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Key Points

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  • Disease summary:

    • Thoracic aortic aneurysms (TAAs) are an enlargement of the aortic root, ascending aorta, or both; thoracic aneurysms can also involve the descending thoracic aorta but are not the focus of this chapter. Thoracic aortic dissections can originate at the ascending aorta (termed as type A dissection by the Stanford classification) or at the descending aorta just distal to the origin of the left subclavian artery (termed as type B dissection). This chapter reviews the heritable bases of thoracic aortic aneurysms and aortic dissections (TAAD), which are typically considered as a single genetic entity.

    • Approximately 20% of individuals with TAAD but without an identified genetic syndrome also have a first-degree relative with TAAD (termed familial thoracic aortic aneurysm and dissection or FTAAD).

    • FTAAD is primarily inherited in an autosomal dominant pattern with reduced penetrance and variable expressivity.

    • The clinical presentation of FTAAD is variable in terms of age of onset, aortic disease presentation, and associated features such as bicuspid aortic valve, patent ductus arteriosus, other arterial aneurysms, and occlusive vascular disease leading to early-onset stroke and coronary artery disease (CAD).

    • The clinical heterogeneity is due to underlying genetic heterogeneity, with seven genes identified to date for FTAAD.

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  • Differential diagnosis:

    • Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, Turner syndrome, aneurysms-osteoarthritis syndrome (AOS)

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  • Monogenic forms:

    • Mutations in the ACTA2, MYH11, MYLK, TGFBR1, TGFBR2, SMAD3, and FBN1 genes have been identified to cause FTAAD. Approximately 25% of FTAAD families have mutations in one of these genes. The identification of large families with FTAAD in which the phenotype is not linked to these genes confirms further genetic heterogeneity for this condition.

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  • Family history:

    • Approximately 20% of individuals with TAAD have a first-degree relative with TAAD. The 80% of patients without a family history are classified as “sporadic” TAAD.

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  • Twin studies:

    • No twin studies have been published for this disease.

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  • Environmental factors:

    • Hypertension and the presence of a bicuspid aortic valve (BAV) are the major risk factors for this disease. Other environmental risk factors include cocaine or other stimulant use, trauma, weight lifting, infections of the aortic wall. Pheochromocytoma, aortic coarctation, inflammatory vasculitis, and polycystic kidney disease are other conditions associated with thoracic aortic dissection.

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  • Genome-wide associations and copy number variant analysis:

    • Single-nucleotide polymorphisms (SNPs) in the linkage disequilibrium block at chromosome 15q21.1 are associated with sporadic TAAD. This block encompasses FBN1, the gene that causes Marfan syndrome. Recurrent duplications of 16p13.1 confer an 11-fold increased risk for TAAD.

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Diagnostic Criteria and Clinical Characteristics

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Diagnostic Criteria for TAAD

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Diagnostic evaluation should include at least one of the following:

  • Enlargement of the aortic root at the sinuses of Valsalva and/or the ascending aorta based on age, gender and body surface area.

  • Aortic dissection involving the ascending and/or the descending thoracic aorta.

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