disease and the VEGFR-3 mutation phenotype","volume":"2","author":"Brice","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1399-0004.2007.00741.x","article-title":"Three children with Milroy disease and de novo mutations in VEGFR3","volume":"71","author":"Carver","year":"2007","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00439-008-0586-5","article-title":"Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas","volume":"124","author":"Connell","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1111\/1346-8138.15627","article-title":"De novo plice-site mutation in FLT4\/VEGFR3 is associated with Milroy disease","volume":"48","author":"Shibata","year":"2021","journal-title":"J. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1549-8719.2010.00030.x","article-title":"Lymphatic dysfunction, not aplasia, underlies Milroy disease","volume":"17","author":"Mellor","year":"2010","journal-title":"Microcirculation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/humu.22223","article-title":"FLT4\/VEGFR3 and Milroy disease: Novel mutations, a review of published variants and database update","volume":"34","author":"Gordon","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1136\/jmg.40.9.697","article-title":"Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphedema","volume":"40","author":"Evans","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_10","first-page":"256","article-title":"Diagnosis of primary lymphedema with indocyanine green lymphography","volume":"34","author":"Yu","year":"2018","journal-title":"Chin. J. Plast. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/micc.12299","article-title":"Abnormal mural cell recruitment in lymphatic capillaries: A common pathological feature in chronic lymphedematous skin?","volume":"23","author":"Yu","year":"2016","journal-title":"Microcirculation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/75997","article-title":"Missense mutation interfere with VEGFR-3 signalling in primary lymphodema","volume":"25","author":"Karkkainen","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1161\/CIRCRESAHA.118.313250","article-title":"Whole exome sequencing reveals the major genetic contributors to non-syndromic Teralogy of Fallot","volume":"124","author":"Page","year":"2019","journal-title":"Circ. Res."},{"key":"ref_14","first-page":"27","article-title":"Aplasia of superficial lymphatic capillaries in hereditary and connatal lymphedema (Milroy\u2019s disease)","volume":"16","author":"Bollinger","year":"1983","journal-title":"Lymphology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/bjd.17120","article-title":"A Milroy case with FLT4\/VEGFR3 mutation and an unusual skin biopsy","volume":"180","author":"Liu","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/84651","article-title":"Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3","volume":"7","author":"Makinen","year":"2001","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature07083","article-title":"Blocking VEGFR-3 suppress angiogenic sprouting and vascular network formation","volume":"454","author":"Tammela","year":"2008","journal-title":"Nature"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1611\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:12:49Z","timestamp":1760166769000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1611"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,13]]},"references-count":17,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["genes12101611"],"URL":"https:\/\/doi.org\/10.3390\/genes12101611","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,13]]}}}