Aortopathies in Pediatric Cardiology and Cardiac Surgery

Marfan Syndrome

First described in 1896, MFS is an inherited disorder resulting from mutations in the FBN1 gene; it most commonly affects the ocular, skeletal, and cardiovascular systems. Although the syndrome is most commonly inherited in an autosomal dominant pattern, approximately 25% of cases result from de novo mutations. MFS has a prevalence of 1 in 5000 to 10,000 individuals. The syndrome is characterized by a high degree of clinical variability, although ocular, cardiovascular, and skeletal manifestation are the true hallmark of this disorder.

Up to 90% of patients with a clinical diagnosis of MFS have mutations in FBN1 , which codes for fibrillin-1, a structural component of ECM microfibrils that provide mechanical stability and critical elastic properties to connective tissues. Furthermore, recent studies suggest that the fibrillin-deficient state of MFS leads to upregulation of the effects of the cytokine transforming growth factor beta, which then results in dysregulation of this signaling cascade. This derangement in signaling is thought to be responsible for the diverse and variable phenotypic expression of the disease. Several hundred FBN1 mutations responsible for altered fibrillin-1 structure have been reported, although no major correlation between the specific mutation and subsequent phenotypic manifestations have been identified. Furthermore, clinical variability exists even in patients with identical genotypic mutations, suggesting a potential role of modifier genes in the phenotypic expression of MFS.

The clinical diagnosis of MFS is based on the revised Ghent criteria ( Box 58.1 ). These diagnostic criteria place a greater emphasis than in previous versions on cardiovascular manifestations. The cardinal features of MFS based on the Ghent nosology are aortic root aneurysms and ectopia lentis. In the absence of family history, the presence of these two clinical manifestations is sufficient for the diagnosis of MFS. In the absence of either aortic root aneurysm or ectopia lentis, the presence of an FBN1 mutation or a combination with a systemic score 7 is sufficient for diagnosis. With a positive family history, an isolated finding of ectopia lentis, aortic root enlargement, or a systemic score equal to or greater than 7 suffices for diagnosis.

Cardiovascular pathology is the leading cause of morbidity and early mortality in MFS. The most prominent cardiovascular manifestations of MFS are mitral valve prolapse and aortic dilation. Mitral valve prolapse in MFS is thought to develop as a result of fibromyxomatous changes in the leaflets and chordae tendineae, calcification of the annulus, abnormal annular compliance and distensibility, and in some cases mitral valve enlargement. These abnormalities result in the prolapse of leaflets followed by mitral regurgitation and, in severe cases, rupture of the chordae tendineae. Mitral valve pathology is the most common structural heart pathology encountered in MFS, but tricuspid valve prolapse, dilation of the proximal pulmonary artery, supraventricular arrhythmias, and impaired systolic and diastolic left ventricular function are not uncommon. FBN1 mutations also lead to the formation of arterial aneurysms, particularly of the ascending aorta. Although the walls of the entire arterial tree are weakened, dilation most commonly occurs at the sinuses of Valsalva. As the weakened proximal aorta dilates, coaptation of the aortic valve leaflet diminishes and central regurgitation ensues. Eccentric regurgitation is seen when asymmetric enlargement of the root or prolapse of the cusp develops. These changes in the proximal aorta make aortic pathology the leading cause of mortality in MFS.

Although most patients with MFS present in late childhood or adolescence, a more severe form of MFS (infantile MFS) has been described. This typically presents with early onset of cardiovascular disease as well as severe skeletal manifestations, chest wall deformities, arachnodactyly, hyperextensible joints, micrognathia, and various ocular pathologies. The most salient and life-threatening feature of infantile MFS is its aggressive cardiac and vascular phenotype. As many as 61% of infants with this syndrome will have substantial cardiac abnormalities, with the most common being mitral valve prolapse and annular enlargement; these can, in turn, result in severe congestive heart failure, with failure to thrive and ventilator dependence. In early series investigating infantile MFS, mitral valve prolapse was identified on echocardiography in the majority of these children, with almost all of these progressing to various degrees of mitral regurgitation. Thirty percent of these children will also manifest substantial proximal aortic root dilatation.

Nonsurgical cardiovascular management of MFS typically focuses on close follow-up of the vascular tree aimed at the monitoring of aortic diameters and prevention of dissection or rupture. In addition, medical management with losartan and β-blockers is part of the routine long-term nonsurgical management strategy, although the clinical evidence for the efficacy of drug therapy is surprisingly weak, particularly in children. Longitudinal imaging, afterload reduction, and congestive heart failure management are the cornerstone of medical therapy of mitral valve regurgitation, which remains the most common cardiovascular abnormality in these patients. Guidelines for cardiovascular surveillance, indications for surgical intervention, and clinical follow-up strategies are discussed further on.

Over the past 5 decades, the life span of patients with MFS has markedly improved, largely due to advances in both the medical and surgical management of the cardiovascular manifestations of the disease. With appropriate medical surveillance and, when necessary, surgical intervention, the life expectancy of patients with MFS now approaches that of the general population. However, this improvement in outcome is maximized when the patient receives comprehensive cardiovascular care by a multidisciplinary team with extensive knowledge and experience in the care of patients with CTDs.