One of the most common inherited disorders affecting connective tissue, Marfan syndrome (MFS) is an autosomal dominant condition with a reported incidence of 1 in 3000 to 5000 individuals. There is a broad range of clinical severity associated with MFS, ranging from isolated features of MFS to neonatal presentation of severe and rapidly progressive disease involving multiple organ systems. The syndrome is associated with classic ocular, cardiovascular, and musculoskeletal abnormalities, although involvement of the lung, skin, and central nervous system may also occur. Decreased life expectancy occurs primarily due to aortic complications. Outcome improves with early diagnosis, medical treatment to delay or prevent the progression of aortic dilatation, and timely elective surgery.
Although MFS has autosomal dominant inheritance, rare case reports have described recessive fibrillin 1 gene (FBN1) mutations. While most individuals with MFS have an affected parent, 25% of patients develop the disease as a result of a de novo mutation involving the gene (FBN1) encoding the connective tissue protein fibrillin-1. FBN1 is a large gene (65 exons) located at chromosome 15q-21.1 Fibrillin-1 is a matrix glycoprotein that is the main constituent of elastic fibers. In less than 10% of patients with typical Marfan phenotype, no mutation in FBN1 is identifiable, likely due to complete allele deletion or altered regulation of the FBN1 gene. In patients with atypical presentations reminiscent of MFS, a mutation in a gene encoding for transforming growth factor-beta receptor (TGFBR) may be the cause. Some individuals with TGFBR1 or TGFBR2 mutations have clinical features consistent with MFS, while others have features of 1 of 2 other syndromes: Loeys-Dietz syndrome (LDS) or familial thoracic aortic aneurysm (FTAA) syndrome.
Approximately 1 in every 3000 to 5000 individuals is affected. The disease occurs worldwide, with no preference for race or gender. It exhibits complete penetrance with variable expression. Twenty-five percent of cases present sporadically due to de novo mutations. MFS is one of the most common of the single-gene malformation syndromes.
The pathophysiology of aortic dilatation in MFS is a complicated process. Fibrillin-1 is a regulator of TGF-beta bioavailability, which in turn leads to inflammation, fibrosis, and activation of specific matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9. Cystic medial degeneration of the aorta occurs when an accumulation of mucopolysaccharide cysts lead to the loss of vascular smooth muscle cells. Aortic wall weakening is due to increased release of MMP, cytokines, chemokines, prostaglandin derivatives, and elastic degradation fragments. These factors, in conjunction with decreased collagen, reduce aortic structural integrity and lead to aneurysmal dilatation. Reduced or altered forms of fibrillin-1 can stimulate the release of sequestered TGF-beta and increase its activity.MFS is therefore caused by vascular remodeling due to a combination of structural microfibril changes, excess TGF-beta, and overexpression of MMP-2 and MMP-9. The role of TGF-beta in the pathophysiology of MFS has been solidified by the use of the therapeutic angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs), both proven to decrease TGF-beta activity. Early studies in a mouse model of MFS have shown the utility of a TGF-beta-neutralizing antibody or the ARB losartan in the treatment of the disease.Comparatively, mutant mice treated with propranolol only exhibited a moderate reduction in the rate of aortic root dilation. Human studies substantiated that ARB therapy resulted in a significant reduction in the rate of change in the aortic root diameter as compared with beta-blocker therapy alone. Various conditions with pronounced clinical overlap with MFS are caused by primary mutations in genes encoding direct effectors and/or regulators of TGF-beta signaling, including Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS).
Histologic features of the medial layer of the aortic root in patients with Marfan syndrome (MFS) include cystic medial necrosis, fibrosis, and loss of smooth muscle cells. Although cystic medial necrosis and the other histologic findings are not specific for MFS, greater elastin fragmentation has been shown in patients with aortic root aneurysms with MFS compared to those without a connective tissue diagnosis.
History and physical for patients with MFS encompass various organ systems. Of primary concern is cardiac pathology. Aortic root disease, leading to aortic regurgitation, aneurysmal dilatation, and dissection, is the primary cause of morbidity and mortality in MFS, in up to 60% to 80% of patients.
Revised Criteria for Patients with MFS
Dilatation may also involve other segments of the thoracic aorta, the abdominal aorta, the root of the pulmonary artery or even the carotid and intracranial arteries, although this is much less frequent than observed in LDS.
As recommended in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery (ACC/AHA/AATS) thoracic aorta guidelines, echocardiography is recommended at initial diagnosis and 6 months to assess the aortic root and ascending aorta in patients with Marfan syndrome. A 6-month echocardiogram is performed to confirm the stability of the aortic dimension. Nomograms and Z-scores are used to identify aortic dilatation because normal range for aortic diameter varies with body size and age. Undiagnosed and untreated MFS is often associated with aortic dissection that begins above the coronary ostia and can extend the entire length of the aorta known as a type I dissection in the DeBakey classification. Based on a review from the International Registry of Aortic Dissection (IRAD), MFS causes an aortic dissection in 50% of those under age 40, compared to only 2% of older patients with aortic dissection and, no patient over age 70.
Aortic dissection and rupture are preventable in patients with MFS by replacement of the ascending aorta. Prophylactic surgery is recommended when the diameter of the ascending aorta at the level of the aortic sinuses reaches 5.0 cm. Patients with an aortic diameter of less than 2.75 cm/m2 are considered to be at low risk of dissection, those with 2.75 to 4.24 cm/m2 are at moderate risk, and those with greater than 4.25 cm/m2 are at high risk. A family history of dissection, increased rate of aortic dilation (greater than 2 mm per year), severe aortic valve regurgitation with left ventricular dilation, and relative feasibility of aortic valve-sparing surgery are also indicators for early surgical intervention.
Mitral valve prolapse (MVP) is identified in 40% to 54% of patients with MFS. Only 1 point in the systemic score is assigned for MVP since it is nonspecific. The frequency of MVP in MFS increases with age and is more prevalent in women. Tricuspid valve prolapse may also occur. Patients with MFS and MVP have mild regurgitation (MR). In these patients, worsening of MR is due to spontaneous rupture of the chordae tendineae or infective endocarditis. Heart failure caused by MVP and MR represents a major source of morbidity and mortality in young children with rapidly progressive MFS. Due to disrupted granular fibers from the proximal aorta to the base of the innominate artery, care should be taken without cross clamp placement for MFS patients with MVP. The presence of aortic regurgitation should be taken into account when performing cardioplegia to ensure adequate myocardial protection. Freedom from moderate or greater mitral regurgitation at 5, 10, and 20 years has been shown to be about 95%, 89%, and 69%, respectively. Patients with MFS may have cardiomyopathy with biventricular enlargement and mild systolic dysfunction.Patients may exhibit proximal ascending aortic dilation, dilation of the proximal main pulmonary artery, thickening and prolapse of the atrioventricular valves and mitral annular calcification.
Patients with Marfan syndrome have excess linear growth of the long bones and joint laxity. Some have reduced joint mobility, particularly of the elbow and digits. Individuals with MFS are taller than the general population. They have disproportionately long extremities in comparison to the length of the trunk, or dolichostenomelia. Patients typically have arachnodactyly with a positive thumb sign where the entire distal phalanx protrudes beyond the ulnar border of a closed fist. Patients also exhibit a positive wrist sign where the top of the thumb covers the entire fingernail of the fifth finger when wrapped around the contralateral wrist. MFS commonly exhibit either pectus carinatum or pectus excavatum. Pes planus, or flatfoot deformity, caused by ligamentous laxity, leads to longer and narrower feet than the average person.
Patient present with findings diagnostic for scoliosis, including a vertical difference of equal to 1.5 cm between the ribs of the left and right hemithorax, and a Cobb’s angle of at least 20 degrees. If scoliosis is absent, exaggerated kyphotic thoracolumbar spinal curvature can be taken into account to aid in the diagnosis of MFS. Radiographic findings of MFS scoliosis are indistinguishable from those of adolescent idiopathic scoliosis (AIS). Scoliosis associated with MFS is less responsive to a brace; therefore, a brace is only utilized in skeletally immature patients with scoliotic curves less than 25 degrees. Surgery should be considered in patients with curves greater than 45 degrees, although it is associated with higher revision and complication rates as opposed to AIS. In a retrospective, case-controlled study by Gjolaj et al., patients with MFS scoliosis had higher rates of cerebrospinal fluid leaks, an increased likelihood of complications related to implant placement, and more surgical revisions secondary to fixation failure and a spinal fracture. Studies have also reported higher blood loss and longer operative times than in patients with AIS. Surgeons must also take the unique anatomic features of MFS patients into account, including narrow pedicles, wide transverse processes, and vertebral scalloping.
An acetabular protrusion, or protrusio acetabuli, can be diagnosed by medial protrusion of the acetabulum equal to 3 mm beyond the ilio-ischial (Kohler) line. This reflects one of the main causes of osteoarthritis in patients with MFS. Degeneration of the hip joint is secondary to ligamentous laxity combined with this bony abnormality. Thakkar et al. noted that hip dislocations are caused by impingement on the deeper acetabulum or ligamentous laxity, and implant failure may be secondary to osteoporosis or osteopenia. Annual ophthalmologic evaluation is recommended for all patients with MFS secondary to ectopia lentis which occurs in 50% to 80% of patients. It is diagnosed by slit-lamp examination after maximal dilatation of the pupil; the lens is usually displaced upward and temporally. Other ocular findings in MFS include flat cornea, retinal detachment, glaucoma, and early cataract formation.
Dural ectasia results from enlargement of the spinal canal secondary to vertebral bone enlargement most commonly in the lumbosacral region. Dural ectasia is also seen in LDS and SGS, and the vascular form of Ehlers-Danlos syndrome. It is present in more than two-thirds of patients with MFS and commonly presents with pain. Pain may be associated with periosteal pressure, erosion of lumbosacral elements, traction of the nerve roots, or sacral microfractures secondary to osteopenia. A mouse model of MFS revealed higher dural levels of TGF-ß caused by fibrillin-1 deficiency.These changes increase the risk of surgical complications including spinal fracture and dural injury.
Patients with MFS develop lung bullae secondary to emphysematous pulmonary changes predominantly in the upper lobes, predisposing to spontaneous pneumothorax. Patients may exhibit skin striae, or striae atrophicae in MFS, owing to the disease as long as they are not associated with pronounced weight loss or pregnancy. Recurrent or incisional herniae and a high arched palate may occur but are not included in the systemic score since these features are considered nonspecific clinically.
In 1996, criteria for the diagnosis of MFS were originally proposed, known as Ghent nosology. These criteria relied on major and minor clinical manifestations of the syndrome. Aortic root dilatation and ectopia lentis are cardinal features of the disease, and other systemic features involving the skeletal and cardiovascular organ systems, ocular and vertebral anomalies support the diagnosis. Major criteria included: ectopia lentis, aortic root dilatation involving the sinuses of Valsalva or aortic dissection, and lumbosacral dural ectasia by computed tomography or magnetic resonance imaging, family or genetic history, and four of eight typical skeletal manifestations. These criteria underwent revision in 2010 due to various limitations, including insufficient validation, limited applicability to children, and an inability to exclude syndromes such LDS and SGS. The 2010 revised Ghent nosology puts greater weight on aortic root dilatation/dissection and ectopia lentis as the cardinal clinical features of MFS and testing for mutations in FBN1.
The revised Ghent nosology includes the following scoring system for systemic features
In patients with no family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:
In patients with a family history of MFS, the presence of one of any of the following criteria is diagnostic for MFS:
For criteria with an asterisk (*), the diagnosis of MFS can be made only in the absence of discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome and after TGFBR1/2, collagen biochemistry, or COL3A1 testing if indicated. Later data suggest that additional gene mutations should also be excluded, including those in SMAD3, TGFB2, and SKI.
The revised Ghent nosology recommends the following categories for individuals younger than 20 years old with features of MFS who do not meet diagnostic criteria for MFS:
The use of beta-blockers, noninvasive monitoring, restriction of vigorous physical exercise, and elective repair of the aorta have a greatly improved prognosis. In 1968, Bentall and De Bono introduced the Bentall procedure as the standard surgical approach for patients with MFS. A Dacron conduit is attached to a mechanical aortic valve, which then replaces the dilated ascending aorta and aortic root. Both coronary arteries are then reimplanted. Multicenter studies documented an early mortality rate of 1.5% and a survival rate of 84% at five years, 75% at ten years, and 59% at 20 years. Rates of thromboembolism and endocarditis at 20 years have been 7% and 10%, respectively. The mean age of surgery is 32 years old; mechanical aortic valves are the preferred device due to their longevity.
Patients require lifelong anticoagulation secondary to mechanical valve replacement. For patients in whom anticoagulation is not the recommendation, valve-sparing techniques have been adopted including the Yacoub technique and the valve reimplantation or David technique. With the Yacoub technique, the sinuses of Valsalva undergo resection and replacement with a vascular graft and coronary artery reimplantation; optimal patients have sinus and/or aortic dilation without annular dilation. The David technique involves reimplantation of the native aortic valve into a graft and is for patients with annular involvement. Twenty-five percent of MFS patients undergoing valve-sparing procedures have aortic regurgitation at 10 years secondary to disease progression. Valve-sparing procedures have lower operative mortality as opposed to the Bentall procedure at 5 years, 89% vs. 96%, and reduced incidence of reoperation at five years, 92% vs. 84%.
The 2010 ACC/AHA/AATS guidelines for the thoracic aortic disease include recommendations for MFS. Patients should have echocardiography performed at the time of diagnosis and 6 months later to determine aortic root and ascending aortic diameters, as well as their rate of growth. To identify patients at risk for aortic dissection, regular monitoring of the aortic diameter is recommended with the use of computed tomography (CT), transthoracic echocardiography (TTE), and magnetic resonance imaging (MRI). These imaging modalities provide information as to the classification, origin, and extent of dissection, potential areas of hemorrhage and other sequelae. Spiral CT angiography is the most frequently used modality worldwide for diagnosing TAAs and the degree of aneurysmal dilatation. CT limitations include aortic artifact secondary to cardiac motion and implanted devices. Iodinated contrast-induced nephropathy can also occur in selected patients, and the use of repeated episodes of ionizing radiation exposure should be weighed in pediatric patients who will require multiple scans in their lifetime. A Z-score, which designates a number of standard deviations from the mean for appropriate age and size matched the normal population, should be used to monitor aortic diameter via CT scan serially. MRI is an alternative to CT in stable patients with suspected thoracic aortic disease, providing information on aortic morphology, ventricular dimension and function, and valvular regurgitation. MRI also allows monitoring of systemic manifestations of MFS including dural ectasia, scoliosis, chest deformities, and protrusio acetabuli.
TTE is the primary modality in the diagnosis of MFS, although TEE is utilized in situations of suspected dissection to measure the maximal dimension of the aortic root with the parasternal long axis view. The leading-edge-to-leading-edge technique in diastole is implemented in adults, while the inner-edge-to-inner-edge technique in systole, is utilized amongst pediatric cardiologists. For MFS, aortic diameter at the sinuses of Valsalva is the key measurement since this is at greatest risk for aortic dissection, and monitoring is via echocardiography. A greater length of aortic dilation is associated with a worse prognosis. Aortic root measurements should be parallel to the plane of the aortic valve and perpendicular to the axis of blood flow in end-diastole.
In a retrospective analysis of 140 MFS patients with FBN1 mutations who had undergone routine thoracoabdominal CT or MRI as part of their follow-up, about one third had incidental findings of peripheral vascular aneurysms, with 55% of these patients requiring intervention. Another prospective series systematically examined the supra-aortic trunks, the arteries of the upper and lower extremities, the aortoiliac arteries, and the visceral branches of the abdominal aorta in 21 MFS patients. Ten (67%) had peripheral vascular arterial aneurysms, and 2 patients underwent semi-urgent repair.
When ascending aortic dimensions are stable, and there is no identified aortic disease, cross-sectional imaging is repeated every three to five years and prior to elective operation, and annually if the aortic diameter is less than 45 mm. However, if the aortic diameter is 45 mm or is enlarging, more frequent imaging is suggested, up to twice annually, and may indicate the need for surgery. More frequent imaging is also prudent if the aortic diameter shows rapid change (equal to 0.5 cm per year) or if the heart or valve function is circumspect. In the pediatric population with MFS, annual imaging the recommendation if aortic size is stable and not markedly enlarged. Since there are no validated age-specific aortic diameters that can be used to determine imaging intervals, aortic measurement comparisons should use body surface area. Individuals under 20 years of age with systemic findings suggestive of MFS, should have annual echocardiograms due to the potential risk of aortic disease.
As noted in the 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery (ACC/AHA/AATS) thoracic aorta guidelines, beta blockers are recommended in adults with MFS and aortic aneurysm to lower the rate of aortic dilatation. Beta-blockers decrease myocardial contractility and pulse pressure and may improve the elastic properties of the aorta in patients with an aortic root diameter less than 40 mm. Medication is recommended in patients with aortic root enlargement, a family history of aortic root enlargement, or a mutation previously associated with aortic disease. Dosing adjustments should be made to maintain the heart rate after submaximal exercise to less than 100 beats/minute in adults and less than 110 beats/minute in children. Although propranolol was the first beta-blocker demonstrated to slow aortic dilation, longer acting agents such as atenolol and metoprolol are also options. Labetalol is used among pregnant women because atenolol may impair fetal growth.
Beta-blocker therapy is also recommended for children with MFS and aortic aneurysm, though data in children is inconclusive. In an observational study, 44 children and adolescents with MFS were followed for almost 4 years. The 20 patients on beta-blocker therapy and the 6 patients taking a calcium channel blocker had a slower absolute aortic growth rate. In a retrospective study of 63 children in which compared beta-blocker therapy to no therapy, there was no significant variation in the rate of change in aortic root measurements between the 2 groups at the study's end, and there were more side effects in treated patients.
While data are limited, the addition of an angiotensin II receptor blocker as tolerated to beta-blocker therapy may slow the rate of aortic root dilation in patients with MFS as evidenced in the 2010 ACC/AHA/AATS guidelines. Renin-angiotensin system blockers may alleviate the clinical manifestations of MFS by blocking TGF-beta signaling. The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in MFS are attributed to central blood pressure control and the reduction of aortic wall stiffness. In a 2005 nonrandomized study, MFS patients treated with ACE inhibition showed improved outcomes regarding aortic growth rate as compared to those treated with beta-adrenergic blocker therapy over three years. Angiotensin II stimulates the proliferation of smooth muscle cells, increases fibrosis, attenuates the expression of MMP-2 and MMP-9, and reduces apoptosis through binding to the angiotensin type 1 (AT1)receptors in the aortic wall. Data from animal models suggest that AT1 receptor antagonists reduces TGF-beta levels and can prevent the pathogenesis of MFS. Chiu et al., have shown that losartan in combination with beta-blockade slows the progression of aortic root dilation more than beta-blockade alone in patients with MFS. Groenink et al. provided additional evidence in the adult MFS population that losartan delays aortic root dilation of a native aortic root and decreases aortic arch dilation in a patient with prior aortic root replacement.
A randomized trial comparing losartan with atenolol in 608 children and adults with MFS and aortic Z-scores greater than 3.0 found no significant difference in the rate of aortic root dilation between the 2 treatment groups over 3 years. A comparable and significant decline in aortic root dilation relative to body surface area occurred with both treatments. The 3-year rates of aortic root surgery, aortic dissection, and death were similar in the losartan and atenolol treatment groups. There is scant evidence regarding the efficacy of ACE inhibitor therapy in patients with MFS. A small randomized trial comparing perindopril with placebo (in addition to standard beta-blocker therapy) was retracted. Although no other drug therapy has been officially established, statins may attenuate aortic root dilation in a mouse model of Marfan syndrome by reducing the activity of vascular smooth muscle cells in the Marfan aorta.
Both animal and human data suggest that calcium channel blocker therapy may increase the risk of aortic complications. Marfan mice treated with calcium channel blockers demonstrated aneurysm expansion, rupture, and premature death. Patients with Marfan syndrome and other forms of thoracic aortic aneurysm taking calcium channel blockers have an increased risk of aortic dissection and the need for aortic surgery. An American Heart Association expert panel recommends low to moderate intensity exercise (approximately 4 to 6 metabolic equivalents), for most patients with MFS, although those with aortic root and/or valve replacement may tolerate less. MFS patients should avoid contact sports, exercise to exhaustion, and isometric activities that include the Valsalva maneuver.
Elective replacement of aortic root disease in advance of critical enlargement has been shown to be integral as illustrated in a series of 675 patients with MFS from Johns Hopkins in which the 30-day mortality for elective, urgent (within 7 days of surgical consultation), or emergency repair (within 24 hours of consultation) was 1.5%, 2.6%, and 11.7%, respectively. In another review, the actuarial survival at 5, 10, and 20 years of 231 patients who underwent elective aortic root replacement at Johns Hopkin's was 88%, 81%, and 75%, respectively. The 2010 ACC/AHA/AATS guidelines recommend an elective operation for patients with MFS at an external diameter of equal to 50 mm to avoid acute dissection or rupture. Indications for surgical repair at an external diameter less than 50 mm include rapid growth (greater than 5 mm per year), family history of an aortic dissection at a diameter less than 50 mm, or presence of progressive aortic valve regurgitation. The guidelines indicate if the maximal cross-sectional area (square centimeters) of the ascending aorta or root, divided by the patient's height in meters is greater than 10, surgical repair is appropriate. In the pediatric population, dissection is rare; therefore surgical indications include aneurysms that show rapid enlargement (greater than 10 mm per year) and progressive aortic insufficiency.
There is conflicting data on the safety profile of pregnant women with MFS. The 2010 thoracic aortic disease guidelines urge pregnancy avoidance if the aortic root diameter exceeds 40 mm and further recommend prophylactic aortic root replacement in women who will attempt pregnancy. The European and Canadian guidelines report an aortic root diameter of 45 mm to be considered safe. In a 2012 study, there was a significantly higher rate of aortic growth documented during pregnancy than at baseline. In previously pregnant women, adverse outcomes and elective aortic surgery during long-term follow-up were more common than in women who remained childless. In women devoid of cardiac complications with MFS, pregnancy is well tolerated up to an aortic root diameter of 45 mm, with proper clinical care. In the same vein, pregnancy should be strongly discouraged in women with a history of aortic dissection secondary to the high risk of aortic complications.
The lifespan of untreated patients with the classic MFS was approximately 32 years in 1972 but has markedly increased to 72 years in 1993. Beta-blockers, noninvasive aortic imaging, and elective aortic root repair have all contributed to an improvement in survival. Life expectancy is significantly lower in men than in women.
Consultation with a cardiothoracic surgeon should be scheduled in patients whose aortic diameter is more than 4 cm. Genetic counselor consultation is also beneficial. MFS patients who are pregnant should consult a high-risk obstetrician. Ophthalmologic consultation is a strong consideration in patients who have a cataract, glaucoma, lens subluxation (ectopia lentis) and retinal detachment.
MFS may create a substantial mental and physical burden on the patient, with different areas of concern for each person. According to Rao et al., in the United States, the quality of life of patients with MFS is lower than that of control subjects without the disease. Pain is one of the most common concerns for patients with MFS. A recent systematic review of the literature estimated that the prevalence of pain in these patients is 47% to 92%. Adults with MFS report limited physical capacity, reduced endurance, and ultimately, depression and anxiety. Through appropriate diagnosis and treatment, along with timely rehabilitation, patients are better able to lead productive lives. Optimal treatment of chronic pain in patients with MFS should be a focus of future research.
Management of MFS and its related complications involves a multidisciplinary effort by physicians including the patient's primary care physician/pediatrician and with appropriate referrals to a cardiologist, cardiothoracic surgeon, ophthalmologist, and orthopedics. Care coordination should take place between the different physicians as well as with the nurses taking care of these patients so that they can quickly report any potential complications. Pharmacists should be aware of medications that should require avoidance in patients with MFS. Physical therapists should be involved in guiding MFS patients on appropriate exercise activities which should not include high-intensity exercises.
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