This is Marfan syndrome

Published 2019-03-23

Marfan syndrome is an inherited connective tissue disorder characterized by symptoms from the cardiovascular system, skeleton, joints and eyes. The lungs, teeth and skin can also be affected. The symptoms usually appear during the formative years or only in adulthood and the degree of severity varies greatly. If the symptoms are mild, the disease often remains undiagnosed. Many people with the disease have a long and slender build with long and narrow arms, legs and feet. Since many different symptoms can be included, and also be of different degrees of severity, the individual variations between people with the syndrome are very large.

The cause of the syndrome is a change (mutation) in a gene, which leads to altered function of the protein fibrillin 1. The protein is part of the connective tissue that holds together and gives structure to tissues and organs in the body. The changed fibrillin causes the connective tissue to become weakened, and since connective tissue is found throughout the body, several different organ systems are affected by the disease. A serious symptom is that the aorta can expand with the risk of parts of the vessel wall rupturing.

Marfan syndrome is named after the French pediatrician Antoine Bernard-Jean Marfan, who in 1896 described a hereditary connective tissue disease in a 5-year-old girl with long, narrow fingers and skeletal changes.

The incidence of Marfan syndrome is estimated at one person per 10,000-5,000 inhabitants, i.e. between 1,000 and 2,000 in Sweden. Thus, it is one of the most common hereditary connective tissue diseases. However, the number is uncertain, as it can be difficult to diagnose.
The syndrome is equally common among women and men.

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Cause and diagnosis

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The first criteria for diagnosing Marfan syndrome were established in 1986 in Berlin. In 1996, new criteria were developed in the city of Ghent in Belgium, the so-called Ghent criteria. They were revised in 2010 and are now called the Ghent 2 criteria. There are thousands of different variants of mutations, but each person has only one disease-causing mutation.

In people with Marfan syndrome, there is a mutation in the gene (gene) FBN1 located on chromosome 15 (15q21.1). The gene controls the formation of the protein fibrillin, which is part of the body's connective tissue. Connective tissue is found throughout the body and consists of thin interwoven threads that hold the various organs in place. They hold muscles, joints and bones together and attach heart valves and eye lenses. The change in the gene leads to a weakening of the connective tissue.

Fibrillin has a structure similar to one of the body's signaling substances called TGF-β (transforming growth factor beta). Research indicates that some of the symptoms of Marfan syndrome are caused by a defective regulation of TGF-β.

Mutations in the genes for the TGF-β receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, a disease with symptoms similar to those of Marfan syndrome.

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Genetic examination

Gene testing is done by analyzing blood from a venous blood sample. The cost of this is contained within the ordinary healthcare fee. Finding the mutation is a big job. You get the results after about three months if you are the first person in the family to be examined and after a month if the mutation is already known and you know what to look for, for example when you do the test on a child and where the parent's mutation has already been found.

The Ghent 2 criteria for diagnosing people with Marfan syndrome
To diagnose a person with Marfan syndrome, you combine different symptoms. A person does not have to have all the symptoms. The Ghent 2 criteria focus on two symptoms:

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1. that the aorta is either widened or that its walls have split (aortic dissection) and

2. that the lenses of the eyes have ended up crooked (lens dislocation).

Added to this is a list of traits that give a certain number of points per symptom. A basic question is if someone in one's own family has already been diagnosed with Marfan syndrome, then less is required to make a diagnosis.

If someone in the family previously has Marfan syndrome, the following is required for a person to receive the diagnosis

• that the person's lenses are skewed

or

• that the aorta is dilated

or

• that the total score among the other symptoms is at least 7.

If no one in the family previously has Marfan syndrome, the following is required for a person to receive the diagnosis

• that the person's lenses are skewed and that the aorta is either dilated or the vessel wall has split

or

• that the aorta has either been enlarged or that the vessel wall has split and that a mutation in the FBN1 gene has been determined by genetic testing

or

• that the aorta has either expanded or that the vessel wall has split and that the total score among the other symptoms is at least 7.

or

• that the person's lenses are skewed and that a mutation in the FBN1 gene has been determined by genetic testing.

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Other symptoms

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Wrist and thumb signs – 3 points

Wrist or thumb sign – 1 point

The sternum bulges outwards (pectus carinatum) – 2 points

The sternum curves inwards
(pectus excavatum) or sternum asymmetry – 1 point

Malposition of the heel bone and sunken arches - 2 points

Common flatfoot – 1 point

Accumulation of air in the pleura (pneumothorax) – 2 points

Expansion of connective tissue membranes around
spinal cord and spinal fluid (duraectasia) – 2 points

The ball of the femur lies
deep in the hip bone (protrusio acetabuli) – 2 points

Shorter upper body than lower body and
longer arm span than body height without severe scoliosis – 1 point

Spinal curvature (scoliosis or thoracolumbar kyphosis) – 1 point

Decreased ability to stretch the elbow – 1 point

Pale scar-like striae in the skin (striae) – 1 point

Myopia above 3 diopters – 1 point

Mitral valve prolapse – 1 point

Facial features (at least three out of five): long skull (dolichocephaly), drooping eyelids, sunken eyeball (enophthalmia), retracted lower jaw (retrognathia), underdeveloped cheekbones (malar hypoplasia) – 1 point

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Reasons for genetic testing
If a person has an obvious "marfan look" and clear visible signs or signs that are clearly seen in relatives, it is not so urgent to do a genetic test. If, on the other hand, it is a young person where you cannot yet see many clinical signs, or who does not really have any symptoms, then a genetic test can be good.

It is also known today that there are individuals who have all or very many clinical signs (for example body height, curvature of the spine, high palate) but who then do not turn out to have the gene defect. Then it can be good to get certainty.

Genetic testing can also be good for someone who has suspected Marfan syndrome and wants to become a parent. The test may also be valuable in differentiating Marfan from Loey–Dietz syndrome.

It is also good to do a genetic examination to identify the syndrome in close relatives. Then you can start examining the heart and aorta of relatives where the mutation is identified and thus prevent serious, acute heart complications in them.

Risk of confusion
You can often get complete clarity after a genetic test, but there can also be confusion. There are many other conditions that also have mutations in FBN1. Some of them are very different from marfan, for example some types of dwarf plant. Therefore, before you decide to take the test, you should think carefully about how I myself will handle the fact that I may not get complete clarity. It can be difficult to understand the rather difficult-to-interpret result, and taking the test result to a doctor at the health center who does not have special expertise in genetics is not an idea. You must be sure that there is a genetics specialist who can help you understand even before you decide to take the test.

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Heredity
The inheritance of Marfan syndrome is autosomal dominant. This means that if one parent has the disease, i.e. has a normal gene (inheritance) and a mutated gene (altered inheritance), the risk of the child inheriting the disease is 50 percent. The children who did not get the mutated gene do not get the disease and do not pass it on either. In about three quarters, the syndrome has been inherited from one of the parents.

In about a quarter, the change in the gene has arisen as a new mutation (a change in the genetic makeup appears for the first time in the person himself and is not inherited from either parent). Parents of a child with a new mutation therefore in principle have no increased risk of having a child with the disease again. The new change in the child's genetic material is, however, hereditary, and as an adult he risks passing on the mutated gene to his children. Even then, heritability is 50 percent.

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Heart and vessels

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About 90 percent of all people with Marfan syndrome sooner or later have an effect on the heart and blood vessels. These vary greatly between different people. Some children can be seriously ill already at birth, but most have no symptoms at all as newborns, but can get it later in life. It is therefore very important to have regular checks of the heart and the large artery of the body (aorta). The checks are done by a heart doctor, a cardiologist. The most common check is ultrasound (echocardiography/EKO). Then you can see, among other things, the size of the aortic root, the shape and movements of the valves and how the blood flows. With the ultrasound, you can see the heart and the upper part of the aorta, but it is difficult to see further down because the air in the lungs obscures it. Then you can instead do a layered X-ray (computed tomography/CT) or an examination with a magnetic camera (magnetic resonance imaging/MRT).

Classic symptoms of cardiovascular problems are shortness of breath, palpitations, pronounced fatigue, racing heart and pain in the left arm/chest/back.

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Aorta
A normal aorta is about 25–30 mm in diameter in an adult. According to 2014 guidelines, preventive surgery should be considered when the aorta reaches 50 mm, but this also depends on body size and dilation rate.

The aorta contains a lot of fibrillin, which means that the vessel wall can weaken and is at risk of widening in people with Marfan syndrome. Dilation of the aorta usually occurs right at the beginning of the aorta (aortic root), but can occur along the entire aorta (in approximately 10–20 percent of cases). Such an expansion is called aortic dilatation/aortic aneurysm and in itself does not cause symptoms. However, it poses a risk that parts of the vessel wall may rupture and cause so-called aortic dissection. The vessel wall consists of several layers and a dissection means that some layers break, it becomes a tear. There are two types of dissections, type A and type B. Type A means that the dissection is in the ascending part of the aorta, from where the aorta sits in the heart and goes up. Type B is when the dissection is in the part that goes down towards the lower body. Type A is the most common.

If the rupture goes through all the layers of the vessel wall, the blood leaks out into the body. This is called aortic rupture. Aortic dissection and aortic rupture cause severe pain and are a life-threatening condition.

The pulmonary artery can also dilate, but this rarely causes any symptoms.

Signs of aortic dissection
People with Marfan syndrome are up to 250 times more likely to develop aortic dissection than the general population. That's why it's important to know the signs of aortic dissection and what to do.

Symptoms of an aortic aneurysm may be related to the aneurysm's location, size, and rate of growth and may include:

• Pain in the chest, neck and/or back

• Swelling of the head, neck and arms

• Coughing, wheezing or shortness of breath

• Coughing up blood

Symptoms of aortic dissection usually appear suddenly and may include:

• Sudden, constant chest pain and/or upper back pain.

• Pain that feels like it's moving from one place to another

• Unusually pale skin

• Weak pulse

• Numbness or tingling

• Paralysis

• In some cases, there may be no pain, instead there is a feeling that something is terribly "wrong".

If a dissection is suspected, a person needs immediate medical attention and should go to the hospital emergency department immediately.

Important for hospital visits:

• Tell the emergency room staff that you have Marfan syndrome or a related condition to quickly scan   for dissection.

• Communicate effectively with doctors and nurses in the emergency department.

(Source: The Marfan Foundation)

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Heart valves
The heart valves act as valves, which make the blood flow in the right direction. They are also made up of connective tissue. In people with Marfan syndrome, the heart valves in the left side of the heart, i.e. the aortic valve and the mitral valve, can change.

The mitral valve sits between the left atrium and left ventricle and consists of two leaflets held in place by thin wires. In mitral prolapse, the leaflets have become distended and are pushed back into the atrium during heart contraction. When the blood has to be pumped out into the body, some leaks backwards towards the lungs, so-called mitral insufficiency. About three-quarters of people with Marfan syndrome have mitral valve prolapse. For most, it is mild or of no practical importance.

The aortic valve consists of three pockets that sit between the left ventricle and the large body artery, the aorta. The left ventricle pumps the blood out through the aorta into the body at high pressure. The right ventricle receives the deoxygenated blood from the body and pumps it to the lungs at only one-fifth as high pressure. Therefore, the valves in the right half of the heart are much less stressed than those in the left.

The valves can become distended and thus cause leakage so that the blood flows back through the valves. Large leaks in the aortic valve and mitral valve (aortic insufficiency and mitral insufficiency) can lead to heart failure, which mainly manifests itself as decreased fitness with shortness of breath and fatigue. You can become short of breath even at rest, especially when lying down.

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Treatment and advice
It is important to keep the body in good physical shape, but since the heart's valves and the body's arteries can be so strongly affected, one should refrain from statically strenuous activities, where the blood pressure rises sharply, for example weightlifting.

Dilation of the aorta can be slowed with drugs and everyone with Marfan syndrome should be treated preventively. Either one can take beta blockers, or ACE inhibitors or angiotensin II receptor antagonists (ARBs). Many people with Marfan syndrome have low blood pressure and therefore it may feel unnecessary to be treated with blood pressure-lowering medication, but this treatment is usually tolerated and the advantages outweigh the disadvantages.

Many studies are underway to investigate how the drug losartan (ARB) can be used by people with Marfan syndrome. One study shows that children have the greatest benefit from being medicated with losartan, precisely because it prevents the aorta from starting to expand, while other studies have shown no difference between beta blockers and losartan.

The most important thing is that you are treated with some medicine to reduce the load on the aorta and reduce the pressure against the walls of the aorta, i.e. reduce the blood pressure. Blood pressure should be 120/80 or lower.

If the carotid artery is severely dilated, an operation may be necessary. Then one goes in through the chest and replaces the part of the aorta that is enlarged with a vessel prosthesis (composite graft) made of the material dacron.

As for the flaps, there are two different surgical methods. Method one involves replacing the part of the aorta that is enlarged and at the same time getting a mechanical aortic valve. If you have a mechanical valve prosthesis, treatment with blood-thinning drugs is required for the rest of your life, to prevent blood clots from forming.

Method two (David plastic surgery), means that you operate a little earlier, before the valves have had time to deteriorate. Then you save your own aortic valves and thus avoid taking blood-thinning medication. However, it has been shown that the valves can still go bad later on and may require re-operation and replacing them with a mechanical valve in any case. Both methods have advantages and disadvantages and one must judge on a case-by-case basis which is best.

When the dilation of the aorta increases rapidly, or if aortic rupture has occurred in a close relative, the reasons for preventive surgery increase. Through these measures, people with Marfan syndrome now have roughly the same average life expectancy as everyone else.

After an operation on the aorta, where the sternum was sawn open, it takes about 12 weeks for the skeleton to heal properly.

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Lungs and breathing

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Lungs
The elastic tissue in the lungs is weakened. If the lung tissue is damaged, for example by smoking, emphysema can occur. In emphysema, the alveoli become fewer and larger, which increases the risk of them bursting. These problems only appear in adulthood.

Spontaneous lung collapse, pneumothorax, usually results from the bursting of alveoli in one lung. The pleura is then filled with air, while the elastic lung is pulled together. This can lead to shortness of breath and chest pain and requires urgent hospital care even if the condition is not life-threatening

Treatment and advice
Spontaneous lung collapse with sudden chest pain and shortness of breath occurs in about five percent. The treatment consists in the air being sucked out of the pleura, and you are fully recovered. Some may get recurrent pneumothorax, and it may then be appropriate to have an operation for preventive purposes.

Due to the risk of lung complications, people with Marfan syndrome should refrain from smoking.

Breath
Because the syndrome affects the heart and lungs, problems with breathing can occur. The function of the lungs can also be impaired by a deformed chest and spine. The deformity can make it impossible to take deep breaths properly. Sleep apnea, asthma, poor breathing muscles and lung collapse also have an impact on breathing.

Treatment and advice
If the measurement between the spine and sternum is less than 3.5 cm in combination with a funnel chest, i.e. that the sternum is pressed in, surgery should be considered. When it is so crowded, both the heart and lungs are negatively affected. A metal disc is then surgically inserted to push out the sternum. It stays for a few years and is then picked out.

Scoliosis, that the spine is S-shaped and sometimes twisted, can also be operated on. A not too strong curvature rarely causes major problems, but if it is greater than 40 degrees, surgery should be considered.

However, surgery is not the only solution. Other measures are to train the lungs so that they work better and in various ways ensure that you get enough oxygen.

Before deciding on surgery or other treatment, tests of the function of the lungs must be done, as well as mapping sleep and fitness.

Published in Lungs and breathing, About Marfan syndrome

Skeleton and joints

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A tall and thin build, with very long and narrow arms, legs, fingers and feet is very common, but it doesn't always have to be that way.

Long arms and legs with weak muscles put increased strain on ligaments, bone membranes and muscle attachments, which can lead to sprains and pain.

50-60 percent of those with the syndrome are hypermobile (over-mobile) in one or more joints. The joints are loose and unstable, easily overstretched or dislocated. It is more common to have loose and unstable joints at a young age.

When the joints are repeatedly overloaded, the connective tissue is damaged and it becomes irritated and inflamed and pain occurs. In the knees, fluid can form in the knee joint. In the long run, it can lead to wear and tear in the joints and therefore there is an increased risk of osteoarthritis.

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Treatment and advice
Support bandages and orthoses of various kinds are good for those who have unstable joints in, for example, feet, hands, knees or elbows. These correct, stabilize and support. They prevent incorrect loading or incorrect movements and can thus relieve pain. There are good support bandages to buy in sports shops or search for "orthoses" online. In a specialty store, healthcare store or similar, you can have the orthosis specially tested. Those who have major problems can get orthoses on referral from a doctor.

Many are hypermobile on one side of a joint and this can cause mobility on the opposite side to be restricted. To counteract this, it is good to try to maintain "normal" muscle length using, for example, yoga, core or other gentle forms of exercise.

Length growth
The increased extensibility of the connective tissue means that the length growth of the skeleton is not slowed down in the normal way. Most newborns with the syndrome are taller than normal and growth is faster than normal until it stops at puberty.

It is above all the tube bones in the forearms and lower legs as well as the bones in the feet and hands that grow more than normal in length. What this is due to is not yet fully understood, but one theory is that the regulation of TGF-β is altered. Many of the children grow tall; for boys it can be a final length of up to 200 centimeters and for girls 180 centimeters.

Treatment and advice
Hormone therapy is sometimes given to accelerate puberty and thereby end height growth. Children who are much taller than their peers early on should be referred to an endocrinologist well before puberty. Most often, a first assessment is made when girls are around 170 cm and boys 180 cm. By giving sex hormones at the right time, the puberty period is shortened and approximately half of the remaining expected height growth is not achieved.

An alternative to hormone treatment is to scrape out the growth zones around the knee in the shins and femurs. It is a fairly mild operation with a relatively short convalescence, which only affects the length growth of the legs. The body then becomes more proportional.

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(Source: text copied from the Swedish marfan association)

Link:https://marfan.se/category/marfansyndrom/

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