Loeys-Dietz Syndrome

Loeys-Dietz syndrome is a genetic condition that affects the body’s connective tissue, causing problems with blood vessels, bones, skin, and other body parts. This disorder can lead to serious complications, especially in the heart and blood vessels, but with proper diagnosis and care, many people with the condition can live full lives.

Table of contents

• What is Loeys-Dietz Syndrome?
• Medical Identification Codes
• Parts of the Body Affected
• Key Features and Symptoms
• Causes and Types
• How It Is Passed Down in Families
• How the Condition Is Diagnosed
• Treatment and Management
• Living with Loeys-Dietz Syndrome

What is Loeys-Dietz Syndrome?

Loeys-Dietz syndrome is a disorder that affects the connective tissue in many parts of the body^[1]. Connective tissue is like the glue that holds your body together, providing strength and flexibility to structures such as bones, ligaments, muscles, and blood vessels^[1]. When this tissue doesn’t form correctly, it can lead to problems with many areas in the body, including the cardiovascular system, musculoskeletal system, gastrointestinal system, and skin^[12].

The disorder was first observed and described by Dr. Bart Loeys and Dr. Hal Dietz at Johns Hopkins University in 2005^[4]. Before this discovery, healthcare providers often misdiagnosed it as Marfan syndrome, which is another connective tissue disease that affects the body in similar ways^[3].

You are born with Loeys-Dietz syndrome, but you might not notice signs and symptoms until childhood or adulthood^[3]. The condition affects each person differently, with health impacts that range in severity^[3]. The prevalence of Loeys-Dietz syndrome is unknown, although types I and II appear to be the most common forms^[1].

Medical Identification Codes

Healthcare providers use specific codes to identify Loeys-Dietz syndrome in medical records and systems. These codes help ensure accurate diagnosis and treatment.

Parts of the Body Affected

• Heart and blood vessels
• Bones and joints
• Eyes
• Skin
• Intestines, spleen, and uterus
• Brain and spinal cord (dura)

Key Features and Symptoms

Loeys-Dietz syndrome shows a wide range of signs and symptoms that can vary greatly among individuals, even within the same family^[5]. There are four main characteristics that suggest the diagnosis of this condition. These features are not usually seen all together in other connective tissue disorders^[4].

The Four Main Characteristics

The four key features include aneurysms (widening or dilation of arteries), which are most often observed in the aortic root through imaging but can also be seen in other arteries throughout the body^[2]. Arterial tortuosity refers to arteries that twist and wind, most often occurring in the vessels of the neck^[4]. Hypertelorism means widely spaced eyes, which is a distinctive feature of the condition^[3]. Finally, a bifid or broad uvula describes the little piece of flesh that hangs down in the back of the mouth being split or bigger than usual^[3].

It is important to note that these findings are not observed in all patients and do not concretely lead to a diagnosis on their own^[2]. However, when a person has these particular features, it is important to be evaluated for Loeys-Dietz syndrome^[2].

Cardiovascular Features

The most serious concern with Loeys-Dietz syndrome is problems with the heart and blood vessels. The condition is characterized by enlargement of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body^[1]. The aorta can weaken and stretch, causing a bulge in the blood vessel wall called an aneurysm^[1]. Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall, known as aortic dissection^[1].

People with Loeys-Dietz syndrome can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns^[1]. Some individuals have congenital heart disease, which includes conditions such as patent ductus arteriosus, atrial or ventricular septal defect, and bicuspid aortic valve^[3].

Skeletal Features

Individuals with Loeys-Dietz syndrome often have skeletal problems^[1]. These may include premature fusion of the skull bones called craniosynostosis, an abnormal side-to-side curvature of the spine known as scoliosis, either a sunken chest called pectus excavatum or a protruding chest called pectus carinatum^[1].

Other skeletal features include an inward- and upward-turning foot known as clubfoot, flat feet, or elongated limbs with joint deformities called contractures that restrict the movement of certain joints^[1]. Many people with the condition have long fingers and toes and overly flexible joints^[3]. Malformation or instability of the spinal bones in the neck is a common feature and can lead to injuries to the spinal cord^[1].

Facial and Head Features

Several distinctive facial and head features are associated with Loeys-Dietz syndrome. These include widely spaced eyes, eyes that do not point in the same direction called strabismus, a split in the soft flap of tissue that hangs from the back of the mouth called bifid uvula, and an opening in the roof of the mouth known as cleft palate^[1]. Some individuals may also have flat cheek bones, a slight downward slant to the eyes, or a small or receding chin^[4].

Skin Features

People with Loeys-Dietz syndrome may bruise easily and develop abnormal scars after wound healing^[1]. The skin is frequently described as translucent, meaning almost see-through, often with stretch marks and visible underlying veins^[1]. The skin may feel soft or velvety to the touch^[3].

Other Features

A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged in a condition called dural ectasia^[1]. In individuals with Loeys-Dietz syndrome, this typically does not cause health problems^[1].

Some individuals develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung or a protrusion of organs through gaps in muscles called hernias^[1]. Eye problems may include nearsightedness, eye muscle disorders, or in rare cases, detachment of the retina^[4].

Individuals with Loeys-Dietz syndrome frequently develop immune system-related problems such as food allergies, asthma, or inflammatory disorders such as eczema or inflammatory bowel disease^[1]. The hollow organs such as intestine, uterus, and spleen can be prone to rupture^[4].

Causes and Types

Changes to certain genes cause Loeys-Dietz syndrome^[3]. These genes play roles in how cells function during growth and development. They also manage the formation of structures in the spaces between cells, which is important for tissue strength and repair^[3].

Gene Mutations

There are five types of Loeys-Dietz syndrome, labeled types I through V, which are distinguished by their genetic cause^[1]. Different gene changes cause these distinct types, although symptoms can overlap between all five types^[3].

The genes involved include TGFBR1 (causing type I), TGFBR2 (causing type II), SMAD3 (causing type III), TGFB2 (causing type IV), and TGFB3 (causing type V)^[1]. These five genes play roles in a cell signaling pathway called the transforming growth factor beta pathway, which directs the functions of the body’s cells during growth and development^[1]. This pathway also regulates the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells and is important for tissue strength and repair^[1].

Mutations in these genes result in the production of a protein with reduced function^[1]. Even though the protein is less active, signaling within the pathway occurs at an even greater intensity than normal in tissues. This is what causes the problems seen in people with Loeys-Dietz syndrome^[1].

How It Is Passed Down in Families

An estimated 3 out of 4 people with Loeys-Dietz syndrome have no biological family history of the syndrome^[3]. For unknown reasons, a gene changes for the first time. The disorder results from a new gene mutation in 75 percent of cases and occurs in people with no history of the disorder in their family^[6].

In about 1 out of 4 cases, you inherit the condition from a biological parent^[3]. Loeys-Dietz syndrome has an autosomal dominant pattern of inheritance^[3]. This means inheriting one copy of the faulty gene is enough to cause the syndrome. A parent with Loeys-Dietz syndrome has a 1 in 2, or 50 percent, chance of passing the syndrome to each of their children^[3].

In some forms of the condition, such as types 4 or 5, some family members can appear entirely unaffected despite inheriting the causal mutation from an affected parent^[15]. This is called nonpenetrance. A child of this apparently unaffected individual who inherits the same mutation can go on to show the signs and symptoms. This situation is sometimes called a “skipped generation”^[15].

How the Condition Is Diagnosed

Diagnosing Loeys-Dietz syndrome can be challenging because some children have very mild symptoms^[12]. The diagnosis is established in a person with characteristic clinical findings or by the identification of a genetic mutation in one of the six genes known to cause the condition^[5].

Clinical Evaluation

When a doctor suspects Loeys-Dietz syndrome based on physical features or family history, they may order several tests^[12]. An echocardiogram, which is a cardiac ultrasound, can be used to examine the heart^[12]. Cardiac magnetic resonance imaging or cardiac computed tomography can provide detailed images of the heart and blood vessels^[12].

Genetic Testing

Genetic testing to look for gene mutations is a key part of diagnosis^[12]. This testing can confirm the diagnosis and identify which specific type of Loeys-Dietz syndrome a person has. A medical professional such as a primary care provider or geneticist can start the diagnostic process and discuss the steps and considerations^[7].

Treatment and Management

Treatment for Loeys-Dietz syndrome varies depending on a person’s specific symptoms^[12]. An individualized approach is important because the condition can affect individuals in different ways^[7].

Team-Based Care

A multidisciplinary team of medical professionals is essential. Since the syndrome affects various parts of the body, you will need a team of healthcare providers to manage it^[3]. This team may include a primary care provider, cardiologist, orthopedist, clinical geneticist, ophthalmologist, cardiothoracic surgeon, mental health professional, and any other specialists needed to treat a patient’s symptoms^[14].

Shared decision-making between medical professionals, patients, and families is key^[7]. It considers the patient’s needs and wants, helps the patient and family to understand the condition and treatment options, and is particularly important for events such as surgery or pregnancy^[7].

Medications

The most serious complication of Loeys-Dietz syndrome is the rupture of an aneurysm. To manage aneurysms and reduce the risk of rupture, doctors may recommend medications to help slow heart rate and lower blood pressure in the arteries^[12].

Many people with Loeys-Dietz syndrome take classes of medication known as angiotensin receptor blockers, such as Losartan, Candesartan, or Irbesartan, and beta-blockers, such as Atenolol, Propanolol, or Metoprolol^[11]. In research studies, angiotensin receptor blockers have been shown to decrease aneurysm growth in mice with the condition^[11]. Medications should generally be taken at an optimal dose and continued after vascular surgery^[14].

During pregnancy, beta-blockers should be taken instead of angiotensin receptor blockers as these medications can cause serious complications for the fetus^[11].

Monitoring and Imaging

Close monitoring of the aorta and arteries for aneurysms is essential^[12]. The goal of vascular imaging is to spot and monitor aneurysms and dissections^[14]. It is recommended that the aorta is imaged each year by echocardiogram, and that the head to pelvis area is imaged every one to two years by magnetic resonance imaging or computed tomography^[14].

Surgery

Important considerations when managing cardiovascular features include that aortic dissection can occur at smaller aortic diameters and at younger ages than observed in Marfan syndrome, and vascular disease is not limited to the aortic root^[5]. Aneurysms are amenable to early and aggressive surgical intervention^[5].

Many children with Loeys-Dietz syndrome require surgery to reduce the risk for rupturing of enlarged blood vessels^[12]. Surgery to repair aortic aneurysms is essential for treatment^[6]. Surgical fixation of cervical spine instability may be necessary to prevent spinal cord damage^[5].

Other Treatments

Management of orthopedic manifestations should be done under the care of an orthopedist^[5]. Many people with Loeys-Dietz syndrome require early surgical intervention for a variety of orthopedic conditions and may be at an increased risk for surgical complications^[13].

Management by a craniofacial team is preferred for treatment of cleft palate and craniosynostosis^[5]. Hernias tend to recur after surgical intervention, and a supporting mesh can be used during surgical repair to minimize recurrence risk^[5].

Activity Restrictions

Avoiding certain high-impact activities, such as competitive contact sports and weightlifting, is recommended because they can increase the chances of a rupture^[12].

Living with Loeys-Dietz Syndrome

Living with Loeys-Dietz syndrome requires ongoing care and attention, but many people with the condition can live full lives with proper management^[3]. It was previously believed that the life expectancy of an individual with this condition was around 30 to 40 years of age, however with progressive treatments such as possibilities for surgery and medications it is proven now that life expectancy can be full age with the correct medical attention and scans^[6].

Important Considerations

While the severity of signs and symptoms can vary widely among individuals, the condition itself does not go away or become dormant or inactive^[15]. In some cases, signs or symptoms may seem less pronounced or may stabilize for a time, but the underlying genetic mutation that causes the condition remains present^[15].

Even if you do not have prominent physical features, you should still be concerned about the condition^[15]. The most serious concerns are vascular issues, such as aneurysms and arterial dissections, which can occur even in individuals who do not have obvious external characteristics^[15].

Pain Management

Chronic pain is best managed by a multidisciplinary team of professionals who understand chronic pain and connective tissue disorders^[16]. The team may include a primary care provider, chronic pain specialist, psychiatrist, psychologist, physical therapist, and occupational therapist^[16]. While pain may not go away completely, proper pain management can help to decrease pain levels and improve quality of life^[16].

Support and Resources

Caregivers play an invaluable role in the lives of people with Loeys-Dietz syndrome^[20]. Support from friends, family, professionals, and caregiver- or condition-specific networks can help^[20]. Organizations dedicated to Loeys-Dietz syndrome provide resources, information, and support for patients and families affected by the condition.