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Genetic and Congenital
Video

What to know about Vascular Ehlers-Danlos Syndrome and how to distinguish the condition from other rare conditions

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October is Vascular Ehlers-Danlos Syndrome (VEDS) Action Month. Rare Disease 360, in partnership with The Marfan Foundation, spoke with Hal Dietz, MD, a cardiologist and geneticist at Johns Hopkins University, about the importance of educating primary care physicians and emergency department physicians on the signs and symptoms of VEDS.

Question:

October is Vascular Ehlers-Danlos Syndrome Action Month. What is the importance of highlighting and raising awareness for VEDS?

Hal Dietz, MD:

Vascular Ehlers-Danlos syndrome is a somewhat rare connective tissue disorder that affects many parts of the body. It can lead to serious complications, even fatal complications, including vascular rupture or bowel perforation.

The genetic cause of the condition is well-known. It’s caused by changes in the gene that encodes type III collagen, leading to a deficiency of collagen throughout the body. For many years, it was thought that a deficiency of type III collagen leads to an obligate structural predisposition for the tissues to fail. They’re simply weak and they will tear or burst at some point in time. In essence, the mindset was that there’s not much you could do after someone is born with this diagnosis.

But in the last 5 years or so, I think that our understanding of vascular EDS has undergone a renaissance. We’re now aware, using animal models and human studies, that there are important cellular responses to the deficiency of type III collagen, and that these abnormal cellular responses can be modified. They can be altered using medications for example.

With this very exciting potential that these medical modifications will delay or even prevent some of the serious complications of vascular EDS, we also have learned that lifestyle changes can make a difference. For example, what types of activities someone chooses to pursue or even what dietary modifications are used to try to help support the connective tissue.

Finally, we’re now at a point where we understand the usefulness of surgical intervention for people with vascular EDS. Again, the old mindset was that these tissues are so weak and the risks of surgery are so great that you shouldn’t even try to intervene until someone will clearly succumb from their clinical problems within hours. It’s truly a last-ditch effort to a catastrophic situation.

It is true that many people in that circumstance did have bad outcomes from surgery, but it was also obvious that many people had successful surgeries before they were diagnosed with vascular EDS, before people were taking these extreme precautions.

The new mindset is that if you diagnose problems early, if you intervene when someone is still healthy and before they’ve reached a point of desperation, then the surgical outcomes will be much better. That’s actually playing out. It really is now the general mindset that we should be very proactive with diagnosing and managing problems.

From the standpoint of a renaissance in knowledge about the disease, with a standpoint of a new appreciation of the potential for medical intervention, and a new mindset for surgery, I think the outlook for someone with vascular EDS is really much brighter than it used to be.

But the important piece of the puzzle that still requires attention is to educate primary care physicians and emergency department physicians about what they should be noticing, what physical features should capture their attention, lead to testing for vascular EDS, that has the potential to allow these life-saving measures.

Awareness is critical, and I think that’s why many patient advocacy groups are appropriately putting their efforts in educating the general public, but also very importantly, medical professionals.

Question:

What are the symptoms of VEDS? What should physicians and individuals be aware of about the presentation of this condition?

Hal Dietz, MD:

Vascular Ehlers-Danlos syndrome involves a deficiency of the protein type III collagen that is found in many tissues throughout the body. Because of that, the features of vascular EDS can be seen in multiple organ systems.

The organ systems that are most likely to trigger an earlier diagnosis prominently include the musculoskeletal system and the skin. I think the skin is often the body part that has the greatest potential to alert someone to a problem that needs to be understood.

People with vascular EDS typically have very easy bruising. It’s not just garden variety easy bruising; I occasionally have a bruise that I don’t know how I got, but rather these people can’t remember ever looking down at their legs and not seeing multiple bruises that are in different stages of resolving. Easy bruising I think is an important telltale sign.

In the skin, there’s also often a translucent quality to the skin. It’s easy to see the underlying veins in the skin shining through. That often is a tip-off for an observant clinician. There can be some healing problems in vascular EDS, skin healing problems. It doesn’t tend to be as extreme as in some other connective tissue disorders.

The people expect individuals with Ehlers-Danlos syndrome to have loose joints. It’s really one of the cardinal manifestations of the Ehlers-Danlos syndrome. But what’s important to know is that it’s not very prominent in vascular Ehlers-Danlos syndrome as opposed to, for example, hypermobile Ehlers-Danlos syndrome.

People with vascular EDS can have some joint laxity. It tends to be most obvious in the small joints of the hands and the feet, for example, but it does not tend to be the severe large joint laxity with joint dislocations that you can see in other forms of EDS. If you see lots of skin bruising, you see translucent skin, and you’re not all that impressed with joint laxity, vascular EDS should come to mind.

There is a facial constellation of features that’s characteristic of vascular EDS. I’m not sure that just the casual observer would necessarily notice something, but clinicians who have seen vascular EDS before, especially multiple cases of vascular EDS, come to recognize a constellation of facial features that often include prominent-appearing eyes, a sort of narrow or pinched appearance to the nose. The earlobes tend to be attached rather than separated, so that can be a giveaway.

The gastrointestinal system is often involved in vascular EDS. The most severe complication is a spontaneous bowel rupture. If a person has a bowel rupture without an explanation, that should trigger a consideration of a connective tissue disorder, very prominently including vascular EDS.

There can be less specific bowel issues, for example, often fitting under the broad category of irritable bowel syndrome. If someone is coming with frequent bowel complaints in combination with some of these other findings, that should trigger a diagnostic evaluation.

Certainly, anyone who does not have an obvious reason to have a blood vessel enlargement or a large blood vessel tear that experiences one of those events at a young age absolutely needs a comprehensive connective tissue evaluation.

There are some more rare manifestations of vascular EDS, something called clubfoot deformity, for example, and occasionally a cleft in the palate of the mouth can be seen. But my greatest confidence is that if people understood the skin, skeletal, and facial manifestations of vascular EDS, that would have the greatest impact on earlier diagnosis.

Question:

You and Dr. Bart Loeys discovered Loeys-Dietz syndrome in 2005, which previously was often diagnosed as Marfan syndrome. Can you explain the distinctions between Loeys-Dietz syndrome and Marfan syndrome?

Hal Dietz, MD:

Marfan syndrome is caused by a deficiency of a protein called fibrillin-1. Loeys-Dietz syndrome is caused by a deficiency of a variety of proteins that govern a cellular signaling pathway called the TGF-beta signaling pathway. Currently, there are 6 different genes that can cause Loeys-Dietz syndrome.

Marfan syndrome and Loeys-Dietz syndrome have some features in common. For example, a chest wall deformity such as a chest wall that protrudes outward or indents inward. Curvature of the spine is common in both conditions, can show long fingers. Joint laxity is seen in both conditions and enlargement of the base of the aorta, the so-called aortic root, is seen in both conditions.

Marfan syndrome has a number of features that are unique that distinguish it from Loeys-Dietz syndrome. For example, individuals with Marfan syndrome typically have very long arms and long legs and are extremely tall for their family. While you may see a subtle presentation of that in Loeys-Dietz syndrome, it’s generally not a major feature of the condition.

Loeys-Dietz syndrome also has many distinctive cranial facial features that can be seen such as hypertelorism. Widely-spaced eyes would be a general description of hypertelorism. Loeys-Dietz syndrome often shows a cleft palate or a split in the uvula in the back of the throat, a so-called bifid uvula. There are other facial features of Loeys-Dietz syndrome that can be distinctive, such as a skin rash that’s called milia on the face.

People with Loeys-Dietz syndrome have other skin manifestations that make it distinct from Marfan syndrome, often showing easy bruising and translucent skin, whereas those findings are less common or not seen in Marfan syndrome.

Loeys-Dietz syndrome, as I mentioned, does have enlargement of the base of the aorta, which is also typical of Marfan syndrome, but Loeys-Dietz syndrome can show aneurysms and a risk of blood vessel tear throughout the entire arterial tree from the head all the way down into the legs.

Whereas echocardiography that looks at the base of the aorta is a good screening tool for both conditions, people with Loeys-Dietz syndrome also require additional imaging, such as use of a CT scan or an MRI scan to look at all of the arteries throughout the body.

Marfan syndrome has a very common eye feature called lens dislocation, which is not seen in Loeys-Dietz syndrome. That’s a really a very distinct discriminating finding. If you see eye lens dislocation and aortic aneurysm, you can be very confident that the diagnosis will be Marfan syndrome.

Question:

What are some ongoing research needs for VEDS, Loeys-Dietz syndrome, and Marfan syndrome? Is there any research that you are particularly interested in?

Hal Dietz, MD:

There’s a lot of need for research in all 3 conditions. Appropriately and understandably, a lot of the attention has focused on the cardiovascular system. That is the major cause of early death in these conditions. But as I mentioned, there are many other problems throughout the body that influence the quality of life.

Many of the patient advocacy groups have been hearing from their constituents who say, “Yes, I want to live longer, but I also want to live a high-quality life, so please pay attention to the foot pain or the frequent headaches, or the visual impairment or the breathing issues that I have with my condition.”

I think that there is going to be a lot more emphasis on those other organ systems over the course of the next few years. With regard to the cardiovascular system, a lot of the work has focused on animal models that faithfully recreate the many features of these conditions.

But there is now the exciting opportunity to perform clinical trials in people with these conditions. For example, in vascular EDS, there are a number of trials that are either ongoing or are currently planned to test new medical therapies. The same is true for both Marfan syndrome and Loeys-Dietz syndrome. I think the era of clinical research rather than preclinical animal model research is really upon us.

One area of research that I’m really excited about is essentially asking the question, why do some but not all people with a DNA change in one of these genes show the features of the condition? How does nature protect some people with even a very severe DNA change?

What we and others have observed is if you look at large families with these conditions where all the family members carry the same underlying DNA change that causes the condition, you can see extreme variation in the severity of the condition, ranging from early life-threatening manifestations in childhood to no physical features of the condition in late adult life.

We and others are trying to answer that question, how does nature protect some people with this condition? Our strong hypothesis is that it relates to genetic modifiers. We all carry variation in our thousands of genes. Sometimes those variants cause a disease. Other times those variants modify a disease. They can make it less severe, even if you have a very severe underlying DNA change that has the capacity to cause very severe disease.

We’ve had great success over the last few years of understanding nature’s strategies to protect people. Our hope is that once we learn about those strategies, we’ll be able to use medications to mimic the mechanism by which nature can afford protection. That’s an area that I am extremely excited by.

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