Hereditary and Familial Lymphedema

Abstract

Just 10 years ago, a chapter could not have been written about the genetic basis of familial or hereditary lymphedema. Whereas the familial or hereditary occurrence of peripheral lymphedema has been described for at least 150 years in the literature, along with numerous syndromes listed in the database Online Mendelian inheritance in Man (OMIM™),¹ it was not until 2000 that the first of a series of unrelated “lymphedema genes” was discovered. The location had been identified on the long arm of chromosome 5 two years earlier by three independent research groups, but was not pinpointed.^2-4 In a few of the other described syndromes, genes contributing to the disease now have been identified using new molecular tools. Together with advances in understanding the growth and development of the lymphatic vasculature (lymphvasculogenesis and lymphangiogenesis) and diverse lymphatic functions, which have uncovered an array of candidate genes underlying these processes, the field is advancing at a much faster pace. Some of the genes identified to date seem to have a clear function related to the lymphatic system such as the mutation in the FLT4 gene, which encodes the vascular endothelial growth factor receptor-3 gene (VEGFR3), important in lymphatic vessel development and function. Other genes (e.g., FOXC2) have identified proteins important in lymphatic structures as well as other organs, thus explaining the unique and at times baffling phenotypes of and within these syndromes. Some gene discoveries have been the stimulus to look at new pathways or to fill in steps or interrelationships in established pathways in lymphatic growth, development, and function. Detailed description and improved classification and reporting of these syndromes and further imaging studies to more precisely define lymphatic phenotypes (including carriers who may not exhibit overt lymphedema, but have structurally/functionally abnormal lymphatic vessels) will allow use of more precise molecular tools to continue to help identify specific loci responsible for these often multi-system disorders and to carry out pre-natal or ­post-natal screening for detection. Moreover, once the molecular defects are uncovered and understood, more targeted therapeutic agents are likely to be developed.