Marfan Syndrome (MFS)

Practice Essentials

Marfan syndrome (MFS) is a spectrum of disorders caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission.^{[1, 2, 3, 4]}  The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin.^{[1, 5, 6]}  Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate.^{[2, 7, 8]}

The most severe of these clinical problems include aortic root dilatation and dissection, which have historically been the causative factors in early patient demise.^[9]  Skeletal deformities such as thoracolumbar scoliosis, thoracic lordosis, and pectus excavatum, may lead to pulmonary difficulties that include restrictive airway disease and cor pulmonale if the deformities are progressive and untreated. Finally, blindness may result from unrecognized and untreated glaucoma, retinal detachment, and cataracts.

The skeleton of patients with MFS typically displays multiple deformities including arachnodactyly (ie, abnormally long and thin digits), dolichostenomelia (ie, long limbs relative to trunk length), pectus deformities (ie, pectus excavatum and pectus carinatum), and thoracolumbar scoliosis.^{[10, 11]}

In the cardiovascular system, aortic dilatation, aortic regurgitation, and aneurysms ^[12]  are the most worrisome clinical findings.^{[1, 3, 4]} Mitral valve prolapse that requires valve replacement can occur as well. Ocular findings include myopia, cataracts, retinal detachment, and superior dislocation of the lens.^[13]

Given the variable expressivity of MFS, no single sign is pathognomic; the diagnosis is made on clinical grounds on the basis of typical abnormalities. In one study, the physical examination features with the highest diagnostic yield were as follows^[14] :

• Craniofacial characteristics
• Thumb and wrist signs
• Pectus carinatum
• Severe hindfoot valgus

No specific laboratory test exists with which to make the diagnosis of MFS; however, molecular genetic testing can facilitate diagnosis of MFS in certain clinical situations. Skeletal abnormalities are assessed with radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Ocular abnormalities are assessed with ultrasonography (US), slit-lamp examination, and keratometry. Cardiovascular abnormalities are assessed with electrocardiography (ECG), echocardiography, MRI, and magnetic resonance angiography (MRA).

No specific surgical procedure cures MFS; rather, specific medical and surgical interventions may ameliorate certain aspects of the syndrome. 

The majority of medical therapy as it relates to MFS has been targeted at preventing cardiovascular compromise,^{[9, 15, 16]}  with beta blockers and afterload-reducing agents used to reduce stress on the aortic and mitral valves and the aortic root.^[17]  

Mitral valve regurgitation may become so severe that medical therapy must be replaced with surgical intervention. Mitral valve repair is undertaken if possible, to delay eventual mitral valve replacement. The ascending aorta (aortic root) or the incompetent aortic valve may also require repair.

Scoliosis is the most common major skeletal deformity encountered in patients with MFS that necessitates intervention, but no specific medicinal intervention exists to treat it. Nonoperative treatments (eg, bracing) are usually unsuccessful. The major indication for surgery for the musculoskeletal system involves progression of moderate-to-severe scoliosis. Posterior spinal fusion and segmental spinal instrumentation, along with autogenous bone grafting, are the mainstay of treatment. 

• References

Pathophysiology and Etiology

Over many years, several investigators have studied various molecules found in the extracellular matrix in attempts to elucidate the cause of MFS.^{[18, 16]} These molecules have included collagen, elastin, hyaluronic acid, and fibrillin. Sakai et al identified fibrillin, a 350-kd protein, by using monoclonal antibodies raised against myofibrils.^[19] Immunofluorescence studies were then used to compare the reactivity in both healthy subjects and those with MFS. During this period, similar technology was used to construct a genetic exclusion map that led to the localization of the defect to chromosome 15 (bands q15-q23).

Several point mutations have been identified in the fibrillin gene, most of which affect cysteine residues within the microfibril. Thus, these mutations are thought to cause defective fibrillin to be produced. Fibrillin's structure and function are altered by abnormal protein folding due to the alteration of bonding between cysteine residues, which in turn causes defective microfibril production.

Mutations in the FBN1 locus of the fibrillin gene on chromosome 15 have been linked to MFS and other distinct clinical entities with similar findings.

• References

Epidemiology

The estimated incidence of MFS ranges from 1 in 5000 to 2-3 in 10,000 persons.^[1] The mutation in the fibrillin gene causes pleiotropic effects; thus, a wide range of phenotypic features is derived from a single gene mutation. Several other diseases have presentations similar to MFS, making it exceedingly difficult to determine the exact incidence.

• References

Prognosis

Advances in the management of the cardiovascular manifestations of MFS have led to a significant decrease in the morbidity and mortality that are associated with this condition. Before the advent of pharmacologic and surgical therapy for aortic root and valvular disease, the life expectancy for patients with MFS was about two thirds that of the healthy population. Aortic dissection and congestive heart failure due to aortic and mitral valvular anomalies accounted for over 90% of the known causes of death.

Patient longevity now approaches that of persons without MFS, though cardiovascular compromise is still the most common cause of patient death, likely due to sudden death in the previously undiagnosed patient and a new diagnosis in those whose disease process has progressed beyond the scope of medical or surgical cure.

• References

Physical Examination

Given the variable expressivity of Marfan syndrome (MFS), no single sign is pathognomic. The diagnosis is made on clinical grounds on the basis of typical abnormalities (see the image below).

View Image

Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.

The cardiac, skeletal, and ocular systems are generally more focused upon for MFS diagnostic criteria; however, other tissues, including skeletal muscle, fat, skin, fascia, and the respiratory tract, may be affected in this condition as well.^{[18, 16]}  In a prospective study by Sponseller et al, the physical examination features with the highest diagnostic yield were as follows^[14] :

• Craniofacial characteristics
• Thumb and wrist signs
• Pectus carinatum
• Severe hindfoot valgus

• References

Clinical Diagnostic Criteria for Marfan Syndrome

The following list describes the most common clinical findings and the revised Berlin criteria (1986) for diagnosis of MFS. In 1996, the Ghent criteria updated the previous guidelines to include greater emphasis on the skeletal findings, as well as those of the family and genetic history. The Ghent criteria were subsequently updated in 2010 (see below),^{[20, 21, 22, 23]}  the main difference from the 1996 criteria being that more weight was given to aortic root aneurysm and ectopia lentis. (See Genetics of Marfan Syndrome.) 

Skeletal system

For the skeletal system involvement to be used as criteria for the diagnosis, at least two major criteria or one major criterion plus two minor criteria must be present.

Major skeletal system criteria are as follows:

• Pectus carinatum
• Pectus excavatum requiring surgery
• A reduced upper-to-lower segment ratio (ie, the distance from the head to the pubic symphysis divided by the distance of the pubic symphysis to the sole) of less than 0.85
• An increased arm span–to–height ratio that is greater than 1.05
• A positive wrist sign (ie, the thumb and index fingers overlap when encircling the contralateral wrist.)
• A positive thumb (Steinberg) sign (ie, the thumb extends beyond the ulnar border of the hand when the digit is held flexed in the palm.)
• A thoracolumbar scoliosis of more than 20º or spondylolisthesis
• Progressive collapse of the hindfoot, leading to pes planovalgus deformity
• A protrusio acetabuli of any degree (seen on anteroposterior [AP] radiographs of the pelvis)

Minor skeletal system criteria are as follows:

• Pectus excavatum of moderate severity
• Joint hypermobility
• High arched palate, with dental crowding
• Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

Ocular system

For ocular system involvement to be used as diagnostic criteria, the major criterion or at least two minor criteria must be present.^[13]

The ocular system major criterion is ectopia lentis (lens dislocation).^[24]

Minor ocular system criteria are as follows:

• An abnormally flat cornea
• An increased axial length of the globe, as measured by ultrasonography (US)
• A hypoplastic iris or hypoplastic ciliary muscle, causing myopia

Cardiovascular system

For cardiovascular system involvement to be considered diagnostic criteria, only one of the major or minor criteria must be present.^{[25, 26]}

Major cardiovascular system criteria are as follows:

• Dilatation of the ascending aorta, with or without regurgitation, and involving at least the sinuses of Valsalva
• Dissection of the ascending aorta

Minor cardiovascular system criteria are as follows:

• Mitral valve prolapse, with or without regurgitation
• Dilatation of main pulmonary artery in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause in patients younger than 40 years
• Calcification of the mitral valve anulus in patients younger than 40 years
• Dilatation or dissection of the descending thoracic or abdominal aorta in patients younger than 50 years

Pulmonary system

For pulmonary system involvement to be considered diagnostic criteria, one of the minor criteria must be present.^[25]

No major pulmonary system criteria exist.

Minor pulmonary system criteria are as follows:

• Spontaneous pneumothorax
• Apical blebs

Skin and integument

For skin and integument involvement to be considered diagnostic criteria, the major criteria or one of the minor criteria must be present.

The major skin and integument criterion is lumbosacral dural ectasia, as depicted by computed tomography (CT) or magnetic resonance imaging (MRI).

The minor skin and integument criteria are as follows:

• Striae atrophicae that are not associated with pregnancy or repetitive stress
• Recurrent or incisional hernia

Family history

For the family history to be considered contributory to a diagnosis of MFS, one of the major criteria must be present.

The major family history criterion is a parent, child, or sibling who meets the following diagnostic criteria independently:

• Presence of a mutation in FBN1 known to cause MFS
• Presence of a haplotype around FBN1, inherited by descent that is known to be associated with unequivocally diagnosed MFS in the family

No minor family history criteria exist.

Requirements for a diagnosis of MFS

Requirements for a diagnosis of MFS include the following:

• Index case – Major criteria in at least two different organ systems and involvement in a third organ system
• Family member – Presence of a major criterion in the family history, one major criterion in an organ system, and involvement of a second organ system

Revised (2010) Ghent criteria

In the 2010 revised Ghent nosology for MFS,^{[20, 23]} diagnosis of the syndrome is based on seven rules.^[22] In the absence of a family history, the following four criteria lead to the diagnosis of MFS:

• Aortic root dilatation Z score of 2 or greater and ectopia lentis
• Aortic root dilatation Z score of 2 or greater and identified FBN1 mutation
• Aortic root dilatation Z score of 2 or greater and systemic score of 7 or greater
• Ectopia lentis and FBN1 mutation with known aortic root dilatation

In the presence of a family history, the following three criteria lead to the diagnosis of MFS:

• Ectopia lentis and family history of MFS (as defined by rules 1-4)
• Systemic score of 7 or greater and family history of MFS (as defined by rules 1-4)
• Aortic root dilatation score of 2 or greater (in those aged ≥20 years) or 3 or greater (in those aged < 20 years) and family history of MFS (as defined by rules 1-4)

• References

Laboratory Studies

No specific laboratory test exists with which to make the diagnosis of Marfan syndrome (MFS).

Molecular genetic testing can be performed to assist in making the diagnosis of MFS in the following two clinical situations:

• First, if the specific FBN1 mutation is known in an individual diagnosed with MFS, this information can be applied to help diagnose family members
• Second, linkage analysis can be performed in families with several individuals who are affected with MFS to assess involvement in the remaining undiagnosed relatives

It is known that the FBN1 locus is associated with MFS; however, it is possible that other genes may cause a marfanoid habitus with phenotypic manifestations similar to those seen in MFS.^[27]  The role of molecular genetics testing in the sporadic case is minor. In general, the diagnosis is made on a clinical basis using the previously described Ghent criteria (see Presentation).

• References

Imaging Studies

Skeletal system

Standard radiography

Hand radiographs may be taken to demonstrate the typical finding of arachnodactyly. Specifically, the metacarpal index can be calculated by measuring the ratio of the average length and width of the second through fourth metacarpals. A ratio of more than 8.8 in males and 9.9 in females is indicative of arachnodactyly. Camptodactyly can be associated with MFS; this abnormal flexion at the interphalangeal (IP) joint should be noted clinically and on standard radiographs.

Spine radiographs may demonstrate a variety of abnormalities. Many patients are affected by scoliosis. Posteroanterior (PA) and lateral radiographs of the spine demonstrate the severity of the scoliotic curve and any thoracic lordotic or thoracolumbar kyphotic deformity. Thoracic lordosis, if present, should be addressed, as it can restrict pulmonary function. Thoracic lordosis is also a contraindication to the use of bracing on a scoliosis that is present at a lower level. Vertebral height is typically greater than normal. Spondylolisthesis is more prevalent in MFS and usually occurs at L5-S1.

Anteroposterior (AP) radiographs of the pelvis may demonstrate protrusio acetabuli, which occurs frequently in MFS. This condition may be present and progressive during childhood until it becomes symptomatic after the patient reaches maturity. Developmental dislocation of the hip may also occur; this is likely due to the patient's overall ligamentous laxity. The dislocated or subluxed hip is easily visualized on the AP and frogleg lateral views in the pediatric patient.

Chest radiographs (PA and lateral) may demonstrate pectus excavatum or carinatum, which may be found in patients with MFS. The anterior chest deformity is most easily detected when the chest is tilted in the axial plane.

Foot radiographs (AP and lateral weightbearing views) may demonstrate pes planovalgus secondary to the ligamentous laxity that is found in patients with MFS.

Skull radiographs (AP and lateral) may demonstrate a high arched palate, increased skull height, and an enlarged frontal sinus.

Computed tomography

Axial computed tomography (CT) images of the hips can be taken in order to detect subtle protrusio acetabuli.

Magnetic resonance imaging

Axial magnetic resonance imaging (MRI) of the hip can also be taken to detect subtle protrusio acetabuli. Dural ectasia, which involves enlargement of the thecal sac that contains cerebrospinal fluid (especially common in the sacral region), can be identified on MRI.

Ocular system

Ultrasonography (US) of the globe may demonstrate megalocornea that occasionally occurs with MFS. The axial length of the cornea is increased (normal length in adults, < 1 cm).

Cardiovascular system

Once electrocardiography (ECG) shows abnormal findings in the patient with MFS, transesophageal echocardiography (TEE) or MRI is usually the next modality that is used to elucidate any clinically significant structural abnormalities.

To identify aortic root enlargement, either a cross-sectional echocardiogram in the parasternal long-axis view or a standard MRI should be performed. This enlargement typically occurs near the sinuses of Valsalva, although the ascending aorta and more distal aspect of the aorta may be involved (associated with a worse overall prognosis).

Once an echocardiogram or MRI is obtained, the patient's results can be compared with their body size with the use of nomograms that are appropriate for the patient's age. The following equation describes how the aortic root dimensions are obtained for comparison with normal levels:

• Aortic root dimension = 24(BSA)1/3 + 0.1(age) – 4.3

where BSA stands for body surface area.

Because the aortic root diameter typically does not change, the expected aortic root diameter (determined with the above equation) is then compared to the patient's actual aortic root dimensions as seen on either echocardiography or MRI. The normal ratio should approximate 1.0. If the ratio is greater than 1.18, the patient is likely undergoing aortic root enlargement with an increased likelihood of aortic valvular abnormalities and dissection.

In patients with MFS, the risk of developing aortic regurgitation is directly related to the overall size of the aortic root. In patients with roots that are less than 40 mm in diameter, the risk of developing aortic regurgitation is remote; however, in patients with roots greater than 60 mm, the aortic regurgitation is almost always present.

Mitral valve prolapse may also be detected via echocardiographic analysis. One study demonstrated a unique anatomic abnormality that was thought to be specific for MFS. These authors found that all visible chordae tendineae arose from the posterior left ventricular wall rather than from one of the major papillary muscles.

Because vascular dilation beyond the aortic root can be found in MFS, thoracoabdominal magnetic resonance angiography (MRA) may be useful by providing a complete assessment of the arterial system.^[28]

• References

Other Tests

Ocular system

A slit-lamp examination is performed with full pupillary dilatation in order to characterize lens abnormalities. The most worrisome finding is that of retinal detachment, which may herald the onset of blindness. Lens dislocation can be diagnosed and usually occurs in a superolateral direction, though other directions are possible. Iridodonesis (fluttering of the iris) is also a common finding with ectopia lentis. Open-angle glaucoma, severe myopia, and cataracts are more common in patients with MFS and can be diagnosed via slit-lamp examination as well.

Keratometry is a study of the radius of curvature of the cornea. In general, patients with MFS have flatter corneas, and increasing flatness is associated with ectopia lentis.

Cardiovascular system

ECG is useful because valvular abnormalities are common in MFS; atrial and ventricular electrical conduction abnormalities, as well as cardiomyopathy, may be present in some patients. ECG represents the best initial screening test for cardiac dysfunction in MFS because more than 80% of the patients have cardiac dysfunction over the course of their lives. Common findings on ECG include T-wave inversions (mitral valve prolapse) and the development of anterior electrical forces across the precordial leads (pectus excavatum or cardiomegaly with leftward heart shift).

• References

Approach Considerations

No specific surgical procedure exists to cure Marfan syndrome (MFS); however, specific medical and surgical interventions may ameliorate certain aspects of the syndrome. System-specific treatment options are discussed below. Any evidence of aortic dilatation must be treated medically or surgically, before any spinal reconstruction is attempted for scoliosis. Any evidence of imminent cardiac compromise would preclude surgical intervention until that issue is addressed.

Many new areas of investigation into MFS exist. With regard to the skeletal system, investigators are seeking to discover new modalities by which to delay or reduce the progression of scoliosis and assess the effect of hypermobility on joint degeneration and deformity. Cardiovascular research has focused on trying to identify patients at risk for compromise as early as possible and to determine if medications other than beta blockers are useful in terms of their cardioprotective effects.

Some preliminary data based on murine studies indicated that an angiotensin II receptor antagonist (eg, losartan) or transforming growth factor (TGF)-β neutralizing antibodies may have the potential to reverse some of the primary clinical manifestations in MFS, such as aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction.^[7]

Researchers are also focusing on the effects of laser surgery on the cornea and lens, as well as the correction of cataracts and the preservation of sight.

• References

Medical Therapy

The majority of medical therapy as it relates to MFS has been targeted at preventing cardiovascular compromise, which is the most likely cause of demise in this patient population.^{[9, 15, 16]} Beta blockers and afterload-reducing agents are used to reduce stress on the aortic and mitral valves and the aortic root.^[17]

Given that patients with MFS often have abnormal or prosthetic valves, all patients must receive routine antibiotic prophylaxis before undergoing procedures that could produce bacteremia. Researchers have demonstrated that the entire aorta, and especially the root, is stiffer than normal in patients with MFS.

Beta blockers have been used in attempts to decrease the onset and rate of aortic root dilatation and dissection. Studies have demonstrated a synergistic effect with regard to the reduction of aortic stiffness, decreased vascular resistance, and improved cardiac compliance when nitroprusside and beta blockers are used concomitantly.

Beta blockade is used because it is believed to reduce both inotropy and chronotropy and thereby reduce the stress on the aortic root. Nitroprusside reduces overall systemic vascular resistance, which serves to reduce overall afterload and stress on the heart. Whether these effects translate into decreased morbidity and mortality at this time is unclear, no long-term studies have been performed yet. Calcium-channel blockers (eg, verapamil) are being investigated to assess their effects on cardiovascular physiology in patients with MFS.

Scoliosis is the most common major skeletal deformity encountered in patients with MFS that necessitates intervention. No specific medicinal intervention exists to treat scoliosis. Nonoperative means of treatment (eg, bracing) may be attempted but are usually unsuccessful. Scoliosis occurs in approximately 50-70% of patients with MFS and differs from idiopathic adolescent scoliosis with regard to curve pattern, progression, and symptoms.^[29] The double major right thoracic–left lumbar curve is the most common type among patients with MFS, whereas a single pattern is usually seen in the idiopathic type. Pelvic obliquity is uncommon in both types, however.

Unfortunately, these patients often have an earlier onset of scoliosis with severely rigid, painful, and deforming curves, as well as a high incidence of curve progression. The curve progression may average 7-10° per year after the onset of scoliosis, and the curve often progresses rapidly in the early adolescent period during maximal vertebral growth. This is also in contrast to the idiopathic type, which is typically not painful and is not as progressively deforming as the scoliosis in patients with MFS. Scoliosis, in combination with poor musculature and chest deformities, can cause significant respiratory compromise, which mandates early detection and prevention, if possible, in this patient population.

Nonoperative intervention for the scoliosis typically involves observation followed by the use of a thoracolumbosacral orthosis (TLSO) if the curve is mild and reveals signs of progression. Bracing is controversial; many surgeons believe that the bulk of curves in patients with MFS progress regardless of bracing and thus require operative intervention to prevent worsening deformity.

For patients with curves less than 25°, observation and serial radiographs every 3-4 months is the recommended management. When the curve is in the range of 25-40°, Milwaukee bracing or an underarm TLSO is used. This may be a bridge to future surgical intervention. Bracing is only used in patients with mild curves (ie, 25-40°) and no sagittal plane deformity (ie, thoracic lordosis or lumbar kyphosis). Bracing is not indicated for curves that are rigid, large, or have associated sagittal deformities.

• References

Surgical Therapy

Mitral valve regurgitation may become so severe that medical therapy must be replaced with surgical intervention. The mitral valve is often found to have a dilated anulus, redundant and flaccid cusps, and ruptured chordae tendineae. Mitral valve repair is undertaken if possible, to delay the eventual mitral valve replacement; this is done because these patients often present at a young age and may require further reconstructive surgery later. Surgical repair also preserves papillary muscle function and obviates chronic anticoagulation, unlike artificial valve replacement.

The ascending aorta (aortic root) or the incompetent aortic valve may also require repair. Either a composite graft or a valve-sparing technique is performed.^[30] The valve-sparing technique is usually performed in patients whose aorta has dilated to approximately 50 mm. Patients with widely dilated aortic roots or significantly attenuated aortic cusps typically undergo a composite graft repair. This is also the procedure of choice in the case of an acute aortic root dissection. Some surgeons advocate prophylactic composite grafting in patients who have a history of increasing aortic dilatation and a family history of sudden cardiovascular death.

The most important aspect in the preoperative evaluation of patients with MFS is to rule out any imminent cardiac compromise. A complete cardiac workup, including electrocardiography (ECG) followed by echocardiography, is mandatory. It is well known that aortic dilatation and subsequent rupture can develop throughout these patients' childhood and adult life; thus, one must be diligent to exclude these entities before any surgical undertaking. Any evidence of aortic dilatation must be treated medically or surgically before any spinal reconstruction is attempted.

The major indication for surgery for the musculoskeletal system involves progression of moderate-to-severe scoliosis. Chest-wall deformities may also be so severe that they impact cardiopulmonary mechanics; these can be surgically corrected as well. In the past, patients with MFS did not have these chest-wall deformities addressed, and most died at an early age due to intrinsic cardiovascular disease. The advent of successful aortic root surgery as well as aortic and mitral valve replacement has changed the overall long-term outlook for patients with the disease.

Adequate treatment should be provided for those with scoliosis to reduce pain, to improve overall cosmetic appearance, and, most important, to improve pulmonary mechanics through reduction of spinal and chest-wall deformities.

It must be kept in mind that surgery for MFS differs from surgery for adolescent idiopathic scoliosis. These differences must be taken into account in surgical planning.^[29]

As previously described, bracing can be considered in patients with mild curves (see Medical Therapy). However, most patients with MFS will have significant curve progression that eventually warrants surgical intervention. Patients with curves greater than 40-50º or with associated abnormal sagittal curvature deformities require surgery.

Posterior spinal fusion and segmental spinal instrumentation, along with autogenous bone grafting, are the mainstays of treatment. Most authors agree that scoliosis can be corrected with this approach; however, the overall incidence of complications varies in different series. Pseudoarthrosis and loss of correction can occur and are problematic; the incidence figures range from 12% to 40%.

Most authors recommend aggressive bone grafting, rigid internal fixation, and adequate patient surveillance postoperatively to diagnose complications early in the clinical course. Sagittal malalignment (kyphotic deformity) may require an anterior fusion (excision of disks) followed by posterior spinal fusion and segmental spinal instrumentation to achieve satisfactory correction of the sagittal alignment.

Complications of scoliosis surgery for MFS have been well reviewed by Levy et al.^[31]  

• References