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.6,15 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.19 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.1 Loeys-Dietz Syndrome LDS is an autosomal dominant CTD characterized by aortic aneurysms and generalized arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate that was first described in 2005.20–22 Although the clinical features of this disorder share some similarities with MFS, LDS is caused by mutations in the genes encoding the transforming growth factor beta receptor 1 (TGFBR1) or 2 (TGFBR2).23,24 Additional syndromic features may include craniosynostosis, Chiari malformation, club feet, patent ductus arteriosus, and the potential for aneurysmal enlargement or dissection throughout the arterial tree.11 In contrast to MFS, LDS less commonly presents with long bone overgrowth or lens dislocation Additionally, aortic aneurysms in LDS tend to have accelerated growth as compared with those observed in MFS As a consequence of this highly malignant vascular phenotype, children with LDS tend to present for surgical intervention at a younger age LDS results from mutations in the mothers against the decapentaplegic homolog 3 (SMAD3) gene and the transforming growth factor β2 ligand gene (TGFB2), which lead in turn to anomalies of TGFBR1 and/or TGFBR2 Chromosomal deletions are responsible for these malformations, and the size of the microdeletion is thought to correlate with the broad spectrum of clinical presentations in LDS.20 Although LDS can be divided into four types based on the specific mutation, significant clinical variability exists within and between individuals of each type; therefore guidelines for management and treatment are similar across all types The main organ systems affected in LDS include the skeletal, craniofacial, cutaneous, and cardiovascular systems Indications for surgical intervention are detailed in subsequent sections, but compared with MFS, arterial dissection can occur at diameters smaller than those seen in MFS, implying a need for earlier surgical intervention in LDS.1,11 Arterial tortuosity is observed throughout the entire arterial tree, and resulting complications may occur at any location Therefore frequent and comprehensive surveillance as well as early surgical intervention are warranted Originally LDS patients were categorized into two types depending on the prevalence and severity of craniofacial (type 1) or cutaneous features (type 2) However, more recently, four types of LDS have been described based on genotype (Table 58.1).20 LDS types 1 and 2 have significant craniofacial anomalies and the most severe cardiovascular manifestations of disease Type 4 is the least severe form of LDS in terms of risk of cardiovascular catastrophe The various subtypes of LDS, associated genetic mutations, and phenotype characteristics are summarized in Table 58.1 Table 58.1 Loeys-Dietz Syndrome Subgroup Classification System Subtype Gene TGFBR1 TGFBR2 SMAD3 TGFB2 Other Disorders Reported Thoracic aortic aneurysm and dissection Thoracic aortic aneurysm and dissection, Marfan syndrome type 2 Aneurysms-osteoarthritis syndrome Aortic and cerebral aneurysm, arterial tortuosity, and skeletal manifestations Rapidly progressive aortic aneurysmal disease is a distinctive feature of LDS.20 Aortic dissection has been reported in children as young as 3 months.21 The initial reports of LDS types 1 and 2 described a mean age of death of 26.1 years, with aortic dissection and cerebral hemorrhage as the primary causes of death.24 Although improvements in diagnosis, surveillance, and early interventions have improved the life span of affected individuals, the severity of the cardiovascular manifestations of LDS cannot be overstated Congenital heart defects such as bicuspid aortic valve, atrial septal defects, and patent ductus arteriosus are more commonly seen in children with LDS types 1 and 2 as compared with the general population In addition to mitral valve prolapse and dysfunction, pulmonary root dilation and tricuspid valve regurgitation have been observed Of note, children with LDS may require aortic or mitral valve interventions even without the presence of aortic root dilation.20 Atrial fibrillation, ventricular hypertrophy, ventricular arrhythmias, and heart failure have also been described In view of the wide range of rapidly progressive cardiovascular disease, individuals diagnosed with LDS require echocardiography at frequent intervals (every 6 to 12 months) to monitor the status of the heart valves, aortic root, and ascending aorta.20 Additionally, frequent imaging with magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) with threedimensional reconstruction is recommended to monitor the entire arterial tree for aneurysmal enlargement and dissection Although MRA and CTA may expose the patient to ionizing radiation and anesthesia, serial imaging is critical to the prevention of cardiovascular catastrophe Many advocate for surveillance CTA or MRA every 1 to 2 years depending on the severity of disease Williams and colleagues reported that 33% of their originally reported surgical cohort of LDS 1 and 2 required multiple vascular surgical interventions, highlighting the need for judicious lifelong surveillance.21 The management of children with LDS mirrors that of MFS and is summarized in Box 58.2 However, given the aggressive nature of disease, thresholds for intervention tend to be lower than with MFS Well-defined guidelines for surgical intervention are limited and vary slightly based on the type of LDS and the severity of disease Aortic dissections have been reported in individuals with maximal aortic diameters of less than 4.0 cm in LDS types 1, 2, or 3 and at less than 5.9 cm in LDS type 4 Therefore, given the aggressive nature of the disease and the relatively low rate of complications with proximal aortic surgery in experienced centers, aortic root replacement is indicated when the root diameter reaches a threshold of 4.0 cm for LDS types 1 and 2 In children with LDS type 3, which is caused by mutations in the SMAD3 gene and is moderately aggressive, aortic root replacement is recommended for aneurysms between 4.0 and 4.5 cm in size LDS type 4 is the mildest phenotype and