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Review Article

Marfan Syndrome

Shirley, LCDR Eric D. MD, MC, USN; Sponseller, Paul D. MD

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Journal of the American Academy of Orthopaedic Surgeons: September 2009 - Volume 17 - Issue 9 - p 572-581
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Abstract

The skeletal features of Marfan syndrome, including tall stature and slender digits, were first described in a 5-year-old girl by the French pediatrician Antoine Marfan in 1896.1 However, in retrospect, it seems more likely that the patient had congenital contractural arachnodactyly. Later, Marfan associated these features with ectopia lentis (ie, dislocation of the ocular lens) and mitral valve disease. In 1955, McKusick2 described aortic dissection and regurgitation in patients with Marfan syndrome and determined that the syndrome was a heritable disorder of connective tissue, affecting the cardiovascular, ocular, and musculoskeletal systems. The genetic cause was determined in 1991, when Dietz et al3 reported that a mutation of fibrillin-1 results in classic Marfan syndrome.

Epidemiology and Cause

Marfan syndrome occurs in 1 to 2 per 10,000 persons and affects males and females equally.4 Clinical manifestations tend to become more apparent with increasing age. In data reported before 1972, the life expectancy of patients with this syndrome was lower than that for the general population, but prophylactic treatment of aortic valve and root disease has resulted in a nearly normal life expectancy.5 Inheritance is autosomal dominant, although 25% of Marfan syndrome cases are the result of new mutations. Most cases result from mutations in genes encoding for fibrillin-1.3,6,7

Fibrillin-1 is an extracellular matrix glycoprotein essential to fibrinogenesis. It is the main component of the elastic matrix microfibrils that are found in tissues with manifestations of the syndrome, including bone and the aortic media. The fibrillin-1 gene, FBN1, is located on chromosome 15.6FBN1 mutations are present in >90% of patients with Marfan syndrome.8FBN1 mutations have been shown to increase the susceptibility of fibrillin-1 to proteolysis in vitro, leading to fragmentation of microfibrils.6 In addition, fibrillin mutations may cause changes in cell-to-cell signaling through latent binding transfer protein. Other manifestations are caused by other effects of the fibrillin mutations. The dominant inheritance results from the negative effect of the mutated protein on the function of the normal protein encoded by the normal FBN1 gene, which is termed a dominant negative effect. Other mutations of FBN1 may result in conditions such as mitral valve prolapse syndrome, familial ectopia lentis, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome, and the mitral, aortic, skin, and skeletal (MASS) manifestations phenotype.

Transforming growth factor (TGF)-β is a cytokine that plays a role in the regulation of cell proliferation, differentiation, extracellular matrix formation, cell-cycle arrest, and apoptosis.7 In addition to forming microfibrils, fibrillin also helps stabilize latent TGF-β-binding proteins that hold TGF-β in an inactive state. Thus, abnormalities of fibrillin can result in excess signaling by TGF-β. Initially, it was thought that the pathophysiology of Marfan syndrome was the result of abnormalities of microfibril structure. However, it now appears that dysfunctional TGF-β signaling caused by fibrillin mutations may play a more prominent role in the pathophysiology of Marfan syndrome.9 In addition, increased TGF-β activation and signaling secondary to mutations in the TGFBR1 gene on chromosome 9 and the TGFBR2 gene on chromosome 3 have been identified in groups of patients with Marfan syndrome or Marfan-related disorders.7,10

Diagnosis

Suspicion for Marfan syndrome is raised by the presence of its cardinal manifestations, including tall stature, thin habitus, long slender limbs (ie, dolichostenomelia), arachnodactyly, pectus deformity, and scoliosis. Other musculoskeletal findings include flat feet, ligamentous laxity, and camptodactyly. Associated findings, such as high arched palate, skin striae, and history of recurrent hernia or pneumothorax, increase suspicion for this diagnosis. Arachnodactyly can be evaluated with testing for wrist and thumb signs (Figure 1). The wrist sign is positive when the thumb overlaps the distal phalanx of the small finger while grasping the contralateral wrist. The thumb sign is positive when the entire nail of the thumb projects beyond the ulnar border of the hand when the thumb is clenched without assistance.

Figue 1
Figue 1:
Clinical photograph demonstrating positive wrist sign for Marfan syndrome. The thumb overlaps the distal phalanx of the small finger when grasping the contralateral wrist.

Diagnosis is critical to initiating appropriate prophylactic medical and surgical treatment and preventing lethal aortic dissection. Diagnosis is guided by the Ghent nosology11 (Table 1). The Ghent nosology was developed as an improvement on the Berlin diagnostic criteria of 1986,12 which did not clearly distinguish individuals with Marfan syndrome from those with mild connective tissue phenotypes or those with variants of normal anatomy. Included in the Ghent nosology are more stringent requirements for diagnosis in relatives of an affected individual, skeletal involvement as a major criterion when at least four of eight manifestations are present, potential contribution of molecular analysis, and delineation of initial criteria for diagnosis of other heritable conditions with partially overlapping phenotypes.11

Table 1
Table 1:
The Ghent Nosology for the Diagnosis of Marfan Syndrome

Because of the age dependence of many Marfan features, the Ghent nosology does not exclude Marfan syndrome in children.9 Patients aged <18 years should be reevaluated when they have many manifestations but not enough to confirm the diagnosis by the nosology.

Under the Ghent nosology, clinical features of seven systems are assessed to determine whether major criteria and system involvement are present. Certain criteria are deemed major because they are infrequent in other conditions and have high specificity. In an index case in which family/genetic history is not contributory, diagnosis requires the presence of major criteria in at least two different organ systems and involvement of a third organ system.11 When the index case has a mutation known to cause Marfan syndrome in others, diagnosis requires one major criterion in an organ system and involvement of a second organ system.11 In a relative of an index patient, diagnosis requires meeting a major criterion in the family history and one major criterion in an organ system, and involvement of a second organ system.11

In addition to a complete history and physical examination, other diagnostic tests can detect major and minor criteria conditions. For example, a pelvis radiograph can identify protrusio acetabuli, and an MRI scan of the lumbar spine may show dural ectasia. Consultations with ophthalmology and cardiology specialists can identify other manifestations, and an echocardiogram is required for cardiovascular assessment. The Ghent criteria are best applied by a geneticist. However, the orthopaedic surgeon must be able to recognize the collection of skeletal findings and make the appropriate referral.

Family history is not always positive; approximately 25% of cases are the result of new mutations.13,14 Genetic testing for fibrillin-1 mutations can be used when a positive result would make the diagnosis. However, genetic testing is difficult because >90% of fibrillin-1 mutations are unique to an individual or family, and >135 mutations in the fibrillin gene have been identified.8 In addition, fibrillin-1 mutations may also cause other, Marfan-like disorders. Finally, 9% to 34% of affected patients have no identifiable fibrillin-1 mutations.8 Currently, molecular diagnosis lacks sensitivity and specificity and is neither efficient nor helpful in all cases.8,10 The inability to detect a mutation in FBN1 or molecular abnormality in fibrillin-1 does not exclude the diagnosis. Mutation analysis is best used to determine whether a presymptomatic individual has inherited a defined phenotype seen in the family.

The differential diagnosis of the patient with Marfan-like skeletal features includes the MASS phenotype as well as Loeys-Dietz syndrome, homocystinuria, Beals syndrome, Marshall-Stickler syndrome, and Ehlers-Danlos syndrome.9 The MASS phenotype is characterized by long limbs, thoracic cage deformity, striae atrophicae, mitral valve prolapse, and nonprogressive dilatation of the aortic root. However, in persons with the MASS phenotype, other findings of Marfan syndrome are not present, and the diagnostic criteria for Marfan syndrome are not met.15 Diagnosis may be difficult, especially in children, and follow-up is needed to distinguish this entity from Marfan syndrome.

Loeys-Dietz syndrome is similar to Marfan syndrome in its association with scoliosis, pectus deformity, and aortic root aneurysms.16 However, unlike Marfan syndrome, Loeys-Dietz syndrome is also associated with hypertelorism, cleft palate, clubfoot, Chiari I malformation, and easy bruising. The aortic aneurysms in patients with Loeys-Dietz syndrome dissect at young ages and small sizes; thus, surgery in such patients is indicated for smaller lesions than in patients with Marfan syndrome.16 Loeys-Dietz syndrome is caused by mutations in TGF receptors 1 and 2, which result in increased TGF-β signaling.

Homocystinuria is associated with mitral valve prolapse as well as skeletal and ocular features similar to those of Marfan syndrome. There is also a predisposition to thromboembolism and coronary artery disease. Inheritance is autosomal recessive. Diagnosis is facilitated by an elevated urinary homocysteine excretion, which can be identified by measuring total plasma homocysteine.

Finally, there are severe forms of Marfan syndrome (eg, neonatal Marfan syndrome) that usually are the result of de novo mutations. Features include pulmonary emphysema, ectopia lentis, arachnodactyly, joint contractures, and loose skin. Mitral and/or tricuspid valve prolapse with regurgitation can lead to congestive heart failure.

Manifestations

Cardiovascular

The aorta in an individual with Marfan syndrome may undergo cystic medial degeneration, which is characterized by fragmented elastic fibers, a decrease in smooth muscle cells, and the deposition of collagen and mucopolysaccharides between cells of the media.9 Elastic fiber fragmentation results in decreased aortic compliance. These abnormalities can produce aortic root dilatation and, subsequently, aortic dissection—the most severe, and potentially fatal, cardiovascular complication of Marfan syndrome. Risk factors for aortic dissection include diameter of the sinus of Valsalva >5 cm, extensive aortic dilatation, dilatation rate of >1.5 mm per year, and a positive family history.17 Aortic valve insufficiency may also occur.

Serial echocardiograms performed yearly or more frequently are necessary for detecting increasing dilatation. β-blocker medications are considered for all patients, including children, to lessen the ejection impulse. In a randomized prospective trial, Shores et al18 showed that β-blockers were effective in reducing the risk of aortic dissection and improving survival. However, additional data in support of the use of such medications are limited, and randomized trials are needed to validate their usefulness further. When a patient cannot tolerate β-blockers because of side effects, angiotensinconverting enzyme-inhibitor medications may be prescribed.

Surgical repair of aortic root aneurysms has improved the life expectancy in persons with Marfan syndrome from two thirds of normal to nearly normal.5,13 Prophylactic aortic root surgery is considered when the aortic diameter at the sinus of Valsalva is >5 cm.11,17 Earlier surgery may be recommended when the root is rapidly enlarging or with family history of dissection. The outcomes of prophylactic aortic root surgery are superior to those of emergent surgery.19 The preservation of the aortic valve during aortic root surgery is controversial and is under evaluation.

Other cardiovascular manifestations include mitral valve prolapse, left ventricular dilatation, and pulmonary artery dilatation. For the patient with myxomatous or prosthetic valves, or who has had valve-sparing aortic root surgery, antibiotic prophylaxis for bacterial endocarditis is recommended before dental, gastrointestinal, and genitourinary procedures.

Ocular

Ocular manifestations include ectopia lentis, myopia, glaucoma, cataracts, and retinal detachment. Ectopia lentis is present in approximately 60% of affected persons.20,21 This condition occurs in utero and thus can be diagnosed at the first ophthalmologic examination. Annual ophthalmologic follow-up is required to recognize the development of other manifestations.

Musculoskeletal

Overgrowth

Disproportionate growth of the long bones is often the most obvious manifestation of Marfan syndrome. Overgrowth can be quantified by an arm span length >1.05 times height or a reduced upper-to-lower segment ratio. Arachnodactyly in combination with loose joints results in the wrist and thumb signs described previously.

Scoliosis

Scoliosis is present in 60% of patients with Marfan syndrome22 (Figure 2). The curves resemble those of idiopathic scoliosis, but there is a higher prevalence of double thoracic and triple major curves.23 The sagittal profile varies widely. Alignments include hypokyphosis, hyperkyphosis, and thoracolumbar kyphosis with thoracic lordosis; 40% of patients have kyphosis >50°.24 In a review of spinal deformity in patients with Marfan syndrome, Sponseller et al24 found that progression of scoliosis occurred past skeletal maturity in patients with curves >40° and could result in deformity, respiratory deficits, and back pain. In addition, the authors found that curve progression may be faster in such patients than in patients with idiopathic scoliosis because curves >50° progress at a mean rate of 3° ± 4° per year in adulthood.24

Figue 2
Figue 2:
Clinical photograph of a patient with scoliosis associated with Marfan syndrome.

Characteristic vertebral anomalies are also found in these patients. Osseous abnormalities include narrow pedicles, wide transverse processes, and vertebral scalloping.24 Other abnormalities include thin laminae, increased transitional vertebrae, and sacral scalloping. Vertebral bone mineral density may be less than that in the normal population.

Most curves are of small magnitude and do not require treatment. Treatment of larger curves can be challenging. Nonsurgical treatment of scoliosis in patients with Marfan syndrome is less successful than in those with idiopathic scoliosis. Sponseller et al23 evaluated bracing in patients with Marfan syndrome, curve ≤45°, Risser sign of grade 0 to 2 at the beginning of bracing, and recommended brace wear ≥18 hours per day. Success was defined as curve progression ≤5° and a final curve ≤45°. Treatment was successful in 4 of 22 patients who completed brace wear.23 Bracing is currently indicated for growing children with Marfan syndrome and curves of 15° to 25° and is an option for curves between 25° and 45°, although the low likelihood of success in either situation must be discussed before initiation.

Surgery is considered for patients with curves >45°. In young patients, growing rod instrumentation may be necessary. Iliac fixation may be helpful in some cases25 (Figure 3). In the skeletally mature patient or the patient closer to maturity, definitive fusion may be done.

Figure 3
Figure 3:
PA radiographs of a 6-year-old patient with scoliosis and Marfan syndrome before (A) and after (B) treatment with growing rod instrumentation and iliac anchors.

In a retrospective review of patients with Marfan syndrome receiving surgical correction for spinal deformity, Jones et al26 found that the number of surgical complications associated with spinal fusion was higher in patients with Marfan syndrome than in the normal population. The complications of the 39 patients who underwent surgical treatment of kyphosis or scoliosis included increased blood loss, dural tear (8%), infection (10%), and pseudarthrosis (10%), mostly because of fixation failure (21%). Average blood loss was 2,150 mL after primary posterior arthrodesis and 5,300 mL after revision arthrodesis.

Failure of fixation is a common complication in patients with Marfan syndrome because of the thin laminae, thin pedicles, and osteopenia. Because of these properties, Jones et al26 suggested that the number of fixation points should be maximized. Pedicle screws are preferred, and appropriate pedicles can be identified with preoperative CT scan.27 Sublaminar wires should be tightened slowly, and rod compression and distraction should be done gradually.26 Upper and lower end anchor stability should be achieved to the surgeon's satisfaction, and, if needed, the arthrodesis should be extended for stability.

“Adding on” of curvature—that is, the development of scoliosis or kyphosis at upper or lower fusion levels—may also occur after surgery. Jones et al26 found this complication in the coronal plane in 8% and in the sagittal plane in 21% of patients. The selection of the arthrodesis levels is critical; care must be taken to include all major and structural curves and avoid fusing too short a segment25 (Figure 4). To decrease the risk of adding on, Jones et al26 suggested that any curve >30° should be included in the arthrodesis. Selective thoracic arthrodesis for double curves may not be successful. Arthrodesis of all vertebrae in the Cobb angle and extension to the sagittal stable zone is recommended.26 However, despite appropriate selection of levels, adding on may still occur.26

Figure 4
Figure 4:
Preoperative PA (A) and lateral (B) radiographs of a patient with scoliosis. PA (C) and lateral (D) radiographs of the same patient following posterior spinal fusion with instrumentation.

Other factors may play a role in postoperative curve decompensation. The weaker connective tissue present in persons with Marfan syndrome may contribute to this complication.26 Jones et al26 suggested limiting dissection to the amount needed for instrumentation and fusion, specifically minimizing dissection of the interspinous ligaments. Patients in the series with curve decompensation exhibited high postoperative correction percentages, suggesting that extreme curve correction may result in curve decompensation. These authors advocated using preoperative bending films to plan the final correction instead of achieving the greater degree of correction that might be feasible in the operating room after releases and instrumentation.

Because of possible comorbidities, cardiopulmonary status should be evaluated before spinal surgery. Preoperative evaluation should also address the risk of aortic dissection and the need for anticoagulation in the patient with prosthetic valves. Clotting parameters should also be checked.

Dural Ectasia

Dural ectasia, an enlargement of the outer layer of the dural sac and nerve root sleeves, is defined by enlargement of the neural canal anywhere along the spinal column, thinning of the cortex of the pedicles or laminae, widening of the neural foraminae, or an anterior meningocele.11 Dural ectasia, most frequently located between L5 and S2, is common in individuals with Marfan syndrome; it is present in up to 95% of affected patients as identified by MRI28,29 (Figure 5). In many cases, dural ectasia is associated with back pain.30 Other symptoms are headaches and leg, abdominal, and perineal pain.

Figure 5
Figure 5:
T2-weighted axial MRI scan demonstrating dural ectasia.

Definitions of dural ectasia vary, and the diagnosis can be challenging. Morphologic criteria include bulging of the dural sac, lack of epidural fat at the posterior wall of the vertebral body, and the presence of radicular cysts.31 Ahn et al32 suggested two major and two minor criteria for dural ectasia: major, dural sac width below L5 greater than that above L4, and anterior sacral meningocele; minor, scalloping at S1 >3.5 mm, and L5 nerve root sleeve diameter >6.5 mm.

Cervical Spine Abnormalities

The cervical spine occasionally demonstrates abnormalities in patients with Marfan syndrome. Hobbs et al33 reviewed 104 patients with Marfan syndrome; 16% had focal kyphosis and 54% had increased atlantoaxial translation. An increased prevalence of radiographic basilar impression (36%) was partly related to increased odontoid height. Cervical stenosis is rare,33 as is multilevel cervical subluxation.34

Protrusio Acetabuli

Protrusio acetabuli is the protrusion of the medial wall of the acetabulum into the pelvic cavity. The prevalence in Marfan syndrome is 27% according to the center-edge-angle criterion of >50% and 16% according to the acetabular-ilioischial distance criterion of ≥3 mm in males and ≥6 mm in females.35 Affected individuals are asymptomatic until hip osteoarthritis develops. Radiographic parameters of protrusio include crossing of the teardrop figure; center edge angle of Wiberg >40°; crossing of the ilioischial line by the acetabular line medially by ≥3 mm in men, >1 mm in boys, ≥6 mm in women, and >3 mm in girls; and crossing of the iliopectineal line by the acetabular line36 (Figure 6). Diagnosis usually requires the presence of two of these findings.

Figure 6
Figure 6:
AP pelvis radiograph demonstrating bilateral protrusio acetabuli in a patient with Marfan syndrome.

For patients aged 8 to 10 years with progression of protrusio, Steel37 proposed epiphysiodesis of the triradiate cartilage. However, radiographic indices of acetabular depth tend to remain stable after age 20 years.35 In addition, in patients aged >40 years with Marfan syndrome, Iowa hip scores in those with protrusio were not much lower than in patients without protrusio (P < 0.38).35

When protrusio does result in symptomatic osteoarthritis in older patients, total hip arthroplasty may be performed. Nonstructural bone grafting of the medial cavity is often required.36 Patients aged <40 years with minimal arthritis can be treated with valgus intertrochanteric osteotomy. This procedure provides pain relief by reducing the transverse vector of forces driving the head into the acetabulum.36

Other Features and Considerations

Children and adults with Marfan syndrome may have other musculoskeletal conditions. Some patients have joint hypermobility, but some of the joints with laxity, particularly the elbows and fingers, may develop contractures. Pes planus (ie, flatfoot) is often present. Bone mineral density is reduced, but no difference in fracture incidence compared with that in the general population has been reported.38 Limb-length discrepancy is more common than in the general population and is associated with an increased risk of scoliosis.39 Hypotonia and myopathy may also occur. Finally, persons with Marfan syndrome have a high incidence of pain: 70% to 96% report pain in at least one location in the body.40 The cause of the pain has not been established. Other considerations in patients with Marfan syndrome include respiratory system abnormalities, sports participation risks, and pregnancy counseling.

Respiratory System

Pectus excavatum is present in up to two thirds of children with Marfan syndrome.41 A restrictive ventilatory defect may occur, although surgery usually is done for cosmesis and not for respiratory function. Because this condition can recur postoperatively in children, surgical intervention should be delayed whenever possible. Spontaneous pneumothorax occurred in 4.4% of patients with Marfan syndrome aged >12 years in one series.42 Recurrence of pneumothorax is common.

Sports Participation

Patients with Marfan syndrome may safely participate in low-intensity dynamic exercise (eg, swimming, biking, jogging) but should avoid highintensity activities such as static exercise (eg, weight lifting)43 and sports with rapid acceleration and deceleration (eg, martial arts, soccer, sprinting). Dynamic exercise is allowed because diastolic blood pressure decreases during such activities. The aerobic level of work should be <50% of capacity with the heart rate below 110 bpm.43 Contact sports are contraindicated to protect the aorta and the lens. Recommendations may be stricter for individual patients based on echocardiogram findings.

Pregnancy

Genetic counseling may be offered to patients wishing to begin a family, and prospective parents should be informed that approximately one half of all offspring will inherit the disorder. Ultrasonagraphic diagnosis in utero or in the newborn is not reliable. Children should be followed for the development of manifestations.

Pregnant patients with Marfan syndrome need to be followed carefully for the development of aortic dissection. The risk of dissection in pregnant patients increases with an aortic diameter >4 cm.44 Pregnant patients who have a mechanical prosthetic aortic valve require anticoagulation. However, anticoagulation with warfarin is associated with a risk of fetal demise, and anticoagulation with lowmolecular-weight heparin might not prevent valve thrombosis.45 Thus, frequent cardiovascular monitoring is necessary for such patients.

Summary

Marfan syndrome is an autosomal dominant disorder secondary to mu tations of fibrillin-1. Diagnosis is primarily clinical, using the Ghent nosology. Manifestations occur in the cardiovascular, ocular, and musculoskeletal systems. Cardiovascular manifestations include aortic dissection, mitral valve prolapse, left ventricular dilatation, and pulmonary artery dilatation. Ocular manifestations include ectopia lentis myopia, glaucoma, cataracts, and retinal detachment. Musculoskeletal manifestations include arachnodactyly, pectus abnormalities, scoliosis, pes planus, and protrusio acetabuli. The orthopaedist should recognize this constellation of signs and make appropriate referrals. After diagnosis, the orthopaedic surgeon may then make appropriate treatment decisions regarding scoliosis and protrusio acetabuli, and can help make recommendations for sports participation.

References

Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 18 is a level II randomized controlled study, and references 17 and 30 are level III case-control studies. The other references are level IV case series (5, 13, 19, 23, 26, 41, and 44), level V expert opinion series (22, 25, and 37), or anatomic, cadaver, and radiographic studies.

Citation numbers printed in bold type indicate references published within the past 5 years.

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