Loeys-Dietz Syndrome

What Causes Loeys-Dietz Syndrome?

A change (pathogenic variant) in a gene that helps control the transforming growth factor beta (TGF-β) signaling pathway causes Loeys-Dietz syndrome. This pathway is important for the development of connective tissue. Changes in these genes can weaken arteries and tissues.

LDS is usually inherited in an autosomal dominant pattern, which means a child only needs one changed copy of the gene to have the condition.

A gene change may be:

• Inherited: Some children with Loeys-Dietz syndrome inherit the gene change from a parent who also carries the same gene change. The parent may have obvious signs of LDS or milder features that weren’t recognized until the child’s diagnosis. Each child of a parent with LDS has a 50% (1 in 2) chance of inheriting the same gene change.
• Spontaneous (de novo): The majority of children with LDS are the first in their family to have the condition. In these cases, the gene change happens while a baby is developing in the womb. Parents without the gene change are typically not at increased risk of LDS themselves. However, the child can pass the condition on to their future children.

What Are the Types of Loeys-Dietz Syndrome?

Clinicians usually describe Loeys-Dietz syndrome by the affected gene, rather than by the type numbers listed below. The most common genes involved in this disease are TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.

Historically, LDS was grouped into numbered types. You may still see this older naming in some materials:

• Type 1: Caused by a change in the TGFBR1 gene
• Type 2: Caused by a change in the TGFBR2 gene
• Type 3: Caused by a change in the SMAD3 gene
• Type 4: Caused by a change in the TGFB2 gene
• Type 5: Caused by a change in the TGFB3 gene
• Type 6: Caused by a change in the SMAD2 gene

Some genetic variants tend to be associated with more aggressive artery involvement. For example, many people with TGFBR1 or TGFBR2 gene changes need earlier aortic surgery. Other genetic variants are more strongly associated with joint problems or early osteoarthritis. Your care team will talk with you about what is known about your child’s specific genetic variant and family history.

What Are the Signs and Symptoms of Loeys-Dietz Syndrome? 

Loeys-Dietz syndrome affects every child differently. Some children have many symptoms, while others have only a few. Even within the same family, symptoms can range from mild to severe. Symptoms vary depending on the affected body system.

Heart and Vascular Symptoms

LDS can affect any part of the aorta as it travels from the heart down into the abdomen and pelvis. The aorta typically enlarges first near the heart, either in the aortic root or ascending aorta. Some children have heart disease at birth. Your child will need ongoing, in-depth imaging to monitor the aorta and other arteries over time.

Features of heart and artery issues can include:

• Aneurysms in other arteries in the neck, brain, chest, abdomen or pelvis
• Arterial tortuosity (twisting or curving arteries)
• Aortic valve or mitral valve leakage
• Congenital heart defects, such as atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA) and bicuspid aortic valve (BAV)
• Enlargement (dilation) of the aortic root and ascending aorta

Bone and Joint Symptoms

Loeys-Dietz syndrome can affect growth, posture and joint stability. Skeletal features may include:

• Chest wall differences, such as pectus carinatum (protruding) or pectus excavatum (sunken in) chest walls
• Clubfoot
• Early-onset osteoarthritis, particularly in those with SMAD3-related disease
• Instability of the vertebrae in the neck (cervical spine)
• Joint hypermobility (very flexible joints)
• Long, slender fingers and toes
• Scoliosis (curved spine) or kyphosis (rounded upper back)

Head and Face (Craniofacial) Symptoms

Certain facial and skull features are common in LDS and can be important clues for diagnosis. These may include:

• Blue tint to the whites of the eyes
• Cleft palate 
• Downward slant to the eyes
• Early fusion of an infant’s skull bones (craniosynostosis)
• Flat cheekbones
• Small or recessed chin
• Split or broad uvula (the small tissue that hangs in the back of the throat)
• Widely spaced eyes (hypertelorism)

Skin Symptoms

Skin changes in Loeys-Dietz syndrome can include:

• Eczema and other inflammatory skin conditions
• Skin that appears thin or translucent, with visible veins
• Skin that bruises easily or scars easily
• Soft or velvety skin
• Stretch marks (striae) not explained by weight gain 

What Are the Complications of Loeys-Dietz Syndrome?

Loeys-Dietz syndrome affects every child differently. The most serious complication is weakening of the walls of the aorta (aortopathy). The condition can also weaken arteries in the neck, brain, chest, abdomen and pelvis. These artery problems can happen at a younger age and at smaller sizes (aortic diameters) than in other conditions. Your child’s care plan will include imaging of the entire arterial tree, not just the aorta. Close monitoring and early, preventive heart surgery are key to protecting your child’s health.

Artery weakening can lead to:

• Aortic aneurysm: A bulge forms in a weakened section of the aorta or another artery. Aneurysms can grow over time and are more likely to tear or rupture if not treated.
• Aortic dissection (aortic tear): A tear in the inner layer of the artery wall allows blood to flow between layers of the wall. It can cut off blood flow to vital organs and may lead to stroke, heart attack or kidney failure.
• Aortic rupture: There’s a complete tear through all layers of the artery wall. A rupture causes life-threatening internal bleeding.

How Is Loeys-Dietz Syndrome Diagnosed?

A diagnosis of Loeys-Dietz syndrome is based on a combination of your child’s medical and family history, physical examination and heart and artery imaging. Your team may recommend genetic counseling and genetic testing if they suspect Loeys-Dietz syndrome. At Lurie Children’s, children are evaluated by a team that includes pediatric cardiologists, medical geneticists, genetic counselors and other specialists. 

Genetic Testing

Genetic testing is an essential part of confirming an LDS diagnosis. Our genetics team will meet with your family to review testing options and explain what results might mean for your child and other family members.

Testing usually involves taking a small sample of blood or saliva from your child. Many children are tested using a multi-gene panel that includes the genes that cause LDS and other genes that can cause similar conditions. In some cases, we may recommend a broader test called exome or genome sequencing. We also offer genetic testing to parents and siblings if we identify a disease-causing gene change in your child.

We partner with high-quality genetics laboratories to process these tests. Our medical geneticists and genetic counselors will review the results with you and help coordinate care and testing for other family members when appropriate.

Learn more about what to expect during genetic counseling.

Heart Tests

Your child will have heart and artery imaging to check for enlargement of the aorta, aneurysms in other arteries and any congenital heart defects. Because arteries can change over time, your child will need ongoing imaging throughout life. Test frequency depends on your child’s age, the size and growth rate of the aorta, the specific gene change and family history. 

Heart and vascular tests for children with Loeys-Dietz syndrome may include:

• Echocardiogram (echo): This heart ultrasound assesses heart function, valve function and the size of the aortic root and ascending aorta. It also detects congenital heart defects. 
• Cardiac MRI or MR angiography (MRA): These tests use powerful magnets and radio waves (not radiation) to produce detailed pictures of the heart and arteries. They help your child’s provider view the aorta and other arteries.
• CT angiography (CTA): This test uses X-ray techniques to produce rapid, detailed pictures of blood vessels, organs, bones and soft tissues. It’s especially helpful for viewing the entire aorta and other arteries.
• Four-dimensional MRI (4D flow MRI): This advanced imaging technique shows blood flow patterns through the heart and aorta. A 4D flow MRI helps doctors understand how blood flow might affect aneurysm growth.

How Is Loeys-Dietz Syndrome Treated?

Because Loeys-Dietz syndrome can affect multiple parts of the body, children benefit from care by a multidisciplinary team. At Lurie Children’s, our Connective Tissue Disorders Program brings together a team of experts to help your child. They benefit from a personalized care plan tailored to their unique diagnosis, symptoms and needs.

Heart and Blood Pressure Medications 

Medications can reduce stress on the aorta and slow the rate of aortic enlargement. Your child’s care team will work with you to find the right medication plan and blood pressure targets. They may adjust medications over time as your child grows.

Medications include:

• Angiotensin receptor blockers (ARBs): ARBs, such as losartan or other related medications, help relax arteries and lower blood pressure.
• Beta-blockers: These medications slow the heart rate and reduce the force of the heartbeat, reducing pressure on the aorta.

Heart and Aortic Surgery

Many people with Loeys-Dietz syndrome will eventually need heart surgery to prevent aortic dissection or rupture. The most common operation is aortic root replacement. During this procedure, our pediatric heart surgeon removes the weakened portion of the aortic root and replaces it with a durable synthetic tube (graft). When possible, they perform valve-sparing aortic root replacement to preserve and reimplant your child’s natural aortic valve. 

At Lurie Children’s, pediatric heart specialists use regular imaging to monitor your child’s aorta and other arteries. They recommend surgery at the safest time. The decision to operate takes into account:

• Family history of aortic dissection or rupture
• Patient’s age, body size and other health issues
• Size and growth rate of the aortic root and other aneurysms
• Specific gene involved in the patient’s disease and any known higher-risk variants

Many surgeries take place in adolescence or young adulthood. But some children with more aggressive disease may need surgery earlier. A patient may need additional procedures in the future if other parts of the aorta or other arteries enlarge over time.

After heart surgery, your child may participate in our Cardiopulmonary Rehabilitation Program. Experienced exercise physiologists and heart specialists help your child safely regain strength and stamina and return to daily activities.

Physical Activity Recommendations

Physical activity is important for overall health and well-being. However, certain types of exercise can put extra strain on the aorta. Your child’s care team will work with you to create an activity plan that supports your child’s heart health while minimizing risk.

In general, children with Loeys-Dietz syndrome should:

• Avoid high-impact collision sports (such as football and hockey), heavy weightlifting or resistance training and intense muscle-contracting exercises, such as strenuous push-ups, sit-ups and planks. 
• Focus on low- to moderate-intensity aerobic activities, such as walking, biking, swimming, hiking and recreational (noncompetitive) sports approved by their care team.

Other Treatments for Loeys-Dietz Syndrome

Depending on your child’s symptoms, care may also include:

• Allergy and immunology care for environmental allergies, food allergies and eczema
• Gastroenterology care for inflammatory bowel disease or other digestive problems
• General surgery for chest wall differences or hernias 
• Ophthalmology (eye) care and surgery for vision issues
• Orthopedic surgery and orthotics for clubfoot or scoliosis 
• Neurosurgery for spinal instability
• Plastic and craniofacial surgery for cleft palate, craniosynostosis or other head and face differences
• Pulmonary and sleep medicine care for asthma and sleep disorders
• Physical therapy and occupational therapy to support strength, coordination, fine motor skills and daily functioning

What Is Lurie Children’s Approach to Caring for Children With Loeys-Dietz Syndrome?

The Connective Tissue Disorders Program at Lurie Children’s provides coordinated, family-centered care for children and young adults with Loeys-Dietz syndrome and related conditions. We are the only program in the region with a dedicated team of pediatric heart and genetic specialists focused on connective tissue disorders. We make it easier for your child to see multiple experts in one place.

Your family benefits from:

• Dedicated care team: Our team includes pediatric cardiologists, cardiovascular surgeons, medical geneticists, genetic counselors and specialists in orthopedics, ophthalmology, dermatology, gastroenterology, allergy/immunology and more. We partner closely with your family to create a personalized care plan and coordinate testing, treatments and follow-up care.
• Comprehensive genetic services: Specialists in the Edwards Family Division of Genetics and Rare Diseases and the Cardiovascular Genetics Center offer advanced genetic testing, counseling and support. We help your family understand what the diagnosis means for your child, family and other relatives, as well as how it may affect future family planning.
• Nationally recognized heart care: Your child receives heart care at one of the nation’s top children’s hospitals for pediatric cardiology and cardiac surgery, as recognized by Newsweek and U.S. News & World Report. Our teams have extensive experience caring for children with LDS and other aortic conditions.
• Specialized heart imaging: Your child’s echocardiograms and other heart imaging take place in the only pediatric echo lab in Illinois accredited by the Intersocietal Accreditation Commission for Echocardiography. We perform thousands of echocardiograms and advanced heart tests every year. When needed, we offer child-friendly sedation for MRIs.
• Advanced surgery center: Surgeries take place at our Level 1 Children’s Surgery Center. We were the first pediatric hospital in Illinois to receive this distinction from the American College of Surgeons (ACS), which recognizes our ability to provide the highest level of pediatric surgical care.
• Seamless transition to adult care: As your child becomes a young adult, we work closely with partners, such as the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, to ensure a smooth transition to adult cardiology and genetics care.

Lurie Children’s Connective Tissue Disorders Program

Since 1999, the Connective Tissue Disorders Program at Lurie Children’s has provided comprehensive care and genetic services to children and young adults with Loeys-Dietz syndrome, Marfan syndrome and related conditions. Surgeons with specialized expertise in connective tissue disorders treat children who need surgery. Our cardiology and genetic teams are active in national connective tissue disease research to improve outcomes and quality of life for all patients. 

Our team helps coordinate the imaging, medical treatments and follow-up visits your child needs over time. We also help families plan for a smooth transition to adult medical services when the time is right. We take a family-centered approach that supports both the child and their caregivers.

Learn more aboout our Heart Center