Diagnostic Syndromes and Associated Aortopathy The most common connective tissue diseases affecting the cardiovascular system include Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS), osteogenesis imperfecta (OI), and nonsyndromic conditions such as familial thoracic aortic aneurysmal disease All CTDs carry varying degrees of risk for aortic dissection and other cardiovascular pathology; as such, they require close surveillance and management to avert the risk of cardiovascular catastrophe Patients with CTDs and proximal aortic aneurysms will often require aortic root replacement to prevent aortic dissection or rupture, often warranting surgical intervention at an early age Although children and young adults with bicuspid aortic valves, conotruncal abnormalities, Turner syndrome, and other anomalies may require surgical replacement of the proximal aorta (see disease-specific chapters in this text), they do not fall into the CTD syndromes described in detail later Marfan Syndrome First described in 1896,7 MFS is an inherited disorder resulting from mutations in the FBN1 gene; it most commonly affects the ocular, skeletal, and cardiovascular systems.8,9 Although the syndrome is most commonly inherited in an autosomal dominant pattern, approximately 25% of cases result from de novo mutations.9 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-1,1 a structural component of ECM microfibrils that provide mechanical stability and critical elastic properties to connective tissues.10 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.11 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.11 The clinical diagnosis of MFS is based on the revised Ghent criteria (Box 58.1).12 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.10,13 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.13 Box 58.1 Criteria for Marfan Syndrome Diagnosis From the Revised Ghent Criteria In the Absence of Family History Ao z-score ≥2 and ectopia lentis = MFS Ao z-score ≥2 and fibrillin-1 mutation = MFS Ao z-score ≥2 and systemic score ≥7 = MFS Ectopia lentis and fibrillin-1 mutation = MFS In the Presence of Family History Ectopia lentis and a family history of MFS = MFS Systemic score ≥7 and family history of MFS = MFS Ao z-score ≥2 (>20 years), ≥3 (