Genetic syndromes with vascular malformations - update on molecular background and diagnostics

Abstract

Vascular malformations are present in a great variety of congenital syndromes, either as the predominant or additional feature. They pose a major challenge to the clinician: due to significant phenotype overlap, a precise diagnosis is often difficult to obtain, some of the malformations carry a risk of life threatening complications and, for many entities, treatment is not well established. To facilitate their recognition and aid in differentiation, we present a selection of notable congenital disorders of vascular system development, distinguishing between the heritable germinal and sporadic somatic mutations as their causes. Clinical features, genetic background and comprehensible description of molecular mechanisms is provided for each entity.

Keywords: arterial malformation; arteriovenous malformation; capillary malformation; lymphatic malformation; vascular malformation; venous malformation.

Figure 1

A simplified model of Ras activation as a part of the MAPK/ERK signaling pathway. Ras proteins play a key role in regulation of numerous subsequent signaling cascades and pathways. Mutations in the RASA1 gene may cause a change in Ras activity, resulting in development of CM-AVM syndrome and PWS. There is some evidence that KTWS might also be caused by abnormal Ras function. The complete genetic background of KTWS remains unknown [–38]

Figure 2

A simplified model of the TGF-β signaling pathway. Abnormalities of this cascade may lead to different types of HHT. Several genes are indicated in HHT pathogenesis. Endoglin, the product of ENG gene expression, is responsible for signal modulation between ALK1 and ALK5 receptors. Mutations in ACVRL1 result in faulty interaction of ALK1 with other TGF signaling proteins. BMP9 protein, the product of GDF2, interacts with both ALK1 and endoglin. SMAD4 is involved in later steps of this signaling cascade together with other SMAD proteins. Its malfunction may also lead to HHT [59, 60]

Figure 3

A model of CCMs related proteins’ interaction with VE-cadherin, HEG1 and integrin-β₁. They are responsible for coupling of extracellular and intracellular signaling pathways. Alterations in KRIT1, PDCD10 and CCM2 may lead to CCMs type 1, 3 and 2, respectively [97, 98]

Figure 4

A – A simplified model of protein ubiquitination by RING-type E3 enzyme. The ubiquitination of target protein is completed by interaction with a ubiquitin-conjugating enzyme (E2). B – Due to glomulin binding to E3, E2 accession to the complex is prevented and the entire process is inhibited. Mutations of GLMN prevent inhibition of ubiquitination. This may lead to development of GVMs [, –133]

Figure 5

Interactions among ANGPT1, ANGPT2, ANGPT4 and Tie2. Several signaling pathways are triggered by this activation. The most important one in the context of vascular development is PI3K/AKT/mTOR with its numerous subsequent cascades. Alterations of TEK/TIE2 were demonstrated to result in VMCMs. This might suggest that VM has a genetic background similar to VMCMs [151]

Figure 6

A model for G protein activity and its role in triggering of RAS-MEK-ERK and phospholipase C pathways. The external signal causes activation of G protein by exchanging a GDP particle bound to the G protein for a GTP. The α subunit of G protein (a GNAQ expression product) is then released and activates enzymes and effector proteins involved in signaling pathways necessary for vascular development. Alterations of GNAQ are indicated in SWS pathogenesis [159, 164, 165]

Figure 7

A simplified model of the PI3K-AKT-mTOR growth-signaling pathway. The product of PIK3CA gene expression, the PI3K protein, is essential for the regeneration of phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is required for further phosphorylation steps, first PDK1 by PIP3 and then AKT by PDK1. This triggers further steps of the PI3K-AKT-mTOR cascade important for cell proliferation, growth and survival. Alterations of PIK3CA are responsible for many diseases including those related to vascular system development such as CLOVES syndrome, FAH, MCAP and possibly even VMs [181, 193, 194]