Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.1.0
• GENE/GENE PANEL: TGFBR1, TGFBR2, SMAD3
• Condition: Loeys-Dietz Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Clinically Significant Aortic Aneurysm / Surveillance	3	3C	3C	3	12CC
Clinically Significant Aortic Aneurysm / Risk Reducing Surgery	3	3C	Not Scored	Not Scored	N/A
Aortic Dilation Progression / Beta-blockers	3	3C	3C	3	12CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of Loeys-Dietz syndrome (LDS) is unknown. [1, 2]

Clinical Features

LDS presents a continuum of clinical presentation. LDS is mainly characterized by vascular (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections; arterial tortuousity) and skeletal (pectus deformity, scoliosis, joint laxity, arachnodactyly, club foot) manifestations. Patients may also display craniofacial (widely spaced eyes, bifid uvula, cleft palate, and craniosynostosis) and cutaneous (translucent skin, easy bruising, dystrophic scars) manifestations. Mutations in TGFBR1 and TGFBR2 are clinically indistinguishable and are associated with 2 types of LDS: Type I (~75% of cases) with vascular, skeletal, cutaneous, and craniofacial manifestations and Type II (~25% of cases) with minimal or absent craniofacial manifestations. SMAD3 mutations are associated with a rare Type III which overlaps with Types I and II, but is characterized by an increased risk of osteoarthritis. [1, 2, 3, 4]

Natural History

The vascular disease is aggressive, with a mean age of death of 26 years. There is a high incidence of pregnancy-related complications, including aortic dissection/rupture and uterine rupture during pregnancy or delivery and aortic dissection/rupture in the immediate postpartum period. No ethnic/racial or gender difference has been reported. [1, 2, 3]

2. How effective are interventions for preventing harm?

Patient Management

Prophylactic surgical repair is typically recommended at an aortic diameter of > 4.2 cm, but this threshold can vary depending on rate of expansion. Timely repair of aortic aneurysms prolongs survival and approaches that of age-matched controls in patients with Marfan syndrome; however, evidence on effectiveness was not provided for patients with LDS. (Tier 2) [3, 4, 5, 6]

Beta-blockers or other medications can be used to reduce hemodynamic stress. (Tier 4) [1, 2]

Individuals with either a TGFBR1 or TGFBR2 mutation should be taught the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet. (Tier 2) [4]

Surgical fixation of the cervical spine may be necessary to prevent damage to the spinal cord. (Tier 4) [2]

Surveillance

Patients should undergo complete aortic imaging at initial diagnosis and 6 months later to determine the rate of aortic enlargement followed by regular imaging, followed by echocardiograms annually or at least every 6 months if aortic root dilation is detected. (Tier 2) [3, 4, 5, 6]

During pregnancy there is a high incidence of pregnancy-related complications including death and uterine rupture. Thus women should be monitored by a high-risk obstetric clinic and undergo more frequent aortic imaging during pregnancy and in the weeks following delivery. (Tier 4) [1, 2]

Patients should have yearly magnetic resonance imaging from the cerebrovascular circulation to the pelvis. (Tier 1) [3]

Patients should undergo radiographs to detect skeletal manifestations, such as scoliosis, may require attention by an orthopedist. (Tier 4) [2]

Patients should undergo craniofacial examination for evidence of cleft palate and craniosynostosis. (Tier 4) [2]

Patients should undergo an eye examination by an ophthalmologist with expertise in connective tissue disorders. (Tier 4) [2]

Circumstances to Avoid

Patients should avoid contact sports, competitive sports, and isometric exercise; agents that stimulate the cardiovascular system including routine use of decongestants; activities that cause joint injury or pain; and for individuals at risk for recurrent pneumothorax, breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., scuba diving). (Tier 4) [1, 2]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Information on the prevalence if genetic mutations associated with LDS was unavailable.

Penetrance

While non-penetrance in LDS has been documented, 98% of individuals have aortic root aneurysms that lead to aortic dissection and 53% develop aneurysms of other vessels. (Tier 4) [2, 3]

Information on the penetrance of variants was not available for the Adult context.

Relative Risk

Information on relative risk was unavailable.

Expressivity

Identical mutations in TGFBR1 and TGFBR2 can lead to either LDS Type I or II. Intrafamilial clinical variability has been noted. (Tier 4) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

The identified interventions involve invasive prophylactic surgery, which is likely associated with high risk and morbidity.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

The major source of morbidity and early mortality in LDS is related to cardiovascular outcomes, such as predisposition for aortic dissection and rupture (Tier 4), which would likely not be detected through routine clinical care. (Tier 4) [2]

Date of Search: 03.20.2015

Reference List

1. Arslan-Kirchner M, Epplen JT, Faivre L, Jondeau G, Schmidtke J, De Paepe A, Loeys B. Clinical utility gene card for: Loeys-Dietz syndrome (TGFBR1/2) and related phenotypes. Eur J Hum Genet. (2011) 19(10).

2. BL Loeys, HC Dietz. Loeys-Dietz Syndrome. 2008 Feb 28 [Updated 2013 Jul 11]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1133

3. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. J Am Coll Cardiol. (2010) 55(14):e27-e129.

4. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. (2012) 14(1):171-7.

5. Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, Shahian DM, Schaff HV, Akins CW, Bavaria JE, Blackstone EH, David TE, Desai ND, Dewey TM, D'Agostino RS, Gleason TG, Harrington KB, Kodali S, Kapadia S, Leon MB, Lima B, Lytle BW, Mack MJ, Reardon M, Reece TB, Reiss GR, Roselli EE, Smith CR, Thourani VH, Tuzcu EM, Webb J, Williams MR. Aortic valve and ascending aorta guidelines for management and quality measures. Ann Thorac Surg. (2013) 95(6 Suppl):S1-66.

6. Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol. (2014) 30(6):577-89.