Download Loeys-Dietz syndrome

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
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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
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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.
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