Marfan syndrome

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Marfan syndrome
Classification and external resources
Myxomatous aortic valve.jpg
Micrograph demonstrating myxomatous degeneration of the aortic valve, a common manifestation of Marfan syndrome
ICD-10 Q87.4
ICD-9 759.82
OMIM 154700
DiseasesDB 7845
MedlinePlus 000418
eMedicine ped/1372 orthoped/414
MeSH D008382

Marfan syndrome (also called Marfan's syndrome) is a genetic disorder of human connective tissue. It has various expressions ranging from mild to severe: the most serious complications are defects of the heart valves and aorta, which often lead to early death. The syndrome also may affect the lungs, eyes, dural sac surrounding the spinal cord, the skeleton, and the hard palate. People with Marfan tend to be unusually tall, with long limbs and long, thin fingers.

The syndrome is caused by the misfolding of the protein fibrillin-1. Fibrillin-1 is coded by the gene FBN1.[1][2] Fibrillin-1 protein forms fibers in connective tissue. In addition to providing structural support, the normal fibrillin-1 protein also contributes to cell signaling activity, binding to the protein transforming growth factor beta (TGF-β). Mis-regulated TGF-β has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Researchers now believe, secondary to mutated structural fibrillin, excessive TGF-β at the lungs, heart valves, and aorta weakens the tissues and causes the features of Marfan syndrome. Since angiotensin II receptor antagonists (ARBs) also reduce TGF-β, ARBs (such as losartan) have been tested in a small sample of young, severely affected people with Marfan syndrome. In some, the growth of the aorta was reduced.[3]

The disease is an autosomal dominant disorder, meaning that people who inherit only one copy of the Marfan FBN1 gene from either parent will develop Marfan syndrome and be able to transmit it to their children. The gene linked to the disease was first identified by Hal Dietz[4][5] and Francesco Ramirez in 1991.[6]

Marfan syndrome is named after Antoine Marfan,[7] the French pediatrician who first described the condition in 1896.[8][9]

Signs and symptoms[edit]

More than 30 different signs and symptoms are variably associated with Marfan syndrome. The most prominent of these, affecting the skeletal system, are found in numerous other diseases (see Differential Diagnosis, below). Thus, it is not possible to make a diagnosis of Marfan syndrome simply by the person's appearance. Instead, distinguishing Marfan syndrome from other "marfanoid" syndromes (without recourse to DNA testing) requires the assessment of non-skeletal clinical and laboratory findings, especially of the eyes, aorta, and heart. Complicating the physical assessment of such persons, considerable clinical variability occurs within families carrying an identical DNA variant.

Skeletal system[edit]

Most of the readily visible signs are associated with the skeletal system. Many individuals with Marfan syndrome grow to above-average height. Some have long, slender limbs (dolichostenomelia) with long fingers and toes (arachnodactyly). An individual's arms may be disproportionately long, with thin, weak wrists. In addition to affecting height and limb proportions, Marfan syndrome can produce other skeletal anomalies. Abnormal curvature of the spine (scoliosis), abnormal indentation (pectus excavatum) (which can occur in an asymmetrical fashion) or protrusion (pectus carinatum) of the sternum are not uncommon. Other signs include abnormal joint flexibility, a high palate, malocclusions, flat feet, hammer toes, stooped shoulders, and unexplained stretch marks on the skin. It can also cause pain in the joints, bones and muscles in some patients. Some people with Marfan have speech disorders resulting from symptomatic high palates and small jaws. Early osteoarthritis may occur. Other signs include limited range of motion in the hips due to the femoral head protruding into abnormally deep hip sockets (protrusio acetabuli).[10]



Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness and astigmatism are common, but farsightedness can also result. Subluxation (dislocation) of the crystalline lens in one or both eyes (ectopia lentis) (in 80% of patients) also occurs and may be detected by an ophthalmologist or optometrist using a slit-lamp biomicroscope. In Marfan the dislocation is typically superotemporal whereas in the similar condition homocystinuria, the dislocation is inferonasal. Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina.[citation needed] Early onset glaucoma can be another related problem.[citation needed]

Cardiovascular system[edit]


Because underlying connective tissue abnormalities cause Marfan syndrome, there is an increased incidence of dehiscence of prosthetic mitral valve.[11] Care should be taken to attempt repair of damaged heart valves rather than replacement.



Pulmonary symptoms are not a major feature of Marfan syndrome,[13] but spontaneous pneumothorax is common.[14] In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed. This can cause pain, shortness of breath, cyanosis, and, if not treated, it can cause death. Other possible pulmonary manifestations of Marfan syndrome include sleep apnea and idiopathic obstructive lung disease.[medical citation needed] Pathologic changes in the lungs have been described such as cystic changes, emphysema, pneumonia, bronchiectasis, bullae, apical fibrosis and congenital malformations such as middle lobe hypoplasia.[13]

Central nervous system[edit]

Dural ectasia, the weakening of the connective tissue of the dural sac encasing the spinal cord, though not life-threatening, can reduce the quality of life for an individual. It can be present for a long time without producing any noticeable symptoms. Symptoms that can occur are lower back pain, leg pain, abdominal pain, other neurological symptoms in the lower extremities, or headaches. Such symptoms usually diminish when the individual lies flat on his or her back. These types of symptoms might lead a doctor to order an X-ray of the lower spine. Dural ectasia is usually not visible on an X-ray in the early phases. A worsening of symptoms and the lack of finding any other cause could eventually lead a doctor to order an MRI of the lower spine. Dural ectasia that has progressed to the point of causing these symptoms would appear in an MRI image as a dilated pouch wearing away at the lumbar vertebrae.[15] Other spinal issues associated with Marfan syndrome include degenerative disk disease, spinal cysts and dysautonomia.


Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15,[16] which encodes the glycoprotein fibrillin-1, a component of the extracellular matrix. Fibrillin-1 protein is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors.[17] Elastin fibers are found throughout the body, but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye; consequently, these areas are among the worst affected. It can also be caused by a range of intravenous crystal treatments in those susceptible to the disorder.

A transgenic mouse has been created carrying a single copy of a mutant fibrillin-1, a mutation similar to that found in the human gene known to cause Marfan syndrome. This mouse strain recapitulates many of the features of the human disease and promises to provide insights into the pathogenesis of the disease. Reducing the level of normal fibrillin 1 causes a Marfan-related disease in mice.[18]

Transforming growth factor beta (TGF-β) plays an important role in Marfan syndrome. Fibrillin-1 directly binds a latent form of TGF-β, keeping it sequestered and unable to exert its biological activity. The simplest model of Marfan syndrome suggests reduced levels of fibrillin-1 allow TGF-β levels to rise due to inadequate sequestration. Although it is not proven how elevated TGF-β levels are responsible for the specific pathology seen with the disease, an inflammatory reaction releasing proteases that slowly degrade the elastin fibers and other components of the extracellular matrix is known to occur. The importance of the TGF-β pathway was confirmed with the discovery of the similar Loeys-Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGF-β.[19] Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two pathologies.[20]


Diagnostic criteria of Marfan syndrome were agreed upon internationally in 1996.[21] A diagnosis of Marfan syndrome is based on family history and a combination of major and minor indicators of the disorder, rare in the general population, that occur in one individual — for example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual. The following conditions may result from Marfan syndrome, but may also occur in people without any known underlying disorder.

Revised Ghent Nosology[edit]

Thumb sign; upper: normal, lower: Marfan syndrome

According to the US National Marfan Foundation, in 2010 the Ghent Nosology was revised, and new diagnostic criteria superseded the previous agreement made in 1996. The seven new criteria can lead to a diagnosis:[unreliable medical source?][32][33]

In the absence of a family history of MFS:

  1. Aortic root Z-score ≥ 2 AND ectopia lentis
  4. Ectopia lentis AND an FBN1 mutation with known aortic pathology


  1. Ectopia lentis
  2. Systemic score* ≥ 7
  3. Aortic root Z-score ≥ 2

The thumb sign (Steinberg's sign) is elicited by asking the patient to flex the thumb as far as possible and then close the fingers over it. A positive thumb sign is where part of the thumb is visible beyond the ulnar border of the hand, caused by a combination of hypermobility of the thumb as well as a thumb which is longer than usual.

The wrist sign (Walker's sign) is elicited by asking the patient to encircle the thumb and fingers of one hand around the other wrist. A positive wrist sign is where the little finger and the thumb overlap, caused by a combination of thin wrists and long fingers.[34]

Differential diagnosis[edit]

Many disorders have the potential to produce the same type of body habitus (i.e. shape) as Marfan syndrome.[35] Distinguishing among these "marfanoid" disorders can be facilitated by genetic testing, and by evaluating signs and symptoms other than body habitus. Among the disorders capable of producing a marfanoid body habitus are:


There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades and is now similar to that of the average person.[37] Clinical trials are also under way for promising new treatments.[38] At present (2013), the syndrome is treated by simply addressing each issue as it arises and, in particular, preventative medication even for young children to slow progression of aortic dilation if such exists.

Marfan syndrome is expressed dominantly. This means a child with one parent a bearer of the gene has a 50% probability of getting the syndrome. However, as the gene causing Marfan syndrome is known, arduous genetic techniques are able to circumvent this. In 1996, the first preimplantation genetic testing therapy for Marfan was conducted;[39] in essence PGT means conducting a genetic testing on early stage IVF embryo cells and discarding those embryos affected by the Marfan mutation.

Regular checkups by a cardiologist are needed to monitor the health of the heart valves and the aorta. The goal of treatment is to slow the progression of aortic dilation and damage to heart valves by eliminating arrythmias, minimizing the heart rate, and minimizing blood pressure. Beta blockers have been used to control arrythmias and slow the heart rate. Other medications might be needed to further minimize blood pressure without slowing the heart rate, such as ACE inhibitors and angiotensin II receptor antagonists. If the dilation of the aorta progresses to a significant diameter aneurysm, causes a dissection or a rupture, or leads to failure of the aortic or other valve, then surgery (possibly a composite aortic valve graft or valve-sparing aortic root replacement) becomes necessary. Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis.[40] Surgery in the setting of acute aortic dissection or rupture is considerably more problematic. Elective aortic valve/graft surgery is usually considered when aortic root diameter reaches 50 millimeters (2.0 inches), but each case needs to be specifically evaluated by a qualified cardiologist. New valve-sparing surgical techniques are becoming more common.[41] As Marfan patients live longer, other vascular repairs are becoming more common, e.g., repairs of descending thoractic aortic aneurysms and aneurysms of vessels other than the aorta.

The skeletal and ocular manifestations of Marfan syndrome can also be serious, although not life-threatening. These symptoms are usually treated in the typical manner for the appropriate condition, such as with various kinds of pain medication or muscle relaxants. It is also common for patients to receive treatment from a physiotherapist, using TENS therapy, ultrasound and skeletal adjustment.[citation needed] This can also affect height, arm length, and life span. A physiotherapist can also help improve function and prevent injuries in individuals with Marfan syndrome. The Nuss procedure is now being offered to people with Marfan syndrome to correct 'sunken chest' or (pectus excavatum).[42] Because Marfan syndrome may cause asymptomatic spinal abnormalities, any spinal surgery contemplated on a Marfan patient should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery.


Research in laboratory mice has suggested the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome.[43][44] A large clinical trial sponsored by the National Institutes of Health comparing the effects of losartan and atenolol on the aortas of Marfan patients was scheduled to begin in early 2007, coordinated by Johns Hopkins.[45]


"As recently as 40 years ago, people with Marfan syndrome faced a virtually hopeless situation on account of chronic mitral and aortic regurgitation, heart failure, and acute and chronic aortic dissection. Life span was reduced by at least one third, with many patients succumbing in the second and third decades. Today, cardiovascular manifestations of Marfan syndrome remain among the central issues in diagnosis and management, but it is incumbent on the physicians who encounter these patients to stress the prophylactic monitoring and therapies that now can result in a nearly normal life expectancy."[46]


Marfan syndrome affects males and females equally,[47] and the mutation shows no ethnic or geographical bias.[48] Estimates indicate about one in 3,000 to 5,000 individuals have Marfan syndrome.[48] Each parent with the condition has a 50% risk of passing the genetic defect on to any child due to its autosomal dominant nature. Most individuals with Marfan syndrome have another affected family member. Approximately 15–30% of all cases are due to de novo genetic mutations;[17] such spontaneous mutations occur in about one in 20,000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.[49][50] It is associated with variable expressivity; incomplete penetrance has not been definitively documented.


Marfan syndrome is named after Antoine Marfan,[7] the French pediatrician who first described the condition in 1896 after noticing striking features in a five-year-old girl.[8][9] The gene linked to the disease was first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.[6]

Society and culture[edit]

Contributors to public perception of Marfan syndrome include Flo Hyman, an Olympic silver medalist in women's volleyball (1984) who died suddenly at a match from an aortic dissection;[51] Jonathan Larson, author and composer of Rent, who also died from aortic dissection the day before the opening of the musical;[52][53] Vincent Schiavelli, an actor and spokesperson for the National Marfan Foundation, who had the syndrome but died from an unrelated cause,[54] and Isaiah Austin, a basketball player who was diagnosed with it, and forced to give up his dream of an NBA career.[55][56]

Studies suggest that Akhenaten, a Pharaoh of the eighteenth dynasty of Egypt, may have suffered from Marfan's syndrome.[57][58] Abraham Lincoln was once thought to have had the disease, but that view has been discounted.[59][60][61]


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    See also:
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