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Loeys-Dietz Syndrome (LDS)

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Overview

What is Loeys-Dietz Syndrome? Loeys-Dietz Syndrome (LDS) is a rare genetic disease that affects connective tissue in many parts of the body, especially the heart. LDS can be caused by changes in any of several genes, which are called TGFBR1, TGFBR2, SMAD3, and TGFB2. The American College of Medical Genetics recommends testing and returning results related to three of these: TGFBR1, TGFBR2, and SMAD3. Symptoms of LDS vary from person to person, but can be divided into four main areas: 1. Blood vessels and heart (vascular), 2. Bones (skeletal), 3, Face or head (craniofacial) and 4. Skin (cutaneous).


1. LDS - Blood vessel (vascular) and heart problems:
  • People with LDS often have heart problems. The aorta, the main blood vessel that carries blood from the heart, will often have a root that is too large and at risk of tearing.
  • Another common symptom is called 'tortuosity', where the blood vessels have a winding course, and can be seen most often in the head and neck
  • Weakness in the walls of blood vessels, which can cause aneurysms - bulges in the vessels, which again are at risk of tearing and bleeding

2. Skeletal/bone problems:
  • The rib cage and sternum can either sink into the body (called 'pectus excavatum') or stick out ('pectus carinatum')
  • The spine can sometimes have a curved shape (also called 'scoliosis'), or be mishapen
  • Lax joints, particularly fingers, that can bend or extend quite far
  • Permanently bent fingers (called 'camptodactyly')
  • Fingers and toes can be unusually long (this is called 'arachnodactyly')
  • Club foot (also called 'talipes equinovarus), where one foot or both feet are permanently rotated at the ankle

3. Face or head (craniofacial) symptoms:
  • A wide space between the eyes
  • Cleft palate - an opening in the top lip
  • Problems in skull development where the joints in the skull fuse together too soon (i.e. as a baby), which impairs skull growth (this is called 'craniosynostosis')

4. Skin (cutaneous) problems:
  • Very pale skin, which can seem a little transparent
  • Easy bruising
  • Scars
Nearly everyone with LDS with have problems with blood vessel, skin, and bone development, while three-quarters will also have head/face (craniofacial) symptoms.


Treatments for LDS focus on individual symptoms of the syndrome, and often involve doctors and healthcare professionals from many departments, including genetics, cardiology, orthopedics, ophthalmology, and surgery. The Treatment tab looks at different treatments in more detail. While people with LDS should remain active, contact sports, competitive sports, and isometric training (most strength training) should be avoided.

The aorta is the main artery in the human body. For people with LDS, about 95 in 100 have an enlarged aorta. For people who do not have LDS, the rate is less than 1 in 100. Image created by Iconarray.com. Risk Science Center and Center for Bioethics and Social Sciences in Medicine, University of Michigan. Accessed 2017-09-12.

What is the genetic test?
Genetic testing allows us to identify people at risk of developing LDS. Changes in several genes including TGFBR1, TGFBR2, and SMAD3 have been shown to cause LDS. There is a large risk that people with known genetic risk factors in these genes will develop heart problems and other symptoms, often at a young age. Genetic testing allows us to identify people at risk of LDS, where they can be monitored closely, and advised to take extra steps to help avoid major health problems.

How will this affect my health care?
If genetic test results suggest a person is found to be at risk of developing LDS, regular health checks are recommended. The following tests are recommended:

  • Echocardiography: This is a test that takes images of the heart, and is used to measure and check for problems in the aorta.
  • Magnetic Resonance Angiography (MRA) or computerized (CT): These are scans that can be used to give 3D images of blood vessels, and again are used to check for problems.
  • Radiographs: These are x-rays to check for bone problems or in skeleton development. People with spine or skeletal problems should be followed by an orthopedist, a medical expert that deals with the skeletal system
  • Head and face exams: To check for cleft palate or unusual head/facial features.
  • Eye exam: This is usually done by an ophthalmologist with experience in connective tissue disorders
      Tests should be carried out regularly, and all people with LDS should be seen at a medical center with experience managing the syndrome. Importantly, aneurysms associated with LDS can be treated with early surgery. A range of treatment options are recommending in managing different symptoms of LDS, which are covered in more detail under the Treatment tab.

      Who is at risk?
      LDS is a rare syndrome, though the exact prevalence is not known. However, if a person’s mother or father has a change in the gene that is linked to LDS he or she has a 50% of inheriting this risk (i.e. a 1 in 2 chance). Similarly, if a person’s brother or sister has a LDS risk gene, they will have a 50% risk of inheriting this risk.

      Does my ancestry affect my risk?
      There is no strong evidence linking familial thoracic aortic aneurysm with ancestry.

      More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.

Treatment

If genetic testing shows that a person has a risk of developing LDS, they should have regular imaging tests to monitor symptoms. Early surgery can be important to reduce the risks posed by aneurysms.

Testing


All people with LDS should be seen at a medical center familiar with the syndrome. The following tests are recommended, and should be carried-out regularly:
  • Echocardiography: This is a test that takes images of the heart, and is used to measure and check for problems in the aorta.
  • Magnetic Resonance Angiography (MRA) or computerized (CT): These are scans that can be used to give 3D images of blood vessels, and again are used to check for problems.
  • Radiographs: These are x-rays to check for bone problems or in skeleton development. People with spine or skeletal problems should be followed by an orthopedist, a medical expert that deals with the skeletal system
  • Head and face exams: To check for cleft palate or unusual head/facial features.
  • Eye exam: This is usually done by an ophthalmologist with experience in connective tissue disorders

      Treatments

      Different LDS symptoms are managed by different groups of teams, working together to manage healthcare. Treatments for the main symptoms are discussed below:
      Blood vessel (vascular) and heart problems:
      • The main vascular problem with LDS occurs in the aorta, but is also often more widespread. The imaging scans outlined above are important to identifying vascular problems
      • Beta-adrenergic blockers (or, simply beta-blockers) are types of medication used to help manage blood flow
      • People with LDS are at high risk of developing aneurysms, bulges in the blood vessels. Early detection of aneurysms with imaging scans provides an opportunity for early surgery, which can be life-saving
      • An important surgery called 'valve-sparing aortic root replacement' can be used to treat aneurysms in the aorta. The surgery replaces the root of the aorta but leaves the aortic valve in place
      • Because valve-sparing aortic root replacement surgery is relatively safe, it can be recommended even in children with severe problems in the aorta

      Skeletal/bone problems:
      • People with LDS can have problems in the structure of the spine. Surgery can be used to prevent damage of the spinal cord and curved spine (scoliosis)
      • Similarly, surgery can be used to correct clubfeet, bone overgrowth, and other bone problems
      • Supports and orthotics) can be useful to help manage flatfoot (pes planus)
      Face or head (craniofacial) problems:
      • Cleft palate can be corrected with surgery, and is usually performed at a young age. A majority of patients with cleft palate will need more than one surgery
      • Craniosynostosis, a problem in skull development where the skull joints fuse together, is also treated with surgery. Along with cleft palate, the surgery usually requires a dedicated craniofacial team
      Eye problems
    • An ophthalmologist, a medical expert that specializes in treating the eye, should manage eye problems. An ophthalmologist with a background in connective tissue disorders is best-placed to manage LDS-related problems
    • For young children with eye disorders such as amblyopia (sometimes called 'lazy eye') treatment should be started as early as possible
    All people with LDS should have regular testing for problems with blood vessels and heart,bones (skeletal), face or head, skin (cutaneous), and other symptoms.
    While people with LDS should remain active, contact sports, competitive sports, and isometric training (most strength training) should be avoided.

    Problems

    Can treatments cause any problems?
    • Hernias (bulging of tissues or organs) often occur after surgery. A supporting mesh can be used during surgery to reduce the risk of recurrence.
    • Several problems are associated with surgery to remove growths, and will depend on the the size of the growth and where it is located. Some common problems include bleeding, blood clots, damage to nearby tissues, damage to other organs, pain, infections, and slow recovery.
    • Surgical removal of growths may require a general anesthetic. Any surgery that requires a general anesthetic can carry a risk to the heart, or of chest infection. These risks are not great for people of a young age, but do increase with older age.
    • Sedatives used during surgeries can cause an allergic reaction, which can occasionally be severe.
    • Other drug treatments can have side-effects, some of which can be significant. Your doctor should be able to discuss these with you.
    More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.

Genetic Test

Why do a genetic test? Genetic testing tells us who is most at risk of LDS. Testing for certain genes is particularly important if they are considered to be 'medically actionable' - meaning test results can be used to improve health care. Testing for LDS offers the chance of early health management.

In the embedded video, Dr. Dan Roden of Vanderbilt University discusses how genetic testing has begun to influence treatment of patients.

What is the test?
To do a genetic test, a medical professional will use your DNA to try to see if you have a change in genes linked to LDS, including TGFBR1, TGFBR2, and SMAD3.

Many of the people who use this website are patients in hospitals who are part of the eMERGE network. These hospitals are using DNA sequencing to test patients for a number of diseases, including LDS, as recommended by the American College of Medical Genetics and eMERGE network members. Test results found to be medically ‘actionable’ (meaning they can be used to in patient health care) will be returned to patients.

I am concerned whether I should be tested or not, what should I do?
The decision to be tested might be one of the most important decisions you have to make. There are many things you may want to consider. For some people, genetic testing can have positive health benefits, while others may feel a lot of stress and worry. You can read more about these issues in the Concerns & Risks section. It may help to think about testing for a while before making a decision. You may also find it helpful to discuss issues with those close to you, or with your doctor/health professional.

What will the test result mean?
This test will tell your doctor whether you are at risk of developing LDS. We test for a number of other diseases, as recommended for testing by the American College of Medical Genetics and the eMERGE network. If you are found to be at risk, your doctor or genetic counselor should help you understand your health care options.

What happens if I am found to be at risk?
If you are found to be at risk for any of the diseases that we test for, a health professional at your local site will attempt to contact you as soon as possible. Once we contact you, your doctor or genetic counselor should help you understand your health care options. These may include include increased monitoring of your health, including

  • Imaging the heart and blood vessel, testing for check or bone problems, head and face exams, skin problems, and other symptoms of LDS. These are discussed under the Treatment tab.
  • At a certain point, surgery may be recommended
  • Family members may also be tested for risk.
  • What happens if I am NOT found to be at risk?
    If you are found NOT to be at risk for any of the diseases that we test for, you will likely NOT be contacted. However, a small number of patients may receive a medical report with results, while other patients may be re-contacted about another research study

    If you have not been rec-contacted, please DO NOT ASSUME that you have been tested. There are a number of reasons testing may not have happened yet. For example, studies can sometimes take a very long time to complete, and DNA samples are often not usable because of quality-control issues.

    How is the test being performed?
    Testing is performed on your DNA, usually from a blood sample. For many patients, your hospital or treatment center may already have some of your DNA stored in a biobank. You may be asked for an additional sample or be asked to give us permission to do testing on the existing samples.

    Will it hurt?
    For some patients, we may need an additional blood sample. Taking blood may cause some pain, bleeding or bruising at the spot where the needle enters your body. Rarely, taking blood may cause fainting or infection.

    Is it safe?
    There is a risk that you may experience pain or bleeding if you need to give an additional blood sample. Risks concerning privacy are discussed under Concerns & Risks.

    How long will I have to wait for results?
    Unfortunately, we cannot give an accurate estimate for the time you will have to wait for results - this will depend on the resources available at the location where you receive treatment and were tested.

    Is this a standard test?
    Although increasingly more common, this test is not yet standard, and is typically offered as part of a research study.

    What type of test is this?

    • Is this test intended to help make a diagnosis? Yes
    • Is this test intended to predict a family history of disease? Yes
    • Is this test intended to check if I am a carrier for a particular disease? Yes
    • Is this test intended to screen for genetic disorders? Yes
    • Is this test intended to screen for disorders related to pregnancy? No
    • Is this test intended to screen for disorders related to newborns? No

    Will I need to have this test done more than once?
    No, you should not need to have this test done more than once. You will need to keep track of your testing result in order to share with all of your doctors, including those you see at other medical care centers.

    More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.

    Family

    Will my genetic test results affect my family?
    Your genetic test results may affect your family. In the embedded video, Maureen Smith, a researcher at Northwestern University, recommends first discussing genetic test results with your doctor. Your doctor may refer you to a genetic counselor, who can help you understand test results and guide you toward brochures and websites that can provide information for both you and your family.

    • Before your genetic test: Because genetic information is inherited, it is important to be aware that your genetic test results are often relevant to your family members as well. Results may indicate that you are at risk, or that you are a carrier (see below). Before you have a genetic test, it can be a good idea to think about if and how you would like to share results with your family. Your doctor or genetic counselor should be able to provide more information about this.
    • After your genetic test: For many of the diseases we test for, genetic test results may be relevant to your family members, as well as to you. You may be at risk, and you may be a carrier (see below). If you already have results, it is again important to think about sharing them with family. Again, your doctor or genetic counselor should be able to offer advice on how genetic testing may affect your family members.

    Can you (briefly) explain heritability?
    We each have about 24,000 genes, which carry the instructions for making and maintaining our bodies. For each gene we typically have two copies – one inherited from each parent. If genetic test results suggest you are at risk of developing a heritable disease, you will have inherited the risk from one or both your parents. Your brothers, sisters, children, parents, and other relatives may also be at risk of developing the same disease.
    There are several ways we can inherit a genetic disease, which relates to whether it is recessive or dominant.

    • For a dominant condition, only one copy of a gene needs to be faulty to cause a disease. In this case, if you have one copy of a faulty gene, you may be at high risk of developing the disease. You could pass this faulty gene to one your child or children. LDS is a dominant condition.
    • For a recessive condition BOTH copies of a gene must be faulty to cause a disease. In this case, if a person has only one copy of a faulty gene, they may not be at much greater risk. However, they may pass the faulty gene to their children. Again, this person is called a carrier. LDS is NOT a recessive condition.
    Please note that the Resources section provides links to a number of websites that provide a much more detailed explanation of inheritance! Learn.Genetics at the University of Utah have a much more detailed explanation, which we find quite good – you can check it out here.

    What family members could be affected?
    If you have LDS, there is a 50% your child will too. Other family members are also at a much higher risk of having LDS.

    My children are under 18 years of age – should they be tested?
    The American College of Medical Genetics recommend testing children for most of the diseases listed on this website, including LDS.

    More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.

    Concerns & Risks

    What Should I Do If I Have Concerns About Genetic Test Results?
    If you are concerned about genetic test results you have received, you should discuss your concerns with your doctor. Your doctor should be able to explain results to you, and may recommend you to a genetic counselor or another doctor that can further help you understand your results. Maureen Smith, a researcher at Northwestern University, discusses these concerns in the embedded video.

    Is there a reason why I may be a specific risk?
    For most of the disorders discussed on this site, the American College of Medical Genetics recommends genetic testing for individuals with available genetic data.

    Are there any implications for having children?
    Yes, please see the Family section

    Can I expect to experience emotional consequences related to my test result?
    A range of reactions are possible and normal. Some patients may experience anxiety or other negative reactions related to genetic testing and results. If this is the case, please discuss with your doctor, who can address your concerns and refer you another health professional if required.

    Can I expect to experience social consequences related to my test result?
    Some people may feel that there is a stigma attached to having a genetic disease. If you do experience or anticipate any negative social reactions, please discuss with your doctor who can address your concerns.

    Can I expect to experience an increase in anxiety?
    Many individual experience increased anxiety related to genetic testing. Again, please discuss with your doctor if this is the case.

    Are there any implications in terms of discrimination arising from the test result?
    Health insurance companies are prevented by law from discriminating against you based on your genetic test results. However, the same law does not apply to long-term disability insurance or to life insurance. Maureen Smith, a researcher at Northwestern University discussed these issues in the video on this page.

    If I am found to be at increased risk for developing a disease, are there similar health implications for my family?
    Yes, your results may have similar health implications for your family. Please see the Family section.

    More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.

    Sharing

    Should I tell other health care providers about my test result?
    We do recommend that you share this information with your health care providers. However, as explained by Maureen Smith, a researcher at Northwestern University, what you decide to do with your results is up to you.

    Who will see my test results?
    People who have access to your medical record will be able to see your genetic test result. This may include health professionals such as doctors, nurses, pharmacists, and genetic counselors. However, health professionals from other centers or hospitals will likely not have access to your results.

    Should my other family members be tested?
    If you are found to be at risk for a heritable genetic disease, your family may also be at risk. We discuss this further in the Family section.

    Will this affect my health insurance?
    No, your health insurance will not be affected by this test result. However, as discussed below by Maureen Smith, a researcher at Northwestern University, your life insurance and other areas may be affected.

    Who can I contact if they have any more questions?
    You can contact your local center, where you received the test. The Resources section also includes a lot of websites that we recommend.

    Is it there a risk to my privacy?
    Research that uses information from medical records and that involves genetic testing can affect your privacy. Your participation in this research will be held strictly confidential, and only coded numbers will be used to identify specimens and research records. While it is impossible to absolutely guarantee that information in our secure system will never be known by others, we are taking every possible precaution to see that this does not happen.

    More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.

    Resources

    We are compiling a list of websites to help you understand genetics and genetic test results. If you would like to suggest other resources for this section, please feel free to This email address is being protected from spambots. You need JavaScript enabled to view it.!
    INFORMATION ABOUT FAMILIAL THORACIC AORTIC ANEURYSM AND DISSECTION:

    Weblink to Marfan Foundation, LDS ResourceThe Marfan Foundation
    The Marfan Foundation have put together a very useful fact-sheet brochure, which can be downloaded in pdf form from their website.


    Weblink to Genetics Home ReferenceGenetics Home Reference
    Extensive resource about rare and genetic and genetic diseases. The above link leads to their LDS pages. A link to the main site is provided below as well.


    Weblink to Genetic and Rare Diseases Center (GARD) - LDS ResourcesGenetic and Rare Diseases Center (GARD)
    Supported by the NIH, this website has great resources for a huge range of genetic and rare diseases. The above link is to their LDS resource. A link to the main GARD site is provided below as well.


    Weblink to My46 LDS pageMy46.org
    My46.org maintains an extensive catalog of genetic diseases and conditions. The above link leads to their section on Loeys-Dietz Syndrome.


    Weblink to Society for Vascular Surgery PagesSociety for Vascular Surgery
    Great patient resources and up-to-date information about vascular problems and surgery. This is a direct link to their Thoracic Aortic Aneurysm and Dissection resources.


    INFORMATION ABOUT GENETICS AND GENETIC TESTING:

    Weblink to Genetics Home Reference Genetics Home Reference
    Consumer-friendly information about the effects of genetic variations on human health. Federally-supported resources, include reviews of more than 800 genetic diseases and more than 1000 genes.


    Weblink to Learning Resources from the NHGRILearning Resources from the NHGRI
    Lots of very good resources from the NHGRI, including major sections about The Human Genome Project, Facts Sheets, and educational resources for teachers and students.


    Weblink to National Society of Genetic CounselorsFind a Genetic Counselor
    The National Society of Genetic Counselors have a searchable database of genetic counselors. Their website also includes some education materials for patients and healthcare professionals.


    Weblink to NHGRI Talking GlossaryNHGRI Talking Glossary
    Talking glossary of genetic terms developed by the National Human Genome Research Institute. A huge range of definitions is provided by researchers from around the world.


    Weblink to Help Me Understand GeneticsHelp Me Understand Genetics
    Help Me Understand Genetics is a handbook from the National Institutes of Health that contain useful information about genetics in clear language and provides links to even more online resources. The entire handbook can also be downloaded as a pdf.


    Weblink to the Genetic and Rare Diseases Information CenterGenetic and Rare Diseases Information Center (GARD)
    A joint project from The Office of Rare Diseases Research (ORDR) and the National Human Genome Research Institute (NHGRI) that provides searchable information about genetic conditions and rare diseases. It also includes a list of FDA-Approved drugs and other medical products for treating rare disease.


    Weblink to NORDNational Organization for Rare Disorders - Resources for Parents/Families
    The National Organization for Rare Disorders (NORD) is a volunteer organization dedicated to empowering the rare disease community. Again, they have some very nice web resources.


    Weblink to ELSIEthical, Legal and Social Implications Research Program
    The ELSI Research Program supports examinations and investigations of the ethical, legal and social implications of genetics research.


    Weblink to GINAGenetic Information Nondiscrimination Act of 2008
    The Genetic Information Nondiscrimination Act of 2008, also referred to as GINA, is a new federal law that protects Americans from being treated unfairly because of differences in their DNA that may affect their health.


    Weblink to Learn.GeneticsLearn.Genetics, University of Utah
    Excellent resources, especially for those involved in education. Includes a catalog of animations, videos, interactive features, and virtual labs.


    Weblink to the Dolan DNA Learning CenterDolan DNA Leaning Center
    The DNALC provides genetics learning resources for teachers and students.


    INFORMATION FOR RESEARCHERS:

    Weblink to the ClinVar ACMG recommendations pageClinVar: ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing
    Clinvar's dedicated ACMG page - a useful jumping-off point to the Genetic Testing Registry, OMIM, MedGen, and local ClinVar pages for each gene.


    Weblink to Loeys-Dietz SyndromeGeneReviews
    Loeys & Dietz. GeneReviews: Loeys-Dietz Syndrome (updated July, 2013).


    About

    What is the purpose of this information?
    Our aim is to provide information about why we do genetic testing. We try to answer some common questions and offer guidance on some personal and practical issues. This information is for anybody with questions about genetic testing for any of the diseases and drugs listed in this site.

    Are there geographical differences in testing, service or treatment?
    Different centers have different policies in terms of how tests are administered and results shared. However, the results discussed in this document should be relevant to most individuals tested for risk of developing genetic disease.

    How is this paid for?
    If you received this test as part of the eMERGE research study, neither you nor your insurance company will have to pay anything toward this test

    When was this content last updated?
    September 12, 2017.

    More Questions? The National Society of Genetic Counselors has developed a directory to help locate genetic counseling services near you.
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