Familial thoracic aortic aneurysm and dissection

Familial thoracic aortic aneurysm and dissection (familial TAAD) is a disorder that involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax).

In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers.

Aortic dilatation is generally the first feature of familial TAAD to develop, and it may appear in early childhood or later. People with familial TAAD may develop aneurysms or aortic dissections at any time during their life. The occurrence and timing of these abnormalities may vary even within the same family.

Aortic aneurysms typically have no symptoms. Aortic dissections usually cause severe, sudden chest pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias), or paralysis.

Both aortic aneurysms and dissections increase the risk that the aorta will suddenly tear open (rupture), causing massive internal bleeding. Without surgery to prevent aortic rupture, these blood vessel abnormalities can be life threatening.

Familial TAAD is usually not associated with other signs and symptoms. Occasionally, affected individuals may develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have congenital heart abnormalities, a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries).

Familial TAAD is believed to cause about 20 percent of thoracic aortic aneurysms and dissections. These abnormalities may also be caused by damage to the walls of the aorta from aging, tobacco use, injury, or disease.

While aortic aneurysms are common worldwide, it is difficult to determine their exact prevalence because they usually cause no symptoms unless they rupture. Ruptured aortic aneurysms and dissections are estimated to cause almost 30,000 deaths in the United States each year.

Mutations in any of several genes are associated with familial TAAD. Mutations in the ACTA2 gene have been identified in 14 percent of people with this disorder, and TGFBR2 gene mutations have been found in 2.5 percent of affected individuals. Mutations in other genes are believed to account for a smaller percentage of cases.

The ACTA2 gene provides instructions for making a protein called smooth muscle alpha (α)-2 actin, which is part of the actin protein family. Actin proteins are important for cell movement and the tensing of muscle fibers (muscle contraction).

Smooth muscle α-2 actin is found in vascular smooth muscle cells. Layers of these cells are found in the walls of the aorta and other blood vessels that carry blood from the heart to the rest of the body (arteries). Within vascular smooth muscle cells, smooth muscle α-2 actin forms the core of structures called sarcomeres, which are necessary for muscles to contract. This ability to contract allows the arteries to maintain their shape instead of stretching out as blood is pumped through them.

ACTA2 gene mutations that are associated with familial TAAD change single protein building blocks (amino acids) in the smooth muscle α-2 actin protein. These changes likely affect the way the protein functions in smooth muscle contraction, interfering with the sarcomeres' ability to prevent the arteries from stretching. The aorta, where the force of blood pumped directly from the heart is most intense, is particularly vulnerable to this stretching. Abnormal stretching of the aorta results in the aortic dilatation, aneurysms, and dissections that characterize familial TAAD.

TGFBR2 mutations are also associated with familial TAAD. The TGFBR2 gene provides instructions for making a protein called transforming growth factor-beta (TGF-β) receptor type 2. This receptor transmits signals from the cell surface into the cell through a process called signal transduction. Through this type of signaling, the environment outside the cell affects activities inside the cell. In particular, the TGF-β receptor type 2 protein helps control the growth and division (proliferation) of cells and the process by which cells mature to carry out specific functions (differentiation). It is also involved in the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells.

TGFBR2 gene mutations alter the receptor's structure, which disturbs signal transduction. The disturbed signaling can impair cell growth and development. It is not known how these changes result in the specific aortic abnormalities associated with familial TAAD.

Mutations in other genes, some of which have not been identified, are also believed to be associated with familial TAAD.

Read more about the ACTA2 and TGFBR2 genes.

See a list of genes associated with familial TAAD.

This condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to predispose an individual to thoracic aortic aneurysms and dissection. In most cases, an affected person has one parent with the condition.

People with mutations in the gene inherit an increased risk of thoracic aortic aneurysms and dissection, not the conditions themselves. Not all people with these aortic abnormalities have a mutation in a gene associated with familial TAAD, and not all people with a gene mutation will develop thoracic aortic aneurysms or dissection.