Clinical Guidance

More than 600 unique COL3A1 pathogenic variants have been aggregated into the Ehlers Danlos Syndrome Variant Database with an additional 250 in ClinVar. Approximately 5% of COL3A1 variants result in haploinsufficiency. Individuals with a COL3A1 null variant have a 15-year delay in onset of complications, improved life expectancy (close to that of the US population), and significantly fewer obstetric and bowel complications than are seen with other types of COL3A1 pathogenic variants . Among the 1,200 individuals with vEDS described by , survival depended in part on the nature of the pathogenic variant.

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"

Penetrance

In families identified on the basis of clinical complications, penetrance of the vEDS phenotype appears to be close to 100% in adults with a missense or exon-skipping alteration; the age at which the pathogenic variant becomes penetrant may vary. COL3A1 null variants have significantly later penetrance in part because of the rarity of minor clinical features in the majority of individuals with vEDS identified with a pathogenic null alteration . In rare individuals with heterozygous null variants no clinical signs are present in the eighth and ninth decades.

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"

Diagnostic Criteria

No consensus clinical diagnostic criteria for vascular Ehlers-Danlos syndrome (vEDS) have been published. When the diagnosis is suspected on clinical grounds, molecular diagnostic testing of COL3A1 is indicated due to the presence of clinical phenocopies and variable expression of the vEDS phenotype. Criteria established in 2017 are useful to guide the approach to genetic testing .

Suggestive Findings

Vascular EDS should be considered in individuals with any one (and especially with two) of the following major clinical findings or several minor diagnostic criteria, particularly in those younger than age 40 years.

Major clinical findings

• Arterial aneurysms, dissection, or rupture

• Intestinal rupture, most often in the sigmoid colon

• Uterine rupture during pregnancy

• Family history of vEDS

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"

Differential Diagnosis

Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies or molecular analysis of COL3A1. lists selected EDS-related genes and other genes of interest in the differential diagnosis of vascular Ehlers-Danlos syndrome (vEDS). Table 2. Disorders to Consider in the Differential Diagnosis of vEDS

Management Guidelines

Evaluations Following Initial Diagnosis

There has been a gradual transition in the approach to both surveillance and intervention prior to arterial events in individuals with vascular Ehlers-Danlos syndrome (vEDS). This shift appears to reflect increased recognition of the diagnosis of vEDS both at the time of an event and before, the creation of centers of excellence and experience for vEDS both in the United States and in other countries, and differences in surgical techniques and approaches with a move away from open intervention and increased use of endovascular approaches. Nonetheless, there is still no consensus regarding the appropriate extent of evaluation at the time of initial diagnosis. To establish the extent of disease and needs in an individual diagnosed with vEDS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) provide a baseline with which to evaluate progression.

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"

Clinical Guidance

Trauma. Because of inherent tissue fragility, it is prudent for individuals with vEDS to avoid collision sports (e.g., football), heavy lifting, and weight training with extreme lifting. Note: No evidence suggests that moderate recreational exercise is detrimental. Arteriography. Conventional arterial angiography (with contrast injection) should be discouraged because it has been associated with added de novo complications . Arterial tear/dissection may result at the site of entry of the catheter; furthermore, injection pressure may lead to arterial aneurysms. Arteriography is currently best used as part of a planned interventional procedure, such as coil embolization or stenting of bleeding arteries. Routine colonoscopy. There are several reports of colonoscopy-associated bowel perforation in individuals with vEDS. Virtual colonoscopy, which also involves insufflation, may have similar complications. Routine colonoscopy for cancer screening is discouraged in the absence of concerning symptoms or a strong family history of colorectal cancer. Individuals with vEDS who have a family history of colon cancer are encouraged to use genetic testing for colon cancer risk assessment (provided the genetic etiology of colon cancer has been established in an affected family member) and screening of stool DNA to detect luminal malignancies. Use of capsular cameras may provide sufficient data in at-risk individuals. Elective surgery.

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"

Therapies Under Investigation

A clinical trial in France to determine if addition of an angiotensin receptor blocker to celiprolol decreases arterial complications and extends life expectancy is currently under way (NCT02597361). Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"

Surveillance Guidelines

The use of surveillance of the arterial vasculature assumes that effective interventions will decrease the risk of arterial dissection or rupture and prolong life. At a time when an open surgical approach was the only option, the benefit of surveillance could not be established. As endovascular approaches to management of aneurysms and dissection become more available, earlier intervention is considered and surveillance may have greater benefit. There are, however, no published data assessing the efficacy of screening strategies in identifying the regions in the arterial vasculature at highest risk; conversely, there are examples in which regions of concern in the arterial vasculature failed to progress and arterial rupture occurred at other, more distant sites. Thus, the benefit of controlled studies cannot be overemphasized. If undertaken, noninvasive imaging such as ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast is preferred to identify aneurysms, dissections, and vascular ruptures . Because arterial tear/dissection may result at the site of entry of the catheter and at sites of high-pressure injection, conventional arteriograms are not recommended. When surveillance is undertaken, repeat measure depends on the pathology identified, but in the presence of a normal vascular tree, screening at 18- to 24-month intervals appears to be the common practice.

Source: GeneReviews — "Vascular Ehlers-Danlos Syndrome"