Pathophysiology of carotid-cavernous fistulas in vascular Ehlers-Danlos syndrome: a retrospective cohort and comprehensive review

Salma Adham,Denis Trystram,Valérie Domigo,Juliette Albuisson,Xavier Jeunemaitre,Anne Legrand,Michael Frank

doi:10.1186/s13023-018-0842-2

Abstract

BackgroundVascular Ehlers-Danlos syndrome (vEDS) is a rare condition characterized by connective tissue fragility. Direct spontaneous carotid-cavernous fistula (sCCF) is reportedly pathognomonic of vEDS. We conducted this study to understand the possible mechanisms of occurrence of sCCF in this subset of patients.MethodsWe conducted a retrospective analysis of a monocentric vEDS cohort along with a literature review regarding sCCF in this condition.ResultsOf 133 patients regularly followed in our centre between 2000 and 2017, 13 (9.8%) had a diagnosis of direct sCCF (92.3% female, median age 33.0 years, interquartile range (IQR) [26.0–39.5]). There were 7 Glycine missense and 6 splice-site variants but no variant leading to haploinsufficiency. The literature search identified 97 vEDS patients with direct sCCF (79.4% female, 7.2% sex not reported, median age 31.0 years, IQR [24.0–39.0]). Increased carotid circumferential wall stress, higher carotid distensibility and lower carotid intima-media thickness could contribute to a higher risk for direct sCCF in vEDS. There is no predictive factor for the occurrence of sCCF apart from female sex in vEDS.ConclusionsIn vEDS, anatomical and pathophysiological features of the intra-cavernous internal carotid artery make it prone to shunting in the cavernous sinus, due either to a spontaneous rupture or to a spontaneous dissection with pseudoaneurysm formation. Direct sCCF in seemingly healthy young individuals should be highly suggestive of vEDS and prompt further investigation.

Highlights

Vascular Ehlers-Danlos syndrome is a rare condition characterized by connective tissue fragility
We report in this article a series of 13 molecularly proven Vascular Ehlers-Danlos syndrome (vEDS) patients diagnosed with direct spontaneous carotid-cavernous fistula (sCCF) along with a review on literature regarding direct sCCF occurring in vEDS patients
We identified 15 individuals either with variants leading to haploinsufficiency (n = 12) or with non-Glycine missense variants within the triple helix and non-Glycine missense variants or in-frame insertions-deletions in the N- or C-terminal part of the protein (n = 3)

Summary

Introduction

Vascular Ehlers-Danlos syndrome (vEDS) is a rare condition characterized by connective tissue fragility. Direct spontaneous carotid-cavernous fistula (sCCF) is reportedly pathognomonic of vEDS. Vascular Ehlers-Danlos syndrome (vEDS, OMIM #130050) is a rare inherited connective tissue disorder with a prevalence estimated at 1/150000. It is an autosomal dominant transmitted disorder caused by diverse mutations in the COL3A1 gene which encodes the pro-alpha chain of type. Intestinal and uterine fragility are classical features of vEDS, but generalized arterial fragility dominates the clinical picture with spontaneous dissections, aneurysms and arterial ruptures [2]. It is unsurprising that vEDS has been associated with the development of spontaneous direct carotid-cavernous fistula (sCCF). Carotid-cavernous fistula (CCF) is an abnormal communication between the

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