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Stage I: Rule-Out Dashboard Incidental Findings in Adults GENE/GENE PANEL: TGFBR1, TGFBR2, SMAD3 DISORDER: Loeys-Dietz syndrome PENETRANCE ACTIONABILITY 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? YES NO 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? Yes No Surveillance or Screening NO SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? NO NEXT STEPS Family Management 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all “YES”? Circumstances to Avoid NO 3. Is the result actionable in an undiagnosed adult with the genetic condition? YES YES YES Patient Management YES (≥ 1 of above) 4. Is there at least one known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population? NO YES (Proceed to Stage II) NO (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1 Stage II: Summary Report Incidental Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening GENE/GENE PANEL: TGFBR1, TGFBR2, SMAD3 Topic Narrative Description of Evidence DISORDER: Loeys-Dietz syndrome Ref 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Signif/Burden of Condition Prevalence of the genetic disorder Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) The prevalence of Loeys-Dietz syndrome (LDS) is unknown. 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. 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) (1-4) (1-3) 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. 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) Patient Management 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) 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) Surveillance (3-6) (2) (3-6) 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) 2 Stage II: Summary Report Incidental Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Family Management Circumstances to Avoid Patients should undergo an eye examination by an ophthalmologist with expertise in connective tissue disorders. (Tier 4) First degree relatives should undergo aortic imaging. (Tier 2) First degree relatives should be offered genetic counseling and genetic testing when the causal mutation is known. Mutation carriers only should then be offered aortic imaging. (Tier 2) 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) (2) (6) (6) (1;2) Description of sources of evidence: Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources Tier 5: Evidence from a non-systematically identified source GENE/GENE PANEL: TGFBR1, TGFBR2, SMAD3 Topic Narrative Description of Evidence DISORDER: Loeys-Dietz syndrome Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Autosomal dominant Information on the prevalence if genetic mutations associated with LDS was unavailable. Prevalence of Genetic Mutations Penetrance OR Relative Risk 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 relative risk was unavailable. (include high risk racial or ethnic subgroups) 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.(2) (2) Date of Search (MM.DD.YYYY): 03.20.2015 Reference List 3 Stage II: Summary Report Incidental Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening 1. Arslan-Kirchner M, Epplen JT, Faivre L, Jondeau G, Schmidtke J, De PA, et al. Clinical utility gene card for: LoeysDietz syndrome (TGFBR1/2) and related phenotypes. Eur J Hum Genet 2011 Oct;19(10). 2. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. GeneReviews. 2013. 3. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Jr., et al. 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 Apr 6;55(14):e27-e129. 4. Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med 2012 Jan;14(1):171-7. 5. Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, et al. Aortic valve and ascending aorta guidelines for management and quality measures. Ann Thorac Surg 2013 Jun;95(6 Suppl):S1-66. 6. Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, et al. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol 2014 Jun;30(6):577-89. 4