EWHA WOMANS UNIVERSITY SEOUL HOSPITAL

Thoracic aorta aneurysm is a disease in which the aorta enlarges like a balloon. The number of patients by year in Korea is 1,434 in 2010, 2,869 in 2015, and 4,192 in 2020, doubling every 5 years. The problem is that 20% to 25% patients are caused by hereditary thoracic aorta aneurysm. In fact, as the diagnosis of aortic disease increases, the diagnosis of patients with hereditary aortic disease is also increasing. For example, according to data from the Health Insurance Review and Assessment Service, the number of patients with Marfan syndrome, a typical hereditary aortic disease, is increasing every year.

This is clearly a different aspect from the past. Until the 1990s, aortic disease was a ‘silent assassin’ without symptoms and there were many cases in which aortic dissection or aortic rupture caused sudden death. However, with the generalization of computed tomography (CT), diagnosis of aortic disease became easier, and as aortic surgery became specialized, outcomes of surgical results have improved dramatically. Subsequently, with the development of molecular genetic diagnostic technology since the 2000s, ‘NGS (Next-Generation Sequencing)' emerged. The diagnosis of hereditary diseases has become sophisticated and rapid. With the development of genetic diagnosis technology, the diagnosis of other hereditary aortic diseases excluding Marfan syndrome began to increase, and genetic analysis for rare diseases has become easier along with the concept of precision medicine.

Ewha Womans University Aortic and Vascular Hospital not only treats the aortic artery, but also precisely diagnoses hereditary aortic disease and provides patients hereditary counseling for family based treatment with more accurate diagnose through professional medical staff who have experienced about 600 aortic surgeries and procedures per year and over 3,000 aortic surgeries over 10 years. In order to proceed so, we opened ‘Marfan Syndrome / Hereditary Aortic Disease Center'.

Marfan syndrome has the longest history and the most representative hereditary aortic disease. It was first reported in 1896, and it wasn’t until a century later in 1991, that the FBN1 gene abnormality was identified as the cause of Marfan syndrome by molecular genetic technology. Since then, with the new revision of diagnostic standards in 2010, genetic testing has become a new axis of diagnostic standards.

Syndrome is a group of symptoms. In the case of Marfan syndrome, the FBN1 gene mutation causes various combinations of symptoms such as aortic problems, eye problems, spine problems, heart problems, thoracocyllosis and pneumothorax. Therefore, sometimes it is not easy to diagnose simply by clinically revealing phenotypes. According to the Ghent nosology diagnostic standards revised in 2010, with the addition of genetic diagnosis as a new criterion based on various symptoms, it became possible to confirm the relationship between genotypes and phenotypes, and diagnosis became easier.

An overview of the diagnostic criteria is as follows:

Based on family history, if there are no patients with Marfan syndrome in the family 1) aortic problems, 2) eye problems, 3) the FBN1 gene abnormality, 4) a full-body index score of 7 or higher; if two of these combinations are satisfied, it is diagnosed as Marfan syndrome.

If there is no patient with Marfan syndrome in your family member 1) aortic problems, 2) eye problems, 3) a full-body index score of 7 or higher; if only one of them is satisfied, it is diagnosed as Marfan syndrome.

Theoretically, 50% of children of Marfan syndrome patients may have Marfan syndrome. Since a thoracic aortic aneurysm grows without symptoms and then develops as aortic dissection, and it varies from teens to 60s, so patients diagnosed with Marfan syndrome need family-based genetic counseling and constant management and follow-up at the clinic.

Marfan syndrome is not the only one, that thoracic aortic aneurysm caused by gene mutation. As an extension of molecular genetic studies of Marfan syndrome since the 2000s, it has been found that a number of related gene mutation, including 1) overactivation of TGF beta signaling, 2) Extracellular Matrix factor, and 3) smooth muscle cell contractility factor, are cause of thoracic aortic aneurysm. Aortic diseases caused by newly discovered gene mutation, excluding the FBN1 gene, are commonly diagnosed as Hereditary Aortic Disease. Currently, about 50 genes that causes hereditary aortic disease have been identified and are continuously being discovered.

These causative genes have several characteristics.

First, most of them have dominant heredity, and at a 50% probability, hereditary aortic disease is transmitted to the next generation.

Second, most of the causative genes are associated with connective tissue, so in addition to aortic problems, mutation in the causative gene cause problems in skin, bones, joints, heart, and vascular tissues, resulting in various symptoms.

Third, there are many types of syndromes, which are various combinations of symptoms, and there are many ambiguous symptoms, so it can be diagnosed only when suspected.

Although the diagnostic criteria for Marfan syndrome, which is historical and representative, are well established. Other hereditary aortic diseases can only be diagnosed by gene testing because the diagnostic criteria are not clear. This is why gene test is so significant.

Clinical diagnosis of hereditary aortic disease requires meticulous examination and various tests.

1) Whether any of your family members or relatives have had heart or aortic surgery, 2) previous treatment for connective tissue diseases, such as eye or spine problems, thoracocyllosis and pneumothorax, 3) occur of aortic disease at a relatively young age (less than 50 years of age), 4) whether there are characteristics of hereditary aortic disease through imaging techniques such as CT and ECG, and 5) we utilize various and complex methods such as whether the causative gene was found through gene testing. And it is necessary to analyze these clinical and genetic information.

The problem is that there are not a few discrepancies between clinical and genetic information, so a precise diagnosis through close consultation between the clinical departments dealing with aorta and connective tissue and the diagnostic genetics department dealing with genetic information is required. And since most diseases are syndromes, treatment and management are required in various clinical departments, such as cardiovascular surgery for aortic problems, ophthalmology for eye problems, thoracic surgery for thoracocyllosis or pneumothorax, and orthopedics for spine and joint problems. As part of family planning, close cooperation with obstetrics and gynecology for pregnancy and pediatrics for for the management and follow-up of children with causative gene mutations is also required. Finally, providing information about education and welfare for patients and their families is also important.

Therefore, Marfan Syndrome and Hereditary Aortic Disease Center aims to provide world-class aortic surgery and family unit treatment and management to patients through information exchange and close consultation with various clinical departments.