What is Marfan Syndrome?
Marfan syndrome is a common genetic disorder that affects the body’s connective tissues, which are like the body’s building blocks that give structure to our organs, skin, blood vessels, and more. This syndrome is caused by changes in a gene on chromosome 15 that normally helps create a protein called fibrillin, essential for connective tissue. It’s estimated to occur in about 1 out of 3,000 to 5,000 people.
In Marfan syndrome, the severity can vary a lot from person to person. Some might only have mild symptoms, while others may experience serious issues that can affect multiple organs from a young age. Typically, this syndrome affects the eyes, heart, and skeleton, but it can also involve the lungs, skin, and central nervous system (the brain and spinal cord).
People with Marfan syndrome often have characteristic physical traits. They may have unusually long limbs compared to their trunk, excessively long and slender fingers and toes, and abnormal curvature of the spine or chest. They might also develop problems with their heart and blood vessels, including an enlarged aortic root (the part of the largest artery in the body where it connects to the heart) and aneurysms (swelling or bulging of blood vessels) which can be life-threatening. Other possible issues include eye conditions like dislocated lens and cataracts.
Diagnosing Marfan syndrome is typically based on identifying these unique physical characteristics, although genetic testing can confirm the diagnosis. While there’s no cure for Marfan syndrome, medical treatments are available that can help manage and improve certain symptoms. Medications known as beta-blockers can help reduce strain on the heart and large blood vessels. Timely detection and treatment can significantly improve the prognosis and enable people with Marfan syndrome to live well-managed lives.
What Causes Marfan Syndrome?
Marfan syndrome (MFS) is typically passed down from parents to their children in a pattern called “autosomal dominant inheritance”. However, there are rare instances where it has been linked to mutations in the fibrillin 1 gene (FBN1), which is not a typical inheritance pattern.
Most people with Marfan syndrome usually have a parent with the same condition. Yet, about 25% of patients get the syndrome due to a spontaneous change in the FBN1 gene that happened during their own development, rather than inheriting it from a parent.
The FBN1 gene, which exists on chromosome 15q-21.1 and is made up of 65 parts known as “exons”, creates a protein called fibrillin-1. This protein is a main ingredient in a type of tissue fiber called “elastic fibers”.
However, for less than 10% of people who show signs of Marfan syndrome, no changes are found in the FBN1 gene. This could be because the entire gene is missing, or because the instructions controlling the gene have changed somehow.
In some cases, a person may have symptoms similar to MFS, but their condition is actually caused by a change in a gene related to a substance called “transforming growth factor-beta receptor” (TGFBR). Some people with changes in TGFBR1 or TGFBR2 genes may show signs of MFS, or they may show signs of either Loeys-Dietz syndrome (LDS) or familial thoracic aortic aneurysm (FTAA) syndrome, two conditions related to MFS.
Risk Factors and Frequency for Marfan Syndrome
Marfan Syndrome (MFS) is a condition that affects about 1 in every 3,000 to 5,000 people. It is a global condition, meaning it can affect anyone, regardless of their race or sex.
- One unique aspect of MFS is that it shows complete penetrance with variable expression. This means that if you inherit the gene for it, you will have the disease, but how the disease affects you can vary greatly.
- About 25% of MFS cases occur randomly due to new mutations in the gene.
- MFS is considered one of the most common disorders caused by a single gene mutation.
Signs and Symptoms of Marfan Syndrome
Marfan syndrome is a medical condition that can affect several parts of the body, but the heart is the main area of concern. The condition leads to heart-related problems in 60-80% of patients. These problems include aortic root disease, which can cause the aorta valve to leak (aortic regurgitation), the aorta to widen (aneurysmal dilatation), or the aorta to tear or rupture (dissection).
Patients with Marfan syndrome are often diagnosed based on a set of criteria which include:
- Widening of the aortic root
- Family history of aortic root widening
- A mutation in the FBN1 gene, which has previously been associated with aortic root widening
Besides the aortic root, other parts of the body such as the thoracic and abdominal aorta, the root of the pulmonary artery, and even arteries in the head and neck can also widen. Doctors often use an echocardiogram, a type of ultrasound, to measure the aorta in patients diagnosed with Marfan syndrome. These measurements are vital in managing the condition and assessing the risk of serious complications like aortic dissection, which can happen if the condition is not diagnosed or treated. Such complications are preventable with timely surgery.
Heart valve problems are also common in Marfan syndrome patients, with 40-54% having mitral valve prolapse. As the condition progresses, this can cause heart failure in young children. Other potential heart issues include aortic regurgitation, cardiomyopathy with ventricle enlargement, and heart rhythm problems.
Other common features of Marfan syndrome include long limbs, mobility issues in joints like the elbow and fingers, a high arch in the foot, and distinct skeletal and spinal issues. People with Marfan syndrome may have tall stature, extra-long fingers, and deformities of the chest. Patients may also experience eye conditions, lung complications, skin changes, and problems with the dura, the protective covering of the brain and spine. Professional assessments from heart specialists and ophthalmologists (eye doctors) are recommended for people with Marfan syndrome to help manage and prevent related health issues.
Testing for Marfan Syndrome
In 1996, experts developed guidelines, called Ghent nosology, to diagnose Marfan syndrome (MFS). Marfan syndrome is a genetic disorder that affects the body’s connective tissue, and thus can impact various body systems including the skeletal, cardiovascular, and ocular systems.
These guidelines focused on a few key symptoms of the disease. An enlarged aortic root and a condition known as ectopia lentis, where the lens of the eye dislocates, are crucial symptoms. Other features like skeletal issues, heart problems, eye anomalies, and deformities in the vertebrae also support the diagnosis.
However, in 2010, these criteria were revised as the original ones had some limitations. They weren’t very applicable to children, and they weren’t efficient at ruling out similar syndromes. The new 2010 version emphasizes more on the enlargement or tearing of the aortic root and ectopia lentis, and tests for FBN1 gene mutations, which are common in Marfan syndrome.
A scoring system was also introduced in this revision. Points are assigned to the presence of specific characteristic signs like wrist and thumb signs, various bone deformities, the shape and structure of the chest, foot deformities, abnormal air accumulation in the chest (pneumothorax), shape of the hip joint, and a few more. Certain facial features and conditions like nearsightedness and loose heart valves also contribute to the overall systemic score. A total score of seven or above indicates a significant involvement of the body’s systems and helps in diagnosing Marfan syndrome.
The criteria to diagnose Marfan syndrome differ depending on whether there’s a family history of the syndrome or not. If there’s no family history, diagnosis requires an enlarged or dissected aortic root and ectopia lentis or a mutation in the FBN1 gene or a systemic score of 7 or above. However, in patients with a family history, the presence of ectopia lentis, or a systemic score of 7 points, or an enlarged aortic root is enough for diagnosis. These criteria have to be validated after considering other syndromes like Shprintzen-Goldberg, Loeys-Dietz, and vascular Ehlers-Danlos which share some common features with Marfan syndrome. It’s also advised to check for mutations in other genes apart from FBN1.
Young individuals below 20 years, who show signs of Marfan syndrome but do not meet the diagnostic criteria, are categorized under nonspecific connective tissue disorder if the systemic score is less than 7, or ‘potential MFS’ if an FBN1 mutation is identified but the aortic root measurement is less than 3.
Treatment Options for Marfan Syndrome
For people with Marfan syndrome (a genetic condition affecting the body’s connective tissue), medications like beta-blockers, regular check-ups, and limit on heavy physical exercise can help manage their condition. However, sometimes a person’s aorta (main artery supplying blood to the body) may dilate or ‘stretch out’ to an extent that necessitates surgery.
An established surgical technique for Marfan patients is the Bentall procedure, where an artificial tube connected to a mechanical valve replaces the enlarged part of the aorta. This procedure also involves resetting the coronary arteries (the vessels supplying the heart). Such a procedure has been found to have low early mortality rates (1.5%) and reasonably good long-term survival rates. Patients who get a mechanical aortic valve will need to take blood-thinning medication for life.
For those patients where blood-thinning medication isn’t recommended, different surgical technique ‘valve-sparing’ can be used. This procedure saves their own aortic valve, and despite a risk of aortic regurgitation (backward blood flow) later, it still has a lower risk of death and need for reoperation compared to the Bentall procedure.
People with Marfan syndrome are recommended regular echocardiogram (an ultrasound of the heart) and other monitoring techniques like CT scan or MRI to measure the diameter of the aorta. This is crucial as the size and how quickly it’s increasing can give signs of an impending aortic tear, which is a serious condition. These tests, while useful, can have side effects. For example, CT scans include radiation exposure which must be considered, especially in younger patients who need numerous scans throughout their life.
Any medication aiming to control heart rate and blood pressure has been found beneficial in Marfan syndrome patients. This includes beta-blockers and angiotensin 2 receptor blockers, both of which help in managing aortic expansion.
Exercise is recommended but within limits. Activities causing exhaustion or requiring a Valsalva maneuver (exhaling against a closed airway) should be avoided.
Operating on the enlarged aorta well before it is critically large has shown better survival rates. However, if the aortic diameter increases rapidly or if there is a family history of the condition, surgery may be warranted even if the aorta isn’t critically large yet.
Finally, women with Marfan syndrome should be cautious when considering pregnancy. If the aorta’s size exceeds certain limits, pregnancy may be strongly discouraged due to high risk of aortic complications.
What else can Marfan Syndrome be?
When a doctor is evaluating someone with Marfan syndrome, they need to consider several other conditions that have similar features. These conditions may include:
- Loeys-Dietz syndrome (LDS)
- Shprintzen-Goldberg syndrome (SGS)
- Mitral valve prolapse syndrome
- Congenital contractural arachnodactyly (CCA)
- Weill-Marchesani syndrome (WMS)
- Ectopia lentis syndrome (ELS)
- Familial thoracic aortic aneurysm and dissection syndrome (FTAAD/FTAA)
- FTAAD with bicuspid aortic valve
- FTAAD with patent ductus arteriosus
- Homocystinuria
- Arterial tortuosity syndrome (ATS)
- Ehlers-Danlos syndrome (vascular type)
- Ehlers-Danlos syndrome (cardiac valvular subtype)
- Stickler syndrome (hereditary arthro-ophthalmopathy)
- Klinefelter syndrome
- Congenital bicuspid aortic valve disease with associated aortopathy
- Aortic coarctation with associated ascending aortic enlargement
In order to determine the exact diagnosis, the doctor needs to carefully evaluate the patient’s symptoms and medical history, and may also need to administer certain tests.
What to expect with Marfan Syndrome
The life expectancy of people with Marfan syndrome (a genetic disorder affecting the body’s connective tissue) was around 32 years in 1972 but has significantly increased to 72 years in 1993. This improvement has been achieved through the use of medications known as beta-blockers, non-invasive heart imaging, and planned heart surgery.
Although men with Marfan syndrome generally live shorter lives than women with the condition, the overall life expectancy is now almost the same as for people without the syndrome. However, heart problems are still the most common cause of death. This happens mainly because of sudden death in patients who aren’t aware they have the condition or who have been recently diagnosed but the disease has already progressed too far to be treated through medical or surgical means.
Possible Complications When Diagnosed with Marfan Syndrome
Marfan syndrome (MFS) is a disease that affects multiple systems in the body, resulting in a variety of complications:
- Balloon-like swelling (aneurysm) and tears (dissection) in the aorta, the body’s main artery
- Improper closing of the mitral valve in the heart (mitral valve prolapse)
- Backflow of blood through the mitral valve in the heart (mitral regurgitation)
- Backflow of blood through the aortic valve in the heart (aortic regurgitation)
- Displacement of the lens in the eye (lens subluxation, also known as ectopia lentis)
- Vision problems including cataracts, glaucoma and retinal detachment
- Sudden collapse of the lung (spontaneous pneumothorax)
- Protruding abdominal organs through the inguinal canal in the abdomen (inguinal hernias)
- Abnormal curvature of the spine (scoliosis)
Preventing Marfan Syndrome
Marfan syndrome, often shortened to MFS, can create significant physical and mental strain for the people living with the condition. Everyone’s experience is unique, implicating different areas of concern. Based on a study by Rao and his team, in the United States, people with MFS generally have a lower quality of life compared to those without the disease. Among the many challenges they face, pain is a common one. Recent study reviews suggest that between 47% to 92% of people living with MFS experience pain.
Adults with MFS might also encounter physical limitations, have less energy, and possibly experience depression and anxiety. However, with the right medical diagnosis and treatment, in a timely manner, along with physical rehabilitation, these people can live more fulfilling and productive lives. Making strides in how chronic pain in MFS patients is managed should be a focal point of future medical research.
