Genetic Basis, New Diagnostic Approaches, and Updated Therapeutic Strategies of the Syndromic Aortic Diseases: Marfan, Loeys-Dietz, and Vascular Ehlers-Danlos Syndrome

Abstract

Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndromes currently identified as Marfan, Loeys-Dietz, and vascular Ehlers-Danlos are characterized by a complex clinical picture. In this contribution, we provide an overview of the genetic mutations currently identified in order to have a better understanding of the pathogenic mechanisms. Moreover, an update is presented on the basis of the most recent diagnostic criteria, which enable an early diagnosis. Finally, therapeutic strategies are proposed with the goal of improving the rates of patient survival and the quality of life of those affected by these SADs.

Keywords: Loeys–Dietz syndrome; Marfan syndrome; aneurysm; dissection; syndromic aortic diseases; vascular Ehlers–Danlos syndrome.

Figure 1

Classification of the genes responsible for SADs. Modified by [3].

Figure 2

FBN1 mutation. Mutation of the FBN1 gene causes a dysregulation of the TGF-β pathway, leading to increased activation. Adapted with permission from [6].

Figure 3

FBN1 mutation and aortic aneurysms. The overexpression of metalloproteinases (MMP2; MMP9) and pro-apoptotic factors, causing a structural alteration of the smooth muscle cells (SMCs), determines the formation of aortic aneurysms. Adapted with permission from [7].

Figure 4

EDS 2017 Classification. The correlation between the gene defect and the affected protein determines the type of EDS. Modified by [21].

Figure 5

Age of onset of first major complication in relation to COL3A1 variant type. * Glycine. Adapted with permission from [25].

Figure 6

Protocol for the genetic study. Modified by [28].

Figure 7

Revised Ghent criteria and scoring of systemic features. Modified by [32].

Figure 8

Aortic aneurysm in MFS. (a,c) Aortic root aneurysm by MRI measured in sagittal projection and transversal projection, evaluating cusp to cusp diameters at end-diastole; (b) 3D reconstruction of CTA imaging (d–f) of an aortic root aneurysm; the double acquisition of sagittal and coronal images allows for a more correct transversal diameter of the aortic lumen. Adapted with permission from [37].

Figure 9

Arterial anomalies in LDS. (A): Aortic root aneurysm by 3D CT angiography (CTA); (B) Stanford type A aortic dissection extending into the brachiocephalic trunk; (C) aneurysm of the truncus pulmonalis by CT; (D) aneurysm of the splenic artery by RMI; (E) tortuosity of the abdominal aorta, suprarenal aneurysm of the abdominal aorta and aneurysms of the coeliac trunk, and left common iliac artery by 3D CTA; (F) Stanford type B aortic dissection of abdominal aortic with dissection flap extending into the left common iliac artery; (G) saccular aneurysm of the right ophthalmic artery by RMI; (H) fusiform aneurysm of the left vertebral artery by 3D CTA; (I) fusiform dilatation of basilar artery by RMI. Adapted with permission from [42].

Figure 10

Stanford type A dissection in patient with vEDS. Arrow: intimal tear in the aortic arch; asterisk: pericardial effusion. Adapted with permission from [46].

Figure 11

FET technique in SS Annunziata Hospital. (A) Intraoperative image of aortic root and aortic arch replacement with single reimplantation of the epiaortic vessels; (B) image processed by 3D CT showing (arrow) the stent grafting in the descending thoracic aorta.