Loeys-Dietz syndrome is a genetic disorder of the body’s connective tissue. It has some features in common with Marfan syndrome, but it also has some important differences.
People with Loeys-Dietz syndrome features need to see a doctor who knows about the condition to decide if they have the disorder; often this will be a medical geneticist.
It is very important that people with Loeys-Dietz syndrome get an early and correct diagnosis so they can get the right treatment.
What causes Loeys-Dietz syndrome?
Loeys-Dietz syndrome is caused by a genetic mutation of either one of the two genes that tell the body how to make proteins, including the proteins in connective tissue.
These genes are called transforming growth factor beta-receptor 1 (TGFβR1) and transforming growth factor beta-receptor 2 (TGFβR2).
When either of these genes has a mutation, growth and development of the body’s connective tissue and other body systems is disrupted, leading to the signs and symptoms of Loeys-Dietz syndrome.
What are the key features of Loeys-Dietz syndrome?
Because connective tissue is found throughout the body, Loeys-Dietz syndrome features can occur throughout the body, too, including the heart, blood vessels, bones, joints, skin, and internal organs such as the intestines, spleen, and uterus.
One of the key features of Loeys-Dietz syndrome is an enlargement of the aorta, the large blood vessel that carries blood from the heart to the rest of the body.
The aorta can weaken and stretch, 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).
This is a life-threatening complication that can occur without warning. In Loeys-Dietz syndrome, aneurysms and dissections also can occur in arteries other than the aorta.
Typical signs and symptoms of Loeys-Dietz syndrome may include:
- Aortic and arterial tortuosity (spiraled or twisted arteries)
- Enlarged or bulging aorta (aortic aneurysm), which may evolve to aortic rupture or dissection (a tear in the vessel wall)
- Aneurysms in arteries other than the aorta
- Risk of blood clots at the site of the aneurysm
- Pregnancy-related complications including death and uterine rupture
- Skeletal abnormalities such as premature fusion of skull bones (craniosynostosis), a curved spine (scoliosis), chest malformations, an inward- and upward-turning foot (clubfoot), elongated limbs with joint defects that restrict movement, and poor mineralization of the bones (osteoporosis), making the bones weaker
- Easy bruising and abnormal or wide scarring
- Joint pain (osteoarthritis)
- Widely spaced eyes
- A bifid uvula (a piece of connective tissue that hangs from the back of the mouth and plays a role in articulation)
- A cleft palate (an opening in the palate)
- Skin abnormalities; the skin may become translucent, leaving the underlying veins visible
Depending on the type of Loeys-Dietz syndrome, some symptoms may be absent or vary in severity.
In cases where an aortic dissection or rupture occurs, typical signs are a sudden, severe chest pain, a shortness of breath, sudden difficulty speaking, reduced vision, and loss of consciousness.
Ruptures will produce life-threatening internal bleeding and require immediate medical intervention.
Most thoracic aneurysms are asymptomatic and are typically detected when the chest is imaged for unrelated reasons (typically via chest x-rays, CT (computerized tomography) scans, MRI (magnetic resonance imaging), echocardiogram, etc.).
Currently, a diagnosis of Loeys-Dietz syndrome is usually based on family history and the presence of typical physical features.
If there is suspicion of Loeys-Dietz syndrome, imaging is performed to identify and evaluate any aortic aneurysms.
A genetic test can identify the exact underlying genetic defect, which can provide confirmation of the diagnosis and prediction of clinical outcomes.
Since the aneurysms tend to rupture when patients with Loeys-Dietz syndrome are young, early and accurate diagnosis is crucial.
Surgical and clinical methods for management of the complications of Loeys-Dietz syndrome are are rapidly being developed.
Currently, management of aneurysms is focused on prevention and consists of regularly monitoring the size of the aneurysm, controlling blood pressure, and treating any cardiovascular risk factors.
Regular follow-ups are used to follow the progression of any aortic dilations, typically using imaging techniques like CT or MRI scans.
Surgical repair of the aneurysm before a rupture or dissection presents is generally successful and can greatly enhance the patient’s outcome.
Patients can also benefit from treatments that lower the heart rate and blood pressure, such as beta-blockers, angiotensin II receptor blockers (angiotensin II narrows your blood vessels), or cholesterol-lowering drugs.
These relieve the pressure the blood flow places on the aortic wall.
Skeletal complications may require treatment through orthopedic surgery or other interventions such as bracing or harnesses.
Preliminary experiments in mouse models have shown promising results for medication that antagonizes TGF ß, the growth factor that is central to the pathogenesis of Loeys-Dietz syndrome.
However, this approach still requires validation in additional animal models and clinical trials.
The mean life expectancy of patients with Loeys–Dietz syndrome is 37 years, which is quite low compared to related connective tissue disorders.
The reduced life expectancy is due to the fact that aortic dissections occur at smaller diameters (from 40 mm) and at a younger age (26.7 years) in Loeys-Dietz syndrome patients.
It is expected that the outlook for affected individuals will continue to improve as more is learned about the disorder and a diagnosis can be made at an earlier age.
When an aortic aneurysm is detected early and treated promptly, the chance of survival greatly improves.
Identification of the exact genetic defect can distinguish between Loeys–Dietz and related conditions, and enables individualized counseling and preventive disease management.