July 18, 2011

Marfan Syndrome — An Elusive and Complicated Genetic Disorder
By Carolyn Gutierrez
For The Record
Vol. 23 No. 13 P. 24

Early detection and the use of a blood pressure medication are key weapons in the battle against MFS.

Marfan syndrome (MFS), a rare, complex, and potentially life-threatening connective tissue disorder, affects one in every 5,000 Americans. Marked by a constellation of disease manifestations, including skeletal dysfunction, ocular lens dislocation, and, most troubling, aortic dilatation and aneurysm, MFS is challenging to diagnose because its signs and symptoms are similar to other connective tissue disorders.

Warning Signs
A clinician may suspect a patient has MFS by noting certain physical characteristics such as a long, lean skull; a protracted thumb that extends past the pinkie when making a fist; an arm span longer than 1.05 times the patient’s total height; and a high and arched mouth palate.

Patients with MFS tend to be tall and have severely flat feet. Long, slender limbs; narrow wrists; and either pectus excavatum (“hollow chest”) or pectus carinatum (“pigeon chest”) are common. Chronic pulmonary conditions are found in MFS patients, and sometimes the pectus deformities can exacerbate lung problems. MFS patients may have loose joints and severe scoliosis, and the dural sac encasing the spinal cord may also be affected.

Complicating matters, not all MFS patients display the disorder’s classic signs. According to Paul Sponseller, MD, chief of pediatric orthopedic surgery at Johns Hopkins Children’s Center, “At least 15% of Marfan patients don’t really have anything external that can be a clue to the diagnosis other than finding it by chance. There will always be a few patients who don’t get diagnosed because there’s really nothing much to suggest it. In most patients, the skeleton is the most obvious window for the diagnosis of Marfan syndrome—the skeletal findings are the most noticeable.”

If a physician suspects a patient has MFS based on his or her skeletal features, an eye examination may be performed to determine whether there is dislocation of the eye lens, an MFS hallmark. According to the National Marfan Foundation, approximately six of 10 people with MFS have dislocated lenses in one or both eyes. This is caused by zonules, or minute pieces of connective eye tissue, stretching and tearing, causing the lens to become unstable and slip out of place. Marfan patients can have other ocular problems as well, such as severe myopia, astigmatism, amblyopia (“lazy eye”), glaucoma, and retinal detachment.

If lens dislocation is discovered, an echocardiogram is performed to examine the aorta because approximately nine of every 10 patients with MFS experience cardiovascular dysfunction. The aortic root, the aortic segment closest to the heart, can become enlarged in MFS patients, warranting close observation.

 “There are many important disease manifestations of Marfan syndrome, but the one that appropriately receives the most attention is aortic enlargement and the predisposition for aortic tear. This receives the most attention because it is the cause of early mortality in Marfan syndrome,” says Harry Dietz, MD, a pediatric cardiologist, geneticist, and director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins. “People who have aortic enlargement in Marfan syndrome, specifically aortic root aneurysm, tend to feel fine until the day that aneurysm ruptures. There aren’t a lot of warning signs to tell someone that a problem is emerging. That further emphasizes the need for early diagnosis and close follow-up of people with Marfan syndrome. We do know that the aorta does not tend to tear until the size of the aortic root reaches close to 5 cm. So it gives us a fairly reliable threshold when we’re doing echocardiograms to look at the aorta in our decision-making regarding performing surgery.”

A Genetic Disorder
MFS is caused by a mutation in the gene that encodes the structural protein known as fibrillin-1. Normally, the fibrillin-1 protein is transported out of the cell and acts as a bolster, reinforcing the delicate network of microfibrils that make up elastic fibers. These intricate elastic fibers are essential to the function of flexible connective tissues such as blood vessels, heart valves, cartilage, and ligaments. In MFS, the structural protein is compromised by a mutation in the gene, and the production of the protein is altered—either it slows down or the amount of protein is reduced entirely—leading to weakened structural support in the skeletal system, the eyes, and the heart.

The fibrillin-1 gene, identified by Dietz in the 1990s, is large and can have more than 300 mutations, but not all cause MFS. There is a broad spectrum of connective tissue diseases, some severe and some so subtle that only one abnormality is found. The heterogeneity of MFS has confounded researchers and physicians trying to pinpoint early diagnosis.

“There are literally thousands of different changes in the fibrillin-1 gene that cause Marfan syndrome, so there’s no efficient test,” Dietz notes. “You can’t just pick the most common mutation and send a screening test. It really requires comprehensive sequencing of the entire gene, which is too large to establish a molecular diagnosis of Marfan syndrome. So I don’t think there’s any efficient means, for example, of population screening. It would be very expensive and very inefficient.”

Early Detection
According to Dietz, early detection of MFS is complicated by three factors. The first is family history; in 75% of patients, MFS is caused by an inherited change in the fibrillin-1 gene. However, in 25% of MFS cases, there is no family history—it occurs due to a new mutation in the gene that is generated during the formation of the egg or sperm cell and contributes to the conception of an MFS patient who would be the first in his or her family to have the disorder. In these cases, early diagnosis is dependent on perceptive primary care clinicians.

“The second complicating factor,” says Dietz,  “is that many of the outward features of Marfan syndrome are fairly common in the general population. If you asked how many people are tall and thin, there would be a large number. If you asked how many people have a chest wall that indents or protrudes outward, that’s really a fairly common finding. If you asked how many people have curvature of the spine, that’s also fairly common.

“What a physician has to pay attention to are circumstances where those findings are found in combination,” he continues. “So while chest wall indentation is common, to have a really tall, thin person who has a chest wall indentation and curvature of the spine should send up a red flag.”

The third complicating factor is that many MFS features develop as a patient ages. A 5-year-old may show subtle symptoms or none at all, yet when he or she experiences a growth spurt, the skeletal features may become more pronounced.  According to Sponseller, a significant number of people with MFS are not diagnosed until after the age of 25.

In 2010, researchers revised the clinical criteria for the diagnosis of MFS, emphasizing the cardiovascular component of the disorder in the hopes of prompting earlier and more beneficial treatment.

According to Margaret McGovern, MD, a professor and the chair of the department of pediatrics and physician-in-chief at Stony Brook Long Island Children’s Hospital, the revised diagnostic criteria “relies on a combination of findings, so it’s not just one finding that’s going to help you make the diagnosis of Marfan syndrome. For example, if there’s no family history, you have to meet different criteria than if you know one of your parents or siblings has Marfan syndrome because a positive family history in itself is built into the diagnostic criteria. Very specific findings, such as dislocation of the lens of the eye or changes in the size of the root of the aorta, would have to be physically looked for.”

Within the context of the physical findings, if there is a family history of MFS, genetic testing can be done to identify the particular mutation, and family members can be tested to determine whether they carry the mutant gene.

“Certain mutations may predict a more or less severe phenotype,” says McGovern, “so that information becomes important for a lot of reasons. If you tell a patient they have Marfan syndrome, it has profound implications on activities they might participate in. You’re committing them to having serial echocardiograms for the rest of their life, measuring their aortic root, etc, and now we know that many patients in the past who’d been given a diagnosis of Marfan syndrome actually had something else, so it’s very important to understand what you’re diagnosing because it has profound implications for these patients and their families.”

Managing MFS
Given the ocular and skeletal manifestations of MFS, proper management of the disorder generally includes the involvement of an ophthalmologist and an orthopedist. To monitor any cardiovascular manifestations, MFS patients should receive at least yearly imaging of the aorta to determine its size and rate of growth.

Patients are also advised to monitor physical activity. “While patients should remain active, they have to choose their exercises carefully and should specifically avoid contact sports like tackle football, competitive sports where they’re routinely pushing themselves to exhaustion, and, most importantly, muscle-straining activities,” Dietz says. “During the time that you’re bearing down and straining against a resistance, your blood pressure will triple. It will go from a nice healthy blood pressure of 120 up to a blood pressure of 400 during straining, and we know that needs to be avoided.”

Beta Blockers and Losartan
To address the cardiovascular manifestations of MFS, beta blockers have historically been the standard of care. By slowing heart rate and reducing blood pressure, the drugs—if used long-term—may slow the rate of abnormal aortic growth, although they may not stop the growth altogether. Researchers believe that by reducing hemodynamic stress, beta blockers may delay the need for aortic surgery in some patients.

In studies performed on mice seven years ago, Dietz and his team learned that structural protein deficiency wasn’t the only critical factor causing MFS. The excessive activity of a molecule called transforming growth factor-beta (TGF-beta) caused damage by setting off aberrant signals within the cells that made up blood vessels. The researchers discovered that by using the blood pressure medication losartan, an angiotensin receptor blocker, TGF-beta activity was greatly reduced.

“We tried losartan in our mouse model of Marfan syndrome and found that it prevented aneurysms from forming for the lifetime of the Marfan mice,” Dietz notes. “Unlike beta blockers, it didn’t just slow things down, it actually prevented aneurysms. The treatment also resulted in a dramatic improvement in the architecture of the blood vessel wall. The blood vessel wall looked stronger, looked healthier, and aneurysms did not form. So on that basis, we felt compelled to treat a subset of children with the most severe form of Marfan syndrome even before more broad clinical trials had been performed. It was already an FDA-approved drug. We knew it lowered blood pressure, which was thought to be at least half the equation.”

In a small group of pediatric patients, the researchers found that the use of losartan reduced the rate of aortic growth 10-fold compared with how the aorta had performed while those same children took other blood pressure medications. “On average,” says Dietz,  “they were growing their aorta by 4 mm per year, every year, prior to losartan and only 0.4 mm per year after losartan.”

Young MFS patients have the benefit of early detection and treatment, but Dietz and his team are optimistic that losartan may also help adults with long-established MFS. In describing a series of mouse models, Dietz notes that “in one trial, we gave losartan before birth to the pregnant mice, and we saw dramatic protection. In another trial, we gave losartan around the time of birth but after being born, and we saw dramatic protection. And then in the third trial, we gave losartan to older mice even after fairly sizable aneurysms had been established, and we also saw that there was dramatic protection. In fact, we saw that the use of losartan could actually cause regression in aortic size over time. It’s something that still needs to be addressed, but I think that there’s strong potential that this strategy will help adults with MFS.”

A large multicentered trial following 600 MFS patients taking either losartan or beta blockers is currently under way, according to Dietz.

 In mouse models, researchers have found evidence that losartan can also address other manifestations of MFS besides aortic aneurysm, including lung emphysema and skeletal muscle weakness. However, researchers are still uncertain what cellular events lead to skeletal manifestations.

In the end, early diagnosis remains paramount for rare connective tissue disorders such as MFS.

“There’s a strong belief that early therapeutic intervention makes a big difference, that you should be trying to prevent disease manifestations from happening rather than wait and react to them once they’re advanced,” says Dietz. “But it really requires a pediatrician or internal medicine doctor to develop an appropriate index of suspicion. Unfortunately, the curriculum within medical schools does not tend to emphasize genetic disorders in general and rare genetic disorders in particular. I think that is an important educational mission of the National Marfan Foundation, for example, to really get the word out about the clinical features of Marfan syndrome.”

— Carolyn Gutierrez is a freelance writer based in New York City.