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  Disease summary:

  
  
  
  
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    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.

    
    
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    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).

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

    
    
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    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).

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

  
  

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  Differential diagnosis:

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

  
  

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  Monogenic forms:

  
  
  
  
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    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:

  
  
  
  
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    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:

  
  
  
  
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    No twin studies have been published for this disease.

  
  

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  Environmental factors:

  
  
  
  
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    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:

  
  
  
  
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    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.

  
  

Diagnostic Criteria for TAAD

Diagnostic evaluation should include at least one of the following:

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

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

Familial TAAD is based on the diagnosis of TAAD in at least two first- or second-degree members of a family in which the affected members do not have the features of a known syndrome.

The presence of syndromic features may be diagnostic for the following conditions:

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

Clinical Characteristics

The major diseases affecting the ascending thoracic aorta are aortic aneurysms (defined as a localized, permanent dilatation of an artery) and acute aortic dissections, collectively designated as TAAD. TAAs may involve the aortic root at the level of the sinuses of Valsalva, the ascending thoracic aorta, or both. The natural history of TAAs is to asymptomatically enlarge over time until an acute tear in the intimal layer leads to an ascending aortic dissection (termed as Stanford type A dissections). With dissection, blood penetrates into the aortic wall and separates the aortic layers, which can lead to aortic rupture and other complications. Type A aortic dissections cause sudden death in up to 40% of individuals, while survivors have a 1% per hour death rate until they undergo emergent surgical repair. Less-deadly aortic dissections originate in the descending thoracic aorta just distal to the branching of the subclavian artery (Stanford type B dissections) and are also part of the TAAD disease spectrum. Therefore, clinical and genetic predictors are needed to identify who is at risk for TAAD.

It has been recognized for many years that there are genetic syndromes that predispose individuals to TAAs and dissections. Most prominent among these syndromes is Marfan syndrome where virtually every affected patient will have a TAA primarily involving the aortic root during their lifetime. Marfan syndrome arises from mutations in the FBN1 gene encoding fibrillin and is characterized by ocular, musculoskeletal, integumentary, and other cardiovascular features. More recently, Loeys-Dietz syndrome due to mutations in the genes for the transforming growth factor receptors type I and II, TGFBR1 and TGFBR2, respectively, has been described with musculoskeletal, cutaneous, and craniofacial features, along with arterial tortuosity, aneurysms, and dissections. Additionally, mutations in TGFBR2 confer a high risk for aortic dissections at smaller aortic diameters; some reports indicate that TGFBR1 mutations confer a similar risk. Recently a new syndromic form of TAAD due to SMAD3 mutations, referred to as AOS, and characterized by arterial aneurysms and tortuosity, early-onset joint disease such as osteoarthritis, and mild craniofacial abnormalities including hypertelorism and abnormal uvula has been described.

A majority of individuals with TAAD do not have a characterized genetic syndrome and approximately 20% of these individuals have a first-degree relative with TAAD. A predisposition to TAAD in the absence of syndromic features can be inherited in an autosomal dominant manner with decreased penetrance and variable expression, termed as FTAAD. FTAAD exhibits clinical heterogeneity which is apparent in the variation observed within and among families in the following areas: age of onset, location of the TAAs, aortic disease presentation, and progression, risk for early dissection, and associated features, such as BAV, patent ductus arteriosus, abdominal aortic aneurysms, aneurysms, and/or dissections of other arteries (including intracranial aneurysms), and occlusive vascular diseases including early-onset stroke and CAD. Mutations in seven genes have been identified to cause nonsyndromic familial TAAD: ACTA2, MYH11, MYLK, TGFBR1, TGFBR2, SMAD3, and FBN1, which are responsible for approximately 25% of families with FTAAD. The clinical variability of FTAAD and the identification of multiple genes and loci associated with the disease confirm the genetic heterogeneity of FTAAD.

Screening

In FTAAD families, individuals at risk for inheriting the presumed defective gene predisposing to TAAD should be imaged for aortic disease. If TAAD in the family is associated with only aortic root aneurysms involving the sinuses of Valsalva, echocardiography may be sufficient to screen and monitor aortic disease in at-risk individuals. If the aneurysms involve the ascending aorta, computed tomography (CT), or magnetic resonance (MR) imaging may be necessary to adequately visualize on the ascending aorta. If there are associated features present in the family, such as intracranial and other arterial aneurysms or BAV, then at-risk family members need to be screened for these diseases also.

The relatives of individuals presenting with sporadic TAAD who do not have a family history or syndromic features are also at an increased risk for TAAD. Current recommendations are to screen the first-degree relatives of these patients for aortic disease, especially in patients presenting with TAAD under the age of 55 years.

Molecular genetic testing for ACTA2 mutations, which are responsible for 10% to 14% of familial aortic disease, is recommended in patients with FTAAD. Sequencing of the other six genes (TGFBR1, TGFBR2, MYH11, FBN1, MYLK, and SMAD3) may be considered in individuals with TAAD and other clinical findings associated with mutations in these genes. Genetic testing should also be considered for patients with early-onset sporadic TAAD without other predisposing factors.

Counseling