Chapter: Lymphatic malformations
Article: 2 of 14
Update: Mar 15, 2021
Author(s): Tinschert, Sigrid
The development of the lymphatic system and the maintenance of tissue fluid homeostasis are regulated by a complex network of signal transduction pathways (VEGF-C/VEGFR-3 pathway, MAPK pathway and PIK3/AKT/m-TOR pathway). Mutations in different genes of this network (more than 20 genes) lead to an alteration of signal transduction in terms of gain or loss of function, resulting in impairments of the structure and function of the lymphatic system.
Primary lymphedema in isolated form (type 1A-1C) and also syndromal (e.g., lymphedema-distichiasis syndrome, Leung syndrome (microcephaly, lymphedema and chorioretinopathy), Emberger syndrome, Noonan syndrome, Hennekam syndrome) are caused by germline mutations and are autosomal dominant or autosomal recessive hereditary. In contrast, cystic lymphatic malformations (LM), both isolated and syndromal, are based on postzygotic mutations. They are not hereditary (exception: Cowden syndrome, syn.: PTEN hamartoma syndrome, see there).
The VEGF-C/VEGFR-3 signaling pathway plays a central role in the pathogenesis of primary lymphedema. VEGFR3 (vascular endothelial growth factor receptor 3) is expressed in the endothelial cells of lymphatic vessels and mediates the action of growth factors from the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D). Loss-of-function mutations in the FLT4 gene encoding VEGFR-3 or in the gene encoding its ligand VEGF-C lead to autosomal dominant hereditary primary lymphedema (Nonne-Milroy-Meige syndrome). Lack of stimulation of the VEGF-C/VEGFR-3 pathway by mutations in the CCBE1 gene (CCBE1 (collagen and calcium-binding EGF domain-1) is required for activation of VEGF-C) leads to autosomal recessive Hennekam syndrome. Inactivating mutations in the nuclear transcription factor FOXC2 or GATA2 genes, which are involved in the expression of genes downstream of VEGFR-3, are associated with autosomal dominant lymphedema-distichiasis syndrome and Emberger syndrome (deafness-lymphedema-leukemia syndrome), which is also autosomal dominant.
Primary lymphedema is also frequently found in diseases caused by mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway (e.g., PTPN11 mutations in autosomal dominant Noonan syndrome). As a consequence, activation of the MAPK signaling pathway results. The same effect can be caused by a loss of function of negative modulators of this pathway. Thus, RASA1 mutations are causative for the autosomal dominant hereditary syndrome CM-AVM and its non-hereditary variant, Parkes Weber syndrome.
Mutations in genes of the PIK3/AKT/m-TOR pathway (PIK3CA as well as AKT1) leading to activation of the same are associated with circumscribed LM and/or lymphedema in the context of sporadically occurring syndromes with regional overgrowth (CLOVES syndrome, Klippel-Trénaunay syndrome). PIK3CA mutations are the most common cause of isolated (non-syndromic) LM. Mutations that cause failure of the negative modulator of the PIK3/AKT/m-TOR pathway, PTEN, are causative of autosomal dominant Cowden syndrome (syn.: PTEN hamartoma syndrome), its segmental type 2 variant, and PTEN Hamartoma Of Soft Tissue (PHOST) with mixed vascular malformation, including LM.