Genetic testing is critical to get an accurate diagnosis of vascular Ehlers-Danlos syndrome (vEDS) as clinical criteria alone is insufficient, and given its overlap with other disorders, suggests a real-world study carried out at American and European institutions.
The research also highlights the importance of getting a trained geneticist to analyze the results correctly, because not all variations in the COL3A1 gene lead to the disease.
The study, “A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis,” was published in the Journal of Vascular Surgery.
Ehlers-Danlos syndromes (EDS) are a group of related disorders (13 in total) that are caused by different genetic defects in collagen, one of the major structural components of the body.
One type of EDS is vEDS, which is caused by mutations in the COL3A1 gene that provides instructions for making type III collagen. This syndrome is marked by spontaneous arterial dissections (tears in the lining of arteries), aneurysms (outward bulging in vessels), and ruptures at a young age, which can lead to life-threatening bleeds.
Pneumothorax (when air collects between the lung and chest wall, impairing breathing) is also a common indication of this syndrome, as well as intestinal perforation, and uterine rupture.
Because of its rarity and variety of clinical manifestations, the diagnosis of vEDS can be difficult, even for experienced clinicians. A diagnosis is suspected based on clinical findings and confirmed by molecular testing, which includes a skin biopsy and genetic testing for COL3A1 variants.
In the study, researchers reviewed the diagnostic criteria — clinical only or with molecular testing — used to identify vEDS in 173 individuals (35.3% male), who were referred to 11 institutions in the U.S., Germany, and Italy.
Nearly one-third of the patients (56 individuals; 34.5%) were diagnosed based solely on clinical criteria, without molecular testing. In half of the patients, a final diagnosis was obtained by genetic testing (82 individuals; 50.6%), or by a skin biopsy (five patients; 3.1%).
An additional 20 individuals (12.3%), for whom genetic data were unavailable, were included in the group that was diagnosed using clinical data only. Eleven subjects, who tested negative for vEDS-causing mutations, were excluded.
The results showed that although the rate of death by any cause was similar between the groups, significant differences were noted between those diagnosed solely by clinical criteria and those patients who had a molecular test diagnosis.
Patients diagnosed by clinical criteria more frequently had mitral valve prolapses (problems in closing one of the heart’s valves) — 10.5% vs 1.2% in patients diagnosed through molecular testing. Joint hypermobility (joints that can stretch farther than normal and dislocate easily) were also observed more often in patients diagnosed by clinical criteria — 68.4% vs 40.7% in patients diagnosed with molecular testing.
In contrast, these patients had fewer problems in the arteries (21.1%), compared with the other individuals who were diagnosed through molecular testing (61.6%). Specifically, they were less affected by arterial rupture, as well as intestinal perforation, pneumothorax, or hemothorax (blood between the lung and chest wall).
The patients diagnosed by clinical criteria also had a lower frequency of easy bruising (23.7% vs 64% in those with a molecular test diagnosis), and thin translucent skin (17.1% vs 48.8%).
Patients with a clinical diagnosis had features more consistent with hypermobile EDS or classical EDS, rather than vEDS, according to the researchers.
“This finding suggests that, at least for this cohort, the diagnosis of vEDS in the absence of confirmatory testing cannot be trusted,” they wrote.
“A confirmation of the diagnosis by molecular testing is critical for several reasons. Not only are there clinical features that overlap with the other subtypes of EDS, there are clinical features that overlap with other heritable connective tissues disorders and genetically triggered arteriopathies [artery diseases],” they added.
The team emphasized the importance of having a trained professional to interpret the genetic results: “Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis.”
Nearly 10% of the studied individuals who were suspected of having vEDS based on clinical criteria ended up testing negative for vEDS mutations.
This study highlights the importance of getting a correct diagnosis, which “has serious implications for life-long screening, and medical and surgical management strategies for the affected individual and family members,” the researchers said.