What Is Loeys-Dietz Syndrome?

Overview

Loeys-Dietz syndrome is a connective tissue disorder. It is caused by genetic mutations to certain genes. The disorder was discovered by two doctors, Dr. Bart Loeys and Dr. Hal Dietz, in 2005.¹ Loeys-Dietz syndrome can affect many organs including the heart, bones, blood vessels, skin, and eyes. Most notably, this connective tissue disease causes an enlarged aorta (the body’s largest artery), which increases the risk of aortic aneurysms.² Taking blood pressure medications and receiving regular screenings reduces the risk of life-threatening problems arising from Loeys-Dietz syndrome.

Read on to find out about the causes, symptoms and types of Loeys-Dietz syndrome, as well as how it is diagnosed and treated.

Causes of Loeys-Dietz syndrome

Loeys-Dietz syndrome is caused by certain changes to genes. All the mutations causing Loeys-Dietz syndrome affect a cell signalling pathway known as the ‘transforming growth factor-β (TGF-β) signalling pathway’. Most cases of Loeys-Dietz syndrome are caused by mutations in either the TGFβR1 or TGFβR2 gene, however, mutations in some other genes can also cause Loeys-Dietz syndrome.³

Loeys-Dietz syndrome is inherited in an autosomal dominant pattern. In short, this means that having just one copy of the faulty gene (i.e. from one parent) causes the disease. If you have Loeys-Dietz syndrome, you have a 50% likelihood of passing this faulty gene to each of your children. This mode of inheritance accounts for 25% of cases.^2,3

According to MedlinePlus, the remaining 75% of Loeys-Dietz syndrome cases are caused by a sporadic new gene mutation. This means that an individual with this connective tissue disorder will not have any family history of Loeys-Dietz. 

Types of Loeys-Dietz syndrome

There are 5 distinct types of Loeys-Dietz syndrome. They are caused by 5 different gene mutations. However, all 5 types of Loeys-Dietz have similar symptoms.²

Types 1 and 2 are caused by mutations in the TGFβR1 or TGFβR2 genes, respectively. Type 1 and type 2 are the most common forms of Loeys-Dietz syndrome. Type 3 is caused by a mutation in a gene called SMAD-3, type 4 is caused by a mutation in the TGFβ2 gene, and type 5 is caused by a mutation in the TGFβ3 gene. 

Signs and symptoms of Loeys-Dietz syndrome

The signs and symptoms of Loeys-Dietz syndrome can vary in severity between individuals. This is attributed to the specific mutation an individual has that is causing their Loeys-Dietz syndrome. The symptoms of this connective tissue disorder might be present at birth, or develop during childhood or adulthood. Loeys-Dietz syndrome causes a wide range of symptoms and many different parts of the body are usually affected.^2,4

The signs and symptoms of Loeys-Dietz syndrome can be cardiovascular, skeletal, and musculoskeletal amongst others. 

Cardiovascular symptoms

The most common cardiovascular symptom is an enlarged aorta. This is seen in almost all Loeys-Dietz patients. Enlargement of the aorta increases the risk of both aortic aneurysms and aortic dissections. This is because the enlargement stretches the aorta, weakening it. Furthermore, this increases the risk of developing an aortic rupture. An aortic rupture requires emergency treatment and is a serious, life-threatening problem.

Loeys-Dietz syndrome can also increase the risk of aneurysms, dissections, and ruptures in other arteries, arterial tortuosity (twisting or spiralling arteries) and congenital heart defects. 

Skeletal and musculoskeletal symptoms

Loeys-Dietz symptoms associated with the skeleton and muscles include:

• Paediatric, adolescent, or adult scoliosis (curvature of the spine)
• Osteoarthritis (joint inflammation in the hands, wrists, spine, and knees)
• Osteoporosis and bone fractures
• Craniosynostosis (premature fusion of an infant’s skull bones)
• A sunken or protruding chest
• Degenerative disk disease (a lack of cushioning between the disks of the spine)
• Clubfoot (inward turning feet) or flat feet

Additional symptoms

Loeys-Dietz syndrome is also associated with other symptoms and conditions.¹ These include:

• Translucent (see-through) skin that is velvety soft
• Hypertelorism (widely spaced eyes)
• Nearsightedness
• Joint hypermobility
• Cleft lip and palate
• Bruising and scarring easily
• A broad or split uvula
• Allergies and asthma
• Issues with the digestive system (for example inflammatory bowel disease (IBD), diarrhoea and abdominal pain)

Diagnosis

If your healthcare provider suspects you or your child may have Loeys-Dietz syndrome, they will refer you to a geneticist (a specialist in genetic conditions). Your geneticist may perform genetic testing to confirm the diagnosis. This is usually done via a blood test that checks for the known mutations that cause Loeys-Dietz syndrome. 

In addition, it is important to check for the cardiovascular symptoms associated with Loeys-Dietz syndrome. Therefore, tests such as an echocardiogram, computed tomography angiogram (CTA), or magnetic resonance angiogram (MRA) may be performed. These can be used to check for aortic issues, defects of the heart, aneurysms, and arteries that are twisted. 

Management and treatment for Loeys-Dietz syndrome

As the symptoms and severity of Loeys-Dietz syndrome can vary from person to person, the treatment is personalised to the specific case. Common treatments currently used for Loeys-Dietz syndrome include:

Treatment of cardiovascular symptoms

• Blood pressure medications are used to lower the risk of aneurysms and dissections
• Complex aorta surgery or Marfan syndrome heart surgery may be performed as either treatment or prevention for aneurysms and dissections⁵
• Regular (yearly) CTAs and MRAs to monitor any artery problems that could arise³

Furthermore, being physically active can help manage the cardiovascular-related symptoms of the condition by promoting a healthy heart rate and blood pressure. For Loeys-Dietz syndrome patients, it is important to avoid strenuous, isometric exercises, or competitive and contact sports. Instead, activities like hiking, biking, and swimming are normally recommended. A good rule of thumb is that you should be able to maintain a conversation whilst taking part in these activities. This ensures you are not over-exerting yourself. It is important to check with your healthcare provider before pursuing any new activities. 

Treatment for other symptoms

• X-rays for spinal issues
• Orthopaedic surgeries/devices for scoliosis, clubfoot or other skeletal problems

Complications

In addition to the aforementioned symptoms, people with Loeys-Dietz syndrome have an increased risk of having a retinal detachment, a ruptured spleen, a collapsed lung, or a perforated bowel, according to the Cleveland Clinic. 

FAQs

How can I prevent Loeys-Dietz syndrome?

If you have Loeys-Dietz syndrome and are planning on having children, it may be beneficial to meet with a genetic counsellor. A genetic counsellor can discuss and advise you on options that may reduce the risk of you passing the faulty gene to your children. For example, pre-implantation genetic diagnosis (PGD) could be an option for you.⁶ This allows embryos to be selected that don’t have the faulty gene. These embryos can then be implanted into the uterus using in vitro fertilisation (IVF). 

However, as 75% of Loeys-Dietz syndrome cases arise from sporadic new gene mutations, most occurrences of the disease cannot be prevented.

How common is Loeys-Dietz syndrome?

Loeys-Dietz syndrome is thought to be a rare connective tissue disorder.⁷ However, it is a relatively new diagnosis and therefore experts do not know how many people have the disease.

Who is at risk of Loeys-Dietz syndrome?

Those with a parent who has Loeys-Dietz syndrome are at the greatest risk of having the condition.

What can I expect if I have Loeys-Dietz syndrome?

As Loeys-Dietz syndrome is a relatively new disease, medical experts are still learning the implications the disorder has on both life expectancy and quality of life. An increased awareness of the disease, earlier treatments and personalised treatments all work to improve the length and quality of life of those with Loeys-Dietz syndrome.

When should I see a doctor?

If you suspect that you or your child may have Loeys-Dietz syndrome, or if you have a family history of the condition, you should contact your healthcare provider promptly. Early diagnosis and management of Loeys-Dietz syndrome can improve the outcome and prevent possible complications associated with the condition.

Summary

Loeys-Dietz syndrome is a newly-discovered rare genetic connective tissue disorder. This connective tissue disorder is inherited in an autosomal dominant pattern. However, 75% of reported cases have arisen because of a new gene mutation in one of the five genes known to cause the disease. Loeys-Dietz syndrome is associated with a broad range of organ systems, with the most notable being an enlarged aorta. The treatment and management for the condition is dependent on the needs of each individual patient and their symptoms.