Receive a Loeys-Dietz Syndrome Diagnosis

After receiving a Loeys-Dietz syndrome (LDS) diagnosis, patients and families may feel a range of complicated and intense emotions such as disbelief, fear, anxiety, anger, guilt, and a loss of control.

Each step of the way, we are here for you.

Loeys-Dietz Syndrome Diagnostic Criteria

For a person without a family history of LDS, a diagnosis is made when both of the following criteria are met:

  1. Genetic testing finds a variant (change) in the SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, or TGFBR2 gene. The variant must be pathogenic (known to cause disease) or likely pathogenic (likely to cause disease) for LDS
  2. The individual presents with either of the following:
    • Aortic root enlargement or type A dissection
    • Characteristic features of LDS, including a combination of vascular, skin, skeletal and/or craniofacial manifestations.

For a person with a documented family history of LDS, a diagnosis is made based on genetic testing (as described above), even if physical features, such as vascular symptoms, are not yet visible.

Loeys-Dietz Syndrome Diagnostic Process

If there is suspicion of LDS, it is recommended that individuals be evaluated by a medical geneticist who is familiar with connective tissue disorders. You can find a medical geneticist by asking your primary care provider for a referral, calling the physician referral service at your local hospital, or finding a genetic clinic near you. During the initial visit, a detailed family and medical history will be taken and a comprehensive physical examination will be conducted to check for 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 a diagnosis of LDS. 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 (computed tomography angiogram) or MRA (magnetic resonance angiogram) of the entire arterial tree from head to pelvis (head, neck, chest, pelvis and abdomen). These imaging studies will detect aneurysms in other arteries.

Three-dimensional reconstruction of CTA or MRA imaging is recommended to check for arterial tortuosity, a common finding in individuals with LDS, particularly in the head and neck. This finding in itself does not typically cause medical concern but can suggest more evidence to support a diagnosis of LDS.

Genetic testing for mutations (changes) within the SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, and TGFBR2 genes is available if there is high suspicion of LDS. Testing can confirm a diagnosis of Loeys-Dietz syndrome and, in Canada, may be covered by provincial health care, private plan, or employee benefits.  

Tests should be ordered by a geneticist as they will be able to accurately interpret and communicate the test results and will be able to determine if genetic testing is appropriate for other family members. To test for Loeys-Dietz syndrome, options include:

  • Serial single-gene testing. Genes in which mutations can cause LDS are evaluated one by one, typically in the following order: TGFBR2, TGFBR1, SMAD3, TGFB2, SMAD2, and TGFB3. This test may be used when LDS is suspected because of manifestations and/or family history 
  • Multigene panel. A number of genes linked to Loeys-Dietz syndrome, Marfan syndrome, and hereditary aortic aneurysms and dissections are evaluated, including SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, and TGFBR2. The specific genes included in the test may differ based on the suspected condition, ordering physician, or testing laboratory. This test may be used when LDS is suspected because of manifestations and/or family history.
  • Comprehensive genomic testing. The entire genome (an individual’s complete set of genetic information) or part of the genome is evaluated. This test may be used when an individual’s signs and symptoms are found in a number of inherited conditions.

We recommend meeting with a geneticist and/or genetic counsellor before and after testing. These professionals support families through education, advocacy, resources, and health management. They provide information on the nature, inheritance, testing, and implications of genetic disorders to help patients make informed medical and personal decisions.

Genetic test results may be positive, negative, or of unknown significance.

  • A positive result means that the test identified a pathogenic variant (mutation known to cause disease) or likely pathogenic variant (mutation likely to cause disease). 
  • A negative result indicates that test found a benign variant (mutation not known to cause disease) or likely benign variant (mutation not likely to cause disease), or did not find a mutation. 
  • A variant of unknown significance (VUS) result means that the test found a mutation that may or may not cause disease. Researchers will need additional studies and ​patient data to determine if the mutation is associated with disease. 

In the case of a negative or VUS result, individuals may consider DNA banking (storage) for future genetic testing. Future testing may provide new results as mutations and disease genetics become better understood over time. In the meantime, medical professionals can use a personal and family history to discuss diagnosis and treatment.

Loeys, B. L., & Dietz, H. C. (2008, February 28; updated 2018 March 1). Loeys-Dietz Syndrome. GeneReviews. Retrieved October 11, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK1133/. 

 

Questions and answers for patients. Blueprint Genetics. (n.d.). Retrieved October 11, 2022, from https://blueprintgenetics.com/app/uploads/2016/05/PatientE28099s_guide_to_understanding_genetic_testing-_PATMIN1-01.pdf 

 

What is a genetic counsellor? CAGC. (n.d.). Retrieved October 11, 2022, from https://www.cagc-accg.ca/index.php?page=353 

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