About Loeys-Dietz Syndrome

Four main characteristics suggest the diagnosis of LDS. These features are not usually seen all together in other connective tissue disorders as major characteristics. These symptoms include:

• Aneurysms (widening or dilation of arteries), which can be observed by imaging techniques. These are most often observed in the aortic root (base of the artery leading from the heart) but can be seen in other arteries throughout the body

• Arterial tortuosity (twisting or spiraled arteries), most often occurring in the vessels of the neck and observed on imaging techniques

• Hypertelorism (widely spaced eyes)

• Bifid (split) or broad uvula (the little piece of flesh that hangs down in the back of the mouth)

LDS manifests itself in a number of ways; therefore, no two persons with LDS will have identical medical characteristics. It is recommended that you consult your physician or a local geneticist if you have questions about individual health concerns.

Categorized by system, below is a more detailed list of symptoms recorded in individuals diagnosed with Loeys-Dietz syndrome:

There are several clinical evaluations that are currently pursued together to determine a diagnosis of Loeys-Dietz syndrome.

If there is suspicion of LDS, it is recommended that individuals be evaluated by a geneticist who is familiar with connective tissue disorders. During the initial visit, a detailed family and medical history will be taken and a comprehensive physical examination will be conducted to evaluate the skeletal, craniofacial and skin-related features that are typically present in individuals with LDS.

If there is continued suspicion of LDS, an echocardiogram (ultrasound imaging of the heart) should be performed to assess if there is aortic enlargement and/or other structural heart defects that are consistent with the diagnosis. A consultation with a cardiologist will be necessary to help interpret the cardiac findings.

A physician may also suggest further imaging of the arteries throughout the body. This is done by obtaining a CTA (CT angiogram or computed tomography angiogram) or MRA (MR angiogram or magnetic resonance angiogram) of the entire arterial tree (head, neck, chest, pelvis and abdomen). These imaging studies will detect aneurysms in other arteries.

Three-dimensional reconstruction (3D) of CTA or MRA imaging is recommended to check for arterial tortuosity, a common finding in individuals with LDS, particularly in the neck. This finding in itself does not typically cause medical concern but can suggest more evidence to support the diagnosis of LDS.

Genetic testing for mutations (gene changes) within the TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3 genes is clinically available if there is high suspicion of the diagnosis. This test should be ordered by a geneticist, who will be able to accurately interpret and convey the results of the testing. A geneticist will also be able to interpret the family history and determine if genetic testing for other family members is appropriate. If a gene mutation is found in a child, it is typically recommended to test the parents for the same mutation to give accurate recurrence risk information. Testing of offspring of an adult diagnosed with LDS is always recommended.

Loeys-Dietz syndrome is a genetic disorder that is caused by a mutation (gene change) in either the TGFBR1 or TGFBR2 genes (transforming growth factor beta receptor 1 or 2), the SMAD3 gene (mothers against decapentaplegic homolog 3), the TGFB2 gene (tgfbeta 2 or transforming growth factor beta 2 ligand) or the TGFB3 gene (tgfbeta 3 or transforming growth factor beta 3 ligand).

These genes encode for the receptors and other molecules involved in the tgf-beta pathway. Correlation between the genetic cause of LDS and physical manifestation continues to evolve (see gene association fact sheet).

There are five genetic causes of Loeys-Dietz syndrome, with the proposed naming system.

• Loeys-Dietz syndrome 1 caused by mutations in the TGFBR1 gene

• Loeys-Dietz syndrome 2 caused by mutations in the TGFBR2 gene

• Loeys-Dietz syndrome 3 caused by mutations in the SMAD3 gene

• Loeys-Dietz syndrome 4 caused by mutations in the TGFB2 gene

• Loeys-Dietz syndrome 5 caused by mutations in the TGFB3 gene

Although there is significant overlap between the clinical features caused by mutations in the different genes, we are learning about what might be differing features between the types and how this may impact medical management.

The term genetic disorder also indicates that the disorder has been present in an individual since conception. Loeys-Dietz syndrome exhibits an autosomal dominant inheritance pattern. This means that each offspring of an individual with LDS has a 50% chance of inheriting the gene mutation for LDS. There is no way to predict the severity of vascular, skeletal or skin findings that may occur in an offspring.

Many individuals are the first in their family to have the mutation causing LDS. These cases are caused by sporadic (random) mutations that occur during conception. There is no parental cause (medication or alcohol use for example) for the random mutation occurring. It is no one's fault.

For anyone who has the diagnosis of LDS and who is of reproductive age, it is recommended that they review the recurrence risk information with a genetics professional. There are testing options performed during pregnancy (prenatal diagnosis) and through in-vitro techniques (pre-implantation genetic diagnosis) to determine the presence of LDS in the fetus.

Have You Already Recieved a Genetic Test?

Understanding your genetic test results for conditions like Marfan, Loeys-Dietz, or VEDS can be challenging. Here’s a simple Q&A to help make sense of what your results may mean and what you might consider doing next.

LDS manifests itself in a number of ways; therefore, no two persons with LDS will have identical medical characteristics. It is always important to consult your doctor to determine an effective and personalized course of action. On November 2, 2022 new guidelines for the diagnosis and management of aortic disease were published in the Journal of the American College of Cardiology and Circulation. These guidelines, which were created by a team of medical experts on behalf of the American College of Cardiology and American Heart Association, provide recommendations on the diagnosis, evaluation, medical therapy, endovascular and surgical intervention, and long-term surveillance of people with aortic disease based on evidence available in the literature and, in some instances, based on expert consensus opinions. They include specific recommendations for those with syndromic and non-syndromic genetic aortic conditions as well as other types of acute aortic syndromes. They also emphasize the role of shared decision-making.

Medications

Pressure on the aorta (the largest artery leaving the heart) and other arteries can be controlled by the administration of medications that work to lessen the strain on the body’s major arteries by reducing heart rate and blood pressure. In mouse models of LDS the specific class of blood-pressure lowering medications known as angiotensin receptor blockers, has shown great benefit in reducing aneurysm growth. In people impacted by LDS, if this type of medication is used, it should be used at optimal titration. Angiotensin receptor blockers include medications by the name of Losartan, Irbesartan or Candesartan. Many people are also maintained on beta-blockers (Atenolol, Metoprolol). It is recommended that individuals with LDS remain on these medications even after surgical repair of aneurysms.

Imaging

Continued monitoring of the aorta through annual echocardiograms is necessary. A baseline CTA or MRA of the head, neck, chest, abdomen and pelvis should also be performed to detect and monitor aneurysm formation and/or dissections (tears). The frequency of these scans depends on aneurysm size and rate of growth, so it is recommended that individuals consult their doctor on the appropriate intervals for imaging. Individuals should try not to go more than two years without head-to-pelvis imaging. If a person is using MRA imaging for surveillance, every few imaging cycles a CTA of the head and neck should be considered, as this imaging has better clarity of small arteries in the head and neck.

Cervical Spine Imaging

X-rays of the cervical spine in the flexion and extension positions are recommended to assess for vertebral anomalies and/or instability. If there are any anomalies detected, consultation with an orthopedist is recommended. Rarely, surgery for cervical spine fusion is required. It is important to assess for cervical spine instability prior to undergoing any surgery, as this may impact intubation procedures.