Marfan's syndrome

Marfan syndrome
ICD-10	Q87.4
ICD-9	759.82
OMIM	154700
DiseasesDB	7845
MedlinePlus	000418
eMedicine	ped/1372  orthoped/414
MeSH	C17.300.500

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Overview

Marfan syndrome (or Marfan's syndrome) is a connective tissue disorder most often caused by defects in the Fibrillin-1 gene (FBN1). Patients with Marfan's syndrome are at significant risk of skeletal, cardiovascular and ocular complications. People with Marfan's are typically tall, with long limbs and long thin fingers.

Background

In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome, pieds d’aragne (French, spider feet) and dolichostenomalie (French, longheadedness meaning long limbs). In 1902, Emile Charles Achard described a similar syndrome, reporting scoliosis and arachnodactyly (abnormally long and slender fingers) as essential features . Salle contributed the observation in 1912 that patients with arachnodactyly had thickened mitral leaflets, ocular abnormalities and increase in eosinophilic cells in the pituitary . The observation that ectopic lens was associated with other symptoms was first made by Boerger in 1914 . Weve established the autosomal dominant inheritance of the disease, still known as arachnodactyly, in 1931. Weve postulated that the syndrome arose from a defect in mesenchymal tissue and thus designated the syndrome dystrophia mesodermalis congenita typus Marfanis. Association of the syndrome with aortic dilation and dissection, the major causes of mortality in individuals with Marfan Syndrome were identified in 1943 by RW Baer et al. as well as Etter and Glover. Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that mutations in the FBN1 gene are responsible for the disease .

Pathophysiology

Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15, which encodes a glycoprotein called fibrillin-1. Fibrillin is essential for the formation of the elastic fibers found in connective tissue, as it provides the scaffolding for tropoelastin. 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. Without the structural support provided by fibrillin many connective tissues are weakened, which can have severe consequences for support and stability.

Marfan syndrome is inherited as a dominant trait. In so far as the pattern of inheritance is dominant, people who have inherit just one affected FBN1 gene from either parent will develop Marfan syndrome. This expression of the syndrome can range from mild to severe.

A related disease has been found in mice, and the study of mouse fibrillin synthesis and secretion, and connective tissue formation, has begun to further our understanding of Marfan syndrome in humans. It has been found that simply reducing the level of normal fibrillin-1 causes a Marfan-related disease in mice.

High levels of Transforming growth factor beta (TGFβ) are associated with inflammation and also play an important role in Marfan syndrome. Ordinarily, Fibrillin-1 binds TGFβ and inactivates it. In Marfan syndrome, reduced levels of fibrillin-1 allow activated TGFβ to damage the lungs and heart. Researchers now believe that the inflammatory effects of TGF-β, on the lungs, heart valves, and aorta weaken the connective tissues and cause the features of Marfan syndrome. In so far as angiotensin II receptor blockers (ARBs) reduce TGF-β, these agents have been administered to young Marfan syndrome patients, and the expansion of the aorta was indeed reduced.

A defect in the gene TGFβR2 on chromosome 3, a receptor protein of TGFβ, has also been related to Marfan syndrome. Marfan syndrome can often be confused with Loeys-Dietz syndrome, a similar connective tissue disorder resulting from mutations in the TGFβ receptor genes TGFβR1 and TGFβR2.

Differential Diagnosis

The following disorders have similar signs and symptoms of Marfan syndrome:

• Congenital Contractural Arachnodactyly (CCA) or Beals Syndrome
• Ehlers-Danlos syndrome
• Homocystinuria
• Loeys-Dietz syndrome
• MASS phenotype
• Stickler syndrome

Etymology

In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome1, pieds d’aragne (French, spider feet) and dolichostenomalie (French, longheadedness meaning long limbs). In 1902, Emile Charles Achard described a similar syndrome, reporting scoliosis and arachnodactyly (abnormally long and slender fingers) as essential features2. Salle contributed the observation in 1912 that patients with arachnodactyly had thickened mitral leaflets, ocular abnormalities and increase in eosinophilic cells in the pituitary3,4. The observation that ectopic lens was associated with other symptoms was first made by Boerger in 19145 . Weve established the autosomal dominant inheritance of the disease, still known as arachnodactyly, in 19316. Weve postulated that the syndrome arose from a defect in mesenchymal tissue and thus designated the syndrome dystrophia mesodermalis congenita typus Marfanis. Association of the syndrome with aortic dilation and dissection, the major causes of mortality in individuals with Marfan Syndrome were identified in 1943 by RW Baer et al. as well as Etter and Glover7,8. Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that dysregulation of TGF-beta signaling is responsible for the observed manifestations9.

Epidemiology

Marfan syndrome affects males and females equally, and the mutation shows no geographical bias. Estimates indicate that approximately 60 000 (1 in 5000, or 0.02% of the population) to 200 000 Americans have Marfan syndrome. Each parent with the condition has a 50% chance of passing it on to a child due to its autosomal dominant nature. Most individuals with Marfan syndrome have another affected family member, but approximately 15-30% of all cases are due to de novo genetic mutations — such spontaneous mutations occur in about 1 in 20 000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency. It is associated with variable expressivity. Incomplete penetrance, has not been definitively documented.

The prevalence of Marfan syndrome is 1 case per 3000 to 5000 individuals or .033 % (upper estimate) . Neither location nor ethnicity appear to impact this statistic. Populations of certain athletes such as basketball and volleyball players have been shown to have an increased incidence of Marfan syndrome (~0.5%) , perhaps due to skeletal abnormalities associated with the syndrome. While patients now have nearly normal life expectancies, in previous decades, patients’ life expectancies were significantly shortened by the risks of aortic dissection, valvular failure and congestive heart failure. Together, these cardiovascular complications accounted for 90% of the mortality associated with Marfan syndrome such that in the 1970s, an affected individual would be expected to live only two-thirds as long as his unaffected counterparts .

Related disorders

The following conditions that can result from having Marfan's syndrome and may also occur in people without any known underlying disorder. what leads doctors to a diagnosis of marfan syndrome is family history and a combination of major and minor indicators of the disorder that occur in one individual which is a rare manifestation in general population. Example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual.

• Aortic aneurysm or dilatation
• Arachnodactyly
• Bicuspid aortic valve
• Cysts
• Craniosynostosis
• Cystic medial necrosis
• Dural ectasia
• Ectopia lentis
• Flat feet
• Gigantism
• Glaucoma
• Hernias
• Hypermobility of the joints
• Malocclusion
• Mitral valve prolapse
• Myopia
• Obstructive lung disease
• Osteoarthritis
• Pectus carinatum or excavatum
• Pneumothorax
• Retinal detachment
• Scoliosis
• Sleep apnea
• Stretch marks

Symptoms

There are no signs or symptoms that are unique to Marfan syndrome. It is usually a single apparent sign or symptom that leads doctors to look for others and eventually to diagnose the syndrome, which affects connective tissue in diverse organs and systems. Even affected individuals in the same family might exhibit various combinations and severities of symptoms.

Skeletal system

The most readily visible signs are associated with the skeletal system. Many individuals with Marfan Syndrome grow to above average height. Some have long slender limbs with fingers and toes that are also abnormally long and slender (arachnodactyly). An individual's arms may be disproportionately long. In addition to affecting height and limb proportions, Marfan syndrome can produce other skeletal signs. Abnormal curvature of the spine (scoliosis) is common, as is abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum. Other signs include abnormal joint flexibility, a high palate, malocclusions, flat feet, stooped shoulders, and unexplained stretch marks on the skin. Some people with Marfans have speech disorders resulting from symptomatic high palates and small jaws.

Eyes

Lens dislocation in Marfan's syndrome, the lens was kidney-shaped and was resting against the ciliary body.

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's 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. Early onset glaucoma can be another related problem.

Cardiovascular system

The most serious conditions associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations, racing heartbeats, or pain in the left chest, back, shoulder, or arm, can bring an individual into the doctor's office. A heart murmur heard on a stethoscope, an abnormal reading on an electrocardiogram, or symptoms of angina can lead a doctor to order an echocardiogram. This can reveal signs of leakage or prolapse of the mitral or aortic valves that control the flow of blood through the heart. (See mitral valve prolapse.) 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 in the ascending aorta causes an aortic aneurysm or even aortic dissection.

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

During pregnancy, even in the absence of preconceived cardiovascular abnormality, women with Marfan syndrome are at significant risk of acute aortic dissection, which can be lethal if untreated. For this reason, women with Marfan syndrome should receive a thorough assessment prior to conception, and echocardiography should be performed every 6-10 weeks during pregnancy, to assess the aortic root diameter. Most women however tolerate pregnancy well and safe vaginal delivery is possible.

• A typical aortic root in Marfan's syndrome.

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Lungs

Marfan syndrome is a risk factor for spontaneous pneumothorax. 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, death. Marfan syndrome has also been associated with sleep apnea and idiopathic obstructive lung disease.

Central nervous system

Another condition that can reduce the quality of life for an individual, though not life-threatening, is dural ectasia, the weakening of the connective tissue of the dural sac, the membrane that encases the spinal cord.

Dural ectasia 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 should eventually lead a doctor to order an upright MRI of the lower spine.

Dural ectasia that has progressed to the point of causing these symptoms would appear in an upright MRI image as a dilated pouch that is wearing away at the lumbar vertebrae. Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts.

Diagnosis

Several standards of diagnostic criteria for Marfan syndrome have been proposed. In 1986, the Berlin nosology was established which represented a consensus on clinical features diagnostic of Marfan syndrome with an emphasis on skeletal features . Advances in molecular testing and the realization that many individuals diagnosed with Marfan syndrome according to the Berlin nosology did not have mutations in the FBN1 gene, led to the establishment of the Ghent nosology in1996, a new set of criteria with stricter diagnostic requirements . The Ghent nosology remains the current standard for diagnosis, although a revised version of the guidelines was published in 201015. The criteria are divided into major and minor manifestations which have allowed physicians to correctly diagnose 95% of patients as confirmed by molecular analysis of the FBN1 gene . The new criteria establish aortic root aneurysm and ectopia lentis as the principal clinical features of the disease and stress cardiovascular manifestations.

The major criteria for diagnosis of Marfan syndrome are ectopia lentis, aortic root dilation/dissection, dural ectasia, or a combination of more than 4 out of 8 major skeletal features (Table 1). In an individual with no known family history of Marfan syndrome and in the absence of any known FBN1 mutations, major involvement of two organs systems (e.g. skeletal, cardiovascular, ocular) and minor involvement of a third system is required for diagnosis. However, if the patient has a known FBN1 mutation or affected relative, major involvement of only one system and minor involvement of another is sufficient for diagnosis (Table 1). Major manifestations of the cardiovascular system include ascending aortic dilation involving the sinuses of valsalva or dissection of the ascending aorta. Ectopia Lentis is the sole major criterion for involvement of the ocular system, and dural ectasia in the lumbosacral region diagnosed by CT or MRI is the criterion for major involvement of the dura. Having a known FBN1 mutation or a relative who independently satisfies criteria for diagnosis satisfies major involvement of family/genetic history. Physical examination for Marfan syndrome requires extensive evaluation of the skeletal system. Patients must fulfill four of the eight following criteria for major involvement of the skeletal system: pectus carinatum, pectus ex cavatum requiring surgery, reduced upper to lower segment ratio, wrist and thumb signs (Figure 1). Minor criteria for the various systems including pulmonary and skin/integument can be found in the supplement.

Diagnostic Criteria

Skeletal System
Major Criterion.	Presence of at least 4of the following manifestations. • pectus carinatum • pectus ex cavatum requiring surgery • reduced upper to lower segment ratio or arm span to height ratio greater than 1.05 • wrist and thumb signs • scoliosis of > 20" or spondylolisthesis • reduced extension at the elbows (< 170") • medial displacementof the medial malleolus causing pes planus protmsio acetabulae of any degree (ascertained on radiographs)
Minor criteria.	• pectus excavatum of moderate severity • joint hypermobility • highly arched palate with crowding of teeth • facial appearance (dolichocephaly, malar hypo- plasia,enophthalmos,retrognathia,down-Slanting palpebral fissures)
Ocular System
Major criterion.	• Ectopia lentis
Minor criteria.	• abnormally flat cornea (as measured by keratometry) • increased axial length of globe (as measured by ultrasound) • hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis
Cardiovascular System
Major criteria.	• dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva; or • dissection of the ascending aorta
Minor criteria.	• Mitral valve prolapsed • Mitral valve prolapsed with or without mitral valve regurgitation; • dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age of 40 years; • calcification of the mitral annulus below the age of 40 years; or dilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years
Pulmonary System
Minor criteria.	• spontaneous pneumothorax [Hall et al., 19841] • apical blebs (ascertained by chest radiography)
Skin and Integument
Minor criteria.	• striaeatrophicae (stretchmarks) not associated with marked weight changes, pregnancy or repetitive stress • recurrent or incisional herniae
Dura
Major criterion.	• Lumbosacral dural ectasia by CT or MRI
Family/Genetic History
Major criteria.	• having a parent, child or sib who meets these diagnostic criteria independently; • presence of a mutation in FBNl known to cause the Marfan syndrome; • presence of a haplotype around FBNl, inherited by descent, known to be associated with unequivocal- ly diagnosed Marfan syndrome in the family

Adapted from De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417-26.

Molecular diagnostics, namely DNA sequencing can be extremely informative for the diagnosis of Marfan syndrome. A 2008 study showed that while only 79% of known probands could be diagnosed with Marfan syndrome using clinical criteria, 90% of these individuals could be diagnosed using the international criteria when sequencing data was added. In children, this figure leapt from 56% to 85% with sequencing data. The increased diagnostic sensitivity conferred by genetic information promises to be especially useful in children who have not developed clinical manifestations, but in whom new pharmacological interventions may be successful. Currently, laboratories offer complete sequencing of the 65 exon FBN1 gene for approximately $1700.00. The high costs of these diagnostics have delayed the widespread use of molecular diagnostics in the approach to patients suspected of Marfan syndrome. Increasingly less expensive sequencing technologies promise to increase reliance on individual genetic data for diagnosis in the future.

Image A: Skeletal exam of Marfan syndrome. Thumb sign, positive if the thumb protrudes from the clenched fist.	Image B: Skeletal exam of Marfan syndrome. Wrist Sign, positive if thumb and first phalange can overlap when encircling wrist.

Management

There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades, and clinical trials are underway for a promising new treatment. The syndrome is treated by addressing each issue as it arises, and, in particular, considering prophylactic medication, even for young children, to slow progression of aortic dilation.

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, also known as angiontensin receptor blockers (ARBs).

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 [CAVG] or valve-sparing procedure) becomes necessary.

Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis. 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 millimetres, but each case needs to be specifically evaluated by a qualified cardiologist. New valve-sparing surgical techniques are becoming more common. 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. This can also affect height, arm length, and life span. The Nuss procedure is now being offered to people with Marfan syndrome to correct 'sunken chest' or (pectus excavatum). Because Marfan may cause spinal abnormalities that are asymptomatic, any spinal surgery contemplated on a Marfan patient should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery.

Clinical trials have been conducted of the drug acetazolamide in the treatment of symptoms of dural ectasia. The treatment has demonstrated significant functional improvements in some sufferers. Other medical treatments, as well as physical therapy, are also available.

Treatment of a spontaneous pneumothorax is dependant 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 1 to 2 weeks. Recurrent pneumothoraxes might require chest surgery. Moderately sized pneumothoraxes might need chest drain management for several days in hospital. Large pneumothoraxes are likely to be medical emergencies requiring emergency decompression.

Research in laboratory mice has suggested that 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. A large clinical trial sponsored by the National Institutes of Health comparing the effects of losartan and atenolol on the aortas of Marfan patients is scheduled to begin in early 2007, coordinated by Johns Hopkins.

Genetic counseling and specialized clinics are available at many academic medical centers for affected persons and family members.

External links

• International Federation of Marfan Syndrome Organisations
• National Marfan Foundation (USA)
• Marfan diagnosis criteria
• National Institute for Health Marfan syndrome page (USA)
• Marfan Syndrome Center at medicinenet.com
• Marfan Syndrome Research - recent literature on Marfan Syndrome
• Marfan support
• Canadian Marfan Association
• Marfan Association UK
• Marfan de Mexico
• Norwegian Marfan Organization
• Marfan Life blog - mostly links to news articles about Marfan Syndrome
• MarfanSyndrome.Info - Findings in Marfan Syndrome and link collection
• Marfan-List - email discussion list for people and families with Marfan Syndrome
• South African Marfan Syndrome Organisation - support group for Africa
• Eye Findings in Marfan's syndrome

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