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About Loeys-Dietz Syndrome

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Loeys-Dietz syndrome (LDS) is a genetic disorder that affects the connective tissue in the body. The disorder was first observed and described by Dr. Bart Loeys and Dr. Hal Dietz at the Johns Hopkins University School of Medicine in 2005.

Since then, other groups around the world have described additional genetic causes of Loeys-Dietz syndrome. Individuals with LDS exhibit a variety of medical features in the cardiovascular, musculoskeletal, skin and gastrointestinal systems. Information about the natural history and management of individuals with LDS continues to evolve. 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.

Main Characteristics

 

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)

It is important to note, however, that these findings are not observed in all patients and do not concretely lead to a diagnosis of LDS.

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

 

CRANIOFACIAL (HEAD AND FACE)

  • Malar hypoplasia (flat cheek bones)

  • Slight downward slant to the eyes

  • Craniosynostosis (early fusion of the skull bones)

  • Cleft palate (hole in the roof of the mouth)

  • Blue sclerae (blue tinge to the whites of the eyes)

  • Micrognathia (small chin) and/or retrognathia (receding chin)


SKELETAL (BONES)

  • Long fingers and toes

  • Contractures of the fingers

  • Clubfoot or skewfoot deformity

  • Scoliosis (s-like curvature of the spine)

  • Cervical-spine instability (instability in the vertebrae directly below the skull)

  • Joint laxity

  • Pectus excavatum (chest wall deformity that causes the sternum and breast bone to grow inward) / Pectus carinatum (chest wall deformity that pushes the sternum and breast bone out)

  • Osteoarthritis

  • Typically normal stature


SKIN

  • Translucent skin

  • Soft or velvety skin

  • Easy bruising

  • Abnormal or wide scarring

  • Soft skin texture

  • Hernias

 

CARDIAC

  • Congenital (existing at birth) heart defects, which can include patent ductus arteriosus (PDA), atrial or ventricular septal defect (ASD/VSD) and bicuspid aortic valve (BAV)


OCULAR

  • Myopia (nearsighted)

  • Eye muscle disorders

  • Retinal detachment: The retina is the light-sensitive layer of tissue that lines the inside of the eye and sends visual messages through the optic nerve to the brain. When the retina detaches, it is lifted or pulled from its normal position. If not promptly treated, retinal detachment can cause permanent vision loss.


OTHER

  • Food or environmental allergies

  • Gastrointestinal inflammatory disease

  • Hollow organs such as intestine, uterus and spleen prone to rupture 

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Clinical Diagnosis

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.

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Genetics and Inheritance

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.

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Treatment Options

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.

 

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.


Vascular Surgery

Vascular surgery is a widely recommended treatment option as a preventative surgery for individuals with a rapidly enlarging aorta or artery or a pronounced family history of arterial dissection. Aortic root replacement is the most common vascular surgery occurring in individuals with LDS, and it is highly successful. There are many examples of successful arterial repairs for aneurysms throughout the body through a variety of surgical interventions as vascular tissue is not typically weak or fragile in individuals with LDS.


Exercise Restrictions

Exercise restrictions are typically put in place to assist in slowing the rate of aortic and arterial aneurysm growth. It is advised that individuals with LDS avoid competitive sports, especially contact sports, and other exercises or muscle straining activities performed to the point of exhaustion. Individuals can and should remain active with aerobic types of activities that are performed in moderation. Exercises where you have to strain your muscles, such as push-ups, chin-ups, sit-ups, are to be avoided. Activities such as hiking, biking, jogging and swimming that help to naturally lower the heart rate and blood pressure should be a part of an individual's cardiovascular activity. A good recommendation for cardiovascular activities is to exercise only to a level where you can hold a conversation while performing the activity.


Orthopedics

Individuals with LDS may need orthopedic surgery or other interventions such as bracing for scoliosis, orthotics/surgeries for foot deformities or contractures or harnesses for congenital hip dislocation. Typically, surgery for pectus anomalies is pursued for cosmetic purposes and not out of medical necessity.


Allergies

Environmental and food allergies are increased in individuals with LDS and may require a consultation with an allergist or gastroenterologist. Allergic reactions may present as rhinitis or sinusitis, eczema, or hives. Gastrointestinal complaints can include the feeling of food getting stuck in your throat, diarrhea, abdominal pain or difficulty gaining weight. Some individuals have severe inflammatory disease of the esophagus or intestines that may need stricter intervention such as medications or feeding tubes to help with caloric intake.

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Emergency Situations

Following is information regarding potential emergency situations that can arise in someone with Loeys-Dietz Syndrome. Loeys-Dietz syndrome is an aggressive aneurysm syndrome that significantly increases risk for AORTIC & ARTERIAL (head through pelvis) DISSECTION and other complications.


CARDIOVASCULAR

AORTIC or ARTERIAL DISSECTION is a potentially life threatening complication related to aortic aneurysm. Symptoms of aortic dissection include sudden severe chest pain, migrating to the chest, neck, back, abdomen and/or an extremity. Some individuals with aortic dissection have reported nausea, vomiting, shortness of breath, and collapse. Symptoms of aortic dissection warrant activation of the EMS (call 911), and transport to the nearest hospital for aortic IMAGING (CTA, MRA, echocardiography) to confirm or exclude dissection, for stabilization, and appropriate treatment. Stroke symptoms may present with neck artery dissections.


PULMONARY

SPONTANEOUS PNEUMOTHORAX results from rupture of pulmonary blebs. Blebs form due to increased air spaces in the lung. Symptoms of spontaneous pneumothorax include chest, neck or back pain exacerbated by deep breathing, or difficult breathing due to pain. HEMOPTYSIS of unknown etiology has also been seen in LDS.


Ocular

RETINAL DETACHMENT is associated with sudden visual field loss. Although retinal detachment is not life threatening, unrecognized/untreated detachment can result in blindness. Therefore, sudden visual disturbance warrants emergency evaluation.


Hollow organ rupture

Hollow organ rupture or tear of the spleen or uterus has been reported rarely. Bowel rupture may be a very rare complication.

 

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