Diagnosing Vascular Ehlers-Danlos Syndrome

Christin L. Melton, ELS

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders that can vary from loose joints to life-threatening complications, depending on type. The vascular form of EDS, which is estimated to affect 1 in 250,000 people, is considered by many to be the most serious form of the disease because of its high risk of spontaneous arterial, intestinal, and uterine rupture.1 Arterial rupture typically occurs during the third or fourth decades of life and is the most common cause of sudden death.2
In many patients, the disease remains undiagnosed until there is a devastating complication or fatal event, such as an aortic dissection or abdominal aortic aneurysm, making early diagnosis essential for optimizing outcomes by enabling patients to take prophylactic measures. Early diagnosis of EDS requires a keen eye for the signs and symptoms of the disorder, which can vary considerably by patient, and initiating genetic testing when the disease is suspected.

Signs and Symptoms of Vascular EDS

The signs and symptoms of vascular EDS vary by patient; however, easy bruising, even after sustaining only minor trauma, is a common finding.2,3 Patients with this condition may have soft skin that appears thin and fragile, with veins visible beneath the skin, particularly on the chest and abdomen. The hands and feet may have an aged appearance due to premature aging of the skin, but unlike patients with other types of EDS, those with the vascular form do not have overly stretchy skin.2,3
Certain facial characteristics have been associated with vascular EDS, including large protruding eyes, a small chin, sunken cheeks, a thin nose and lips, and lobeless ears.2,3 When joint hypermobility is present, it typically only affects the digits. Other findings may include the early onset of varicose veins; arteriovenous or carotid-cavernous fistula; pneumothorax/pneumohemothorax; gingival recession; and operative and postoperative complications, including wound dehiscence.2,3
The major and minor diagnostic criteria for vascular EDS are summarized in the Table.4
Major and Minor Diagnostic Criteria for Vascular Type Ehlers-Danlos Syndrome (EDS)4
Major Criteriaa
  • Arterial rupture
  •  Family history of vascular EDS
  • Intestinal rupture
  • Uterine rupture during pregnancy
Minor Criteriab
  • Aged appearance of hands and feet
  • Arteriovenous carotid-cavernous sinus fistula
  • Characteristic facial appearance
  • Chronic joint subluxations/dislocations
  • Clubfoot
  • Congenital dislocation of the hips
  • Early-onset varicose veins
  • Easy bruising
  • Gingival recession
  • Hypermobility of small joints
  • Pneumothorax/pneumohemothorax
  • Tendon/muscle rupture
  • Thin, translucent skin
a Any two major diagnostic indicates a high specificity for vascular EDS and warrants biochemical testing for confirmation
b One or more minor criteria should lead to consideration of the diagnosis but is not sufficient to establish the diagnosis

Genetic Testing

When vascular EDS is suspected, genetic testing should be undertaken to look for mutations in the COL3A1 gene.5 This protein-coding gene enables formation of type III collagens, which provide structure and strength to connective tissues, including the skin, blood vessels, and internal organs.5 Mutations in the COL3A1 gene cause a large percentage of type III collagen molecules to assemble incorrectly or levels of type III collagen to be reduced, causing tissue weakness and predisposal to injury. To date, more than 320 mutations have been identified in patients with vascular EDS.5
Because vascular EDS is inherited in an autosomal dominant pattern, a single copy of the altered gene can cause the disorder.2,3 Approximately 50% of cases are inherited from a parent who has the condition, with the remaining cases occurring sporadically.3,4 A skin biopsy can be used to diagnose vascular EDS.

Prognostication Potential

One recently published study assessing mutations in patients with molecularly proven vascular EDS found that the course of the disease is influenced by the type of variant present,6 suggesting testing may eventually improve prognostication. In the study, which included 215 cases of vascular EDS (146 index cases and 69 relatives), the researchers found 126 distinct variants, which they divided into five groups: (1) glycine substitutions (n=71); (2) splice-site and in-frame insertions-deletions (n=36); (3), haplo-insufficiency–inducing variants (n=7); (4) nonglycine missense variants within the triple helix (n=4); and (5) nonglycine missense variants or in-frame insertions-deletions in the N- or C-terminal part of the protein (n=8). Among the entire study cohort, the median age at first complication was 29 years (range, 22-39 years), with arterial (48%) and digestive (24%) ruptures being the most common. Patients with glycine substitutions and splice-site and in-frame insertions-deletions demonstrated significantly greater disease severity than those with the other variants, with the latter groups (ie, 3, 4, and 5) having no digestive events. Patients with mutations located in the C- and N-termini or with those leading to haplo-insufficiency were found to have a milder course of the disease and less prevalent diagnostic criteria, whereas glycine substitutions led to more destabilizing residues of the collagen assembly and greater disease severity. Based on their findings, the researchers suggest that “these findings may help refine diagnostic strategy, genetic counseling and clinical care.”6


1. Genetics Home Reference. Ehlers-Danlos syndrome. Published April 13, 2015. Accessed April 14, 2015.
2. The Ehlers-Danlos National Foundation. Vascular type. Accessed April 14, 2015.
3. Ehlers-Danlos Syndrome: Network C.A.R.E.S. Inc. Ritter Rules for Aortic Diseases. Accessed April 14, 2015.
4. Pepin MG, Byers PH. Ehlers-Danlos Syndrome Type IV. Gene Reviews [Internet]. Updated May 2011. Accessed April 14, 2015.
5. Genetics Home Reference. COL3A1. Published April 13, 2015. Accessed April 14, 2015.
6. Frank M, Albuisson J, Ranque B, et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.
Eur J Hum Genet. 2015 Mar 11. doi: 10.1038/ejhg.2015.32.

"Ehlers-Danlos syndrome3" by Piotr Dołżonek - see below. Licensed under GFDL via Wikimedia Commons -
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