This is part 3, the final portion, of my series on the new diagnostic criteria for Marfan syndrome. Here you can access the portions on the rationale for the revised criteria and the actual new criteria. Today’s post is on the criteria for related disorders. The National Marfan Foundation has put together information on the new criteria. And as a reminder: I am not a doctor, I’m just trying to translate the scientific jargon into an easier to understand format. Any specific questions you have about the new criteria can be directed to Amy Kaplan, RN, at the NMF: akaplan@marfan.org or your doctor.

While I think we can all agree that not enough doctors know about Marfan syndrome and even fewer understand it well, but the fact is that even fewer still know about related disorders. And so, there are many times when doctors observe a few symptoms of Marfan and diagnose it without considering alternative diagnoses, some of which are very new to the field (like Loeys-Dietz syndrome, discovered in 2005). If you recognize any of these symptoms in yourself, talk to your doctor about it. And do not ever take the line “it can’t be _____, that’s too rare” as a reason to not get evaluated. Rare as something may be, people still have it or the diagnosis wouldn’t exist.

Terminology is explained in the 2nd article.

MASS: The patient needs a z-score below 2, no ectopia lentis (dislocated lenses), a systemic score of at least 5 and a skeletal feature. If FBN1 testing has been done and is positive then the patient’s aorta should still be monitored (every 2-3 years if they are an adult). Researchers don’t know how often MASS patients develop into Marfan patients.

Mitral Valve Prolapse syndrome: The patient must have a systemic score of LESS than 5, no aortic enlargement, and no ectopia lentis. Positive symptoms can include pectus excavatum, scoliosis, scoliosis, and mild arachnodactyly (long fingers).

Loeys-Dietz syndrome: The mutation for LDS can be found on TGFB1 or TGFB2. Symptoms that differ from Marfan and are an important part of diagnosis include: hypertelorism (widely spaced eyes), cleft palate, split uvula, arterial tortuosity (twisted arteries), and aortic aneurysm/dissection. Other symptoms that appear, also not associated with Marfan, are: craniosynostosis, chiari malformation, clubfoot, congenital heart disease, cervical spine instability, easy bruising, dystrophic scarring, and skin you can easily see through. An accurate diagnosis of LDS is very important because unlike Marfan, people with LDS can develop aneurysm anywhere in their arteries (Marfan causes aneurysms in the aorta) and they dissect much earlier than do people with Marfan. Uterine rupture has also been observed. But, just like many connective tissue disorders, LDS is still highly variable. Not everyone will have the pronounced facial features, for example. Those who have a TGFB mutation but don’t meet the clinical criteria may get the diagnosis of LDS2 so that they still receive earlier aortic care.

Bicuspid Aortic Valve: Besides having a BAV, some patients may have a chest deformity or scoliosis. A few have an aneurysm in the ascending aorta or other heart disease. BAV does not cause ectopia lentis or systemic score features outside of the two listed above. Some mutations have been shown in NOTCH1 and KCNJ2.

Familial Thoracic Aortic Aneurysm and Dissection syndrome: If I understand correctly this isn’t one disorder but the name for a few disorders that are similar in that they cause thoracic aneurysms. A lot of research still needs to be done to identify more outward features. Mutations have been identified in FBN1, TGFB1, TGFB2, MYH11, and ACTA2. ACTA2 (which my former nurse practitioner helped discover! I’m so proud!) mutations make up 16% of FTAADS patients and can cause: iris flocculi (a kind of eye tumor?), livedo reticularis (mottled veins), brain aneurysms (causing strokes or Moyamoya disease), BVA, PDA, or premature coronary artery disease.

Ehlers-Danlos syndrome, vascular type: Patients with v-eDS can have easy bruising, skin you can easily see through, dystrophic scarring, and intestinal or uterine rupture. It causes rupture of arteries but not necessarily the aorta. Patients with v-EDS need a more complete monitoring then; half of aneurysms occur in the thoracic abdominal area but they can also occur in the head, neck, and limbs. Genetic testing has identified mutations in COL3A1.

Ehlers-Danlos syndrome, kyphoscoliotic type: Patients have kyphoscoliosis, loose joints, muscle hypotonia (low muscle tone), and a risk for aortic dissection/dissection of medium-sized arteries. k-EDS is recessive and the mutation is in PLOD1.

Ehlers-Danlos syndrome, cardiac valvular subtype: This kind of combines the severe cardiac issues of v-EDS with the symptoms of classical-EDS (which weren’t addressed in this paper). The mutation of cvs-EDS is found in COL1A2 (a “complete deficiency” of it).

Arterial Tortuosity syndrome: Patients with ATS have very twisted arteries, aortic stenosis (the aortic valve doesn’t open fully), an aneurysms in the aorta and medium sized arteries. There are other skeletal and skin features as well (the paper does not go into more detail on these). ATS is rare and recessive. Some patients die in infancy but others live into adulthood. The mutation is in SLC2A10.

Ectopia Lentis syndrome: This has already been described in Thursday’s post to an extent. Because aortic aneurysms sometimes occur in ELS patients later on (such as can happen with MASS), a person can not be formally diagnosed with ELS until they are 20 years old. Dominant forms of ELS are caused by FBN1 mutations and recessive forms are caused by mutations in LTBP2 and ASAMTSL4. If the ELS patient has an FBN1 mutation they should receive aortic monitoring for the entire lives.

Weill-Marchesani syndrome: Patients with WMS have lens dislocation but also microspherophakia (“small, rounded and thickened crystalline lens”) and “a shallow anterior eye chamber.” They are also short in stature with stiff joints and brachydactyly (short fingers and toes). So, their physical features are the opposite of Marfan in several key ways. WMS can be dominant or recessive and mutations are in FBN1 or ASAMTS10.

Homocystinuria: Patients have mental retardation and thrombosis (blood clots) as well as lenses that dislocate in a downward fashion.

Stickler syndrome: Many of the skeletal features of Marfan overlap with Stickler, except that Stickler patients can also have cleft palate, hearing loss, and epiphsial changes to the bone (I don’t understand what this means, sorry). Eye characteristics that can overlap with Marfan are retinal detachment, myopia (nearsightedness), and early glaucoma. Stickler patients to not usually have lens detachment.

Shprintzen-Goldberg syndrome: Symptoms include: pectus (chest) deformities, scoliosis, arachnodactyly (long fingers), facial/cranial issues (widely spaced eyes, high arch palate, low set ears, jaw problems, etc.), and developmental delay (most SGS patients have developmental delay). Vascular disease is uncommon.

Congenital Constractural Arachnodactyly: This is also referred to as Beals syndrome. Patients have many outward Marfan features. Distinctive features of CCA/Beals include crumbled ears, contractures of knees/ankles at birth, camptodactyly (fingers that can’t completely straighten, particularly in the pinky finger). Kyphosis or scoliosis can also be found. CCA/Beals does not carry a risk for aortic dissection. It’s caused by mutations in FBN2.

I was surprised that Classical Ehlers-Danlos and Hypermobile Ehlers-Danlos were not included in the paper. Although neither carry aortic complications, their skeletal features and flexibility do overlap with Marfan syndrome.

Naturally, I couldn’t cover everything from the paper in my write-ups; there’s just too much information (like a section on management guidelines for MFS patients). I may do posts on those sections at a later time. If you’d like the full text of the article I can email you a copy; my contact information is at the top of the page.

I’d also like to add that it’s vital that we as patients help spread the word about these changes. I suggest bringing a copy of the NMF website or the paper itself to your doctors at your next appointment, particularly if you have concerns about your diagnosis status.

And again: The opinions offered at Musings of a Marfan Mom are for informational purposes only and are not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of a qualified healthcare provider with any questions you may have regarding Marfan syndrome and any medical condition. Never disregard professional medical advice or delay in seeking care because of something you have read here.

Citation:
Loeys, Bart L., Dietz, Harry C., Braverman, Alan C., Callewaert, Bert L., Backer, Julie De, Devereux, Richard B., et. al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47:485-495.

This is part two of my post on dissecting (pun intended!) the new diagnostic criteria for Marfan syndrome. You can access part one, which discusses the reasons behind the updated criteria, here. I was going to put the new criteria for related disorders in this post as well, but then I realized this post is already too long. So, look for the final part on Monday. The National Marfan Foundation has put together information on the new criteria. And as a reminder: I am not a doctor, I’m just trying to translate the scientific jargon into an easier to understand format. Any specific questions you have about the new criteria can be directed to Amy Kaplan, RN, at the NMF: akaplan@marfan.org or your doctor.

The biggest change behind the new criteria is that it basically redefines Marfan syndrome such that aortic involvement (or the defined potential for aortic involvement) MUST exist. Previous to this, we’d said about 20% of Marfan patients don’t have aortic aneurysms. I’d assume that now that percentage is much smaller.

Before I outline the new criteria, you need to understand what a z-score is. Aortic sizes are plotted on a chart based on age, body size, and the aortic root size at the sinuses of valsalva. This chart will show you where your root fits in the realm of what is considered normal for a person of your age and size. Mark could give you some big explanation on statistics, but the Maya-version is that the z-score takes those different sizes of aorta and groups them. A score of 2 and over (meaning 2+ deviations from normal) is significant in the terms of diagnosing Marfan. That means the aorta is enlarged. Follow me?

You’ll also hear about the systemic score. There are 20 possible points and the features are the skeletal symptoms that made up the former “skeletal criteria,” as well as dural ectasia (it’s been downgraded; no longer its own category), myopia, and pneumothorax. Symptoms that have been shown through research to be tied closely with Marfan are given more points, like being able to do both the thumb and wrist sign (3 points), and those that occur frequently in the general population, like mitral valve prolapse (1 point) have been given less importance.

Finally, there are two types of FBN1 mutations. A small amount (I’ve been told about 12%) are known to cause aortic aneurysms. These are mutations that overlap among unrelated families. The majority of people who test positive for an FBN1 mutation have a mutation that is unique to their family. These are considered mutations not known to cause aortic aneurysms, because they are brand-new mutations. Make sense?

So, if you’re someone without family history of Marfan (like me), you need to meet one of the following scenarios to get a positive diagnosis:
1) A z-score of 2 or more and ectopia lentis (dislocated lenses)
2) A z-score of 2 or more and a mutation found on FBN1
3) A z-score of 2 or more and 7 points or more in the systemic score
4) Ectopia lentis and have a mutation found on FBN1 that is known to cause aortic aneurysms
5) This one is not something I understood from reading the paper, but Dr. Dietz confirmed it with me and since he WROTE the paper, I figure he’s right so I’m adding it: A mutation in FBN1 that is known to cause aortic aneurysms and 7 or more points in the systemic score.

Other possible diagnoses:
1) Ectopia lentis with or without systemic involvement and either no FBN1 mutation or one that hasn’t been identified with aortic aneurysms = a diagnosis of Ectopia Lentis syndrome.
2) A z-score of less than 2 and a systemic score of at least 5 (as long as it includes at least one skeletal feature) and no ectopia lentis = a diagnosis of MASS
3) Mitral valve prolapse and a z-score of less than 2 and a systemic score of less than 5 with no ectopia lentis = a diagnosis of Mitral Valve Prolapse syndrome

If you’re someone with a family history of Marfan, you need to meet one of the following scenarios to get a positive diagnosis:
1) Ectopia lentis and a family history of Marfan syndrome (as defined by above)
2) Systemic score of at least 7 and a family history of Marfan
3) A z-score of 2+ if you are at least 20 years old and a z-score of at least 3 if below 20 years old and a family history of Marfan

One thing to consider is that for some of these scenarios, doctors must first rule out features of related disorders. This is true for scenarios 1 and 3 of not having family history and scenario 2 of having family history.

I’m going to cover the features of the many related disorders on Monday. There is one very important thing to remember: the whole point of this is to ensure that people are being followed appropriately. The authors acknowledge that someone with a MASS diagnosis could, at some point, develop an aneurysm and therefore qualify for a Marfan diagnosis. Therefore, even if your diagnosis has changed you should still get at least periodic echocardiograms.

For a short time, before I talked with Dr. Dietz at conference, I thought my diagnosis of Marfan syndrome had been taken away by this new paper. I was devastated and spent several days freaking out about what this meant (my diagnosis, for those who don’t know, has flip-flopped 3 times over the course of the past 17 years and it’s stressful and sucks and I was not ready for it to happen again). I’m glad to know that I do, in fact, still fit in the Marfan box, but I realize that not all of my friends do any longer. I just want to reiterate that no matter how many times your diagnosis changes, you’re still a part of this community, this Marfamily. And the way research is going, who knows? Maybe in another few years the powers that be will call what you have “Marfan” once again. It’s all part of the “fun” of having a rare disorder!

And again: The opinions offered at Musings of a Marfan Mom are for informational purposes only and are not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of a qualified healthcare provider with any questions you may have regarding Marfan syndrome and any medical condition. Never disregard professional medical advice or delay in seeking care because of something you have read here.

Citation:
Loeys, Bart L., Dietz, Harry C., Braverman, Alan C., Callewaert, Bert L., Backer, Julie De, Devereux, Richard B., et. al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47:485-495.

A few weeks ago the top Marfan researchers released an updated set of diagnostic criteria. I’ve been planning a post about it for awhile, but I wanted to take the time to make sure I fully understood it myself before I undertook the task of writing about it. As it stands, I’m going to split up my analysis/thoughts into two posts. Today I’ll cover the reasoning behind the new criteria and Thursday I’ll break down the new criteria. The National Marfan Foundation has put together information on the new criteria. And as a reminder: I am not a doctor, I’m just trying to translate the scientific jargon into an easier to understand format. Any specific questions you have about the new criteria can be directed to Amy Kaplan, RN, at the NMF: akaplan@marfan.org or your doctor.

I’ll be the first to admit I was surprised by the new criteria. At first reading I felt like the researchers had made some very big changes and I wasn’t sure that I agreed with them. I ended up putting the paper down halfway through to digest what I’d read so far. After discussing it with my Dr. Dietz, people at the NMF, my own cardiologist, and reading through the paper completely, I feel a lot better about it. The new criteria are going to be great for our community.

In 1996 the top Marfan researchers met in Ghent, Belgium, to update the 1955 diagnostic criteria for Marfan syndrome. These criteria have been known as the Ghent criteria for diagnosis of Marfan syndrome. They stipulated (just to generally summarize) that a patient meet two “major” areas of system involvement and one “minor” area to get a diagnosis of Marfan. This was sometimes confusing.

However, there have been amazing advancements in research for Marfan and related disorders over the last decade and it has become clear from that that there are some holes in the Ghent criteria. These include doctors who are handing out the Marfan diagnosis like candy (“Oh, you’re tall, thin, and flexible? Must be Marfan!), which is problematic on two ends: diagnosing patients as having a life-threatening disorder who actually have NOTHING wrong with them, and diagnosing patients as having Marfan who actually have a related, and potentially more serious, connective tissue disorder. Then there are the physicians who are under-diagnosing patients. For example, I know of a patient with lens dislocation and aortic enlargement who was sent away because he was short, so therefore he “couldn’t have Marfan.” (Not true, of course!) Along those lines, there are many doctors who fail to understand that Marfan is progressive and dismiss children who clearly meet some signs of the syndrome, telling their parents that they are fine. Personally, I didn’t meet criteria until I was 22 years old.

So, the purpose of the revised Ghent criteria is to simplify the diagnostic process for physicians to ensure an accurate diagnosis for patients. Some of these related disorders are not well known or, like Loeys-Dietz syndrome, are relatively new. When a diagnosis can be made (and we all know this isn’t always positive at the first try; it took me 12 years), it’s vital because the cause determines the treatment. While beta blockers are used for both Marfan and Loeys-Dietz, for example, surgical guidelines are very different for the two and thus it’s important to know which you have.

I am glad that the paper goes over the diagnostic considerations for a host of other related disorders. My only beef is that they didn’t address hypermobile or classical Ehlers-Danlos syndrome. While I realize neither of these types carry aortic risks, it’s not uncommon for patients who have these disorders to be misclassified as having Marfan syndrome due to the skeletal characteristics. I know several families off the top of my head who have had their diagnosis switched from Marfan to one of those two types just within the last year.

While I think that at first read the new criteria are a little confusing for us “lay” people, I believe this will make things much easier for our doctors. I also encourage everyone to bring a copy of the new criteria to your doctors. We have a responsibility to help spread the word about every advancement, particularly something as big as this! I’ll be bringing a copy of the paper to my son’s pediatrician this week.

And again: The opinions offered at Musings of a Marfan Mom are for informational purposes only and are not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of a qualified healthcare provider with any questions you may have regarding Marfan syndrome and any medical condition. Never disregard professional medical advice or delay in seeking care because of something you have read here.

Citation:
Loeys, Bart L., Dietz, Harry C., Braverman, Alan C., Callewaert, Bert L., Backer, Julie De, Devereux, Richard B., et. al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47:485-495.