Vascular Ehlers-Danlos Syndrome

Vascular Ehlers-Danlos syndrome is an autosomal dominant collagen disorder caused by COL3A1 variants, with spontaneous rupture of arteries, bowel and gravid uterus. It is the most dangerous form of Ehlers-Danlos syndrome, and median survival is about 50 years.

Pathophysiology. Defective type III collagen weakens the media of arteries, the wall of hollow organs and the uterus. Dominant negative variants, mainly glycine substitutions, cause a more severe course than null variants.

Rupture is unpredictable and not tied to aneurysm size. Arterial dissection, aneurysm and carotid cavernous fistula can occur, and bowel perforation commonly involves the sigmoid colon.

Many events happen before diagnosis, so a high index of suspicion in young people with unexplained arterial or bowel rupture is critical.

• Thin translucent skin with visible veins on the chest and abdomen, and easy bruising
• Characteristic face: thin lips, small chin, prominent eyes, thin nose
• Arterial rupture, dissection or aneurysm in medium sized arteries (iliac, renal, splenic, carotid, vertebral)
• Spontaneous colonic perforation, usually sigmoid
• Uterine rupture in pregnancy, and peripartum haemorrhage
• Pneumothorax and haemothorax
• Acrogeria (aged appearing hands), small joint hypermobility, clubfoot, varicose veins at a young age
• Tendon and muscle rupture

• Genetic testing of COL3A1 by sequencing with deletion and duplication analysis. Report the variant type, since glycine substitutions carry higher risk than null variants.
• Clinical suspicion: a family history of arterial or bowel rupture before 40 years, unexplained rupture, or a typical face with thin skin.
• Vascular surveillance imaging: MR angiography or duplex ultrasound of neck, chest, abdomen and pelvis. Avoid catheter angiography because of access site arterial tear.
• Skin biopsy and type III collagen protein studies are not needed when genetic testing is available.
• Family cascade: testing of relatives, including children, after counselling.

Differential diagnosis.

• Loeys-Dietz syndrome
• Classical Ehlers-Danlos syndrome
• Marfan syndrome
• Fibromuscular dysplasia and segmental arterial mediolysis
• Inflammatory bowel disease with perforation
• Familial thoracic aortic aneurysm

• Celiprolol 100 mg orally once daily, increased as tolerated to 200 mg twice daily (400 mg daily total), to reduce arterial events. Check blood pressure and heart rate, and avoid in asthma with significant bronchospasm. If celiprolol is not available, a cardioselective beta blocker (atenolol 25 to 50 mg daily or metoprolol) is an alternative.
• Blood pressure: keep systolic blood pressure at or under about 130 mmHg, avoiding sudden surges.
• Emergency arterial event: manage conservatively where possible. Surgery on friable tissue carries high mortality, so use embolisation or open repair only for life threatening haemorrhage, with experienced vascular surgeons, soft vessel handling and pledgeted sutures.
• Bowel perforation: resect the involved segment with end stoma. Avoid primary anastomosis because of high leak risk.
• Avoid: fluoroquinolones, invasive angiography, colonoscopy unless essential, intramuscular injections and strenuous activity, contact sports, and straining.
• Medical alert card and emergency letter naming the diagnosis and advising against unnecessary invasive procedures.
• Pain and anxiety: paracetamol, with avoidance of NSAIDs where bleeding risk is relevant.

Special groups.

• Pregnancy: high risk of uterine and arterial rupture and maternal death. Offer preconception counselling and consider avoidance of pregnancy. If pregnant, continue the beta blocker, plan delivery by caesarean section at about 34 to 38 weeks in a unit with vascular surgery, and observe for 6 weeks after delivery.

Monitoring. Blood pressure and heart rate at each visit. Non-invasive vascular imaging (MR angiography or duplex) every 1 to 2 years, or sooner when symptoms arise.

Referral and escalation. Refer to a specialist in connective tissue disorders, with vascular surgery and obstetric input. Emergency for sudden severe abdominal, chest, flank or neck pain, neurological deficit, or collapse.