Patient Resources

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GenTAC Alliance Patient Resources: Introduction

Welcome to the GenTAC Alliance. The GenTAC Alliance consists of a team of experts dedicated to caring for patients with genetically-triggered (or heritable) conditions of the aorta, which is the largest artery in the body (see diagram below).

The members of the GenTAC Alliance have compiled a list of descriptions of the most common genetic aortic conditions and some available resources for additional information. Click on the following conditions to learn more about each condition, the features are associated with the condition, testing that is typically done for each condition, treatment, exercise guidelines, concerns regarding pregnancy, and signs and symptoms that might require emergency treatment.

  1. Marfan syndrome                        
  2. Loeys-Dietz syndrome
  3. Vascular Ehlers-Danlos syndrome
  4. Familial Thoracic Aortic Aneurysm and Dissection
  5. Turner syndrome
  6. Bicuspid aortic valve
  7. Genetic testing for Hereditary Thoracic Aortic Aneurysm Disease (HTAD)
  8. Glossary

 

The aorta is the largest artery in the body and carries blood away from the heart to the rest of the body (Figure 1). The size of the aorta is dependent upon one’s age, sex and body size. Disorders of the aorta often cause the aorta to enlarge or dilate. When the aorta enlarges significantly, this is called an aortic aneurysm (Figure 2). An aortic aneurysm in the chest cavity is known as a thoracic aortic aneurysm. 

This images shows the aorta and its branches throughout the body.

 

Figure 1. The aorta and its branches (courtesy of Mayo Clinic)

This figure shows two different images. Image A shows a circulatory system demonstrating aneurysm of the ascending aorta.  Image B shows the aorta and its branches with ascending aortic aneurysm.

 

Figure 2.  A. Circulatory system demonstrating aneurysm of the ascending aorta (arrow).  B. The aorta and its branches with ascending aortic aneurysm (arrow) (Courtesy of Mayo Clinic)

There are many causes of thoracic aortic aneurysms. Aortic aneurysms may be due to acquired conditions such as degenerative (due to atherosclerosis) disease or inflammatory conditions (such as aortitis or infections) or may be related to an underlying genetic aortic condition (known as a hereditary or heritable aneurysm).  Hereditary thoracic aortic aneurysm conditions may be passed from a parent to a child Figure 3).

Figure 3. Thoracic Aortic Aneurysm disease has many causes.

This images depicts a tree of the different causes of Thoracic Aortic Aneurysm disease, starting with Thoracic Aortic Aneurysm Disease (TAD) at the top. One branch underneath TAD leads to Acquired followed by two more branches titled Degenerative or Atherosclerotic and Inflammatory (aortitis). The other branch underneath TAD is Heritable (caused by genetic factors), followed by two more branches titled, Syndromic and Non-syndromic.

The wall of the aorta has 3 layers (Figure 4).  One function of the aorta wall is to maintain the strength of the aorta.

This image shows the wall of the aorta which consists of 3 layers: the intima, media, and adventitia. The intima is the innermost layer; the media, the middle layer; the adventitia, the outer later. This image also shows an aortic dissection which occurs when blood enters the wall of the aorta through a tear or split in the intima.

Figure 4. The wall of the aorta consists of 3 layers: the intima, media, and adventitia. The intima is the innermost layer; the media, the middle layer; the adventitia, the outer later. An aortic dissection occurs when blood enters the wall of the aorta through a tear or split in the intima. (From the International Registry of Acute Aortic Dissection (IRAD), iradonline.org)

Hereditary thoracic aortic aneurysm conditions lead to abnormal structure and strength of the aortic wall and cause the aortic wall to weaken and lead to aneurysm formation. Thoracic aortic aneurysm can be seen by echocardiogram (shown in Figure 5), CT scan or MRI. 

This figure shows echocardiographic images of the aortic root and ascending aorta. Image A shows a normal aorta with measurements. Image B shows dilatation of the ascending part of the aorta, as often seen in Turner syndrome, BAV and nonsyndromic heritable thoracic aortic aneurysm disease (HTAD). Image C shows dilatation of the sinuses of Valsalva, as often seen in Marfan syndrome and Loeys Dietz syndrome (and can be present in nonsyndromic HTAD and BAV).

Figure 5. Echocardiographic images of the aortic root and ascending aorta. A: Normal aorta with measurements. B: Dilatation of the ascending part of the aorta, as often seen in Turner syndrome, BAV and nonsyndromic heritable thoracic aortic aneurysm disease (HTAD). C: dilatation of the sinuses of Valsalva, as often seen in Marfan syndrome and Loeys Dietz syndrome (and can be present in nonsyndromic HTAD and BAV)

 

This images shows an aortic root aneurysm and aortic dissection. The arrow denotes the tear (dissection) in the dilated aortic root.

Figure 6. Aortic root aneurysm and aortic dissection. The arrow denotes the tear (dissection) in the dilated aortic root (From Setty R, et al. Int J Surg Case Reports: 2018; 63: 113-117.)

The basic unit of heredity is a gene.  A gene is a section of DNA with a specific function (Figure 7).  Our genes provide instructions for the proper development and function of our body’s organ systems. A harmful change in the DNA of one gene is called a pathogenic variant (or mutation) (Figure 8).

A mutation in a gene can cause a person to develop an aortic aneurysm or aortic dissection. The GenTAC Alliance has as one of its missions to further research and education about genetically triggered (hereditary or heritable) thoracic aortic aneurysm conditions.

A single mutation in a gene can cause one or multiple physical changes in the body.  When a genetic mutation leads to a recognizable pattern of changes in the body, the condition is called a syndrome. One example of a syndrome is Marfan syndrome that is caused by a pathogenic variant (mutation) in the FBN1 gene.  In Marfan syndrome, one can recognize physical features including tall stature, elongated arms and legs, chest wall deformities, nearsightedness, dislocation of the eye lenses, etc.

This images shows the structure of DNA. The sugar phosphate backbone and the base pairs ladders of the DNA structure are shown. The image also shows the make-up on latters, with adenine and thymine sharing one ladder and guanine and cytosine sharing the others.

 

Figure 7. DNA structure (from the U.S. National Library of Medicine)

 

This figure shows an example of a missense mutation in a gene.  The DNA codes for an amino acid sequence.  When a change in the DNA base occurs (the A is replaced by a C in this example), an incorrect amino acid is made, which leads to abnormal protein structure and function.

Figure 8. Example of a missense mutation in a gene.  The DNA codes for an amino acid sequence.  When a change in the DNA base occurs (the A is replaced by a C in this example), an incorrect amino acid is made, which leads to abnormal protein structure and function.

Some hereditable thoracic aortic aneurysm conditions cause aneurysm disease but do not lead to other outward features of a syndrome.  These are called nonsyndromic thoracic aortic aneurysm diseases (or familial thoracic aortic aneurysm [FTAA] diseases).

Marfan syndrome is caused by mutations in the FBN1 gene, the gene that makes the important connective tissue protein, fibrillin-1. Please click on this link to learn more about Marfan syndrome.

Loeys-Dietz syndrome is caused by a pathogenic variant (mutation) in one of several genes (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3) that are important in the TGF-β signaling pathway. Please click on this link to learn more about Loeys-Dietz syndrome.

Vascular Ehlers-Danlos syndrome is caused by pathogenic variants in the COL3A1 gene, a gene that makes a specific type of collagen. Please click on this link to learn more about Vascular Ehlers-Danlos syndrome.

Familial thoracic aortic aneurysms (FTAA) or familial thoracic aortic aneurysm and dissections (FTAAD) are conditions caused by pathogenic variants in genes that lead to aortic aneurysm or aortic dissections. Generally, these conditions do not cause physical changes in other parts of the body, but in some individuals may lead to brain (cerebral) aneurysms.  Multiple different genes have been identified to lead to FTAA, including many of the genes that also cause the syndromes mentioned above. Please click on this link to learn more about FTAA.

Turner syndrome is a genetic condition in which a female is born with only one X-chromosome or is missing parts of the X chromosome.  Individuals with Turner syndrome have an increased risk of bicuspid aortic valve as well as diseases of the aorta (aortic aneurysm and aortic coarctation). Please click on this link to learn more about Turner syndrome.

Bicuspid aortic valve (BAV) is the condition in which the aortic valve is made up of only 2 leaflets instead of the normal 3-leaflet valve.  BAV is associated with important aortic diseases including ascending thoracic aortic aneurysm, coarctation of the aorta and aortic dissection.  While the great majority of people with BAV and aneurysm disease are not found to have a genetic mutation, BAV disease may run in families.  Please click this link to learn more about bicuspid aortic valve.

Genetic testing is available for genetically triggered thoracic aortic conditions and may be very important in the evaluation and management of many of these conditions. Please click this link to learn more about genetic testing in hereditary thoracic aortic aneurysm disease (HTAD). Please click on this link to learn more about genetic testing.

Because all of these conditions can lead to a weakening of the aortic wall leading to an aortic aneurysm and/or a risk of an aortic dissection, there are important recommendations about medical care, surgery and lifestyle modifications that apply to people with hereditary thoracic aortic aneurysm conditions. Please see each section for general guidelines.