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Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell\u2013autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.<\/jats:p>","DOI":"10.1161\/circresaha.121.318142","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T14:00:40Z","timestamp":1624543240000},"page":"136-154","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":236,"title":["Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies"],"prefix":"10.1161","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-1257","authenticated-orcid":true,"given":"Taija","family":"M\u00e4kinen","sequence":"first","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Sweden (T.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8273-3328","authenticated-orcid":true,"given":"Laurence 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