Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies

Circ Res. 2021 Jun 25;129(1):136-154. doi: 10.1161/CIRCRESAHA.121.318142. Epub 2021 Jun 24.


Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. 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-autonomous 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.

Keywords: capillaries; lymphangiogenesis; mutation; neoplasms; sirolimus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Humans
  • Lymphangiogenesis*
  • Lymphatic Abnormalities / genetics*
  • Lymphatic Abnormalities / metabolism
  • Lymphatic Abnormalities / pathology
  • Lymphatic Abnormalities / therapy*
  • Lymphatic Vessels / abnormalities*
  • Lymphatic Vessels / metabolism
  • Mutation*
  • Phenotype
  • Signal Transduction