Vascular Ehlers-Danlos Syndrome

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: COL3A1 (HGNC:2201)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 09/02/2020
• Curation Status: Released (2.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
COL3A1	Ehlers-Danlos syndrome, vascular type (0017314)	130050	Moderate Actionability

Actionability Assertion Rationale

• The assertion was changed from strong to moderate, as it was based on effectiveness data from extrapolated from Marfan syndrome and multiple scorers expressed concern about the applicability of this condition because of known differences in the natural history of these two conditions. There is a need for better evidence specific to COL3A1 that demonstrates the aggregate impact of risk management and surveillance.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from arterial or organ rupture / Referral to specialists to guide appropriate risk management including surveillance for aneurysm	3	3C	1D	3	10CD

Severity of Outcome

Prevalence of the Genetic Condition

There are no good current estimates of the prevalence of vascular Ehlers-Danlos Syndrome (vEDS), also referred to as Ehlers-Danlos Syndrome type IV, in any population because a large proportion of cases remain undiagnosed. A minimum prevalence of about 1:200,000 can be estimated by extrapolating from the number of known individuals with genetic testing, biochemical, or pedigree-confirmed diagnoses in the United States, but it is suggested that the overall prevalence may approach 1:50,000.

Clinical Features (Signs / symptoms)

vEDS is caused by a reduction in type III collagen due to pathogenic variants in COL3A1 and is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); an aged appearance to the extremities; and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults; spontaenous pneumothorax/hemopneumothorax may also be a presenting feature. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously. Arterial rupture may occur in the thorax and abdomen (66%), head and neck (17%), and extremities (17%) and tissue fragility. About 15% of individuals will experience a gastrointestinal rupture, most frequently in the sigmoid colon, though they also rarely occur in the small bowel and stomach and iatrogenic perforation may occur during colonoscopy. Poor wound healing may complicate surgical repair. Other features include hypermobility of small joints, carotid-cavernous sinus arteriovenous fistula, tendon or muscle rupture, chronic joint subluxations and dislocations, clubfeet, keratoconus, periodontal disease and gingival recession, and early onset varicose veins. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. In children ascertained prior to a major complication, four minor features are frequently present: distal joint hypermobility, easy bruising, thin skin, and clubfeet. Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. Reported pregnancy-related complications have included rupture of the bowel, uterus, aorta, vena cava, vaginal laceration, and postpartum uterine hemorrhage. Patients are at increased risk of intracranial aneurysm (ICA), subarachnoid hemorrhage (SAH), and myocardial infarction.

Natural History (Important subgroups & survival / recovery)

Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. The majority (60%) of individuals diagnosed before age 18 are identified because of a positive family history, though 15% of children have experienced a major complication before the time of testing, and of those tested in the absence of family history, 54% had experienced a major complication.

Death in the first two decades of life most commonly results from arterial rupture; death before age 20 is more commonly reported in males (3:1). Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a COL3A1 pathogenic variant, and may present as sudden death, stroke and neurologic sequelae, acute abdomen/retroperitoneal bleeding, uterine rupture at delivery, and/or shock, with an average age of 31 for first major arterial or gastrointestinal complication. Bowel rupture is very rarely (3%) lethal. Hemoptysis can be severe and recurrent, even life threatening. Carotid cavernous sinus fistulas typically present with sudden-onset ocular symptoms and almost always require rapid intervention to save vision. It affects about 10% of individuals with vEDS with a preponderance among females. Vascular fragility is dominant in the third and fourth decade.

Pregnancy increases the likelihood of a uterine or vascular rupture, with events more likely during the last trimester, delivery, or immediately postpartum.

Studies have differed with respect to whether there is a difference in survival between sexes, with at least one study suggesting a younger median survival (by 5 years) for males. The reported median survival for individuals with vEDS is 48-51 years, but with a very large range (10-81 years).

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

vEDS is usually inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. Biallelic pathogenic variants have been found in less than 1% of all affected individuals.

Prevalence of Genetic Variants

< 1-2 in 100000

Approximately 95-96% of individuals with vEDS have a pathogenic variant in COL3A1, suggesting that the prevalence of pathogenic variants in COL3A1 is similar to the prevalence of the condition.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

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.

Tier 3

>= 40 %

There is 50%-90% mortality by age 48-50 years due to spontaneous rupture of visceral organs and blood vessels.

Tier 3

5-39 %

Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a COL3A1 pathogenic variant.

Tier 3

Unknown

The penetrance is reduced in individuals with null pathogenic variants and the phenotype appears primarily related to vascular events; minor diagnostic criteria are absent in 51% of individuals with a pathogenic null variant

Tier 3

>= 40 %

Angiography has been reported to be associated with a 17-67% complication risk and a 6-19% mortality rate in individuals with EDS (not specific to vEDS).

Tier 1

5-39 %

Pregnancy is associated with death in about 5% of women, and 50% of deaths occur in first pregnancy. Complications occur in about half of all pregnancies.

Tier 3

5-39 %

In two systematic reviews of case series, GI rupture or perforation occurred in 13.4-25.0% of individuals; in studies examining survival, GI complications contributed to the mortality of 0-16.3% of individuals with vEDS.

Tier 1

5-39 %

Spontaneous pneumothorax occurs in 12% of individuals.

Tier 4

Expressivity

Individuals with a COL3A1 null variant have a 15-year delay in onset of complications, improved life expectancy, and significantly fewer obstetric and bowel complications than are seen with other types of COL3A1 pathogenic variants. The phenotype in these individuals appears primarily limited to vascular events, and the penetrance reduced. Survival was observed to be shortest in those with splice donor site variants. However, these differences in populations are difficult to use to counsel individuals because of significant intra- and interfamilial variability in age of complication and survival for the same pathogenic variant. The natural history may also vary by gender.

Tier 3

Intervention Effectiveness

Patient Management

At the time of diagnosis, an affected individual should be referred to a center with experience and expertise in vEDS for lifelong follow-up and a multidisciplinary care team established with the primary care physician as the coordinator. This team should establish a protocol for management during a major complication, and the local emergency department should be given data about the individual. Many symptomatic arterial events are self-limiting and may not require surgical or radiologic management; surgical repair should only occur in the setting of life-threatening complications and in the event of arterial rupture, urgent repair is necessary. Affected individuals should carry an emergency care card to be provided to the ER physician at time of consultation. For younger women planning pregnancy, a high risk team should be assembled including experienced obstetricians and vascular surgeons.

Tier 2

There is currently 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 following are recommended:

• Visualization of the arterial tree. Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made.

• Consultation with medical geneticist and/or genetic counselor.

• Review of lifestyle, particularly sports participation

Tier 4

Guidelines differ on recommendation for prophylactic aortic repair in the case of asymptomatic patients with aortic aneurysm. Some guidelines recommend patients undergo elective operation at diameters of 4.0-6.0 cm depending on location of aortic aneurysm and pregnancy anticipation status. Other guidelines take a more conservative approach, stating that due to the high risk of complications as a result of hemorrhagic tendency, tissue fragility, and poor wound healing in vEDS as well as the lack of specific data in vEDS patients, it is not possible to set threshold for surgical intervention in patients with EDS Type IV and thoracic aortic aneurysm. These guidelines state that decisions to surgically intervene should instead be based on a case-by-case basis and guided by multidisciplinary discussion. For preoperative planning, the entire aorta should be imaged. No evidence for effectiveness of aortic aneurysm repair in vEDS patients was identified. In Marfan syndrome, timely repair of aortic aneurysm prolongs survival, such that it approaches that of age-matched controls.

Tier 2

Patients with vEDS, especially those with identified TAD and/or ICA, and hypertension should have their hypertension monitored and treated aggressively with the intent to minimize chance of arterial dissection or rupture. Guidelines have suggested that beta blockers should be the mainstay of treatment to reduce aortic wall stress, though no evidence exists for their effectiveness at reducing mortality or dissection rate and there are no established blood pressure thresholds. There has been one randomized controlled trial of an antihypertensive therapy in vEDS, a trial of the mixed β1 antagonist and β2 agonist, celiprolol. The study suggests that treatment of individuals with vEDS with the drug extends the time to vascular complications compared to those not treated. However, the study suffered from selection bias: patients were selected on clinical grounds, and it was later found that only two thirds of patients carried pathogenic variants in COL3A1.

Tier 2

Bowel rupture almost always requires surgical intervention.

Tier 2

Death from bowel rupture is uncommon because intervention is generally effective.

Tier 4

Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain.

Tier 4

Guidelines for anesthesia management in patients with vEDS have included recommendations against neuraxial anesthesia due to theoretical risk of spinal hematoma. Avoidance of central venous access and arterial puncturing is also recommended, and if needed should be performed with ultrasound guidance. A thorough medical history of bleeding should be ascertained. Tourniquets should be avoided, anecdotal evidence exits of lethal complications due to the use of tourniquets in elective minor surgery. Prematching of red blood cells should be performed and blood products obtained in advance of surgery in anticipation of transfusion needs. Tracheal intubation should be atraumatic and positive pressure ventilation avoided when possible. Hypertensive episodes should be prevented and treated.

Tier 4

Surveillance

Patients should undergo complete aortic imaging and widespread imaging of the vascular tree. Non-invasive imaging is the preferred approach to evaluating vascular alterations. Some have suggested MRI should be considered first-line surveillance of choice for adolescents and in the adult population under age 50 years, while others include CTA or doppler ultrasound as well in suggested imaging modalities. No consensus exists on frequency of surveillance, but annual surveillance has been suggested when feasible.

Tier 2

Notably, dissection can occur at any aortic root diameter, and especially in vEDS, there is no clear association with aortic root diameter.

Tier 3

Guidelines differ on whether patients with EDS should be considered for screening for ICA, with some stating screening should not be done in all patients with vEDS. Others state that patients with vEDS should be strongly considered for screening for unruptured ICA by CTA or MRA and patients with ≥2 family members with ICA or SAH should be offered surveillance, with guidelines suggesting 1-5 year intervals, including in children. Data is available on family members of individuals with aneurysms, though nonspecific to vEDS. In these cohort screening studies of first-degree relatives of individuals with an ICA, aneurysms were detected in 8.7-19.1% depending on inclusion criteria. The goal of surveillance is to guide repair via surgical clipping or endovascular coiling to prevent rupture, though no data on treatment outcomes were provided for patients with vEDS. Surgical or endovascular treatment is not without risks and the choice of surgery would also be guided by patient factors, aneurysm size and location.

Tier 2

Circumstances to Avoid

In a systematic review of the literature, no studies were found to address the possible association between exercise and vascular events (including aortic dissection) in individuals with vEDS.

Tier 1

However, guidelines have recommended that individuals with vEDS should not participate in low static/low dynamic competitive sports if they have any of the following :

• Aortic root enlargement or dilation, or branch vessel enlargement

• Moderate to severe mitral regurgitation

• Extracardiac organ system involvement that makes participation hazardous.

Tier 2

Other guidelines have suggested an exercise program and recommendations individually tailored to diagnosis, aortic root diameter, family history of dissection and sudden death, and underlying fitness. Individuals with vEDS should not participate in any competitive sports that involve intense physical exertion or the potential for bodily collision.

Tier 2

Activities with rapid acceleration/deceleration should be discouraged.

Tier 2

Because of severe tissue fragility, it is necessary to avoid invasive procedures, such as catheterization, during vascular evaluation

Tier 2

Conventional arteriography should be avoided because it has been associated with de novo complications.

Tier 3

Rectal temperature measurement and intramuscular injections are contraindicated.

Tier 4

Nature of Intervention

Nature of Intervention

Surgical complications in vEDS are common, with a high rate of procedural mortality. Surgical clipping complications in patients with ICAs (including patients without vEDS) are also common, with studies indicating a 1-2.6% mortality and 4.1-10.9% morbidity rate. Endovascular occlusion of ICAs has a complication rate of 5-10%. Additionally, endovascular treatment of ICA requires X-ray fluoroscopy, which is carcinogenic. Recurrent bowel surgery may be associated with ilio-colic fistula formation, though this may be prevented by subtotal colectomy.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Because many families with vEDS are identified only after a severe complication or death, it is likely that individuals/families with pathogenic variants in COL3A1 and a mild phenotype do not come to medical attention and go undetected. In addition, because of the perceived rarity of the disorder, it is seldom considered and nonvascular complications may not raise diagnostic suspicion of vEDS. About half of the probands identified have no family history of vEDS (proportion of patients with a de novo variant is ~50%), and diagnosis is often made in the context of the major complications of the condition. Women presenting with vascular complications related to pregnancy may have no knowledge of their underlying condition until their complications arise. About 60% of individuals who are diagnosed before age 18 are identified due to a positive family history; 15% of these individuals have already experienced a major complication at the time of testing.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			COL3A1			130050	0017314	0007524

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