Echocardiography in Pediatric and Adult Congenital Heart Disease, 2nd Ed.

21. Marfan Syndrome: Aortic Aneurysm and Dissection

The primary cause of morbidity and mortality in patients with Marfan syndrome (MFS) is related to the propensity to aortic aneurysm formation and associated dissection. Noninvasive cardiovascular imaging has contributed to the improved survival noted among patients with MFS in the current era. Ascending aortic dilatation is usually readily detected with transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). Echocardiography is a very important imaging tool in the diagnosis and management of patients with MFS. In addition, both computed tomography angiography (CTA) and magnetic resonance imaging (MRI) play an important role in the diagnosis, management, and surgical planning for patients with MFS and other thoracic aortic diseases.

MFS, an autosomal dominant multisystem disorder, is the most common systemic connective tissue disease, occurring in 2 to 3 per 10,000 individuals. Cardiovascular complications occur in the majority of patients. Classically MFS is caused by a mutation of the fibrillin-1 gene (FBN1), which maps to 15q21. FBN1 mutations increase the susceptibility of fibrillin, a structural protein, to proteolysis in vitro leading to fragmentation of microfibrils. Fragmentation of the elastic fibers in the aortic media is a histological marker of MFS, so-called medial degeneration. Transforming growth factor beta (TGFβ), a regulatory protein, has been shown to bind to fibrillin in microfibrils. The proteolysis of fibrillin in MFS results in increased bioavailability of TGFβ, which in turn causes excess signaling and ultimately leads to abnormal elastic properties that make the aorta stiffer and less distensible than normal.

More than 500 different mutations involving the FBN1 gene have been identified to date, and the penetrance of the fibrillin mutation is high. However, no correlation has been recognized between the specific type of FBN1mutation and the clinical phenotype. In approximately 75% of cases, an individual with MFS inherits the disorder from an affected parent, the remaining 25% result from de novo mutation. Genetic counseling should be provided at the time of initial evaluation or diagnosis, as well as to potential parents.

The revised Ghent diagnostic criteria were published in 2010 (Table 21.1). These criteria give more weight to the cardinal features of MFS, including aortic root aneurysm or dissection and ectopia lentis. They also establish a more prominent role for the use of genetic testing. The involvement of other organ systems contributes to a “systemic score” that is used when the patient does not meet criteria based on aortic disease, ectopia lentis, family history, or FBN1 mutation (Table 21.2). Confirmation of the diagnosis of MFS requires a complete personal and family history and a comprehensive multidisciplinary approach involving genetic, cardiac, ophthalmologic, and, in select cases, orthopedic consultations and various diagnostic tests.

ANATOMY AND PHYSIOLOGY OF THE CARDIAC LESION

The cardiovascular features of MFS were initially reported by McKusick et al. Dilatation of the ascending aorta at the level of the aortic sinuses, also known as the aortic root, is the most common and characteristic cardiovascular manifestation of MFS (Fig. 21.1). Progressive aortic sinus enlargement is present in approximately 50% of adults and children with MFS.

Ascending aortic aneurysm in MFS can be readily detected by TTE in most patients, and serial TTE studies can usually be performed to monitor the size of the dilated ascending aorta. Alternate imaging modalities such as TEE (Fig. 21.2), CTA (Fig. 21.3), or MRI (Fig. 21.4) are used to confirm the diameter of the ascending aorta and to completely assess the arch, descending thoracic, and abdominal aorta, which are often incompletely visualized on TTE. Aortic dissection (Fig. 21.5) or rupture accounts for most of the premature mortality in patients with MFS. Marked improvement in life expectancy in patients with MFS has been noted over the past 30 years. This change in prognosis is largely the result of early diagnosis of MFS, initiation of medical therapy, and serial aortic imaging with recognition of aortic aneurysmal disease and prophylactic aortic root replacement. Thus, it is critically important to consider the diagnosis and to perform serial cardiovascular imaging studies in all patients with confirmed or suspected MFS.

Aortic dissection data suggest that MFS is present in 50% of patients presenting with aortic dissection who are younger than 40 years of age. Risk factors for aortic dissection in MFS include (a) aortic sinus diameter greater than 50 mm, (b) aortic dilatation extending beyond the sinuses of Valsalva, (c) more than 5% per year increase in aortic size in children, or an increase of more than 5 mm per year in adults, and (d) family history of aortic dissection. Aortic diameter should be measured at multiple levels by TTE and compared with normal values based on age and body surface area. The aortic root diameter increases with age and is larger in men than women (Fig. 21.6). Serial measurements are indicated. When adequate assessment of the aorta is not possible by TTE, alternate imaging modalities are used such as CTA, MRI, or TEE.

Patients with MFS are predisposed to dilatation or dissection of the descending thoracic aorta, although this is less common than involvement of the ascending aorta. Complete evaluation of the distal ascending aorta, arch, and descending thoracic aorta is often challenging in adults, and CTA or MRI play an important role in evaluation of the entire aorta (Fig. 21.7). Dilatation or dissection of the descending thoracic aorta is a recognized cardiovascular complication of MFS, and can be evaluated with CTA (Fig. 21.8), TEE (Fig. 21.9, Videos 21.1 and 21.2), or MRI. Nevertheless, life-long imaging of the entire aorta is essential for the optimal management of patients with MFS.

Important cardiovascular manifestations in MFS other than aortic dilatation have been recognized. Mitral valve prolapse (Fig. 21.10) occurs in approximately 60% of patients with MFS. The mitral valve leaflets are longer and thinner, with less posterior leaflet prolapse and more anterior or bileaflet prolapse compared with mitral valve prolapse in non-MFS patients. In addition, patients with MFS develop severe degrees of mitral valve regurgitation and present for surgery at a younger age than non-MFS patients. Less common cardiovascular complications of MFS include mitral annular calcification, tricuspid valve prolapse, and pulmonary artery dilatation in the absence of pulmonary valve disease. These less common complications have been removed from the diagnostic criteria because they are less specific for MFS. Central aortic valve regurgitation caused by annular enlargement occurs as the aorta enlarges (Fig. 21.11, Videos 21.3 and 21.4). There are reports of left ventricular dilatation and systolic dysfunction, regardless of valvular regurgitation in patients with MFS, and other reports suggesting that ventricular dysfunction is uncommon in the absence of valve disease.

CLINICAL PRESENTATION

Despite the progress in management of patients with MFS and sophistication of the health care system, patients with MFS still die of aortic dissection before consideration and diagnosis of the disorder. In retrospect, many of these patients have physical features or a family history of MFS that should have prompted cardiovascular screening before the aortic catastrophe.

Figure 21.1. Aortic Enlargement in Marfan Syndrome. A: Schematic of the typical aortic enlargement in Marfan syndrome. This schematic demonstrates enlargement of the proximal aorta at the level of the aortic sinuses. B: Two-dimensional echocardiogram in the parasternal long-axis image orientation demonstrates dilatation of the ascending aorta at the level of the aortic sinuses. The electronic calipers demonstrate the leading edge–to–leading edge method for ascending aortic measurement. Ao, aorta; LA, left atrium; LV, left ventricle.

Figure 21.2. Transesophageal echocardiogram in the longitudinal image plane at 150 degrees. Dilatation of the ascending aorta at the level of the aortic sinuses (arrow). Ao, aorta; LA, left atrium.

The majority of patients with MFS have a family history of the disorder and are identified during routine family echocardiographic screening. Skeletal, ocular, and occasionally pulmonary features may prompt cardiovascular screening of the patient and family. When a patient is initially diagnosed with MFS, screening of all first-degree relatives is recommended. When MFS is suspected, screening with TTE is recommended to identify cardiovascular disease—most importantly, aortic aneurysmal disease.

Marfan Syndrome in Children

The revised Ghent diagnostic criteria address the issue of making the diagnosis of MFS in children. Previously, this was challenging as the features may be subtle early in life and develop with age. Based on the revised criteria, if an individual <20 years old with suspected MFS does not meet diagnostic criteria as described in Table 21.1, specific recommendations are given based on the findings present. When the systemic score is <7 and/or there is borderline aortic root enlargement (z-score <3) in a patient with no FBN1 mutation and no family history, the term “nonspecific connective tissue disorder” is recommended until follow-up evaluation demonstrates aortic root z-score ≥3. If an FBN1 mutation is identified in a young patient with z-score <3, the term “potential MFS” is used until the aortic root z-score is ≥3. Children with suspected MFS should have comprehensive evaluation during preschool, before puberty, and at age 18 years, because some of the clinical manifestations of MFS become evident with time. Annual aortic imaging follow-up is recommended for children with MFS or when the aorta is enlarged regardless of diagnostic criteria.

Figure 21.3. Computed tomography (CT) examination of the chest using a dual-source CT scanner with intravenous contrast material. Reformatted in the coronal plane, shows marked dilatation of the ascending aorta at the level of the aortic sinuses (arrow) in a patient with Marfan syndrome. Note that the rest of the aorta is near normal caliber.

Figure 21.4. Electrocardiographic-gated, steady state free precession magnetic resonance imaging. The coronal plane (left) and the double oblique plane through the sinus of Valsalva (right) demonstrate dilatation of the aortic root and a tricuspid aortic valve. Ao, aorta; LV, left ventricle; RA, right atrium; LA, left atrium; N, noncoronary cusp; R, right coronary cusp; L, left coronary cusp; RVOT, right ventricular outflow tract.

The majority of patients with MFS demonstrate aortic root dilatation, mitral valve prolapse, or both before age 18 years. It is important to make the diagnosis and to initiate appropriate medical therapy and serial screening in an effort to prevent or slow aortic enlargement and thus delay aortic operative intervention.

Beta-blockers have been demonstrated to significantly decrease the rate of aortic dilatation at the level of the aortic sinuses in children and adults and therefore should be prescribed either at the time of diagnosis or on documentation of aortic enlargement. Angiotensin receptor blockers (ARBs) have been shown to be beneficial in slowing the rate of aortic dilatation in a small cohort of MFS children who demonstrated progressive aortic dilatation on beta-blocker therapy. Multiple trials are ongoing comparing the use of beta-blockers and ARBs in MFS patients with aortic enlargement.

Figure 21.5. Aortic Dissection. A: Two-dimensional transthoracic echocardiogram in the parasternal long-axis image orientation showing dilatation of the ascending aorta and proximal aortic dissection (arrowheads). B: Transesophageal echocardiogram in a longitudinal image orientation showing dilatation of the ascending aorta and proximal aortic dissection (arrowheads). The transesophageal echocardiogram was performed in the operating room before surgical repair. Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.

Figure 21.6. Mean aortic root diameter adjusted for body surface area in men (white bars) and women (black bars) by decade of age. (From Devereux et al., Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons ≥15 years of age, Am J Cardiol. 2012;110[8]:1189–1194.)

Figure 21.7. MRI in a patient with Marfan syndrome and prior composite root replacement. Steady state free precession imaging in an oblique sagittal plane demonstrates severe dilatation of the distal native ascending aorta and arch beginning at the distal anastomosis from the prior aortic root replacement operation (arrow). The proximal descending thoracic aorta is also mildly dilated. G, graft; AA, aortic arch; DA, descending aorta.

Neonatal MFS is a severe form of MFS apparent at birth that carries a poor prognosis. Aortic enlargement with associated severe aortic valve regurgitation is often present. In addition, progressive mitral and/or tricuspid valve prolapse with regurgitation leading to congestive heart failure is common and affects management and patient survival. Characteristic noncardiac features include infantile pulmonary emphysema, ectopia lentis, arachnodactyly, joint contractures, and loose skin.

CARDIAC COMPLICATIONS IN MARFAN SYNDROME

The most important, and life-threatening, cardiovascular complication in MFS is aortic dissection (see Figs. 21.8 and 21.9, Videos 21.1 and 21.2) or rupture. This most commonly involves the ascending aorta but can also affect the descending thoracic aorta. Additional cardiovascular complications include progressive valvular regurgitation, such as aortic regurgitation caused by annular enlargement or mitral or tricuspid valve regurgitation caused by leaflet prolapse.

Prophylactic beta-blockade has been demonstrated to be effective in slowing the rate of aortic dilatation and reducing the development of aortic complications. These medications are generally recommended in patients with MFS. The ARB losartan has been demonstrated to have an important impact on vascular development in the mouse model of MFS. ARBs also slowed the rate of aortic dilatation in a small cohort of children with MFS and studies comparing beta-blockers and ARBs are ongoing in both children and adults. ARBs should be considered as an alternative medication option for patients with MFS intolerant of beta-blockers.

Genetic counseling is recommended for all patients with MFS. Due to the autosomal dominant nature of the disorder, each offspring of an affected Marfan parent has a 50% chance of inheriting the genetic mutation. The risk of transmission to the fetus should be discussed before starting a family.

Figure 21.8. Descending thoracic aorta dissection in a patient with Marfan syndrome and prior composite root replacement. Computed tomography angiography in an oblique sagittal plane demonstrates a dissection originating in the arch and extending into the abdominal aorta (black arrows). Note the artifact in the thoracic spine from prior scoliosis repair and the sacral dural ectasia (white asterisk).

Cardiac Surgical Intervention

Aortic root replacement in patients with MFS is recommended when the ascending aorta reaches a diameter of 5 cm or more because of the increased risk of aortic rupture. Select patients are referred for aortic root replacement with an aortic dimension less than 5 cm; these include patients with a family history of aortic dissection, patients with a rapid rate of aortic dilatation (greater than 5% per year, or more than 5 mm per year in adults), those interested in future pregnancy with an aortic dimension greater than 40 to 45 mm, and those interested in the valve-sparing aortic root replacement (see Fig. 21.13). Alternatively, if the maximal cross-sectional area in square centimeters of the ascending aorta or root divided by the patient’s height in meters exceeds 10, prophylactic surgery can be recommended, as patients with a smaller body size may develop complications at an aortic diameter less than 5 cm. Patients with aneurysms measuring less than 5 cm and no high-risk characteristics require serial follow-up studies to measure the aortic dimensions and decide the appropriate timing of intervention. The surgical options include the Bentall composite aortic valve and ascending aorta replacement (Fig. 21.12) or the aortic valve-sparing root replacement (Fig. 21.13).

Cardiovascular surgery can also be safely performed in children with MFS. Indications for surgical intervention in the pediatric population include (a) rapid rate of growth of the ascending aorta (greater than 5 mm per year), (b) progressive aortic valve regurgitation, or (c) the need for mitral valve surgery in patients with marked aortic enlargement. The surgical options are the same as in adults and include composite graft repair (see Fig. 21.12), or the valve-sparing procedure (see Fig. 21.13). Both procedures have shown excellent results for prophylactic replacement of an enlarged aortic root in older children and adults.

Pregnancy in Patients with MFS

The risk of aortic dissection during pregnancy is increased in patients with MFS. This is the result of a combination of the preexisting medial aortic disease with superimposed hormonal inhibition of aortic collagen and elastin deposition, and the hyperdynamic, hypervolemic circulatory state of pregnancy. There is a reported 11% complication rate associated with pregnancy in patients with MFS, mostly related to aortic rupture and endocarditis. The overall risk of death during pregnancy in patients with MFS is around 1%.

Women with MFS are counseled against proceeding with pregnancy when the ascending aorta exceeds 40 to 45 mm, depending on concomitant risk factors including personal or family history of aortic dissection, and rapid aortic dilatation. The risk of aortic complication is increased during pregnancy in patients with MFS when the aortic root diameter exceeds 40 to 45 mm at the start of pregnancy, and the risk is further increased when the aorta dilates during pregnancy. The risk of dilatation of the aorta during pregnancy in the MFS patient has been reported to be lowest in the first trimester and greatest in the third trimester, as well as during labor and the early postpartum period. Beta-blocker therapy should be continued throughout pregnancy, and patients should have serial follow-up echocardiograms to assess the change in the size of the aorta during pregnancy. ARBs should not be used during pregnancy. The frequency of aortic imaging should be individualized. Aortic root replacement should be considered during pregnancy in patients with MFS with progressive aortic dilatation or for documented aortic dissection.

Figure 21.9. Descending thoracic aortic dissection demonstrated by transesophageal imaging. A: Longitudinal view of the descending thoracic aorta demonstrating dissection flap (arrowheads) with true lumen (TL) and false lumen. B: Transverse view of the descending thoracic aorta demonstrating dissection and true lumen (TL) and false lumen. C: Color flow imaging of the transverse view demonstrating primary flow in the TL of the dissected descending thoracic aorta.

Figure 21.10. Mitral valve prolapse in Marfan syndrome. A: Bileaflet mitral valve prolapse (arrowheads) noted by two-dimensional echocardiographic parasternal long-axis imaging in a patient with Marfan syndrome. B: Associated with severe mitral regurgitation by color flow imaging. Note enlargement of the left atrium and aortic sinuses. Ao, aorta; LA, left atrium; LV, left ventricle; MR, mitral regurgitation; RV, right ventricle.

Assisted vaginal delivery can be considered in patients with MFS when the aortic root diameter is less than 40–45 mm, the aorta has not demonstrated change during pregnancy, and there is no associated severe cardiovascular disease. For patients with MFS with other characteristics, planned cesarean delivery is generally the preferred mode of delivery. Antibiotic prophylaxis administered around the time of delivery is appropriate for those patients with prior root and valve replacement surgery or a past history of endocarditis. Postpartum uterine hemorrhage is a common complication of MFS, occurring in nearly 40% of women. The risk of aortic dissection persists during the early postpartum period, thus these patients should be monitored postpartum.

Figure 21.11. Aortic annular dilation and regurgitation. A: Parasternal long-axis image demonstrating aneurysmal enlargement of the ascending aorta (arrow). B: Color flow imaging demonstrating aortic valve regurgitation caused by annular dilatation. Ao, aorta; AR, aortic valve regurgitation; LA, left atrium; LV, left ventricle.

Figure 21.12. Bentall operation. A: Schematic of the Bentall operation. In this operative procedure, the proximal aorta is replaced with a valved conduit, and the coronary arteries are reimplanted. This schematic demonstrates a mechanical valve prosthesis. Biological prostheses can also be used. B:Transthoracic echocardiographic image of a patient with Marfan syndrome after a Bentall operation. The aortic valve and proximal ascending aorta are replaced with a mechanical valve prosthesis (arrowheads) and aortic graft, respectively. AoG, aortic graft; LA, left atrium; LV, left ventricle; RV, right ventricle.

Figure 21.13. Valve-sparing aortic root replacement. A: Schematic of the valve-sparing aortic root replacement. The ascending aorta is replaced with a graft material, the native aortic valve is preserved, and the coronary arteries are reimplanted. B: Transthoracic echocardiographic image after a valve-sparing aortic root replacement operation. The native aortic valve remains (arrowheads, spared native aortic valve), and proximal ascending aorta is replaced with an aortic graft. AoG, aortic graft; LA, left atrium; LV, left ventricle.

BASICS OF ECHOCARDIOGRAPHIC ANATOMY AND IMAGING

Two-Dimensional Echocardiographic Anatomy and Hemodynamics

A comprehensive TTE examination will often demonstrate the cardiovascular features of MFS in the involved patient but may be normal or near normal despite a confirmed diagnosis of MFS.

Echocardiographic imaging of the aorta includes the parasternal long-axis view to measure the dimensions of the aortic sinuses, sinotubular junction, and ascending aorta. The leading edge–to–leading edge technique was previously used to measure the ascending aorta; however, the current recommendation is to measure the ascending aorta using an inner edge–to–inner edge technique. An off-axis parasternal image also demonstrates the descending thoracic aorta in many patients (Fig. 21.14). The aortic arch and descending thoracic aorta are imaged using the suprasternal window (Fig. 21.15), and the abdominal aorta is imaged from the subcostal format (Fig. 21.16). Aortic dimensions should be compared to normal for patient age and body surface area (see Fig. 21.6).

Aortic distensibility has been reported to be an independent predictor of progressive aortic dilatation, and therefore risk assessment and monitoring in patients with MFS may include not only serial assessment of aortic diameter but also assessment of aortic stiffness. M-mode echocardiography and Doppler tissue imaging assessment of aortic wall mechanics and stiffness have been reported. Systolic blood pressure, aortic stiffness index, maximum wall expansion velocity, and strain have been demonstrated to be predictors of aortic dilatation. Decreased aortic strain, maximum wall expansion velocity, and increased stiffness index have also been found to be predictive of aortic dissection. The clinical utility of these measurements has yet to be determined.

Aortic valve regurgitation is identified in the parasternal long-axis (see Fig. 21.11, Video 21.4), short-axis, and apical images by color flow imaging and Doppler assessment. The severity is assessed according to American Society of Echocardiography recommendations. Similarly, mitral, tricuspid, and pulmonary valve prolapse and regurgitation are identified and the degree of regurgitation is similarly assessed.

Left ventricular systolic and diastolic function is assessed using standard TTE imaging techniques, with parasternal long- and short-axis and apical imaging.

Echocardiographic Assessment of Aortic Dissection

TTE is a reasonable initial imaging modality for proximal aortic dissection because of its availability. The positive predictive value is high, but aortic dissection cannot be excluded in patients with negative findings. A dilated aorta is noted in most patients with aortic dissection by TTE; however, an intimal flap is seen in less than 80% (see Fig. 21.5). False-positive diagnoses of aortic dissection occur in less than 10% of patients using TTE. Another concern regarding TTE in aortic imaging is that the descending thoracic aorta is incompletely visualized in many patients. Therefore, TTE is a rapid screening tool for aortic dissection, but negative findings or a suboptimal examination requires further diagnostic evaluation.

The anatomic relationship between the esophagus and the thoracic aorta usually allows visualization of the entire thoracic aorta using multiplane TEE. The distal portion of the ascending aorta and the proximal aortic arch may be difficult to visualize because of the interposed trachea using a horizontal TEE view. However, this blind area can usually be adequately visualized with the longitudinal view. Multiplane imaging provides a more complete view of the entire aorta; thus, the role of TEE has changed in the diagnosis and management of aortic dissection (see Fig. 21.5).

The International Registry of Acute Aortic Dissection (IRAD) was established in 1996 to assess the presentation, management, and outcomes of acute aortic dissection. Acute aortic dissection was reviewed in 628 patients from 13 international medical centers. Imaging modalities used for diagnosis were assessed. TEE and CTA are now the most common initial imaging tests for the diagnosis of aortic dissection. Two-thirds of the patients in IRAD had two or more imaging studies to confirm the diagnosis.

Figure 21.14. Two-dimensional echocardiographic images of the descending thoracic aorta visualized using off-axis imaging. A: Modified parasternal long-axis window. B: Modified parasternal short-axis window. AV, aortic valve; DAo, descending aorta; LA, left atrium; RA, right atrium.

Figure 21.15. Suprasternal echocardiographic imaging demonstrates the ascending aorta (AscAo), aortic arch, and proximal descending thoracic aorta. DescAo, descending aorta; RPA, right pulmonary artery.

The European multicenter cooperative study was the first to demonstrate that TEE was at least equal to CTA and aortography in the diagnosis of aortic dissection (99% sensitivity). Subsequent studies reinforced the diagnostic accuracy of TEE in aortic dissection. Increased clinical availability of TEE has decreased its diagnostic sensitivity (88%) in the IRAD, compared with CTA (93%). Currently, the initial diagnostic procedure of choice for suspected aortic dissection is TEE or CTA. Although the diagnostic accuracy of MRI is superb in aortic dissection, its clinical role is limited by the longer examination time, difficulties in monitoring patients during the procedure, and the remote location of the imaging facility from the emergency department.

ILLUSTRATIVE IMAGING EXAMPLES

Case 1: Aortic Root Enlargement in a Patient with MFS

This 25-year-old male patient with a family history of MFS has a TTE that demonstrates enlargement of the ascending aorta at the level of the aortic sinuses (see Fig. 21.1). The presence of aortic root enlargement, and a family history of MFS confirm the diagnosis of MFS in this patient. MRI confirmed the aortic sinus measurement noted by TTE and excluded aneurysmal disease involving the rest of the aorta. Beta-blocker therapy and regular clinical and TTE surveillance were recommended. This case emphasizes the clinical importance of echocardiographic imaging in the diagnosis and management of patients with MFS.

Figure 21.16. Subcostal two-dimensional echocardiographic imaging demonstrates the abdominal aorta in a longitudinal view where measurements can be performed. Note the dissection flap (arrowheads) in the abdominal aorta.

Case 2: Mitral Valve Prolapse and Mitral Regurgitation in a Patient with MFS

This 27-year-old male patient with a diagnosis of MFS presents with exertional dyspnea. His TTE demonstrates dilatation of the aortic root (47 mm) and bileaflet mitral valve prolapse with severe mitral valve regurgitation (see Fig. 21.10). Operative intervention with mitral valve repair for severe symptomatic mitral valve regurgitation was recommended. Aortic valve-sparing root replacement was also recommended given the degree of aortic enlargement and the propensity for progressive aortic dilatation. Individualized medical and surgical management is recommended for all patients with MFS. This patient wanted to avoid warfarin anticoagulation. Mitral valve repair and valve-sparing aortic root replacement provided that option for this patient.

Case 3: Imaging after Aortic Root and Valve Replacement in a Patient with MFS

This 85-year-old woman has a personal and family history of MFS. She underwent a Bentall procedure (see Fig. 21.12; aortic valve and ascending aorta composite replacement) approximately 20 years before this echocardiogram. She has bileaflet mitral valve prolapse with moderate mitral valve regurgitation, permanent atrial fibrillation, and associated biatrial enlargement. She has two sons with MFS; both have had aortic valve-sparing root replacement (see Fig. 21.13) for ascending aortic aneurysms. This case highlights some of the postoperative cardiovascular features in MFS, the need for continued surveillance, and the potential longevity of patients with MFS.

How to Obtain Proper Echocardiographic and Doppler Images

Standard TTE imaging windows are usually adequate for assessment of the ascending aorta and the cardiac valves in patients with MFS. Occasionally, nonstandard imaging windows are used to measure the ascending and descending thoracic aorta such as high left parasternal or right parasternal windows. In addition, patients with skeletal abnormalities such as pectus deformity or scoliosis related to MFS may require special imaging windows. TEE, CTA, or MRI can be used to complement the TTE evaluation of patients with MFS.

Differential Diagnoses

The differential diagnosis of MFS includes disorders that involve cardiac, skeletal, or ophthalmologic manifestations. Confirming the clinical diagnosis of MFS is often challenging, especially in the child or adolescent without a family history. Molecular genetic testing can be a very useful diagnostic tool; however, clinical and imaging follow-up may be the only way to differentiate MFS from some of the other disorders.

Figure 21.17. Bicuspid aortic valve. A: Two-dimensional echocardiogram in a parasternal long-axis image plane (left) demonstrates dilatation of the mid-ascending aorta in a patient with bicuspid aortic valve. The leading edge–to–leading edge method is used for ascending aortic measurement. The short-axis image (right) confirms the bicuspid aortic valve (asterisk). There was no aortic valve stenosis or regurgitation. B: Two-dimensional echocardiogram in a parasternal long-axis image plane (left) demonstrates dilatation of the ascending aorta at the level of the aortic sinuses in a patient with bicuspid aortic valve. The leading edge–to–leading edge method is used for ascending aortic measurement. The bicuspid aortic valve (asterisk) functions normally (right). Ao, aorta; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

1.Congenital bicuspid aortic valve disease with associated aortopathy. In patients with bicuspid aortic valve disease with associated aortopathy, the dilatation of the ascending aorta is most often seen at the mid-ascending aortic level (Fig. 21.17A) rather than at the aortic sinuses (Fig. 21.17B) despite histologic similarities between the bicuspid aortic valve–related aortopathy and MFS. The presence of a bicuspid aortic valve is an independent risk factor for progressive aortic dilatation, aneurysm formation, and dissection. Bicuspid aortic valve is associated with accelerated degeneration of the aortic media, indicating an ongoing pathologic process. Focal abnormalities within the aortic media such as matrix disruption and smooth muscle cell loss have been identified, suggesting that a degenerative process causes the structural weakness of the aortic wall. The vascular complications in patients with bicuspid aortic valves are not thought to be secondary to valvular dysfunction and can manifest in young adults without significant aortic valve disease or in patients in whom the native bicuspid aortic valve was replaced with a prosthetic valve. Ascending aortic enlargement occurs in more than 50% of young patients with normally functioning bicuspid aortic valves. This disorder is also inherited in an autosomal dominant manner with reduced penetrance and variable age of aortic dilatation. Family members of the affected individual may demonstrate aortic dilatation without an abnormal valve. Echocardiographic screening is recommended for the first-degree relatives of patients with bicuspid aortic valve with or without associated aortopathy.

2.Coarctation of the aorta may be associated with ascending or descending aortic aneurysm formation and increased risk of aortic dissection. More than 50% of patients with aortic coarctation also have bicuspid aortic valves. The propensity to aneurysm formation in patients with coarctation of the aorta is incompletely understood but may be related to a generalized structural abnormality of the arterial system caused by maldevelopment of the neural crest, which gives rise to the muscular arteries.

3.Loeys-Dietz syndrome is a disorder characterized by arterial tortuosity and aneurysms with an increased risk of dissection throughout the arterial tree, often at small arterial sizes. Additional features include ocular hypertelorism without ectopia lentis and a broad or bifid uvula (Fig. 21.18). Loeys-Dietz syndrome is due to a mutation in the transforming growth factor beta receptor (TGFBR) 1 or 2 genes. Regular imaging of the entire vasculature is recommended. Because of the high risk of lethal aortic complications, an aggressive surgical approach has been recommended in these patients.

4.Ehlers-Danlos syndrome, vascular type (formerly type IV), includes skin laxity, scars, easy bruising, and a propensity toward arterial dilatation and dissection. This is caused by a mutation in COL3A1, the gene encoding type III collagen.

5.Familial thoracic aortic aneurysm or aortopathy is a disorder characterized by a familial tendency to arterial dilatation and dissection in the thoracic aorta, abdominal aorta, and cerebral circulation. Individuals with this disorder do not show any systemic manifestation of MFS. It may be inherited in an autosomal dominant manner with reduced penetrance and varying age of aortic dilatation. Familial thoracic aortic aneurysms may grow at a faster rate than other aortic disorders, exemplifying an aggressive course. Genetic mutations have been identified in FBN1TGFBR1/2MYH11, and ACTA2.

6.MASS phenotype is a familial disorder that includes features similar to MFS with mitral valve prolapse, aortic enlargement, and nonspecific skin and skeletal features. The aortic enlargement is usually mild and nonprogressive.

7.Homocystinuria shares several skeletal and ocular features of MFS, in addition to mitral valve prolapse. Aortic enlargement is not typically seen in this disorder. Homocystinuria is an autosomal recessive disorder that is characterized by an elevated urinary homocysteine excretion and can be diagnosed by measuring total plasma homocysteine. Affected individuals often have subnormal intelligence, a predisposition to thromboembolism, and coronary artery disease.

8.Stickler syndrome is characterized by retinal detachment rather than ectopia lentis; additional features include cleft palate and hearing loss.

9.Congenital contractural arachnodactyly or Beals syndrome is an autosomal dominant disorder manifest by joint contractures, scoliosis, and crumpled ear malformation in addition to a marfanoid appearance. Mutations in the FBN2 gene have been identified in congenital contractural arachnodactyly.

10.Sinus of Valsalva aneurysm is caused by localized absence of the media in the aortic wall that results in aneurysmal dilatation of one of the sinuses of Valsalva, often with a wind-sock appearance. Although sinus of Valsalva aneurysm may be an incidental finding, it can cause compression of adjacent structures or rupture into the adjacent cardiac chambers, most commonly the right atrium or right ventricle, or into the ventricular septum. These aneurysms can be distinguished confidently from aneurysms of the aorta at the level of the aortic sinuses with comprehensive TTE and TEE examinations.

11.Aortitis refers to an inflammation of the aortic wall caused by infection such as syphilitic or mycotic involvement, giant cell arteritis, Takayasu disease, ankylosing spondylitis, rheumatoid arthritis, or relapsing polychondritis. The aortic involvement is usually an expression of the systemic nature of the underlying vasculitis or disease.

Figure 21.18. A 12-year-old patient with Loeys-Dietz syndrome. A: Two-dimensional echocardiogram in a parasternal long-axis image orientation demonstrates dilatation of the ascending aorta at the level of the aortic sinuses (electronic calipers). Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle. B: Photograph of the uvula. Note that the uvula is broad and bipartite.

Potential Imaging Pitfalls

Aortic dissection can be missed by TTE and TEE. When there is clinical suspicion of aortic dissection with enlargement or abnormal TTE images of the ascending aorta, further imaging should be performed promptly. In the majority of patients, the descending thoracic aorta is not adequately visualized to exclude aneurysmal dilatation or dissection by TTE. Thus, when descending aortic aneurysm or dissection is suspected, an alternative imaging modality is recommended.

The ascending aorta can be visualized and reliably measured by TTE in the majority of patients. At the time of initial evaluation, it is reasonable to confirm the size of the ascending aorta and exclude additional aneurysmal aortic disease using an alternative imaging modality. Importantly, aortic dilatation may be incompletely visualized because of imaging difficulties in select patients or because of development of disease in the descending thoracic or abdominal aorta; thus, periodic aortic imaging using TEE, CTA, or MRI is suggested in all patients with MFS.

Aortic imaging is limited in patients with MFS who have had prior aortic root replacement. Although routine TTE is used to assess ventricular and valve function in patients with MFS, regular aortic imaging using CTA or MRI is recommended.

Variations on Classic Anatomy

Patients with confirmed MFS may have a normal echocardiogram; alternatively, patients with echocardiographic features suspicious for MFS may not meet Ghent diagnostic criteria. There is a range of normal aortic dimensions, which are related to age and body surface area (see Fig. 21.6).

Ascending aortic enlargement at the sinus level is classic for patients with MFS; however, aortic enlargement and dissection can affect other parts of the aorta.

Common Associated Lesions and Findings

The revised Ghent criteria for MFS represent the diagnostic features which should be sought when clinical features are suspicious. TTE images demonstrate aortic sinus dilatation, mitral valve prolapse, or other cardiovascular features of MFS (see Table 21.1).

Key Findings That Alter Clinical Management

1.Marked ascending aortic dilatation (see Fig. 21.1)

2.Ascending aortic dissection (see Fig. 21.5)

3.Mitral valve prolapse with regurgitation (see Fig. 21.10)

4.Aortic valve regurgitation (see Fig. 21.11)

5.Descending aortic aneurysm or dissection (see Fig. 21.8)

Interventional and Postinterventional Imaging

Intraoperative TEE is routinely performed during operative intervention in patients with MFS and is particularly important for the patient undergoing valve-sparing aortic root replacement (see Fig. 21.13). Immediate postbypass assessment of the spared aortic valve function affects patient management. When more than mild aortic valve regurgitation is present following the valve-sparing operation, revision or valve replacement is commonly performed. Postbypass assessment of the replaced aortic valve function is also routinely performed to determine the prosthetic valve gradient. The aortic valve composite graft used in patients with MFS does not allow perivalvular regurgitation; thus, the postbypass imaging focuses on prosthetic valve function, gradient, and ventricular and native valve function.

Following the valve-sparing aortic root replacement (see Fig. 21.13), patients with MFS require regular reevaluation of the aorta as well as assessment of aortic valve function. There is a recognized risk of progressive aortic valve regurgitation following the valve-sparing aortic root replacement. A multicenter study funded by the National Marfan Foundation is ongoing to determine the durability of the valve-sparing versus valve replacement operation in patients with MFS undergoing aortic root replacement.

After the Bentall procedure (see Fig. 21.12), a comprehensive TTE evaluation of the aortic valve prosthesis and graft is recommended early after surgery to provide a fingerprint for future assessment of the prosthetic valve and aorta performance. Although the ascending aorta has been replaced, the remaining aortic segments remain vulnerable to aortic dilatation, dissection, or rupture, and regular reevaluation and aortic imaging are indicated.

Pseudoaneurysm of the aorta results from a tear or perforation in the aortic wall and subsequent leakage of blood from the aorta into a contained aneurysmal cavity. It is usually caused by prior operation, infection, or trauma and has been reported late after the Bentall operation. Because pseudoaneurysms tend to rupture, repair is usually recommended. A pseudoaneurysm has a different appearance from a true aneurysm, having a sharply demarcated rupture site where communication occurs between the aorta and the pseudoaneurysm (Fig. 21.19, Videos 21.5 and 21.6). Depending on the location and orientation, TTE or TEE may be able to identify the pseudoaneurysm. CTA or MRI can both be used for further delineation. Another uncommon late complication of both composite and valve-sparing operation is the development of coronary ostial aneurysms (Fig. 21.20, Videos 21.7 and 21.8). These aneurysms develop at the site of coronary artery reimplantation as a result of the postoperative stretch of the weakened aortic cuff of tissue around the coronary ostium and can be visualized by TTE, TEE, CTA, MRI, and standard aortography. Operative intervention is recommended for progressive dilatation.

Figure 21.19. Patient with Marfan syndrome and prior Bentall procedure. A: Parasternal short-axis imaging at the level of the aortic valve demonstrates an echo-free space adjacent to the graft (asterisk). B: The addition of color Doppler to the same image demonstrates flow into that space. C. ECG-gated computerized tomographic angiogram (CTA) in an oblique coronal plane demonstrates a pseudoaneurysm (black asterisk) arising just above the aortic prosthesis with a large amount of thrombus (white asterisk) present. D. Three-dimensional volume rendering demonstrates the size and location of the pseudoaneurysm (white asterisk) and residual dissection in the descending thoracic aorta. Ao, aorta; RA, right atrium; LV, left ventricle.

Potential Roles of Alternative Imaging Modalities

MRI and CTA allow visualization and assessment of the entire thoracic and abdominal aorta and therefore provide critical complementary information to TTE and TEE in the assessment of patients with MFS and related disorders. MRI or CTA should be performed at the time of initial assessment to confirm the size and extent of enlargement of the thoracic aorta and identify additional pathology, and periodically thereafter in the unoperated patient. Both radiologic imaging modalities and TEE have high sensitivity and specificity in the diagnosis of aortic dissection. However, MRI is less often performed in the acute situation because of safety concerns in critically ill patients, longer imaging duration, and less availability.

TEE can be used for serial imaging of the descending thoracic aorta. However, due to the importance of precise reevaluation of aortic size at multiple levels and comparison with prior imaging studies, CTA or MRI is preferred for following patients with descending thoracic aortic dissection or aneurysm because of the ability to make multiple serial aortic measurements at specific levels over time.

Patients with MFS with prior aortic surgery require regular surveillance of the descending thoracic and abdominal aorta by MRI or CTA. Due to the life-long need for aortic surveillance, MRI is preferred by many physicians and patients in an effort to avoid repeated radiation exposure related to CTA. However, CTA offers some advantages in certain circumstances and the newer scanning technologies have allowed for a dramatic decrease in the radiation doses, even with ECG-gated exams. An individualized imaging strategy is recommended.

Figure 21.20. A: 43-year-old patient with Marfan syndrome had a Bentall procedure 15 years before this imaging study. The patient had subsequent descending thoracic aortic replacement for an aneurysm. Routine transthoracic echocardiogram demonstrates a composite graft replacement of the ascending aorta (Bentall procedure) with normally functioning aortic mechanical prosthesis (arrowheads) and aneurysmal dilatation of the anastomosis of the right coronary artery with the aortic graft (CA) noted by two-dimensional (A) and color flow imaging (B). AoG, ascending aortic graft; CA, coronary artery; LA, left atrium; LV, left ventricle. C: ECG-gated computed tomography angiography demonstrates aneurysmal dilatation of the reimplanted coronary arteries (arrows).

SUMMARY

MFS is a multisystem inherited disorder of connective tissue. The life expectancy of untreated patients with MFS is markedly decreased compared to the general population, with an early study reporting the average life span to be about 32 years. However, advances in the understanding of the cause of MFS, as well as timely and accurate diagnosis and implementation of appropriate prophylactic therapy, have dramatically reduced the mortality and morbidity associated with this disorder. In the current era, the median cumulative probability of survival has increased to over 72 years.

TTE is the recommended screening tool for patients with suspected cardiovascular features of MFS, and the diagnosis of MFS may be confirmed based on the cardiovascular features identified by TTE. Echocardiographic imaging is recommended in the serial follow-up of patients with MFS to help identify the appropriate timing for aortic intervention. Additional CTA or MRI imaging is generally performed perioperatively in adults to plan the appropriate intervention. Intraoperative TEE plays a pivotal role in identifying surgical success and potential need for revision. Finally, TTE, in conjunction with CTA/MRI, is used for comprehensive life-long postintervention monitoring of the cardiovascular system.

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Questions

1.A mutation in which of the following genes is associated with a diagnosis of Marfan syndrome?

A.TGFBR1/2

B.FBN1

C.COL3A1

D.ACTA2

E.MYH11

2.A 22-year-old woman undergoes screening echocardiography and the sinus of Valsalva measures 47 mm (Z score 4.6). Her father and brother both have Marfan syndrome and have undergone aortic root replacement. She has a pectus carinatum deformity, pes planus, skin striae, and myopia. What additional testing is needed to make a diagnosis of Marfan syndrome in this patient?

A.Genetic testing for FBN1 mutation

B.Eye exam to look for ectopia lentis

C.No additional testing needed

D.Imaging of the spine to look for dural ectasia

E.MRI of the aorta

3.The patient in Question 2 undergoes genetic testing for the FBN1 mutation and no mutations are found. What is the correct interpretation?

A.Marfan syndrome is not present if the gene test is negative.

B.Marfan syndrome is not present because the systemic score is only 5.

C.Marfan syndrome is present based on the family history of Marfan syndrome and presence of aortic dilatation; genetic testing is not necessary to make the diagnosis.

D.The initial testing was wrong and should be repeated.

E.Additional genetic testing for FBN2 should be performed.

4.The patient in Question 2 was recently married and desires a pregnancy within the next two years. She asks for advice about the timing of pregnancy. What would you recommend?

A.Pregnancy is contraindicated in Marfan syndrome; she should be counseled about options for birth control.

B.Recommend valve-sparing root replacement prior to pregnancy.

C.Recommend mechanical composite root replacement prior to pregnancy.

D.Proceed with pregnancy at this time but initiate beta-blocker therapy.

E.Proceed with pregnancy at this time but initiate angiotensin receptor-blocker therapy.

5.A 28-year-old man with a history of ectopia lentis presents with aortic dissection. He is diagnosed with Marfan syndrome. Which members of his family should be screened?

A.All family members

B.Only his children

C.Only family members that share the same physical features (tall stature, facial features, etc.)

D.All first-degree relatives

E.All first- and second-degree relatives

6.A 60-year-old man presents for echocardiography one year after composite root replacement. The patient is asymptomatic and labs are normal. The aortic prosthesis and proximal graft appear normal, but the arch and proximal descending aorta are not completely visualized. Limited images of the abdominal aorta suggest a possible dissection flap. What is the next step?

A.Repeat the echo in one year

B.Add angiotensin receptor blocker (ARB) therapy

C.Perform TEE

D.Perform CTA or MRA of the thoracic and abdominal aorta

E.Perform dedicated ultrasound of the abdominal aorta

7.A 14-year-old girl presents for echocardiography due to family history of arterial dissections. Her mother had an aortic dissection at age 38 and a maternal aunt had a carotid artery dissection and splenic artery dissection. On exam she has hypertelorism and a bifid uvula. Echo reveals a mildly dilated ascending aorta (Z-score 2.1). What is the next step?

A.Repeat echo in six months

B.Repeat echo in one year

C.MRA brain, chest, abdomen and pelvis

D.Genetic testing for FBN1

E.Eye exam to evaluate for ectopia lentis

8.What genetic mutation would be expected in the patient in Question 7?

A.TGFBR1/2

B.FBN1

C.COL3A1

D.ACTA2

E.MYH11

9.A 32-year-old man with Marfan syndrome presents to the Emergency department with the sudden onset of severe, tearing chest pain. He is hemodynamically stable and labs are all normal. Transthoracic echo performed in the ED shows aortic root dilatation and moderate aortic valve regurgitation. Ascending aorta was incompletely visualized. What is the next best step?

A.Dismiss to home

B.Admit and rule out for MI with serial cardiac biomarkers

C.Treadmill stress test

D.Emergency coronary angiography

E.CTA, TEE, or MRI—whichever is most readily available

10.Aortic dilatation in the setting of a bicuspid aortic valve:

A.is an uncommon finding.

B.usually occurs at the sinus of Valsalva level.

C.occurs only when severe aortic stenosis is present.

D.can occur in patients with normal valve function.

E.is due to a mutation in FBN1.

Answers

1.Answer: B. Marfan syndrome is classically caused by a mutation in the fibrillin-1 gene (FBN1) on chromosome 15. Mutations in FBN1 increase susceptibility of fibrillin to proteolysis leading to fragmentation of microfibrils. Transforming growth factor beta (TGFB) binds to fibrillin and mutations in fibrillin are hypothesized to alter TGFB signaling. Mutations in the TGFB1/2 gene are responsible for Loeys-Dietz syndrome. Mutations in COL3A1 are responsible for the vascular type of Ehlers-Danlos syndrome. Mutations in ACTA2 are responsible for abnormalities in the smooth muscle alpha-2 actin. At least nine different mutations in ACTA2 have been described in patients with familial thoracic aortic aneurysm and dissection. MYH11 mutations have been described in patients with familial thoracic aortic aneurysms.

2.Answer: C. This patient meets criteria for diagnosis of MFS based on the revised Ghent criteria because she has aortic dilatation with a Z score >2 and a family history of MFS. Genetic testing for the FBN1 mutation is not necessary to make the diagnosis but can be helpful for counseling and screening of asymptomatic family members. An annual eye exam is important for detection of complications such as ectopia lentis, retinal detachment, glaucoma, or cataracts; but the finding of ectopia lentis is not necessary to make the diagnosis because the patient already has met the revised Ghent criteria as outlined above. The presence of dural ectasia would give two points toward the systemic score and is a sensitive but not specific sign for MFS and is commonly seen in Loeys-Dietz syndrome or vascular Ehlers-Danlos syndrome. MRI is helpful to confirm the dilatation of the aorta and to examine the entire aorta, but is not necessary to confirm the diagnosis.

3.Answer: C. The patient meets criteria for diagnosis of MFS based on the revised Ghent criteria because she has aortic dilatation with a Z score >2 and a family history of MFS. Genetic testing for the FBN1 mutation is not necessary to make the diagnosis but can be helpful for counseling and screening of asymptomatic family members. In this case, no mutation was identified and family members need to be screened with echocardiography. Mutations in FBN2 have been associated with congenital contractural arachnodactyly, not MFS.

4.Answer: B. Pregnancy in a patient with MFS is associated with increased cardiovascular risk, predominantly related to aortic dilatation and complications such as dissection. These most commonly occur in the third trimester or early postpartum period. The risk of complication is greatest if the aortic root diameter is greater than 40-45 mm before pregnancy. The 2010 Thoracic Aorta Guidelines recommend prophylactic aortic root replacement in women contemplating pregnancy if the aortic root is greater than 40 mm (class IIa recommendation). Pregnancy is not contraindicated in all MFS patients but a thorough discussion of the risks of aortic complication as well as the heritable nature of the disease should be discussed with the patient prior to pregnancy. In this case, the patient is at high risk of complications due to the size of her aorta. Continued observation could be considered appropriate if the patient did not desire pregnancy. Beta-blocker therapy should be initiated in patients with MFS and aortic dilatation and is safe to use during pregnancy, however this patient is at significant risk for complications during pregnancy and thus prophylactic root replacement should be performed prior to pregnancy. ACE inhibitors and ARBs are contraindicated during pregnancy.

5.Answer: D. All first-degree relatives of a patient with MFS or any of the inherited aortopathies should be screened for aortic disease. This can be done with echocardiography, and consideration of genetic testing should be offered to the patient. If the patient is found to have a causative genetic mutation, first-degree relatives can be screened for the mutation and then only those with the mutation require imaging of the aorta. Screening all family members is not cost effective. If a first-degree family member is found to have aortic disease, subsequent screening of their first-degree relatives is indicated and genetic consultation should be considered. Screening of this patient’s children is appropriate, but all first-degree relatives should be screened. Screening only family members with similar physical features is not recommended because the characteristic physical features may not be present in a patient with MFS. This was one of the reasons for revision of the Ghent criteria, to give more weight to the cardinal features of MFS—ectopia lentis and aortic dilatation.

6.Answer: D. Patients with Marfan syndrome and previous surgery on the ascending aorta are at risk for complications including aneurysm and dissection in the rest of the aorta. Both CTA and MRA provide the ability to visualize the entire aorta and look for complications in parts of the aorta that are incompletely visualized with TTE. Repeating a TTE in one year would not be a good option in a patient with possible new dissection in the abdominal aorta. Adding an ARB may be useful, but would not help diagnose the possible complication seen on TTE. TEE may be useful to better visualize the descending thoracic aorta, but the abdominal aorta would not be visualized. Dedicated ultrasound of the abdominal aorta may allow for more complete visualization and diagnosis of aneurysm or dissection, but would not allow for visualization of the descending thoracic aorta.

7.Answer: D. The findings are suggestive of Loeys-Dietz syndrome, and yearly imaging from the cerebrovascular circulation to the pelvis is recommended. MRA is the test of choice to avoid chronic exposure to radiation with CTA, but CTA could be performed if there was a contraindication to MRA.

8.Answer: A. Loey-Dietz syndrome is an autosomal dominant syndrome caused by mutations in the genes encoding the Type 1 or 2 subunit of the transforming growth factor-B receptor (TGFBR1 or 2). Mutations in FBN1 are associated with MFS, mutations in COL3A1 are associated with the vascular type of Ehlers-Danlos syndrome, and mutations in ACTA2 are associated with familial thoracic aortic aneurysm and dissection.

9.Answer: E. Aortic dissection needs to be excluded in all patients with Marfan syndrome presenting with acute onset of chest pain. TTE has reduced sensitivity for detection of aortic dissection, especially if images are challenging. CTA, MRA, and TEE all have similar sensitivity and specificity for diagnosing acute aortic syndromes. Selection of a modality should depend on patient variables and institutional capabilities, with a focus on immediate availability. CTA is performed most often due to the rapidity with which it can be obtained. TEE is sometimes chosen if the patient is too unstable to be transported for imaging. MRI is performed less often because it takes longer and frequently is not conveniently located near the Emergency department. The test that can be done in the shortest amount of time should be chosen, as prompt diagnosis and surgical intervention are important to optimize survival.

10.Answer: D. The aortopathy associated with the bicuspid aortic valve can occur even with normal valve function and is thought to be due to abnormalities in the aortic media. Dilatation of the aorta occurs in at least 50% of patients with bicuspid aortic valve and is most common at the level of the mid-ascending aorta, but can involve the aortic root or distal ascending aorta and arch. FBN1 mutations are associated with Marfan syndrome, not bicuspid aortic valve.