Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete)

Condition: Loeys-Dietz Syndrome
GENEDISEASE PAIRS: SMAD3613795 TGFB2614816 TGFB3615582 TGFBR1609192 TGFBR2610168
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of Loeys-Dietz syndrome (LDS) is unknown.
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Clinical Features
(Signs / symptoms)
LDS represents 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.
Pathogenic variants in TGFBR1 and TGFBR2 are associated with 2 types of LDS that are clinically indistinguishable: Type I (LDS1; ~70% of cases) with vascular, skeletal, cutaneous, and craniofacial manifestations and Type II (LDS2; ~20% of cases) with the systemic manifestations of LDS1 but minimal or absent craniofacial manifestations. SMAD3 pathogenic variants are associated with Type III (LDS3; ~5% of cases), which overlaps with Types I and II, but is characterized by an increased risk of osteoarthritis. TGFB2 is associated with Type IV (LDS4; ~1% of cases), which has classic LDS features but milder phenotype, with club feet and mitral valve disease as the most recurrent features. TGFB3 is associated with Type V (LDS5), which has the typical LDS features of aortic aneurysms and other systemic features, but no striking aortic or arterial tortuosity and no strong evidence for early aortic dissection.
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Natural History
(Important subgroups & survival / recovery)
The vascular disease in LDS is aggressive, with a mean age of death of 26 years. However, recent studies indicate a higher survival rate (80% at age 60) and later age of onset (31 years for LDS1 and 46 years for LDS2) than previous reported. A study of 45 LDS3 patients indicated an age of onset range of 18 to 61 years for joint complaints and 20 to 66 years for cardiovascular abnormalities. A study of 2 LDS4 families reported a median age of aortic disease of 35 years. A study of 12 individuals with LDS5 indicated that 7 presented with aneurysms and dissections between the ages of 40 and 68. 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, though there is evidence that males have a greater risk of aortic events and an earlier age of onset of vascular disease than females.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
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)
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Beta-blockers or other medications can be used to reduce hemodynamic stress. (Tier 4)
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Specifically, the use of an angiotensin II receptor blocker (ARB; e.g., losartan) in addition to beta-blockers has been proposed for Marfan syndrome (MFS), a recommendation that may also apply to LDS. However, data on the effectiveness of beta blockers and ARBs is not available for LDS. A systematic review of beta blocker, angiotensin-converting enzyme inhibitor, and ARB use in MFS concluded that these medications slowed the progression of aortic dilation. Three of the included studies showed that the treatment group’s aortic dilation progressed by roughly 1mm/year less than the non-treatment group, though no information was provided on how this impacted clinical outcomes. (Tier 1)
In addition, two randomized trials in patients with MFS reported reductions in aortic root dilation rate with ARB added to beta blockers at three-year follow-up, indicating that treatment with beta blockers and ARB may be more effective than beta blockers alone. In contrast, a double-blind randomized trial found no significant difference between ARB and placebo on aortic root dilation rate at median 3.5-year follow-up, with most patients in both treatment groups also on beta blockers (86%). (Tier 5)
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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)
Prophylactic antibiotics for any invasive procedure including dentistry are recommended. (Tier 2)
Because of a high risk of cervical spine instability, an x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. Surgical fixation of the cervical spine may be necessary to prevent damage to the spinal cord. (Tier 4)
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Patients should undergo radiographs to detect skeletal manifestations, such as scoliosis, that may require attention by an orthopedist (Tier 4)
Patients should undergo an eye examination by an ophthalmologist with expertise in connective tissue disorders to assess for retinal detachment and blue sclerae. (Tier 4)
During pregnancy there is a high incidence of pregnancy-related complications including uterine rupture, hemorrhage, and death. 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)
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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)
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Patients should have yearly magnetic resonance imaging from the cerebrovascular circulation to the pelvis. (Tier 1)
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)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
Information on the prevalence if genetic variants associated with LDS was unavailable.
(Include any high risk racial or ethnic subgroups)
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)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was unavailable.
Identical mutations in TGFBR1 and TGFBR2 can lead to either LDS Type I or II. Intrafamilial clinical variability has been noted. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
The identified interventions involve medications with potential side effects and 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 settting 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, which would likely not be detected through routine clinical care. (Tier 4)

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Clinically Significant Aortic Aneurysm / Surveillance
Aortic Dilation Progression / Pharmacotherapy, including beta-blockers and angiotensin II receptor blockers
To see the scoring key, please go to:
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.
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; 1993-2019. Available from:
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. 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.
6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Loeys-dietz syndrome 1; lds1. MIM: 609192: 2017 Jul 10. World Wide Web URL:
7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Loeys-dietz syndrome 2; lds2. MIM: 610168: 2017 Jul 11. World Wide Web URL:
8. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Loeys-dietz syndrome 3; lds3. MIM: 613795: 2016 Oct 21. World Wide Web URL:
9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Loeys-dietz syndrome 5; lds5. MIM: 615582: 2017 Jan 30. World Wide Web URL:
10. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Loeys-dietz syndrome 4; lds4. MIM: 614816: 2014 Jul 31. World Wide Web URL:
11. 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.
12. Thakur V, Rankin KN, Hartling L, Mackie AS. A systematic review of the pharmacological management of aortic root dilation in marfan syndrome. Cardiol Young. (2013) 23(4):568-81.
13. Chiu HH, Wu MH, Wang JK, Lu CW, Chiu SN, Chen CA, Lin MT, Hu FC. Losartan added to beta-blockade therapy for aortic root dilation in marfan syndrome: a randomized, open-label pilot study. Mayo Clin Proc. (2013) 88(3):271-6.
14. Milleron O, Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, Attias D, Tubach F, Dupuis-Girod S, Plauchu H, Barthelet M, Sassolas F, Pangaud N, Naudion S, Thomas-Chabaneix J, Dulac Y, Edouard T, Wolf JE, Faivre L, Odent S, Basquin A, Habib G, Collignon P, Boileau C, Jondeau G. Marfan sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J. (2015) 36(32):2160-6.
15. Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, Scholte AJ, van den Berg MP, Spijkerboer AM, Marquering HA, Zwinderman AH, Mulder BJ. Losartan reduces aortic dilatation rate in adults with marfan syndrome: a randomized controlled trial. Eur Heart J. (2013) 34(45):3491-500.
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