Marfan, A “Look-Alike” Disorder, Or Neither? Researchers Offer Simple List of Signs for Early Detect
Johns Hopkins researchers have compiled what they believe are reliable lists of tell-tale physical signs to help doctors recognize children with Marfan and Loeys-Dietz syndromes. Timely and early diagnosis of both genetic disorders can mean the difference between life and death, but some of the most common physical features are also found in people with neither of the syndromes, which can cause confusion.
Published as two separate studies in the August issue of the Journal of Bone and Joint Surgery, the two lists enumerate physical features that in certain combinations are highly suggestive of either Marfan or Loeys-Dietz syndromes, connective tissue disorders similar in presentation but caused by different genetic glitches. Many of the signal features of these disorders involve the face, skull, joints and spine, making them easy to spot during a physical exam, but not always easy to sort out.
“The beauty of our lists is that they require no fancy imaging tests and most of the signs are right there for the pediatricians and the orthopedic surgeons to see,” says co-investigator Paul Sponseller, M.D., M.B. A., director of Orthopaedics at Johns Hopkins Children’s Center. “All they have to do is see the forest for the trees. The lists will help them do so.”
If diagnosed in childhood, both disorders can be managed with drugs or surgery to head off the most life-threatening complications — arterial aneurysms or enlargement and rupture of the aorta — according the investigators.
“We miss that prevention opportunity in people diagnosed as adults,” Sponseller says.
Both Marfan and Loeys-Dietz syndromes affect the connective tissue of the heart, spine, joints and eyes, but Loeys-Dietz is also marked by twisted arteries that are prone to aneurysms, a feature absent in Marfan. And because people who have Loeys-Dietz tend to experience tearing of the aorta earlier than Marfan patients, they often need earlier and more aggressive treatment, including surgery.
Marfan
Starting out with a comprehensive list of 20 or so classic Marfan features, including long tapering fingers, a spinal curvature and a long narrow face, the researchers examined how often they occurred in 183 Marfan and 1,250 non-Marfan patients seen at Hopkins. The researchers calculated the diagnostic potential of each feature based on two factors: how common it was among Marfan patients and how well it could help differentiate between patients with the disorder and those without it. The strongest diagnostic predictor of Marfan in the study was the combination of certain facial features with a very long thumb. With a diagnostic accuracy index of 0.97, this combination correctly predicted Marfan in 97 out of 100 every patients.
What Is Marfan Syndrome?
Marfan syndrome is named after Antoine Marfan, the French doctor who first described the disorder in 1896. Marfan syndrome affects the body’s connective tissue. Connective tissue is found everywhere in the body. Think of it as a sort of “glue” that helps support your organs, blood vessels, bones, joints, and muscles.
In people with Marfan syndrome, this “glue” is weaker than normal. That’s because of a defect in the body’s production of fibrillin (pronounced: fuh-brill-in), a special type of protein that’s found in connective tissue. Weakened connective tissue can lead to problems in many parts of the body, especially the heart, eyes, and joints. For example, people with Marfan syndrome may have very loose, flexible joints as a result of these connective tissue problems.
Although Marfan syndrome has no cure (so the person will always have it), the good news is that doctors can treat just about all of its symptoms. Just a few decades ago, most people with the disease didn’t live past 40. Now, thanks to new research and treatments, people with Marfan syndrome who are diagnosed early and get good medical care have about the same lifespan as everyone else.
What Causes It?
Marfan syndrome is pretty rare. It only happens to about 1 in every 5,000 people.
Marfan syndrome is a genetic disorder. Genetic disorders are caused by a change in genes that is either inherited (passed on from parent to child) or that happens during very early development in the womb. In the case of Marfan syndrome, a defect in a gene found on chromosome 15 causes problems in the production of fibrillin.
Although some genetic disorders can affect people of one gender or a particular ethnic heritage more than others, Marfan syndrome can affect both girls and guys from all ethnic backgrounds.
About 75% of the time, the gene for Marfan syndrome runs in families, getting passed down to children from parents who have the disease. A child born to a parent who has Marfan syndrome has a 50% chance of having the disease too.
In the remaining 25% of cases, though, neither parent has the disease. This means the genetic mutation responsible for causing Marfan syndrome occurs in either the egg or sperm cell at the time of conception. No one knows what causes this mutation, but a child born with Marfan syndrome then has a 50% chance of passing it on to his or her children.
What Are the Signs and Symptoms?
People who have Marfan syndrome tend to share certain physical traits:
- They are often (but not always) much taller than their peers and have a lean, lanky build with disproportionately long arms and legs. Their fingers and toes are usually long and thin.
- Their joints are loose and flexible.
- They may have myopia (nearsightedness) or other vision problems (such as lens dislocation).
- They may have certain facial characteristics, including a long, thin face; deep-set eyes; a small bottom jaw; a high, arched roof of the mouth; and crowded teeth.
Not everyone with these characteristics has Marfan syndrome, of course. Does your friend have it just because he is tall and thin? Probably not. If you’re extremely nearsighted, does it mean you have the disorder? No, again.
People who have Marfan syndrome have very specific symptoms that usually happen together. When these symptoms show up as a group, it alerts doctors to the possibility that a person might have the condition.
Other symptoms of Marfan syndrome can affect the skin and lungs. These symptoms are generally less common and less serious, especially in kids and teens.
Although people with Marfan syndrome often have similar physical features, the disease doesn’t affect everyone in the same way. Some people have very mild symptoms, while others have severe ones — even within the same family. This is known as variable expression, and it makes it almost impossible to predict how the disease will progress in any affected individual.
How Do Doctors Diagnose It?
Several different types of doctors must be involved in diagnosing Marfan syndrome. They include a geneticist (a doctor who specializes in disorders of the genes), a cardiologist (heart doctor), an ophthalmologist (eye doctor), and an orthopedist (bone doctor).
A geneticist will ask whether anyone else in the family had similar symptoms and may even ask if anyone in your family died early of a heart-related death. Then the geneticist will probably do some pretty painless exams, such as taking detailed skeletal measurements, including arm span (hold your arms out to your side — that’s your arm span). This test can help because people with Marfan syndrome often have an arm span that’s greater than their height.
The cardiologist will also do some painless tests. He or she may listen to the heart with a stethoscope to check for a murmur, then may order an X-ray of the chest, an electrocardiogram (or EKG, which measures electrical impulses in the heart), and an echocardiogram (a test that uses sound waves to produce a picture of the heart) to check the size of the aorta and to make sure the valves are functioning well.
An ophthalmologist will probably dilate the eye pupil with special drops, then look into it with a slit lamp, a special type of microscope that can help detect lens dislocation and other eye problems.
An orthopedist will check for curvatures of the spine and breastbone, joint problems, and any other bone abnormalities.
If no one else in the family has the disorder, the patient has to show symptoms in three organ systems before doctors can diagnose Marfan syndrome.
Symptoms of Marfan syndrome may be apparent when a child is very young, while some people don’t have noticeable symptoms until their teen years or even adulthood. But some people go through life never knowing they have the disease, and that can be dangerous. Getting diagnosed early means doctors can do a lot to help keep someone healthy.
A patient with any two of the following signs with high diagnostic potential should be sent to a Marfan specialist:
• One or more cranial or facial signs including a long lean skull, downward slanted eyes, a receding jaw (diagnostic accuracy 0.93) • An extra long thumb: when folded inside the clenched fist of the hand, the thumb reaches the outer rim, past the pinkie (diagnostic accuracy 0.87) • Wrist test: A thumb that covers the entire nail of the same-hand pinky finger when encircling the wrist of the opposite hand (diagnostic accuracy 0.83)
A patient with three or four of the following should be sent to a specialist:
• Cranial and facial features described above • High-arched palate • Hollow chest • Severely flat feet, with or without deformity • Arm span more than 1.5 times longer than the total height
Another potent combination was the pairing of scoliosis (a curvature of the spine) with either facial features or an extra long thumb. Commonly seen in people without Marfan, scoliosis by itself is not a reliable predictor of the disorder, the researchers say.
The researchers warn their tool is not perfect - no screening test is - and may miss some Marfan patients with “silent” syndrome, while raising suspicion about some who don’t have the disorder. Indeed, one in five Marfan patients in the study had none or only one physical feature, while 13 percent of the non-Marfan patients had two skeletal features suggestive of the syndrome.
Loeys-Dietz
Researchers reviewed the charts of 65 Loeys-Dietz patients sent to Johns Hopkins after a diagnosis elsewhere. Investigators say primary-care pediatricians and orthopedic surgeons should be on the lookout for Marfan-like features in all patients, but consider Loeys-Dietz syndrome if they also notice any of the following signs that are not found in Marfan:
• Widely spaced eyes
• Club foot
• Translucent skin that bruises easily
• Bi-forked or split uvula, the dangling protrusion seen in the back of the throat • Cleft palate • Scoliosis with isolated deformities of the upper spine
What is Loeys-Dietz syndrome?
Loeys-Dietz syndrome is a recently-described syndrome characterized by aortic aneurysms (weakened outpouchings of the aorta, the main artery in the body) in children. In Loeys-Dietz syndrome, the aortic aneurysms are prone to rupture at a smaller size than other aneurysms, putting children with Loeys-Dietz at great risk for dying if the aneurysm is not identified and treated early.
The syndrome is named for pediatric geneticist Harry Dietz, director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins University and his colleague, Bart Loeys, who characterized the genetic and physical markers of the syndrome together with Dr. Dietz.
What are the signs and symptoms of Loeys-Dietz syndrome?
Aortic aneurysms and abnormal organization of blood vessels (widespread tortuosity of the arteries in locations other than the aorta) are the hallmarks of Loeys-Dietz syndrome, but many affected children have characteristic physical and facial features that may be the first abnormality to be recognized. Physical characteristics of Loeys-Dietz syndrome include early fusion of the skull bones (known as craniosynostosis), widely spaced eyes, and cleft palate or split uvula. In some individuals with Loeys-Dietz syndrome, other physical abnormalities have been noted, including defects at birth in the heart and brain, osteoporosis (weak bones), and defects of the spine. It is important to note that the severity of the visible physical characteristics varies among affected individuals, but the danger of rupture of aneurysms remains the same no matter how severe or mild the physical characteristics are.
In many cases pediatricians may be able to recognize the characteristic facial features of Loeys-Dietz syndrome, and on this basis suggest further evaluation for the presence of aortic aneurysms and vascular irregularities. Other people with the syndrome are recognized when they seek medical assistance for other reasons, such as heart murmurs or a family history of Marfan syndrome or another condition that may cause aortic aneurysms.
Differential Diagnosis
Although Loeys-Dietz syndrome shows overlap with other disorders such as Marfan Syndrome (MFS), Ehler-Danlos Syndrome (EDS), Shprintzen-Goldberg syndrome (SGS) and others, a variety of differential features set LDS apart from other disorders.
Other investigators included Hal Dietz, Gurkan Erkula, Richard Skolasky, Kristen Venuti, Laura Paulson and Gretchen Oswald, all of Hopkins, and Bart Loeys of Ghent University in Belgium.
Drug Treatment for Marfan Syndrome Looks Promising http://www.hopkinschildrens.org/drug-treatment-marfan-syndrome.aspx