Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes

Abstract

Objective: The management of arterial pathology in individuals with vascular Ehlers-Danlos syndrome (vEDS) remains a challenge. Here we describe the correlation between COL3A1 gene mutation type and the clinical phenotype in individuals with vEDS.

Methods: Individuals with confirmed molecular diagnoses of vEDS were enrolled in a multi-institutional natural history study. Data collected included demographics, clinical and family histories, arterial pathology (aneurysm, dissection, and rupture), operative details, and autopsy reports. Individuals were classified into two cohorts by the type of COL3A1 mutations and their effect on the amount of normal collagen produced: those with mutations that lead to minimal (MIN) production (10%-15%) of normal type III collagen and those with haploinsufficiency (HI) mutations that lead to production of 50% of the normal type III collagen.

Results: A cohort of 68 individuals (72%) from 56 families had arterial pathology (44% male) with 13% HI. The HI group was older at the time of their first vascular event (mean, 42 [range, 26-58] years vs 33 [range, 8-62] years; P = .016) and had a higher incidence of aortic pathology than the MIN group (56% vs 21%; P = .025). Visceral arterial pathology was seen in 43 arteries in 23 individuals in the MIN group vs only one artery in five individuals in the HI group. Emergency surgical procedures were more likely to be undertaken when vEDS diagnosis was not known (81% vs 41%; P = .005), and 81% of these procedures were open surgical repair compared with 19% endovascular repairs (P = .019). Open and endovascular repairs were equally used in the elective setting. Postoperative complications were highest when the diagnosis of vEDS was not known (62% vs 14%; P < .001) and when procedures were undertaken in an emergency setting (5% vs 55% P < .001). Mortality due to arterial complications was 0% in the HI cohort and 21% in the MIN cohort (P = .132).

Conclusions: Arterial pathology in vEDS individuals is related to the underlying COL3A1 mutation type. The arterial pathology in individuals with HI mutations occurs at later ages with a higher incidence of aortic disease compared with other COL3A1 mutation types. Molecular diagnosis is recommended because diagnosis confirmation, appropriate surveillance, and prophylactic interventions in an elective setting improve surgical outcomes.

Figure 1

Spectrum of facial features in individuals with vEDS: variability among patients and does not necessarily correlate with the severity of the underlying arterial pathology. All four individuals here died from vascular complications (A) Caucasian male (MIN mutation, c.2553+1delG) presenting with characteristic vEDS facies including proptotic eyes, long and thin nose, minimal subcutaneous facial fat, and a triangular shaped face. (B) Hispanic female (MIN mutation, c.3545G>A p.G1182E) with mildly proptotic eyes, a long thin nose and a hypotrophic forehead scar, but otherwise normal facial features. (C) Caucasian male (MIN mutation, c.2870G>T, p.G957D) with down slanting palpebral fissures, long and thin nose, thin lips and attached pinna. (D) Caucasian female (c.665G>T, p.G222V) presenting with a long thin nose, but otherwise normal facial features. Written consent was obtained at the time of enrollment for clinical photography and use in medical education.

Figure 2

Cutaneous manifestations of vEDS. (A) Thin translucent skin with visible venous pattern on the lower back of a patient with vEDS (MIN mutation, exon skip). (B) Widened atrophic scar in patient following open abdominal aortic aneurysm repair (HI mutation)

Figure 3

Arterial involvement in vEDS cases by COL3A1 mutations. Though vEDS involves medium sized arteries more commonly, there was an increased prevalence of aortic involvement in the HI cohort compared to the MIN cohort (P = .025) MIN: mutations that lead to minimal normal type III collagen production. HI: mutations that lead to 50% normal type III collagen production. CCF: Carotid Cavernous Fistula.

Figure 4

A 6 cm carotid artery aneurysm which developed in a 34 year old woman acutely in the post-partum period. (A, B) 3-D reconstruction and representative axial image of a computed tomography scan demonstrating the large right internal carotid artery aneurysm. Her arterial pathology led to vEDS diagnosis (MIN mutation, c.1772G>A, p.Gly591Asp) and preoperative multidisciplinary planning accordingly. She was successfully treated with stent-assisted coil embolization of the ICA aneurysm (C). Images courtesy of Johns Hopkins/NIH

Figure 5

Endovascular repair of a right subclavian artery rupture presenting with sudden onset of left shoulder pain radiating to the neck in an 18 year old man with known vEDS (MIN mutation, (c.3847C>T). (A) Arteriogram demonstrating the rupture site and arteriovenous fistula to right internal jugular vein. (B) Knowledge of his diagnosis allowed for the surgical treatment to be tailored to his diagnosis with 7 mm Self expanding covered stents in the common carotid and subclavian arteries without complications. Images courtesy of Dr. Ali Azizzadeh, MD (UT Houston).