Molecular Genetics of Lymphatic and Complex Vascular Malformations

Abstract

Lymphatic malformations (LMs) are due to localized defects in lymphatic development. They usually occur sporadically. There is an important heterogeneity in clinical presentations. LMs can affect any part of the body, be isolated, or be part of a syndrome. They can present as pure or combined lesions. Lymphaticovenous malformation (LVM) is a common example of the latter. They most often cause pain, dysfunction of the affected body part, and disfigurement. Elucidation of the etiopathogenesis of LMs had to wait for the development of next-generation sequencing (NGS) used on endothelial cells isolated from lymphatic malformations or directly on resected lesions. This allowed to discover somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). The mutations are similar to those identified in cancers, venous malformations (VMs), and combined vascular lesions, including the spectrum of PIK3CA-related overgrowth syndromes (PROS). The phenotypic variability is most likely due to differences in developmental time point and type(s) of cells in which the somatic mutations occurred. Some related syndromes are also caused by activating mutations in the PI3K-AKT-mTOR signaling pathway, including Proteus syndrome (mutations in AKT1) and PTEN hamartoma tumor syndrome (mutations in PTEN). This has opened the era for development of targeted precision therapies for these lesions, especially by using small molecule inhibitors. Rapamycin, an inhibitor of mTOR, has already been tested in clinical trials and four studies (78 patients) demonstrated efficacy on selected cases.