Loeys-Dietz syndrome (LDS) is a rare genetic condition that affects the body’s connective tissue. This can alter many parts of the body including the aorta, heart, arteries, skin, and bones. When there is significant enlargement of the artery (an aneurysm), there is a risk of the artery wall tearing (aortic dissection) which can be life-threatening. Many different genetic mutations can cause people to develop LDS. These mutations can occur in any of the following genes: TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SMAD2.
LDS can either be inherited from a parent with the genetic defect or it may be due to a new genetic change (spontaneous mutation) in an individual. Spontaneous mutation occurs in about 3 out of 4 (75%) people who have LDS.
Doctors classify LDS into different subtypes depending on which gene is affected:
There is a lot of overlap in the clinical features of the different LDS subtypes. Since many of these genes were only recently discovered, we are still learning a lot about how they differ. Most of the information about LDS comes from the most common types, LDS1 and LDS2. In the very first cases described, it was common to see very aggressive aortic and arterial disease. More recently, we have found that there is more variation in the severity of the disease. This is because, with more widespread genetic testing and better recognition of the features of the condition, we can identify people with even mild LDS. Also, the prognosis for people with LDS has improved over the years because of better recognition and preventative aortic surgery for enlargement of the aorta and branches.
LDS3 has many of the typical features of LDS, but also has more arthritis of the spine, knees, and ankles. LDS3 is also called Aneurysms-Osteoarthritis syndrome (AOS). LDS4 has some overlapping features of LDS and Marfan syndrome. There is very little information about LDS5 or LDS6.
Figure 5 - CT angiogram demonstrating tortuosity of the abdominal aorta (arrows)
Figure 8 - Bifid Uvula
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.)
Figure 9 - Soft, translucent skin with visible veins in a person with Loeys-Dietz syndrome
Figure 7 - Facial features of Loeys-Dietz syndrome may include wide-set eyes (hypertelorism), blue/grey sclera, prominent forehead, flat cheekbones and a recessed chin
Figure 10 - Facial Milia
It is recommended that you be evaluated by doctors who are familiar with the features of connective tissue disorders like LDS. During the first visit, a detailed family and medical history will be taken and a complete physical exam will take place to look for the typical features in people with LDS. It is helpful to gather information before the visit about any family member who may have LDS, who had an aneurysm, or who had an aortic dissection (tear in the wall of the aorta).
Because one of the major features of LDS is an enlargement of the aorta, it is necessary for the doctor to get an image of your heart with an echocardiogram (Figure 11) (imaging using soundwaves). An echocardiogram is recommended at least every year depending on the size and rate of growth of the aorta.
Figure 11 - Echocardiogram of large aortic aneurysm.
(from Narayanapillai J. Heart Views. Apr-Jun 2017;18(2):64-65. doi: 10.4103/1995-705X.208668. Copyright : © 2017 Heart Views)
Recommendations are also made for additional imaging of your arteries throughout the body from your head to your hips. This typically involves ordering a CTA (computed tomography angiogram which uses x-rays to image- Figure 2) or an MRA (magnetic resonance angiogram which uses a magnetic field to generate images). The frequency of MRA or CTA imaging of the entire aorta and other blood vessels depends on how much your other vessels are involved, but it may be at least every two years.
Three-dimensional (3D) reconstruction of the CTA or MRA imaging is recommended to check for the presence of arterial tortuosity in your neck (Figure 3, above). The cervical (neck) spine may be abnormal in LDS, so x-rays of your cervical spine are recommended to determine if there is a problem. If they find significant abnormalities, it is recommended that you consult with an orthopaedist (bone doctor) or neurosurgeon (brain surgeon).
Genetic testing for a mutation within one of the six genes (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2) causing LDS is available and should be performed when you have features of LDS. When LDS is found in an individual, evaluation of other family members is necessary. If a gene mutation causing LDS is found in a child, it is typically recommended to test the parents for the same mutation. This is to see if there is a risk of having another child with LDS. If you have LDS, each child you have has a 50% chance of also getting LDS. Additionally, genetic testing of the children and siblings of an adult diagnosed with LDS is recommended.
While LDS is a disorder that cannot be cured, survival can be greatly improved with proper treatment and management. The severity of this condition varies greatly from person to person. For most people, management will consist of daily heart medications and some physical activity restrictions. You will also have routine doctor appointments and imaging tests. These may be yearly or more frequent, depending on the size of your aorta and the severity of your other symptoms.
Medications: In an effort to slow the rate of aortic growth, you will be given some medications. The medications typically used are often the same ones used to treat people with high blood pressure:
It is recommended that individuals with LDS remain on their medications even if they have surgery to fix an aneurysm. The US Food and Drug Administration (FDA) also recently warned that people with LDS and other aortic aneurysm conditions should avoid commonly used antibiotics called fluoroquinolones (includes Avelox, Cipro, Factive, Levaquin, and Ofloxacin). The reason for this recommendation is that recent medical studies have shown that people who have taken a fluoroquinolone are twice as likely to have an aortic aneurysm or dissection than those who have not taken one of these drugs.
Surgery: Depending on the size or rate of growth of an aneurysm or artery (usually the aorta), surgery may be recommended to reduce the risk of dissection or vessel rupture. If you have a family history of early aortic dissection, or if your LDS is caused by certain mutations, your care provider may recommend surgery earlier than usual and at an aortic diameter smaller than is recommended for people with Marfan syndrome. In general, preventative aortic root replacement for LDS due to mutations in TGFBR1 and 2 is typically recommended when the aortic root diameter reaches 4.0 to 4.5 cm, depending upon the gene mutated, age, sex, family history, rate of aortic growth, and other features of the condition. For instance, women with TGFBR2 mutations and more severe features of LDS may be at higher risk and surgery at a smaller aortic diameter may be recommended. There is not a lot of information about timing of surgery in the other types of LDS, and a shared decision with your cardiologist, geneticist, and cardiac surgeon is required. Aortic root replacement is the most common aortic surgery for people with LDS, and it is highly successful in centers that have surgeons experienced with their surgery in people with connective tissue conditions. It is likely more successful when you have the surgery electively (for prevention) as opposed to needing the surgery in the case of an emergency (such as with an aortic dissection). In most cases, the valve separating your heart and the aorta can be left in place during an aortic root replacement (so called valve sparing root replacement- Figure 12). This means you won’t have to take warfarin (a blood thinner) which is used for people who have a mechanical aortic valve. In some cases, the valve will have to be replaced (composite valve graft- Figure 13) and a blood thinner is required.
Figure 12 - Valve sparing root replacement procedure. A. aortic root aneurysm (arrow); B. the aneurysm is removed; C. The aortic valve is reimplanted within the surgical graft; D. the graft is sewn to the normal aorta distally (courtesy of Craig Miller, MD)
Figure 13. Composite aortic valve and root replacement (Bentall procedure). A mechanical aortic valve prosthesis (arrow) is at the proximal end of the graft and the coronary arteries are reattached to the graft (courtesy of Mayo Clinic)
Most people with LDS can and should be physically active; however, they should not exercise to the point of becoming exhausted. You should focus on low-intensity (aerobic) and low-impact activities. Nearly every physical activity can be done at different intensity levels. You need to discuss physical activities and activity levels with your physician before beginning any exercise program. As you get older, you should keep talking with your doctor about exercise as your health may change.
Overall, a heart-healthy lifestyle should be followed. You should avoid smoking and illicit drug use, and traditional cardiovascular risk factors such as high cholesterol or high blood pressure should be aggressively managed.
Women with LDS have an increased risk of aortic dissection during pregnancy and the time right after delivery. For this reason, it is recommended that you have a consultation with a cardiologist and high-risk obstetrical or maternal-fetal medicine specialist before considering pregnancy. If there is significant aortic enlargement, the risk of aortic dissection is higher. If an aortic aneurysm is present, your cardiologist may recommend against becoming pregnant. Effective birth control methods should be discussed with your doctors to avoid an unplanned pregnancy. For women who carry the gene changes found in LDS but who have less of the common features, the risk of an aortic dissection related to pregnancy may be lower.
In addition, the associated risks of pregnancy may also vary depending on your LDS subtype. Having had an aortic aneurysm surgery in the past doesn’t necessarily reduce the risks of pregnancy in LDS. There are also reports of uterine rupture in LDS. More frequent aortic imaging follow-up during pregnancy and immediately after delivery is necessary. Medications may need to be adjusted before pregnancy because coumadin and angiotensin receptor blocker medications (ARBs, such as losartan) may harm the developing baby.
In addition to careful assessment of the risk for women contemplating pregnancies, couples in whom the underlying genetic defect is known may consider prenatal or pre-implantation diagnostics.
In both cases, knowledge of the pathogenic variant is an absolute requirement. Dedicated pre-conceptual counseling is also necessary.
We think there are probably 5,000-10,000 dissections a year in the United States. However, it is likely that many dissections are reported as a "heart attack" or "sudden death," when the cause is actually a dissection.
If you have Loeys-Dietz syndrome, you are at much greater risk for an aortic dissection than the general population. There are differences in risks for aortic dissection based on the genes causing LDS. It is important to know the signs of an aortic dissection and what to do.
Signs and symptoms of acute aortic dissection may include:
Chest pain can have many causes, but when you have LDS, it is very important to check for aortic dissection. If you have symptoms that could be due to an aortic dissection, calling 911 and getting to an emergency room right away is necessary. Knowing that you have LDS will help if you have unexplained chest, back, or abdominal pain. Other causes for acute chest pain or shortness of breath in individuals with LDS include a spontaneous collapsed lung (pneumothorax).
Since emergency rooms may be very busy and most likely don’t know a lot about LDS, you and your family should plan to advocate for yourself if you have these symptoms and end up in an ER. Tell the doctors and nurses at the hospital what you know about your condition. By telling your doctors, nurses, and emergency personnel that you have LDS and are concerned about the symptoms related to an aortic dissection, you can be more quickly evaluated for the condition.
A medical alert bracelet can alert emergency personnel right away that you are at risk for a life-threatening dissection. It is also beneficial to have your medical records quickly available, such as through Backpack Health, an app for your smartphone. The link to your emergency information in your “backpack” can be added to your medical alert jewelry for easy access.
The Loeys-Dietz Syndrome Foundation at http://www.loeysdietz.org/
The Marfan Foundation -- related disorders page at https://www.marfan.org/loeys-dietz
Genetic Aortic Disorders Association of Canada http://www.gadacanada.ca/loeys-dietz-syndrome
The National Center for Biotechnology Information https://www.ncbi.nlm.nih.gov/books/NBK1133/