Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients

Abstract

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease.

Methods: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination.

Results: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03).

Conclusions: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Keywords: Ehlers-Danlos syndrome, type IV; aortic aneurysm; collagen; connective tissue; uterine rupture.

Figure 1.

Schematic overview of the COL3A1 gene, with the location of pathogenic and likely pathogenic variants found in our cohort. The boxes represent the coding exons and the colors represent protein domains. Blue boxes represent N and C terminal domains, gray represents the transitional domain, and yellow represents the collagen helical domain. Glycine substitutions are displayed on the left. Each * is an individual with an aortic dissection. Variants in bold are proven de novo variants.

Figure 2.

Kaplan-Meier curves for occurrence of major events. A, Sex and age at occurrence of the first major event. Age at the first major complication correlated with sex in 142 individuals with vEDS. B, Facial features highly suggestive of vEDS and age at occurrence of the first major event. Age at the first major complication correlated with the presence of ≥5 suggestive features of vEDS upon physical examination in 142 individuals with vEDS. C, Age at occurrence of the first major event in the total cohort. Age at the first major complication correlated with the type of P/LP COL3A1 variant in 142 individuals with vEDS. D, Age at occurrence of the first major event in relatives. Age at the first major complication correlated with the type of P/LP COL3A1 variant in 96 relatives with vEDS. P/LP indicates pathogenic/likely pathogenic; splice/delins/del, splice-site/deletion insertion/deletion variant; and vEDS, vascular Ehlers-Danlos syndrome.