examination of the ascending aorta reveals degeneration of the elastic fibers, socalled cystic medial necrosis, which is most severe in patients with aneurysms The leaflets of the aortic valves contain increased amounts of acid mucopolysaccharide The mitral valvar annulus is dilated and may become calcified Pulmonary arterial dilation and aneurysm formation have also been reported.201 The ECG may show signs of left ventricular and left atrial enlargement when there is significant valvar insufficiency Disturbances of rhythm—such as first-degree atrioventricular block, atrial ectopic beats, atrial flutter, fibrillation, and tachycardia—are common Ventricular arrhythmias are present in about one-third of the patients during childhood Progressing with age, they appear to be closely related to mitral valve prolapse.202 Radiographic examination of the cardiac shadow is difficult in the presence of thoracic skeletal deformities Cardiac enlargement may be seen in the presence of valvar insufficiency and dilation of the ascending aorta Serial echocardiographic evaluation is essential Mitral valve prolapse is a very frequent finding Dilation of the aortic root, sometimes with paradoxical motion of the posterior aortic wall, is common Mitral and aortic incompetence will lead to left atrial and left ventricular volume overload Doppler echocardiography should increase the early diagnosis of the valvar abnormalities Cardiac magnetic resonance studies have also become part of the regular assessment of patients with aortopathy to monitor the degree and extent of aortic dilation and associated vascular abnormalities Such studies have also demonstrated decreased aortic distensibility and increased stiffness in children with Marfan syndrome.203 Imaging is recommended 6 months following diagnosis If the aortic root size is stable and less than 4.5 cm, yearly imaging is recommended If aortic root dimensions are greater than 4.5 or there is rapidly progressive dilation (>0.5 cm per year) more frequent imaging is likely needed The pathophysiology of dilation of the aortic root is likely due to a complex interplay between altered vascular mural composition and other destructive processes The defective collagen renders the arterial walls less distensible, but this alone has not proven to lead to arterial dilation The dilation itself may be related to apoptosis of vascular smooth muscle cells, which has been shown to be related to angiotensin II receptor signaling pathways.204 Additionally, defective microfibrils result in excessive activity of transforming growth factor (TGF)-β, which is normally regulated by latent TGF-β binding proteins bound to microfibrils This excessive TGF-β signaling leads to disordered formation of the matrix and may be a principal cause of the vascular dilation found in these patients.205 Patients with Loeys-Dietz syndrome and other disorders similar to Marfan syndrome have been found to have defects in the gene encoding the TGF-β receptor.206 The complex interplay between fibrillin, microfibrils, latent TGF-β binding proteins, TGF-β, and the TGF-β receptor probably accounts for the wide clinical variability in Marfan syndrome and other related disorders Life expectancy is very variable Death usually occurs in the fourth decade, mainly from cardiovascular causes.207 Cardiac failure, dissection or aneurysms of the aorta, and sudden death are the most frequent causes Incompetence of both mitral and aortic valves carries a poor prognosis There is no specific treatment for this condition Cardiac failure is best treated with diuretics and vasodilators, since the positive inotropic effects of digoxin may further damage the aortic root Surgical replacement of the diseased valves and of the ascending aorta may be necessary The timing of surgery for repair or replacement of valves or replacement of the aortic root must be decided in light of the known risks of surgery as well of the risks of not performing surgery Elective replacement of the aortic root can be accomplished with a relatively low risk of mortality.208 On the other hand, replacing the aortic root emergently due to acute dissection carries a much higher risk of short- and long-term mortality.209 Early recommendations suggested elective replacement when the root reached an absolute diameter of 60 mm Many patients suffer dissections at sizes significantly smaller than this, and an annual risk of mortality of nearly 5% has been described for patients with an aortic root greater than 50 mm.210 Surgery is currently recommended for an external root diameter greater than 5.0 cm If there is rapid dilation, family history of earlier dissection, or clinically significant aortic regurgitation, prophylactic repair may be considered earlier Due to the increased risk of dissection in pregnancy, prophylactic repair in women may be considered at an aortic root dimension greater than 4.0 cm.211 In addition, procedures that allow for replacement while maintaining the native aortic valve have been evaluated and appear to be satisfactory, potentially eliminating the need for chronic anticoagulation.212,213 Prophylactic β-blockade has been used to slow the progression of aortic dilation and is recommended in all guidelines More recently, angiotensin receptor blockers and angiotensin converting enzyme inhibitors have also been used alone or in combination with a β-blocker However, in a recent randomized controlled study comparing atenolol with losartan there was no clinically significant difference in the progression of aortic root dilation over a 3-year period In both groups the aortic root z-score decreased significantly over time, and this effect was more pronounced in younger patients.214 Infantile Marfan Syndrome An infantile variant of Marfan syndrome is seen on rare occasions The skeletal and ocular manifestations are similar to the adult forms but the cardiovascular features are distinct.215 There is marked myxomatous thickening and redundancy of the leaflets of the mitral and tricuspid valves, with elongation of the tendinous cords leading to severe valvar insufficiency Morbidity and mortality are primarily related to mitral and tricuspid valvar disease as opposed to aortic dissection and rupture, as seen in the adult form.216 Additionally, patients with the infantile syndrome frequently exhibit pulmonary emphysematous changes Neonates with the infantile syndrome present with CHF that responds poorly to conventional therapy Death often occurs within the first 2 years of life, although surgical repair of mitral valve disease at this age is feasible A family history of Marfan syndrome is much less common in infants who present with severe cardiovascular symptoms early in life.217 Most mutations resulting in the infantile syndrome occur between exons 24 and 32 in the fibrillin gene Loeys-Dietz Syndrome Loeys-Dietz syndrome was first described in 2005 in a cohort of 10 families caused by mutations in the TGFBR1 or TGFBR2 gene It is characterized by hypertelorism, bifid uvula, and/or cleft palate as well as and generalized arterial tortuosity (Fig 59.4) with ascending aortic aneurysmal formation and dissection.218 There is some phenotypical overlap with Marfan syndrome, but the hypertelorism, palatal involvement, and widespread arterial changes help to differentiate this from Marfan syndrome and similar disorders Recognition of this disease is critical, as early evaluation for aortic aneurysm formation may lead to operation at a young age Because of the aggressive nature of root dilation and high risk for dissection at smaller aortic dimensions, replacement is recommended at diameters of 4.0 cm in adults and at even smaller diameters in children.219 Patients with Loeys-Dietz should have imaging at diagnosis and 6 months after diagnosis Due to risk for aneurysms in other vessels not seen by echocardiography, they should also have yearly magnetic resonance imaging