Introduction

With striking heights and long, slender limbs, fingers, and toes, individuals with Marfan syndrome (MFS) may likely get you turning your head for yet another quick look. However, beneath that unforgettable exterior lies a more complex reality of their lives. MFS is a common genetic disorder first discovered in 1896 by Antoine-Bernard Marfan¹, and is known to affect body parts known as connective tissues.

These tissues are found in the heart, lungs, bones, muscles, blood vessels, skin, and eyes.² Similar to glue, connective tissues provide cushioning as they protect and connect different body parts. In MFS, there is typically a disruption to this intricate balance found in connective tissues leading to a range of issues.

Most individuals with MFS experience mild symptoms of the disease such as unusually longer limbs and joint flexibility, nearsightedness, and requiring little to no lifestyle adjustments.^1,2 However, 1 in 10 people with MFS suffer from debilitating features of the disease such as severe deformities in the chest or backbone, poor vision or blindness, and a life-threatening tear in the aorta known as aortic dissection following prolonged enlargement and weakness.³ Such people require significant medical interventions including surgeries in their management.

Untreated, this condition may significantly affect the health status and lifespan of affected individuals leading to devastating outcomes.¹ However, modern medicine has since intervened in improving the quality of life of MFS patients and prolonging the lifespan from the initial average life expectancy of 40 years to even beyond 72 years.⁴

The genetic nature of MFS

About 70-90% of cases of MFS are caused by the inheritance of mutations of different forms in a special gene known as the fibrillin gene, with over 200 types of such genetic mutations or alterations identified so far.³ Genetic mutations are changes in the DNA that make up a gene which leads to changes in how a person looks, and works, and may cause health problems, as in the case of MFS.

Prevalence of MFS

Although many individuals are unfamiliar with MFS, it is quite common, and recorded to affect about 1 in 5000 individuals.^1,2 Interestingly, it affects both males and females, and all races, ethnicities, and geographical locations equally.⁴ 

This piece aims to uncover and demystify the known causes of MFS by expatiating the major genetic and non-genetic mechanisms leading to MFS and how individuals end up with MFS.

Genetic cause of MFS

FBN1 gene mutation

The major gene implicated in MFS is the FBN1 gene which is a large gene located on the long arm of chromosome 15.¹ Although this may sound straightforward, it is a complex interplay of different activities within the gene. These are explored below.

Role of FBN1 gene

The FBN1 gene provides all the instructions required to make a particular protein known as fibrillin-1.^1,2,4 Fibrillin-1 is an important material for building stability and elasticity in crucial body structures known as connective tissues. These tissues are specialised to support, protect, and bind together other delicate tissues and organs all over the body. Some examples are connective tissues of the skin, bones, cartilage, ligaments, fat, and blood.

Alterations in this FBN1 gene, therefore, ultimately change the way the fibrillin-1 protein works to provide support for the body.^1,2,4 In MFS, fibrillin-1 may be deficient or improperly produced, weakening these supportive structures of the body.

Role of fibrillin-1 protein

How does a little change in a gene cause substantial damage to an individual? It is not far-fetched. Fibrillin-1 is a key player in the framework of connective tissues known as microfibrils.^1,2,4 In simple terms, microfibrils act like a sponge that binds to a substance called TGF-B (Transforming Growth Factor Beta) between the connective tissue cells. Together, they provide all the strength and elasticity needed by the blood vessels, bones, skin, and other organs because this bond prevents TGF-B from being hyperactive.

Importance of microfibrils in connective tissue

A defective fibrillin-1 weakens the essential structure of microfibrils, making the intricate design of this scaffolding fall apart.² Moreso, the TGF-B becomes excessively active, ultimately causing inflammation and changes in how these inflamed connective tissues are repaired, and subsequent scarring. Many dire complications of MFS such as aortic wall damage occur because of these defective processes.¹ 

Non-genetic basis of MFS

Most of the MFS cases are due to the FBN1 genetic mutation, it has been documented that approximately 10-30% of individuals have MFS without any identified genetic alterations.^3,4 This makes the diagnosis of MFS based on genetic testing alone an arduous affair with many limitations, including the fact that similar diseases are associated with the FBN1 gene mutation.³

Clinicians currently employ a standardised scoring system that includes necessary features such as family history, enlarged aorta, and eye lens dislocation to diagnose MFS.² This is then followed up by genetic testing for a more balanced approach.

How is MFS ingherited

Autosomal dominant inheritance

In MFS, only a single parent with the mutated genes is enough to pass the gene to the child.^1-4 In other words, a child has a 50% chance of inheriting MFS if even one of his or her parents has the condition. This form of inheritance is called autosomal dominant inheritance and approximately 75% of individuals with MFS wind up with the condition in this manner.

Additionally, everyone with the gene mutation has MFS however, the severity differs.³ Nothing conclusive has been identified that can predict if one would be affected mildly or severely even within the same family. It can also manifest in different ways from individual to individual and often overlaps with other genetic diseases that resemble MFS. 

Sporadic mutation

It is important to note that not all individuals with MFS inherited the condition.^2,4 About 25% of MFS are caused by new cases of mutations in the fibrillin-1 gene even when parents of such individuals do not possess the mutation.² This occurrence is random, and not passed down any family lines.

Why does this happen? Various factors have been identified but no one knows for sure. They include: mistakes in how a gene makes new DNA, environmental factors such as radiation or chemical exposures, high stressors such as high temperatures, and spontaneous changes caused by unstable DNA.^2,4

Risk factors

As mentioned earlier, it only takes one MFS-positive parent to increase the risk of MFS in their offspring.^1-4 This makes family history the major risk factor for MFS. However, the severity of the disease in individuals with the disease is more personal than inherited.

Complicated and severe cases of MFS as mentioned earlier typically involve damage to the aorta, the eyes, and the spine.^1-4 While who will have severe forms of the disease is hard to predict, little children, pregnant women, hypertensives, and people who engage in strenuous exercises are more prone to the most severe complications of MFS. Usually, they need to be closely monitored by a multidisciplinary team of health professionals to improve their overall health and chances of survival.

Summary

• Marfan syndrome is a fairly common and largely genetic disorder that affects multiple body organs. Mutation in the FBN1 gene is crucial to forming the fibrillin-1 protein necessary for connective tissues
• Patients typically have elastic skin, and long, slender bones making them appear lanky
• Symptoms range from mild to life-threatening blood vessel, bone, or eye problems
• Once an individual has MFS, he or she has a 50% chance of passing it down to his or her child, however, the severity of the disease is not familial
• It is important to note that there is a small fraction of people with MFS who, unlike the majority, did not inherit it from their parents
• Diagnosing MFS is based on criteria carefully followed by doctors and treatment options include both medical and surgical interventions tailored to individual requirements