Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released 1.0.3 Status (Adult): Passed (Consensus scoring is Complete) A

Condition: Loeys-Dietz Syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
SMAD30018954 (loeys-dietz syndrome)
Strong Actionability
TGFB20018954 (loeys-dietz syndrome)
Strong Actionability
TGFB30018954 (loeys-dietz syndrome)
Strong Actionability
TGFBR10018954 (loeys-dietz syndrome)
Strong Actionability
TGFBR20018954 (loeys-dietz syndrome)
Strong Actionability
Actionability Rationale
All experts agreed with the assertion computed according to the rubric. Unlike Marfan syndrome, this was not asserted as definitive since the evidence for the effectiveness of the intervention was based on Marfan syndrome rather than isolated thoracic aortic aneurysm.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Clinically Significant Aortic Aneurysm / Aortic surveillance
Aortic Dilation Progression / Pharmacotherapy

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 Condition
The prevalence of Loeys-Dietz syndrome (LDS) is unknown.
1 2
Clinical Features
(Signs / symptoms)
LDS represents a wide phenotypic continuum in which individuals may have various combinations of clinical features. LDS is characterized by vascular (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections; arterial tortuosity) and skeletal (pectus deformity, scoliosis, joint laxity or contracture, arachnodactyly, club foot, cervical spine malformation and/or instability, osteoarthritis) manifestations. Patients may also display craniofacial (widely spaced eyes, bifid uvula, cleft palate, craniosynostosis) and cutaneous (velvety and translucent skin, easy bruising, dystrophic scars) manifestations. Individuals with LDS show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Ocular manifestations include myopia, refractive errors, strabismus, and blue or dusky sclerae. Various clinical presentations have in the past been labeled as LDS type I (associated with TGFBR1; craniofacial features present), LDS type II (associated with TGFBR2; minimal to absent craniofacial features), LDS type III (associated with SMAD3; presence of osteoarthritis); LDS type IV (associated with TGFB2), and LDS type V (associated with TGFB3). These subtype designations provide a general indication of the spectrum of disease severity, from most to least severe: LDS1 = LDS2 > LDS3 > LDS4 > LDS5.
1 2 3 4 5 6 7 8
Natural History
(Important subgroups & survival / recovery)
Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms which are the major source of morbidity and mortality. Aortic growth can be faster than 10mm per year. Aortic dissection has been observed in early childhood, and the mean age of death is 26 years. Other life-threatening manifestations include spontaneous rupture of the spleen, bowel, and uterine rupture during pregnancy. 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.
2 3 5 8
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with LDS, the following evaluations are recommended:
• Echocardiography
• MRA or CT scan with 3D reconstruction from head to pelvis to identify arterial aneurysms and arterial tortuosity throughout the arterial tree
• Radiographs to detect skeletal manifestations that may require attention by an orthopedist (e.g., severe scoliosis, cervical spine instability)
• Craniofacial examination for evidence of cleft palate and craniosynostosis
• Eye examination by an ophthalmologist with expertise in connective tissue disorders
• Consultation with a clinical geneticist and/or genetic counselor. (Tier 4)
Management of LDS is most effective through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. (Tier 4)
1 2
Prophylactic surgical repair is typically recommended at an aortic diameter of ≥ 4.2 cm. However, this threshold may depend on rate of expansion, the presence of extra-aortic features, or specific genes involved (e.g., > 4.0 cm for TGFBR2). In patients with Marfan syndrome (MFS), timely repair of aortic aneurysms prolongs survival and approaches that of age-matched controls; however, evidence on effectiveness was not provided for patients with LDS. (Tier 2)
3 4 9 10 7 11
Beta-blockers or other medications can be used to reduce hemodynamic stress. (Tier 4)
1 2
Though no evidence for effectiveness of these medications is available for LDS, a meta-analysis of five cohort studies among children and adolescents with MFS indicated that beta-blocker treatment decreased the rate of aortic dilation compared to no treatment (standardized mean difference: -1.30; 95% CI: -2.11 to -0.49; p=0.002). A randomized trial of 70 patients with MFS aged 12-50 years showed that beta-blocker vs. no treatment slowed the rate of aortic dissection as measured by the aortic ratio, calculated by dividing the measured aortic diameter by the diameter predicted by the participant’s height, weight, and age (mean slope of the aortic ratio plotted against time: 0.084 vs. 0.023, respectively). However, none of the studies demonstrated an impact on mortality, occurrence of aortic dissection, or the need for elective repair of the aorta and/or aortic valve, though these studies were likely underpowered. (Tier 1)
12 13
In addition, a meta-analysis of six randomized clinical trials among children and adults with MFS indicated that losartan, an angiotensin II receptor antagonist, significantly decreased the rate of aortic dilation compared to no losartan treatment (standardized mean difference: -0.13; 95% CI: -0.25 to 0.00; p=0.04). However, improvements in mortality, cardiovascular surgery, or aortic dissection or rupture were assessed but not observed. Follow-up time in these studies ranged from 35 months to 3.5 years, which may have limited the ability to assess these outcomes. (Tier 1)
Hypertension should be promptly identified and treated (Tier 2)
Individuals with a pathogenic variant in TGFBR1 or TGFBR2 should be taught the signs and symptoms of aortic dissection and should consider wearing a medical alert bracelet. (Tier 2)
Careful and aggressive refraction and visual correction is mandatory in young children at risk for amblyopia. (Tier 4)
Hernias tend to recur after surgical intervention. A supporting mesh can be used during surgical repair to minimize recurrence risk. (Tier 4)
Optimal management of pneumothorax to prevent recurrence may require chemical or surgical pleurodesis or surgical removal of pulmonary blebs. (Tier 4)
Use of subacute bacterial endocarditis prophylaxis should be considered for individuals with connective tissue disorders and documented evidence of mitral and/or aortic regurgitation who are undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. (Tier 4)
Because of a high risk of cervical spine instability, a flexion and extension x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. (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)
3 4 9 10 6
Patients should have yearly magnetic resonance imaging from the cerebrovascular circulation to the pelvis. (Tier 1)
Circumstances to Avoid
Athletes with LDS should not participate in low and moderate static/low dynamic competitive sports if they have more than one of the following:
• Aortic root enlargement or dilation, or branch vessel enlargement
• Moderate to severe mitral regurgitation
• Extracardiac organ system involvement that makes participation hazardous. (Tier 2)
Athletes with LDS should not participate in any competitive sports that involve intense physical exertion or the potential for bodily collision. (Tier 2)
6 7
Patients should also avoid heavy weight lifting (requiring straining). (Tier 2)
Patients should avoid agents that stimulate the cardiovascular system including routine use of decongestants or triptans for migraine headache management. (Tier 4)
1 2
Individuals at risk for recurrent pneumothorax should avoid breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., scuba diving). (Tier 4)
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 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)
1 2 3
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was unavailable.
Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant. (Tier 4)
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 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. These cardiovascular outcomes are unlikely to be detected through routine clinical care. (Tier 4)
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 Condition Associations
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
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:
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. 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:
6. Braverman AC, Harris KM, Kovacs RJ, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 7: Aortic Diseases, Including Marfan Syndrome: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol. (2015) 66(21):2398-2405.
7. Zentner, D. West, M. Ades, L. Updated on the diagnosis and management of inherited aortopathies, including Marfan Syndrome. (2016) Website:
8. Erbel R, Aboyans V, Boileau C, Bossone E, Di Bartolomeo R, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwoger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, von Allmen RS, Vrints CJ. [2014 ESC Guidelines on the diagnosis and treatment of aortic diseases]. Kardiol Pol. (2014) 72(12):1169-252.
9. 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.
10. 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.
11. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez Munoz D, Rosenhek R, Sjogren J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. (2017) 38(36):2739-2791.
12. Koo HK, Lawrence KA, Musini VM. Beta-blockers for preventing aortic dissection in Marfan syndrome. Cochrane Database Syst Rev. (2017) 11:CD011103.
13. Gao L, Mao Q, Wen D, Zhang L, Zhou X, Hui R. The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan's syndrome: a meta-analysis. Acta Paediatr. (2011) 100(9):e101-5.
14. Gao L, Chen L, Fan L, Gao D, Liang Z, Wang R, Lu W. The effect of losartan on progressive aortic dilatation in patients with Marfan's syndrome: a meta-analysis of prospective randomized clinical trials. Int J Cardiol. (2016) 217:190-4.
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