Loeys-Dietz Syndrome

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/20/2015
• Curation Status: Released (1.1.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion 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.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of 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

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of Loeys-Dietz syndrome (LDS) is unknown.

Clinical Features (Signs / symptoms)

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.

Natural History (Important subgroups & survival / recovery)

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.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

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

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

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

Unknown

Tier Not provided

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

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

Intervention Effectiveness

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

Beta-blockers or other medications can be used to reduce hemodynamic stress.

Tier 4

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

Surgical fixation of the cervical spine may be necessary to prevent damage to the spinal cord.

Tier 4

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

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

Patients should have yearly magnetic resonance imaging from the cerebrovascular circulation to the pelvis.

Tier 1

Patients should undergo radiographs to detect skeletal manifestations, such as scoliosis, may require attention by an orthopedist.

Tier 4

Patients should undergo craniofacial examination for evidence of cleft palate and craniosynostosis.

Tier 4

Patients should undergo an eye examination by an ophthalmologist with expertise in connective tissue disorders.

Tier 4

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

Nature of Intervention

Nature of Intervention

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

Context: Adult

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.

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

Arslan-Kirchner M, Epplen JT, Faivre L, Jondeau G, Schmidtke J, De Paepe A, Loeys B. (2011) Clinical utility gene card for: Loeys-Dietz syndrome (TGFBR1/2) and related phenotypes. European journal of human genetics : EJHG. 19(10).

BL Loeys, HC Dietz. Loeys-Dietz Syndrome. (2008) [Updated Jul 11 2013]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1133/

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

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) 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. Journal of the American College of Cardiology. 55(14):e27-e129.

Pyeritz RE. (2012) Evaluation of the adolescent or adult with some features of Marfan syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 14(1):171-7.

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. (2013) Aortic valve and ascending aorta guidelines for management and quality measures. The Annals of thoracic surgery. 95(6 Suppl):S1-66.