At first glance, the characteristics of Marfan syndrome—a tall, slender build with unusually long limbs—might not seem like signs of a medical condition. However, these visible traits are just the outward expression of a complex, systemic genetic disorder. Marfan syndrome affects the body’s connective tissue, the very material that provides strength and structure to our organs, blood vessels, bones, and joints. While its effects on the skeleton and eyes are significant, the most serious and life-threatening complications involve the heart and the body’s main artery, the aorta. With no cure available, a diagnosis of Marfan syndrome can be daunting, but it is important to know that with early diagnosis, proactive monitoring, and modern medical management, individuals with the condition can live long, healthy, and productive lives.

Marfan Syndrome is a genetic connective tissue disorder that affects the body’s ability to maintain structure and strength in various tissues. Connective tissue provides support to organs, joints, blood vessels, bones, and the eyes, and in Marfan Syndrome, a defect in this tissue causes a wide range of physical abnormalities, some of which may be life-threatening.

The condition is best-known for its effects on the skeleton, cardiovascular system, and eyes. People with Marfan Syndrome often have a tall, slender build, long arms and fingers, flexible joints, and problems with the aorta, the major artery that carries blood from the heart.

It is a lifelong condition and varies in severity. While some people may live relatively normal lives with only mild symptoms, others may experience complications that require regular monitoring and medical treatment.

Analogy: Imagine your body’s connective tissue as the rubber bands holding everything together. In Marfan Syndrome, those bands are overly stretchy or weak, so things may bend too far, lose shape, or wear out faster than they should.

Marfan Syndrome is caused by a mutation in the FBN1 gene, which is located on chromosome 15. This specific gene holds the complete set of instructions for the body to produce the protein fibrillin-1. When the FBN1 gene is mutated, the body either doesn’t produce enough fibrillin-1, or the fibrillin-1 it produces is misshapen and defective.

This lack of normal, functional fibrillin-1 disrupts the body’s architecture in two key ways:

1. Structural Weakness: Fibrillin-1 is a primary component of microfibrils, which are intricate structures that act like a supporting framework for the elastic fibers within connective tissue. Without strong microfibrils, the connective tissue loses its strength and elasticity, becoming weak and prone to overstretching. This is why individuals with Marfan syndrome have loose joints and why their blood vessels, particularly the aorta, can stretch and enlarge over time.
2. Growth Factor Dysregulation: Beyond its structural role, fibrillin-1 also helps to regulate a protein called transforming growth factor-beta (TGF-β). TGF-β is a signaling molecule that plays a role in cell growth and development. When fibrillin-1 is defective, it cannot properly regulate TGF-β, leading to an excess of this growth factor in the tissues. Researchers believe this excess TGF-β is responsible for many of the features of Marfan syndrome, including the overgrowth of bones that leads to tall stature and some of the degenerative changes seen in the heart valves and aorta.

Clinically, Marfan Syndrome is recognized not just by the genetic mutation but also by its multisystem features, especially if there’s a family history of sudden cardiac events or aortic rupture.

Marfan syndrome is a genetic disorder, but how a person comes to have it can vary. It is important for families to understand the two primary ways the condition arises.

1. Inheritance (Autosomal Dominant): In about 75% of cases, Marfan syndrome is inherited from a parent who also has the condition. It is passed down in an autosomal dominant pattern. This means:

• The mutated FBN1 gene is on one of the non-sex chromosomes (an autosome).
• Only one copy of the mutated gene (from one parent) is required to cause the syndrome.
• An individual with Marfan syndrome has a 50% chance of passing the mutated gene on to each of their children, regardless of the child’s gender.

2. Spontaneous (de novo) Mutation: In about 25% of cases, an individual with Marfan syndrome is the very first person in their family to have the condition. This is called spontaneous or de novo (“new”) mutation. In these instances, the mutation in the FBN1 gene occurred by chance in either the egg or the sperm cell that formed the child. The parents are not affected and do not carry the mutation. However, once an individual has this new mutation, they can then pass it on to their own children with the same 50% probability.

Marfan syndrome affects people of all genders, races, and ethnic backgrounds equally. It is estimated to affect about 1 in 5,000 people worldwide.

The features of Marfan syndrome can be highly variable, even among members of the same family who share the same genetic mutation. Some people have very mild features, while others experience severe and progressive complications. The signs and symptoms are a direct result of the weak connective tissue and can affect many different body systems.

Skeletal System: The effects on the skeleton are often the most visible signs of the syndrome.

• Tall, Slender Stature: People with Marfan syndrome are typically much taller and thinner than their family members.
• Arachnodactyly: This means “spider-like fingers” and refers to unusually long, slender fingers and toes. Doctors may check for this using the “thumb sign” (the thumb extends past the palm when the fist is clenched) and the “wrist sign” (the thumb and little finger overlap when wrapped around the opposite wrist).
• Disproportionate Limbs: The arms, legs, fingers, and toes may be disproportionately long in relation to the trunk of the body. An arm span that is greater than the person’s height is a classic feature.
• Chest Wall Deformities: The sternum (breastbone) may be sunken in (pectus excavatum) or protrude outward (pectus carinatum).
• Spinal Curvature: Scoliosis (a sideways curve of the spine) or kyphosis (a forward hunching of the upper back) are common.
• Joint Hypermobility: Loose, “double-jointed” joints are common due to lax ligaments.

Cardiovascular System (Heart and Blood Vessels): This is the area of greatest medical concern.

• Aortic Aneurysm and Dilation: The most life-threatening complication is the progressive stretching and weakening of the aorta, the main artery that carries blood from the heart to the rest of the body. This enlargement, or aneurysm, typically occurs at the aortic root, where the artery leaves the heart.
• Aortic Dissection: If the aortic aneurysm is not managed, the inner layer of the weakened aortic wall can tear. This is called an aortic dissection. Blood surges through the tear, forcing the layers of the artery wall apart. This is a catastrophic medical emergency that can be fatal if not treated immediately.
• Valve Problems: The heart valves, particularly the mitral valve, can be affected, leading to mitral valve prolapse, where the valve leaflets are floppy and do not close properly.

Ocular System (Eyes): Eye problems are very common in Marfan syndrome.

• Ectopia Lentis (Dislocated Lens): This is a hallmark feature of the syndrome, occurring in over 50% of patients. The weak connective tissues that hold the eye’s lens in place allow it to move out of its normal position.
• Severe Myopia (Nearsightedness): Most people with Marfan syndrome are very nearsighted.
• Increased Risk of Other Eye Problems: They are also at a higher risk for developing retinal detachment, glaucoma, and cataracts at an early age.

Other Systems:

• Dural Ectasia: The membrane that surrounds the spinal cord (the dura) can stretch and weaken, which can cause back pain or headaches.
• Spontaneous Pneumothorax: Weakened connective tissue in the lungs can lead to the formation of small air sacs that can rupture, causing a collapsed lung.

Diagnosis

Diagnosis is based on a combination of clinical features, family history, and genetic testing. The revised Ghent criteria are commonly used to confirm a diagnosis.

A diagnosis is typically made if a patient has:

• A known family history of Marfan syndrome and one of the major features (like a dislocated lens or aortic dilation).
• No family history, but a significantly enlarged aorta and either a dislocated lens, a confirmed FBN1 gene mutation, or a high score on the systemic features checklist.

Genetic testing for a mutation in the FBN1 gene can be used to confirm a diagnosis, especially in cases where the clinical signs are borderline.

In my practice, once aortic enlargement is found in a tall young person with long fingers and nearsightedness, Marfan Syndrome is strongly suspected, even before genetic testing.

Treatment

There is no cure for Marfan Syndrome, but treatment focuses on preventing or managing complications, especially in the heart and aorta.

Cardiovascular Management:

• Regular Monitoring: Individuals with Marfan syndrome need regular check-ups with a cardiologist, including an echocardiogram at least once a year.
• Medications: Beta-blockers and angiotensin II receptor blockers (ARBs) are commonly used to lower blood pressure and slow the rate of aortic dilation.
• Prophylactic Aortic Surgery: If enlargement reaches critical size, surgeons will recommend a preventative operation to replace the weakened aortic root and ascending aorta.

Skeletal and Eye Management:

• Regular monitoring by an orthopedist is needed to watch for scoliosis, which may require a brace or surgery.
• Annual eye exams with an ophthalmologist are essential to check for lens dislocation, retinal detachment, and other eye issues.

Lifestyle Modifications:

• Activity Restrictions: They should avoid contact sports, competitive sports, and activities that involve intense exertion or heavy weightlifting, as these can put sudden stress on the aorta.
• Safe Exercise: Low-impact and moderate aerobic activities like walking, swimming, or cycling are encouraged to maintain cardiovascular health.

Marfan syndrome is a complex, lifelong condition that requires careful medical management and significant patient awareness. The discovery of its genetic cause and a deeper understanding of its effect on the aorta have revolutionized care. Decades ago, the life expectancy for someone with Marfan syndrome was severely limited. Today, thanks to proactive monitoring with regular echocardiograms, blood pressure-lowering medications, and timely preventative aortic surgery, the outlook is dramatically different. With a knowledgeable healthcare team and by becoming active participants in their own care, people with Marfan syndrome can now expect to live a near-normal lifespan, navigating the challenges of their condition to lead full and meaningful lives.

• The Marfan Foundation. (2024). What is Marfan syndrome? Retrieved from https://marfan.org/what-is-marfan/
• Brooke, B. S., Habashi, J. P., Judge, D. P., Patel, N., Loeys, B., & Dietz, H. C. (2008). Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. New England Journal of Medicine, 358(26), 2787–2795. https://doi.org/10.1056/NEJMoa0706585
• Dietz, H. C. (2017). Marfan Syndrome. In GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1335/
• National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). (2022). What is Marfan syndrome? Retrieved from https://www.nhlbi.nih.gov/health/marfan-syndrome