Marfan syndrome

Source: Wikipedia, the free encyclopedia.
Marfan syndrome
Other namesMarfan's syndrome
Ehlers-Danlos syndrome
MedicationBeta blockers, calcium channel blockers, ACE inhibitors[4][5]
PrognosisOften normal life expectancy[1]
Frequency1 in 5,000–10,000[4]

Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue.[6][7][1] Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes.[1] They also typically have exceptionally flexible joints and abnormally curved spines.[1] The most serious complications involve the heart and aorta, with an increased risk of mitral valve prolapse and aortic aneurysm.[1][8] The lungs, eyes, bones, and the covering of the spinal cord are also commonly affected.[1] The severity of the symptoms is variable.[1]

MFS is caused by a mutation in

autosomal dominant disorder.[1] In about 75% of cases, it is inherited from a parent with the condition, while in about 25% it is a new mutation.[1] Diagnosis is often based on the Ghent criteria, family history and genetic testing[2][4] (DNA analysis).[3]

There is no known cure for MFS.[1] Many of those with the disorder have a normal life expectancy with proper treatment.[1] Management often includes the use of beta blockers such as propranolol or atenolol or, if they are not tolerated, calcium channel blockers or ACE inhibitors.[4][5] Surgery may be required to repair the aorta or replace a heart valve.[5] Avoiding strenuous exercise is recommended for those with the condition.[4]

About 1 in 5,000 to 1 in 10,000 people have MFS.[4][9] Rates of the condition are similar in different regions of the world.[9] It is named after French pediatrician Antoine Marfan, who first described it in 1896.[10][11]

Signs and symptoms

An anterior chest wall deformity, pectus excavatum, in a person with Marfan syndrome

More than 30

symptoms
are variably associated with Marfan syndrome. The most prominent of these affect the skeletal, cardiovascular, and ocular systems, but all fibrous connective tissue throughout the body can be affected.

Skeletal system

Most of the readily visible signs are associated with the skeletal system. Many people with Marfan syndrome grow to above-average height, and some have disproportionately long, slender limbs with thin, weak wrists and long fingers and toes.

The Steinberg sign, also known as the thumb sign, is one of the clinical examination tests for Marfan disease in the hands. It is a clinical test in which the tip of the thumb extends beyond the palm when the thumb is clasped in the clenched hand.[12][13][14]

Besides affecting height and limb proportions, people with Marfan syndrome may have abnormal lateral curvature of the spine scoliosis, thoracic lordosis, abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum, abnormal joint flexibility, a high-arched palate with crowded teeth and an overbite, flat feet, hammer toes, stooped shoulders, and unexplained stretch marks on the skin. It can also cause pain in the joints, bones, and muscles. 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.[15][16]

Eyes

Lens dislocation in Marfan syndrome with the lens being kidney-shaped and resting against the ciliary body

In Marfan syndrome, the health of the eye can be affected in many ways, but the principal change is partial

lens can be detected clinically in about 60% of people with Marfan syndrome by the use of a slit-lamp biomicroscope.[17] If the lens subluxation is subtle, then imaging with high-resolution ultrasound biomicroscopy might be used.[18]

Other signs and symptoms affecting the eye include increased length along an axis of the globe, myopia, corneal flatness, strabismus, exotropia, and esotropia.[16] Those with MFS are also at a high risk for early glaucoma and early cataracts.[17]

Cardiovascular system

The most serious signs and symptoms associated with Marfan syndrome involve the

angina can indicate further investigation. The signs of regurgitation from prolapse of the mitral or aortic valves (which control the flow of blood through the heart) result from cystic medial degeneration of the valves, which is commonly associated with MFS (see mitral valve prolapse, aortic regurgitation). However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the ascending aorta causes an aortic aneurysm or aortic dissection, a surgical emergency. An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.[19]

Because underlying connective tissue abnormalities cause MFS, the incidence of dehiscence of prosthetic mitral valve is increased.[20] Care should be taken to attempt repair of damaged heart valves rather than replacement.[21]

Lungs

Individuals with Marfan Syndrome may be affected by various lung-related problems. One study found that only 37% of the patient sample studied (mean age 32±14 years; M 45%) had normal lung function.

idiopathic obstructive lung disease.[25] 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.[26]

Nervous system

MRI of the lower spine. Dural ectasia that has progressed to this stage would appear in an MRI as a dilated pouch wearing away at the lumbar vertebrae.[27] Other spinal issues associated with MFS include degenerative disc disease, spinal cysts, and dysfunction of the autonomic nervous system.[citation needed
]

Genetics

autosomal-dominant
pattern.

Each parent with the condition has a 50% risk of passing the

dominant negative mutation and haploinsufficiency.[29][30] It is associated with variable expressivity; complete penetrance has been definitively documented.[31]

Pathogenesis

myxomatous degeneration
of the aortic valve, a common manifestation of MFS

Marfan syndrome is caused by mutations in the FBN1

fibrillin 1, a glycoprotein component of the extracellular matrix. Fibrillin-1 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.[28] Elastic 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.

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 MFS. 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.[33]

receptor protein of TGF-β.[34] Marfan syndrome has often been confused with Loeys–Dietz syndrome, because of the considerable clinical overlap between the two pathologies.[35]

Marfanoid–progeroid–lipodystrophy syndrome

dominant negative effect.[39]

Diagnosis

Ultrasound of a person with Marfan syndrome, showing a dilated aortic root

Diagnostic criteria of MFS were agreed upon internationally in 1996.[40] However, Marfan syndrome is often difficult to diagnose in children, as they typically do not show symptoms until reaching pubescence.[41] A diagnosis 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 MFS, but may also occur in people without any known underlying disorder.

Revised Ghent nosology

Thumb sign; upper: normal, lower: Marfan syndrome

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:[57][58]

In the absence of a family history of MFS:

  1. Aortic root Z-score ≥ 2 AND ectopia lentis
  2. Aortic root Z-score ≥ 2 AND an FBN1 mutation
  3. Aortic root Z-score ≥ 2 AND a systemic score* > 7 points
  4. Ectopia lentis AND an FBN1 mutation with known aortic pathology

In the presence of a family history of MFS (as defined above):

  1. Ectopia lentis
  2. Systemic score* ≥ 7
  3. Aortic root Z-score ≥ 2
  • Points for systemic score:
    • Wrist AND thumb sign = 3 (wrist OR thumb sign = 1)
    • Pectus carinatum deformity = 2 (pectus excavatum or chest asymmetry = 1)
    • Hindfoot deformity = 2 (plain pes planus = 1)
    • Dural ectasia = 2
    • Protrusio acetabuli = 2
    • pneumothorax = 2
    • Reduced upper segment/lower segment ratio AND increased arm/height AND no severe scoliosis = 1
    • Scoliosis or thoracolumbar kyphosis = 1
    • Reduced elbow extension = 1
    • Facial features (3/5) = 1 (
      retrognathia
      )
    • Skin striae (stretch marks) = 1
    • Myopia > 3 diopters = 1
    • Mitral valve prolapse = 1

The thumb sign (Steinberg's sign) is elicited by asking the person to

flex the thumb as far as possible and then close the fingers over it. A positive thumb sign is where the entire distal phalanx 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.[citation needed
]

The wrist sign (Walker-Murdoch sign) is elicited by asking the person to curl 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.[59]

Differential diagnosis

Many other disorders can produce the same type of body characteristics as Marfan syndrome.[60] Genetic testing and evaluating other signs and symptoms can help to differentiate these. The following are some of the disorders that can manifest as "marfanoid":[citation needed]

Management

There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades[when?] and is now similar to that of the average person.[62]

Regular checkups are recommended to monitor the health of the heart valves and the

heart arrythmias, minimizing the heart rate, and lowering the person's blood pressure.[63]

Physical activity

The American Heart Association made the following recommendations for people with Marfan syndrome with no or mild aortic dilation:[64][65]

  • Probably permissible activities: bowling, golf, skating (but not ice hockey), snorkeling, brisk walking, treadmill, stationary biking, modest hiking, and tennis (doubles and singles).
  • Intermediate risk: basketball (both full- and half-court), racquetball, squash, running (sprinting and jogging), skiing (downhill and cross-country), soccer, touch (flag) football, baseball, softball, biking, lap swimming, motorcycling, and horseback riding.
  • High risk: bodybuilding, weightlifting (non-free and free weights), ice hockey, rock climbing, windsurfing, surfing, and scuba diving.

Medication

Management often includes the use of beta blockers such as propranolol or if not tolerated calcium channel blockers or ACE inhibitors.[4][5] Beta blockers are used to reduce the stress exerted on the aorta and to decrease aortic dilation.[17]

Surgery

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.[66] 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.[67] As people with Marfan syndrome live longer, other vascular repairs are becoming more common, e.g., repairs of descending thoracic aortic aneurysms and aneurysms of vessels other than the aorta.[citation needed]

The skeletal and ocular manifestations of Marfan syndrome can also be serious, although not life-threatening. These symptoms are usually treated in an appropriate manner for the condition, such as with pain medications or muscle relaxants. Because Marfan syndrome may cause asymptomatic spinal abnormalities, any spinal surgery contemplated on a person Marfan should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery. The ocular complications of MFS can often be treated with surgery. Ectopia lentis can be treated, as artificial lenses can be surgically implanted. In addition, surgery can address glaucoma and cataracts.[17]

Treatment of a spontaneous pneumothorax is dependent on the volume of air in the pleural space and the natural progression of the individual's condition. A small pneumothorax might resolve without active treatment in one to two weeks. Recurrent pneumothoraces might require chest surgery. Moderately sized pneumothoraces might need chest drain management for several days in a hospital. Large pneumothoraces are likely to be medical emergencies requiring emergency decompression.[68]

As an alternative approach, custom-built supports for the aortic root are also being used.[69] As of 2020 this procedure has been used in over 300 people with the first case occurring in 2004.[70][71]

Pregnancy

During pregnancy, even in the absence of preconception cardiovascular abnormality, women with Marfan syndrome are at significant risk of aortic dissection, which is often fatal even when rapidly treated. Women with Marfan syndrome, then, should receive a thorough assessment prior to conception, and echocardiography should be performed every six to 10 weeks during pregnancy, to assess the aortic root diameter. For most women, safe vaginal delivery is possible.[72]

Prenatal testing can be performed in females with Marfan syndrome to determine if the condition has been inherited in their child.[41] At 10 to 12 weeks of pregnancy, examining a piece of placental tissue through a test called chorionic villus sampling can be performed to make a diagnosis.[41] Another prenatal test can be performed called amniocentesis at 16 to 18 weeks of pregnancy.[41]

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. In 1996, the first

IVF
embryo cells and discarding those embryos affected by the Marfan mutation.

Prognosis

Prior to modern cardiovascular surgical techniques and medications such as losartan, and metoprolol, the prognosis of those with Marfan syndrome was not good: a range of untreatable cardiovascular issues was common. Lifespan was reduced by at least a third, and many died in their teens and twenties due to cardiovascular problems. Today, cardiovascular symptoms of Marfan syndrome are still the most significant issues in diagnosis and management of the disease, but adequate prophylactic monitoring and prophylactic therapy offers something approaching a normal lifespan, and more manifestations of the disease are being discovered as more patients live longer.[74] Women with Marfan syndrome live longer than men.[16]

Epidemiology

Marfan syndrome affects males and females equally,[75] and the mutation shows no ethnic or geographical bias.[9] Estimates indicate about 1 in 5,000 to 10,000 individuals have Marfan syndrome.[4]

History

Marfan syndrome is named after

Mount Sinai Medical Center in New York City in 1991.[77]

Famous patients

Notable people who have or had Marfan syndrome include:

Other historical figures and celebrities have appeared on lists of people with Marfan syndrome, but from case to case the evidence is speculative, questionable, or even refuted.[92]

See also

Bibliography

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