Vascular Ehlers-Danlos Syndrome · vEDS

Description

Vascular Ehlers-Danlos Syndrome (vEDS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in COL3A1, which encodes the pro-α1 chain of type III collagen. Type III collagen is concentrated in the walls of arteries, the bowel, and the gravid uterus, and defective synthesis or assembly produces tissue fragility at exactly those sites. Rare cases arise from specific COL1A1 variants at the arginine-to-cysteine substitution sites that produce a vascular phenotype overlapping COL3A1 disease. Approximately half of COL3A1 variants are de novo, so a substantial fraction of people with vEDS have no affected parent.

Natural history data from the Pepin and Byers series at the University of Washington and the French AP-HP cohort, the largest international registry, place median age at first major vascular or visceral event near 29 years and median survival near 51 years. Major events are arterial dissection or rupture, sigmoid colon perforation, and uterine rupture during pregnancy or delivery. Pregnancy carries elevated maternal mortality, reported in the range of several percent per pregnancy in older series and lower with modern surveillance. Skin findings are subtle compared with classical EDS, including thin translucent skin with visible subcutaneous veins, easy bruising, and characteristic facial features in some carriers.

The 2017 international classification by Malfait and colleagues lists major criteria including a family history of vEDS with documented COL3A1 variant, arterial rupture at a young age, spontaneous sigmoid colon perforation in the absence of known diverticular disease, uterine rupture during the third trimester, and carotid-cavernous sinus fistula formation. Minor criteria include bruising unrelated to trauma, thin translucent skin, characteristic facial appearance, acrogeria, hypermobility of small joints, tendon and muscle rupture, early-onset varicose veins, arteriovenous fistula, pneumothorax, gingival recession, and congenital hip dislocation. Confirmatory testing is COL3A1 sequencing, with deletion and duplication analysis when sequencing is uninformative, and biochemical type III collagen analysis on cultured fibroblasts at specialized laboratories when genetic testing is equivocal.

Treatments to date

Management centers on prevention of vascular events and conservative response when they occur. Surgery on fragile vessels and bowel is associated with high morbidity, so non-operative management is preferred when feasible, and emergency operations use techniques adapted to friable tissue.

Celiprolol, a beta-1 antagonist with partial beta-2 agonist activity, showed reduction in arterial events in the BBEST trial reported by Ong and colleagues in The Lancet in 2010. The trial randomized adults with clinical or genetically confirmed vEDS to celiprolol or no treatment and was stopped early for benefit. Celiprolol holds an indication for vEDS in France through AP-HP and is prescribed off-label or through named-patient access in other countries. It is not FDA approved in the United States. Other beta blockers are sometimes substituted where celiprolol is unavailable, without trial-level evidence in vEDS.

Surveillance imaging tracks the aorta, head and neck arteries, and visceral arteries on intervals set by the managing center, often every 12 to 24 months. Pregnancy is managed by maternal-fetal medicine teams with experience in vEDS, with delivery planning that accounts for uterine and arterial rupture risk. Genetic counseling addresses 50 percent transmission risk and the high de novo rate, and family cascade testing identifies relatives who benefit from surveillance before a first event.

Investigational programs include enzastaurin and other agents targeted at vascular wall biology, and registries continue to refine event rates and modifiers.