Asymptomatic bilateral common iliac artery dissections in previously undiagnosed vascular Ehlers-Danlos syndrome

Abstract

We report a case of a 35-year-old woman found to have vascular Ehlers-Danlos syndrome (vEDS) after family history of sudden death due to aortic dissection in her otherwise healthy brother prompted further imaging workup and consideration of an underlying heritable genetic condition. CT angiogram of the aorta with intravenous contrast revealed an abdominal aortic artery dissection below the level of the renal arteries extending from the bifurcation into the left common iliac artery with an additional focal dissection of the right common iliac artery. To the author’s knowledge, this is the first report of asymptomatic bilateral common iliac artery dissections as a part of the initial presentation of a patient with underlying vEDS. Additionally, this case highlights the importance of familial diagnostic screening in inherited vasculopathies. Clinical history, genetic testing and management are discussed.

Background

Ehlers-Danlos syndrome (EDS) is a group of disorders caused by mutations in genes involved in extracellular matrix formation. Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal-dominant variant of EDS associated with risk for vascular dissection and organ rupture. Mutations in the COL3A1 gene seen in vEDS result in structural defects of collagen type III leading to decreased production of procollagen. COL3A1 mutations are inherited from a parent in 50% of cases, whereas the other 50% of affected individuals develop a new onset mutation. Vascular dissection, gastrointestinal perforation or organ rupture are the presenting symptoms in 70% of adults with vEDS.^1–3

There is a wide clinical spectrum of disease due to significant allelic heterogeneity. Patients with vEDS and haploinsufficiency may experience their first disease complication significantly later in life given less abnormal production of Type III collagen.⁴ Phenotypic characteristics of individuals with vEDS include thin skin, easy bruising and characteristic facial appearance with a narrow nose. Patients may have joint hypermobility although this is neither sensitive nor specific. The major concern in this hereditary condition is adult vascular rupture and sudden cardiovascular death with most vascular ruptures occurring in the thoracic and abdominal arteries although ruptures can occur elsewhere.^{3 5} More than 80% of individuals with vEDS experience a major complication by the time they are 40 years old. The median survival in vEDS is 48 years.⁶

We report a case of a 35-year-old woman found to have vEDS after family history of sudden death due to aortic dissection in her young, otherwise healthy, brother prompted further imaging workup and consideration of underlying heritable genetic condition.

Case presentation

The patient, a 35-year-old woman with no significant medical history, presented to the cardiology clinic by referral due to the recent sudden death of her brother at the age of 39. Per the patient, her brother was otherwise healthy; his cause of death was hemopericardium. At the patient’s initial visit, she expressed occasional chest pain that occurred randomly and was associated with shortness of breath. The pain did not radiate and was not associated with nausea or diaphoresis. She endorsed good exercise tolerance with the ability to run for long distances without difficulty. On review of systems, she stated she had occasional bruising unrelated to trauma. Her physical examination at that time was noted to be largely unremarkable. At a later date, she would be noted to have subtle finding of short nose with hypoplastic columella and generalised joint hypermobility using the Beighton scoring system.

Given the brother’s young age and cause of death, a CT angiogram (CTA) of the aorta with intravenous contrast was ordered for the patient to evaluate for heritable genetic vascular disease predisposing to development of aortic dissection and subsequent hemopericardium. The CTA showed an approximately 5.5 cm in length abdominal aortic artery dissection below the level of the renal arteries extending from the bifurcation into the left common iliac artery (figure 1). Additionally, there was a focal dissection of the right common iliac artery. The patient’s dissection measured approximately 2.5 cm in the aorta and 1.5 cm in the iliacs.

Figure 1.

CT angiogram of the aorta shows left common iliac artery dissection (A) and right common iliac artery dissection (B).

The patient was called in to the emergency department for evaluation. In the emergency department, she was asymptomatic and did not have chest pain, dyspnoea or abdominal pain. She was hemodynamically stable with an unremarkable physical examination. She had 2+ pulses in bilateral dorsalis pedis arteries. General labs were unremarkable. Vascular surgery was consulted and recommended that she be seen in the vascular surgery clinic in 6 months and evaluated at that time with a vascular duplex ultrasound of her distal aorta and iliac arteries to evaluate for any increase in size of the dissections. The patient was discharged from the emergency department with return precautions.

A transthoracic echocardiogram was obtained that showed a left ventricular ejection fraction of greater than 65% with normal diastolic dysfunction, normal ascending aorta size and normal aortic valve. At a primary care follow-up appointment, the patient endorsed a history of easy bruising. Her Beighton score for joint hypermobility was 5/9. The patient was referred to a geneticist for consideration of testing for an underlying heritable connective tissue disease.

The geneticist found the findings of a personal history of abdominal aortic dissection, family history of sudden death due to an aortic dissection and easy bruising suspicious for vEDS. A connective tissue disease multigene panel was sent. Genetic testing confirmed the diagnosis of vascular type EDS with identification of a previously reported pathogenic mutation in COL3A1 c.970G>A (p.Gly324Ser). Magnetic resonance angiography of the head and neck was recommended along with interval follow-up imaging every 3–5 years. Recommendations were made for continued monitoring of her known abdominal aortic and iliac artery dissections. Her children underwent predictive genetic testing given the autosomal-dominant nature of this disorder. Additionally, the patient was referred to a vEDS centre of excellence for specialised care.

Differential diagnosis

The differential diagnosis of vEDS includes classic EDS, idiopathic isolated arterial aneurysm, autosomal-dominant polycystic kidney disease, Marfan syndrome and Loeys-Dietz syndrome. These can be distinguished by X-ray, CT and MRI findings³ but should be considered in individuals presenting as described. Analysis of the COL3A1 gene in a qualified laboratory identifies the pathogenic variant in greater than 98% of individuals with vEDS.² A greater understanding of differences in molecular subtypes of vEDS can lead to improved recognition of severity of illness and appropriate screening and intervention. At this time, the appropriate frequency and intensity of surveillance is not known.⁵ Research focusing on the course of asymptomatic vascular anomalies in these patients is needed to better direct elective surgical intervention. Establishing family history of disease course may be especially important in these patients as well.

Young adults presenting with unprovoked arterial dissections/ruptures should raise consideration of an underlying collagen vascular disease, especially vEDS. Evaluation of phenotypic characteristics of vEDS should be conducted and a detailed family history should be taken, focusing on history of dissections or family members dying of sudden cardiovascular death at a young age. Potentially, the diagnosis of vEDS can be considered based on radiographic findings in the right patient population.⁷

Diagnostic criteria have been established to help guide genetic testing. Some of these are a personal history of arterial aneurysms/dissection, intestinal rupture, family history of vEDS, thin skin, characteristic facial appearance, acrogeria and so on.⁸ Vascular genetic testing is reasonable in those with suspected disease (based on phenotypic syndromic findings) and a concerning family history. This patient had family history of unprovoked aortic dissection leading to sudden death in an otherwise health 39-year-old brother. Additionally, she has a personal history of aortic dissection and bilateral common iliac artery dissections. She was identified with a genetic mutation and now her children are receiving screening. Family and personal histories such as this should prompt geneticist referral with consideration for genetic testing.

Diagnosis is confirmed with genetic testing. A recent retrospective review evaluated the effectiveness of genetic testing in patients identified as potentially having a genetic condition predisposing to aortic or arterial dissections and aneurysms. Of the patients considered appropriate for genetic testing, 36% of cases had a pathogenic mutation identified. The percentage of identified pathogenic mutations was higher in those who had a personal history of an ascending aortic aneurysm or dissection.⁹ More than 700 COL3A1 mutations have been identified;⁵ different COL3A1 mutations lead to varying arterial pathology, underlying disease manifestation and presentation. Molecular diagnosis can help determine appropriate surveillance and intervention.¹ Of note, although diagnosis is important in identifying the patients disease process, there are limited available treatment options to modify the disease process.

Treatment

Management of vEDS is multifaceted and complicated. Surgical repair of arterial dissections in this condition is often complicated due to underlying collagen defects.⁶ One study stated operative intervention in vascular complications of vEDS was associated with up to 46% morbidity.¹⁰ Another study recommends intervention with rapid change (growth or dissection) in previously stable aneurysms but otherwise risks and benefits of elective vascular procedures have to be individually considered.¹ Interventional criteria for elective arterial procedures are not well established and endovascular versus open arterial repair remains a question.² Interestingly, conservative management of stable asymptomatic dissections (no intervention) may allow for spontaneous resolution of dissections.¹¹ In many cases, serial monitoring may be all that is required.

Long-term management often includes avoidance of activities that may lead to adverse events (ie, contact sports). Generally, it is recommended that patients with vEDS be referred to centres of excellence in vEDS for follow-up. At this time, no guidelines for disease surveillance exist and practices often vary by institution.

Medical intervention targets blood pressure control with the only medication studied thus far being a beta blocker, celiprolol. This medication has shown a reduction in vascular complications in one clinical trial,¹² and a recent retrospective cohort redemonstrated improvement in vascular outcomes and mortality.¹³ Overall goals of care often include: identifying causative mutations prior to diagnosis, modulating lifestyle, creating a comprehensive and specialised care team, individualising emergency care plans, treating hypertension aggressively and surveillance of vasculature by Doppler ultrasound, CT angiography or MR angiography on an annual basis.² Echocardiographic surveillance is largely unrevealing in most patients as aneurysmal dilation of arteries is often not found.¹⁴ Interventional angiography is not advised due to vascular fragility.³

Outcome and follow-up

The patient had a routine follow-up in cardiology clinic approximately 3 months after diagnosis. She reported she was doing well with review of systems being unremarkable. Unfortunately, on follow-up genetic testing of her children, her son had inherited her COL3A1 gene mutation and thus was diagnosed with vEDS. At this time, she is undergoing routine surveillance screening and is being followed at a vEDS centre of excellence.

Discussion

This is a 35-year-old woman with no significant medical history diagnosed with vEDS after the sudden death of her brother (cause of death found to be spontaneous aortic dissection progressing to hemopericardium) prompted evaluation for potential underlying inheritable genetic disorder. To the author’s knowledge, this is the first report of asymptomatic bilateral common iliac artery dissections as a part of the initial presentation of a patient with underlying vEDS.

Multiple case reports underline the importance of consideration of underlying collagen vascular disease in young patients with unexplained vascular anomalies.¹⁵ Arterial complications (including dissection of the abdominal/thoracic aortic, coronary, carotid, subclavian, vertebral, cervical, renal and iliac arteries) have been reported in patients with already diagnosed or previously undiagnosed vEDS.^15–23 Often further review of family history will reveal a history of arterial dissections or sudden death in family members²⁴ although notably, there can be significant phenotypic variance in disease presentation in family members. One study evaluated patients with cervical artery dissection and family history of cervical artery dissections. One family was found to have the same pathogenic mutation as this patient (COL3A1 c.970G>A). Although the mothers of these patients with this deleterious mutation and cervical artery dissection carried the same mutation, they were asymptomatic carriers, again highlighting the phenotypic variance in this condition.²⁵ Additionally, vascular events have been reported in classic EDS, although this is much less common.^26–28 In one study, arterial aneurysms and dissections were identified as the most common radiological finding in patients with known vEDS, with the iliac arteries being the most involved artery.⁷

This case highlights several important points in the screening, diagnosis and management of vEDS. First, the criteria for screening for vEDS have several limitations. To meet major criteria for vEDS, the patient must have a family history of already documented vEDS or the patient must have suffered a significant complication of their disease already (ie, arterial rupture at young age, spontaneous sigmoid colon rupture and so on). Additionally, screening for vEDS can be considered if the patient meets a combination of other minor criteria (ie, bruising unrelated to trauma, thin translucent skin, characteristic facial appearance and so on) but these findings may be subtle, are non-specific and may be difficult to appreciate for the practitioner that is not experienced with this disease. Thus, this raises the consideration that without the death of her brother, this patient would likely have never received a CT scan that revealed her asymptomatic arterial dissection that led to her diagnosis. Before the findings on this CT scan, the patient likely would not have been considered for testing of heritable genetic disorders. Certainly, once this arterial dissection was identified, the patient did meet minimal criteria suggestive of vEDS given unexplained dissection in individual less than 40 years old. Ultimately, this patient would likely have never received screening for this genetic disorder if she did not have the family history that raised concern for arterial fragility. This highlights that many individuals with this disease are not being identified prior to their first major disease complication. Additionally, even after disease identification, there are limited interventions available to affect the disease process and the diagnosis can be massively distressing as described in the patient’s perspective.

Patient’s perspective.

A year ago, 4 words turned mine and my family’s world upside down.

‘Vascular Ehlers-Danlos Syndrome’.

My brother was only 39 years old when he suddenly passed away from a severe, instant aortic dissection. It was fast and nothing that could have been done to save him.

After his passing, the questions arose ‘why did a seemingly healthy, young guy pass away from something that typically happens to people much older?’ There was talk that it might have been a genetic reason and I was advised to go talk to my doctor. Fast forward a few months and LOTS of doctor referrals later and on 18 May 2018, I had a CT scan to make sure that everything looked good. I had already ‘passed’ an Echo and blood work with flying colours, and this was the last test planned before I would be done and could get back into the normal swing of life. I honestly didn’t think much of the appointment. About 5 min after they were done getting the images, I was surrounded by multiple doctors telling me I needed to go to the ER immediately and that I was also found with an aortic dissection just like my brother as well as a bilateral Iliac dissection! WHAT!?!

As you can imagine the next few hours were a blur, I didn’t know what to think. ‘Would I die right there?’ ‘Am I going into surgery?’ Many thoughts and no clear answers. It was determined that I didn’t need immediate surgery and was sent home with a referral for a geneticist. I was ‘lucky’ and my dissections appeared to have happened a while ago (perhaps when I was pregnant with my twins) and are allowing the blood to flow through and not build up which would cause an aneurysm. When I met with the geneticist a few days later, we agreed to do bloodwork test to see if there was anything. A physical exam was also done where I scored a 5/9 on the Beighton Scale and a medical history was taken where it became clearer that this could indeed be vascular EDS. It was a month later when I got the news that I had in fact tested positive for the genetic mutation.

After getting this news, I did what most people do when they are told they have something they’ve never heard of before… I Googled the hell out of it!! The tricky part, when there is a rare condition, there’s not a lot of information on it. After scrolling through what I could find online, here’s what I got out of it. ‘No cure’, ‘genetic’, ‘shortened lifespan’, ‘median life expectancy of 48 years’, What do I do with this information!?

I now felt like I had a ticking time bomb inside my body ready to go off at any moment.

Any small pain or abnormal feeling I felt sent me into a panic that was close to what I would relate to being considered a panic attack. While this level of anxiety has decreased over the last year, I don’t feel it will ever completely go away.

I was told that since it is a genetic condition my kids had a 50/50 chance of having inherited it. We went through the roller coaster of tests and a few weeks later I got the call. My daughter did not have the gene mutation, but my son had the same gene mutation as myself and was confirmed to have vascular EDS as well. Now, while I was extremely devastated when I discovered I personally had it, for some reason I didn’t cry.

I guess a part of my kind of figured I probably had it.

The day I got that phone call with my kids’ results—I cried harder than I ever had since finding out. I felt guilty for giving this to him. He’s had his fair share of emotions and physical ailments since finding out and were continuing to work through them. It’s a lot to take in and the uncertainty of our future is hard to deal with. Watching your 12-year-old son cry uncontrollably when he is told that he can no longer do simple activities that a normal 12-year-old boy should be able to do without risking his life (soccer, football, track, PE, etc.) is heartbreaking.

I have already begun to see additional complications happen with me. I’m having organ prolapses that typically wouldn’t happen till someone is in their 80s, already happening to me. I will more likely than not have surgery in the near future and I also must decide which surgeries to have as a surgery alone poses more risk to a person with vascular EDS.

The support system I have is phenomenal, but this is my new reality and its hard. Some days are easier than others. I try to stay positive and some days I can almost get through a day without being reminded of this. I hope as time goes on that’ll get easier. I hope that awareness will continue to grow for this’ Zebra’.

Am I still scared to death?…. Absolutely.

Are there still days I want to cry and feel sorry for myself?…. You bet’cha.

Do I have increasing pain and ailments as time goes on?….Yes.

Will I get up each morning thankful for the new day and the breath in my lungs?… 100% YES!!

I truly appreciate each day because there’s a very strong reality that it could be my last.

Learning points.

• Young adults presenting with unprovoked arterial dissections or ruptures should raise concern for an underlying collagen vascular disease, especially vascular Ehlers-Danlos syndrome (vEDS). Unexplained arterial aneurysms or dissections on imagining in otherwise young, healthy individuals should prompt consideration of an underlying connective tissue disease.

• Clinicians must keep their differential broad in these settings and have a low threshold for testing. Screening criteria for vEDS have limitations and many patients with vEDS will not have the typical examination findings associated with other connective tissue disorders.

• Family history of similar presentations, or of sudden cardiovascular death in young relatives, can reveal an underlying hereditary genetic disorder in otherwise seemingly healthy individuals.

• Surgical and endovascular interventions are associated with significant complications in patients with vEDS; thus, consideration of this diagnosis is important prior to interventions.

• Appropriate management of patients with vEDS remains unclear and disease modifying therapies are sparse, but the beta blocker celiprolol may reduce arterial complications and mortality. Ultimately, referral to centres of excellence is important in proper long-term care.