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.