Accuracy of Clinical Diagnostic Criteria for Patients With Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Centre

Abstract

Background: Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disease secondary to mutations within the COL3A1 gene. The diagnosis of vascular Ehlers-Danlos syndrome is challenging, and patient selection for genetic testing relies on diagnostic criteria, which have never been evaluated. Methods: All patients seen at a dedicated tertiary referral center for a suspicion of vascular Ehlers-Danlos syndrome between January 2001 and March 2016 were retrospectively included in a diagnostic accuracy study. Major and minor diagnostic criteria of the Villefranche classification were tested for sensitivity, specificity, positive and negative predictive values, according to results of genetic testing. Results: N=519 patients were eligible for analysis dividing into n=384 probands and n=135 relatives. A pathogenic COL3A1 variant was identified in n=165 (31.8%) patients. The Villefranche criteria were met for n=248 patients with a sensitivity of 79% (95% CI, 0.72–0.85) and a negative predictive value of 87% (95% CI, 0.83–0.91). Diagnostic accuracy was highest for symptomatic probands (sensitivity 92%; negative predictive value 95%) with limited specificity (60%). Probands ≤25 years had the worst diagnostic performance. The revised diagnostic Criteria (2017) were less accurate than the Villefranche classification (overall diagnostic odds-ratio, 4.17 versus 7.8; probands diagnostic odds-ratio, 4.04 versus 18.1; and probands ≤25 years diagnostic odds-ratio, 2.36 versus 5.1) mainly due to a lack of sensitivity. Conclusions: The Villefranche criteria provide accurate detection of symptomatic probands in specialized practice but have limited specificity. The revised diagnostic criteria for vascular Ehlers-Danlos syndrome have increased specificity, but its overall performance is poorer. The early clinical diagnosis of probands without family history is not addressed by both diagnostic classifications.

Application of the 2017 criteria for vascular Ehlers‐Danlos syndrome in 50 patients ascertained according to the Villefranche nosology

“…Concerning minor criteria, positive family history, acrogeria, early‐onset varicose veins, pneumo(hemo)thorax, talipes equinovarus, tendon and muscle rupture, and arteriovenous fistula and/or sCCF were all statistically more frequent in the COL3A1 positive patients, whereas hypermobility of small joints and gingival recession/fragility showed similar rates. Although we did not compare mutation positive and negative patients, the rates of arterial/intestinal/uterine fragility or rupture, thin, translucent skin, extensive bruising, peculiar facial appearance, positive family history, early‐onset varicose veins, talipes equinovarus, and pneumo(hemo)thorax observed in our study are comparable with those of the COL3A1 positive cohort reported by Henneton et al Differences in sample size, ethnicity or patients’ selection bias or subjective interpretation of criteria without a precise formal definition might explain the higher rate of hypermobility of small joints, gingival recession/fragility, arteriovenous, carotid‐cavernous sinus fistula, and tendon and muscle rupture, and the lower rate of acrogeria in our sample.…”

“…Molecular testing, extended to the major molecular differential diagnoses in case of negative results, is always indicated for diagnosis confirmation and optimal clinical management. [15][16][17] The recent study of Henneton et al 8 individuals, in our opinion, the 2017 nosology is more than appropriate when applied in its broadest sense. Molecular testing for vEDS in the presence of any one of the major, minimal, or at least two minor criteria should allow high diagnostic yields.…”

“…The recent study of Henneton et al calculated for the Villefranche criteria an overall diagnostic odds ratio score (DOR) of 7.8%, mainly due to the limited specificity (Sp) of arterial fragility. Indeed, among the 384 index‐patients, who were tested not only in the presence of two or more major diagnostic criteria (209 patients, 54.4%) but also in the context of arterial fragility alone (175 patients, 45.5%), only 105 patients (27.3%) were found to harbor a pathogenic variant.…”

“…Henneton et al also assessed the accuracy of the revised criteria, showing that they were less precise than the Villefranche nosology. In particular, the authors disclosed for probands lower Se (68% vs 92%) and DOR score (4.04 vs 18.1).…”

“…1,2,7 A recent work evaluated the accuracy of the diagnostic criteria of both nosologies in terms of sensitivity (Se), and specificity (Sp), according to the results of genetic testing. 8 The study cohort consisted of 519 patients, who underwent genetic testing that identified a COL3A1 variant in 31.8% of the cases. The Villefranche criteria were met for 47.7% of patients with a Se of 79% and a Sp of 67%.…”