ACTIONABILITY KNOWLEDGE REPOSITORY ACTIONABILITY CURATION INTERFACE

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) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

GENE/GENE PANEL: COL3A1
Condition: Vascular Ehlers-Danlos Syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
COL3A10017314 (ehlers-danlos syndrome, vascular type; edsvasc)
Moderate Actionability
Actionability Rationale
The assertion was changed from strong to moderate, as it was based on effectiveness data from extrapolated from Marfan syndrome and multiple scorers expressed concern about the applicability of this condition because of known differences in the natural history of these two conditions. There is a need for better evidence specific to COL3A1 that demonstrates the aggregate impact of risk management and surveillance.
Final Consensus Scoresa
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Gene Disease Pairs: COL3A10017314
Morbidity and mortality from arterial or organ rupture / Referral to specialists to guide appropriate risk management including surveillance for aneurysm
3
3C
1D 1
3
10CD
1. The effectiveness score is based on data in Marfan syndrome, but multiple scorers expressed concern about the applicability of this condition because of known differences in the natural history of these two conditions. Therefore, the level of evidence was reduced to a D.
a. To see the scoring key, please go to : https://www.clinicalgenome.org/site/assets/files/2180/actionability_sq_metric.png

 
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
There are no good current estimates of the prevalence of vascular Ehlers-Danlos Syndrome (vEDS), also referred to as Ehlers-Danlos Syndrome type IV, in any population because a large proportion of cases remain undiagnosed. A minimum prevalence of about 1:200,000 can be estimated by extrapolating from the number of known individuals with genetic testing, biochemical, or pedigree-confirmed diagnoses in the United States, but it is suggested that the overall prevalence may approach 1:50,000.
1 2 3
Clinical Features
(Signs / symptoms)
vEDS is caused by a reduction in type III collagen due to pathogenic variants in COL3A1 and is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); an aged appearance to the extremities; and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults; spontaenous pneumothorax/hemopneumothorax may also be a presenting feature. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously. Arterial rupture may occur in the thorax and abdomen (66%), head and neck (17%), and extremities (17%) and tissue fragility. About 15% of individuals will experience a gastrointestinal rupture, most frequently in the sigmoid colon, though they also rarely occur in the small bowel and stomach and iatrogenic perforation may occur during colonoscopy. Poor wound healing may complicate surgical repair. Other features include hypermobility of small joints, carotid-cavernous sinus arteriovenous fistula, tendon or muscle rupture, chronic joint subluxations and dislocations, clubfeet, keratoconus, periodontal disease and gingival recession, and early onset varicose veins. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. In children ascertained prior to a major complication, four minor features are frequently present: distal joint hypermobility, easy bruising, thin skin, and clubfeet. Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. Reported pregnancy-related complications have included rupture of the bowel, uterus, aorta, vena cava, vaginal laceration, and postpartum uterine hemorrhage. Patients are at increased risk of intracranial aneurysm (ICA), subarachnoid hemorrhage (SAH), and myocardial infarction.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Natural History
(Important subgroups & survival / recovery)
Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. The majority (60%) of individuals diagnosed before age 18 are identified because of a positive family history, though 15% of children have experienced a major complication before the time of testing, and of those tested in the absence of family history, 54% had experienced a major complication.
 
Death in the first two decades of life most commonly results from arterial rupture; death before age 20 is more commonly reported in males (3:1). Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a COL3A1 pathogenic variant, and may present as sudden death, stroke and neurologic sequelae, acute abdomen/retroperitoneal bleeding, uterine rupture at delivery, and/or shock, with an average age of 31 for first major arterial or gastrointestinal complication. Bowel rupture is very rarely (3%) lethal. Hemoptysis can be severe and recurrent, even life threatening. Carotid cavernous sinus fistulas typically present with sudden-onset ocular symptoms and almost always require rapid intervention to save vision. It affects about 10% of individuals with vEDS with a preponderance among females. Vascular fragility is dominant in the third and fourth decade.
 
Pregnancy increases the likelihood of a uterine or vascular rupture, with events more likely during the last trimester, delivery, or immediately postpartum.
 
Studies have differed with respect to whether there is a difference in survival between sexes, with at least one study suggesting a younger median survival (by 5 years) for males. The reported median survival for individuals with vEDS is 48-51 years, but with a very large range (10-81 years).
1 2 4 5 6 13
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
At the time of diagnosis, an affected individual should be referred to a center with experience and expertise in vEDS for lifelong follow-up and a multidisciplinary care team established with the primary care physician as the coordinator. This team should establish a protocol for management during a major complication, and the local emergency department should be given data about the individual. Many symptomatic arterial events are self-limiting and may not require surgical or radiologic management; surgical repair should only occur in the setting of life-threatening complications and in the event of arterial rupture, urgent repair is necessary. Affected individuals should carry an emergency care card to be provided to the ER physician at time of consultation. For younger women planning pregnancy, a high risk team should be assembled including experienced obstetricians and vascular surgeons. (Tier 2)
2 7 19
There is currently no consensus regarding the appropriate extent of evaluation at the time of initial diagnosis. To establish the extent of disease and needs in an individual diagnosed with vEDS, the following are recommended:
 
•Visualization of the arterial tree. Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made.
 
•Consultation with medical geneticist and/or genetic counselor.
 
•Review of lifestyle, particularly sports participation (Tier 4)
1
Guidelines differ on recommendation for prophylactic aortic repair in the case of asymptomatic patients with aortic aneurysm. Some guidelines recommend patients undergo elective operation at diameters of 4.0-6.0 cm depending on location of aortic aneurysm and pregnancy anticipation status. Other guidelines take a more conservative approach, stating that due to the high risk of complications as a result of hemorrhagic tendency, tissue fragility, and poor wound healing in vEDS as well as the lack of specific data in vEDS patients, it is not possible to set threshold for surgical intervention in patients with EDS Type IV and thoracic aortic aneurysm. These guidelines state that decisions to surgically intervene should instead be based on a case-by-case basis and guided by multidisciplinary discussion. For preoperative planning, the entire aorta should be imaged. No evidence for effectiveness of aortic aneurysm repair in vEDS patients was identified. In Marfan syndrome, timely repair of aortic aneurysm prolongs survival, such that it approaches that of age-matched controls. (Tier 2)
4 6 7 17 19 20
Patients with vEDS, especially those with identified TAD and/or ICA, and hypertension should have their hypertension monitored and treated aggressively with the intent to minimize chance of arterial dissection or rupture. Guidelines have suggested that beta blockers should be the mainstay of treatment to reduce aortic wall stress, though no evidence exists for their effectiveness at reducing mortality or dissection rate and there are no established blood pressure thresholds. There has been one randomized controlled trial of an antihypertensive therapy in vEDS, a trial of the mixed β1 antagonist and β2 agonist, celiprolol. The study suggests that treatment of individuals with vEDS with the drug extends the time to vascular complications compared to those not treated. However, the study suffered from selection bias: patients were selected on clinical grounds, and it was later found that only two thirds of patients carried pathogenic variants in COL3A1. (Tier 2)
2 10 17 19
Bowel rupture almost always requires surgical intervention. (Tier 2)
2
Death from bowel rupture is uncommon because intervention is generally effective. (Tier 4)
1
Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain. (Tier 4)
1
Guidelines for anesthesia management in patients with vEDS have included recommendations against neuraxial anesthesia due to theoretical risk of spinal hematoma. Avoidance of central venous access and arterial puncturing is also recommended, and if needed should be performed with ultrasound guidance. A thorough medical history of bleeding should be ascertained. Tourniquets should be avoided, anecdotal evidence exits of lethal complications due to the use of tourniquets in elective minor surgery. Prematching of red blood cells should be performed and blood products obtained in advance of surgery in anticipation of transfusion needs. Tracheal intubation should be atraumatic and positive pressure ventilation avoided when possible. Hypertensive episodes should be prevented and treated. (Tier 4)
12 13
Surveillance
Patients should undergo complete aortic imaging and widespread imaging of the vascular tree. Non-invasive imaging is the preferred approach to evaluating vascular alterations. Some have suggested MRI should be considered first-line surveillance of choice for adolescents and in the adult population under age 50 years, while others include CTA or doppler ultrasound as well in suggested imaging modalities. No consensus exists on frequency of surveillance, but annual surveillance has been suggested when feasible. (Tier 2)
2 6 17 18 20
Notably, dissection can occur at any aortic root diameter, and especially in vEDS, there is no clear association with aortic root diameter. (Tier 3)
21
Guidelines differ on whether patients with EDS should be considered for screening for ICA, with some stating screening should not be done in all patients with vEDS. Others state that patients with vEDS should be strongly considered for screening for unruptured ICA by CTA or MRA and patients with ≥2 family members with ICA or SAH should be offered surveillance, with guidelines suggesting 1-5 year intervals, including in children. Data is available on family members of individuals with aneurysms, though nonspecific to vEDS. In these cohort screening studies of first-degree relatives of individuals with an ICA, aneurysms were detected in 8.7-19.1% depending on inclusion criteria. The goal of surveillance is to guide repair via surgical clipping or endovascular coiling to prevent rupture, though no data on treatment outcomes were provided for patients with vEDS. Surgical or endovascular treatment is not without risks and the choice of surgery would also be guided by patient factors, aneurysm size and location. (Tier 2)
10 11 22
Circumstances to Avoid
In a systematic review of the literature, no studies were found to address the possible association between exercise and vascular events (including aortic dissection) in individuals with vEDS. (Tier 1)
23
However, guidelines have recommended that individuals with vEDS should not participate in low static/low dynamic competitive sports if they have any 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)
8 9
Other guidelines have suggested an exercise program and recommendations individually tailored to diagnosis, aortic root diameter, family history of dissection and sudden death, and underlying fitness. Individuals with vEDS should not participate in any competitive sports that involve intense physical exertion or the potential for bodily collision. (Tier 2)
8 9 20 21
Activities with rapid acceleration/deceleration should be discouraged. (Tier 2)
2
Because of severe tissue fragility, it is necessary to avoid invasive procedures, such as catheterization, during vascular evaluation (Tier 2)
18
Conventional arteriography should be avoided because it has been associated with de novo complications. (Tier 3)
1
Rectal temperature measurement and intramuscular injections are contraindicated. (Tier 4)
13
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
vEDS is usually inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. Biallelic pathogenic variants have been found in less than 1% of all affected individuals.
1 2 3 4 5 13 14 15 17 18 24
Prevalence of Genetic Mutations
Approximately 95-96% of individuals with vEDS have a pathogenic variant in COL3A1, suggesting that the prevalence of pathogenic variants in COL3A1 is similar to the prevalence of the condition. (Tier 3)
1 24
Penetrance
(Include any high risk racial or ethnic subgroups)
In families identified on the basis of clinical complications, penetrance of the vEDS phenotype appears to be close to 100% in adults with a missense or exon-skipping alteration; the age at which the pathogenic variant becomes penetrant may vary. (Tier 3)
1
There is 50%-90% mortality by age 48-50 years due to spontaneous rupture of visceral organs and blood vessels. (Tier 3)
6 14
Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a COL3A1 pathogenic variant. (Tier 3)
1
The penetrance is reduced in individuals with null pathogenic variants and the phenotype appears primarily related to vascular events; minor diagnostic criteria are absent in 51% of individuals with a pathogenic null variant (Tier 3)
1 5
Angiography has been reported to be associated with a 17-67% complication risk and a 6-19% mortality rate in individuals with EDS (not specific to vEDS). (Tier 1)
14
Pregnancy is associated with death in about 5% of women, and 50% of deaths occur in first pregnancy. Complications occur in about half of all pregnancies. (Tier 3)
2
In two systematic reviews of case series, GI rupture or perforation occurred in 13.4-25.0% of individuals; in studies examining survival, GI complications contributed to the mortality of 0-16.3% of individuals with vEDS. (Tier 1)
15 16
Spontaneous pneumothorax occurs in 12% of individuals. (Tier 4)
2
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available for the Adult context.
 
 
Expressivity
Individuals with a COL3A1 null variant have a 15-year delay in onset of complications, improved life expectancy, and significantly fewer obstetric and bowel complications than are seen with other types of COL3A1 pathogenic variants. The phenotype in these individuals appears primarily limited to vascular events, and the penetrance reduced. Survival was observed to be shortest in those with splice donor site variants. However, these differences in populations are difficult to use to counsel individuals because of significant intra- and interfamilial variability in age of complication and survival for the same pathogenic variant. The natural history may also vary by gender. (Tier 3)
1 5
4. What is the Nature of the Intervention?
Nature of Intervention
Surgical complications in vEDS are common, with a high rate of procedural mortality. Surgical clipping complications in patients with ICAs (including patients without vEDS) are also common, with studies indicating a 1-2.6% mortality and 4.1-10.9% morbidity rate. Endovascular occlusion of ICAs has a complication rate of 5-10%. Additionally, endovascular treatment of ICA requires X-ray fluoroscopy, which is carcinogenic. Recurrent bowel surgery may be associated with ilio-colic fistula formation, though this may be prevented by subtotal colectomy.
2 10 17
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Because many families with vEDS are identified only after a severe complication or death, it is likely that individuals/families with pathogenic variants in COL3A1 and a mild phenotype do not come to medical attention and go undetected. In addition, because of the perceived rarity of the disorder, it is seldom considered and nonvascular complications may not raise diagnostic suspicion of vEDS. About half of the probands identified have no family history of vEDS (proportion of patients with a de novo variant is ~50%), and diagnosis is often made in the context of the major complications of the condition. Women presenting with vascular complications related to pregnancy may have no knowledge of their underlying condition until their complications arise. About 60% of individuals who are diagnosed before age 18 are identified due to a positive family history; 15% of these individuals have already experienced a major complication at the time of testing. (Tier 4)
1 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 Disease Associations
Gene
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
1. MG Pepin, ML Murray, PH Byers. Vascular Ehlers-Danlos Syndrome. 1999 Sep 02 [Updated 2015 Nov 19]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1494
2. Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, Johnson D, Pepin M, Robert L, Sanders L, Wheeldon N. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. (2017) 175(1552-4876):40-47.
3. Ehlers-Danlos syndrome, vascular type. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=286
4. 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.
5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANT. MIM: 130050: 2016 Jul 09. World Wide Web URL: http://omim.org.
6. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwöger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). (2014) 35(1522-9645):2873-926.
7. Zentner D, West M, Adès LC, . Update on the Diagnosis and Management of Inherited Aortopathies, Including Marfan Syndrome. (2017) 26(1444-2892):536-544.
8. 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.
9. 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. (2015) 132(1524-4539):e303-9.
10. Thompson BG, Brown RD, Amin-Hanjani S, Broderick JP, Cockroft KM, Connolly ES, Duckwiler GR, Harris CC, Howard VJ, Johnston SC, Meyers PM, Molyneux A, Ogilvy CS, Ringer AJ, Torner J, , , . Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. (2015) 46(1524-4628):2368-400.
11. Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, Creager MA, Eckel RH, Elkind MS, Fornage M, Goldstein LB, Greenberg SM, Horvath SE, Iadecola C, Jauch EC, Moore WS, Wilson JA. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. (2014) 45(12):3754-832.
12. Wiesmann T, Gaik C, Malfait F, Castori M. Anaesthesia recommendations for Ehlers-Danlos syndrome.. Orphan Anesthesia. (2019) Accessed: 2020-04-15. Website: https://www.orpha.net/data/patho/Ans/en/Ehlers-Danlos-Syndrome.pdf
13. Frank M, Bagou G. Orphanet Emergency: Type IV Ehlers-Danlos Syndrome.. Orphanet Emergency. (2009) Accessed: 2020-04-17. Website: https://www.orpha.net/data/patho/Pro/en/Emergency_Ehlers-DanlosTypeIV-enPro4042.pdf
14. Burcharth J, Rosenberg J. Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: a systematic review. Dig Surg. (2012) 29(4):349-57.
15. El Masri H, Loong TH, Meurette G, Podevin J, Zinzindohoue F, Lehur PA. Bowel perforation in type IV vascular Ehlers-Danlos syndrome. A systematic review. (2018) 22(1128-045X):333-341.
16. Kulas Søborg ML, Leganger J, Rosenberg J, Burcharth J. Increased Need for Gastrointestinal Surgery and Increased Risk of Surgery-Related Complications in Patients with Ehlers-Danlos Syndrome: A Systematic Review. (2017) 34(1421-9883):161-170.
17. 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.
18. Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (JCS 2011): digest version. Circ J. (2013) 77(3):789-828.
19. Baumgartner H, De Backer J, Babu-Narayan SV, Budts W, Chessa M, Diller GP, Lung B, Kluin J, Lang IM, Meijboom F, Moons P, Mulder BJM, Oechslin E, Roos-Hesselink JW, Schwerzmann M, Sondergaard L, Zeppenfeld K, . 2020 ESC Guidelines for the management of adult congenital heart disease. (2020)
20. 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.
21. Pelliccia A, Sharma S, Gati S, Bäck M, Börjesson M, Caselli S, Collet JP, Corrado D, Drezner JA, Halle M, Hansen D, Heidbuchel H, Myers J, Niebauer J, Papadakis M, Piepoli MF, Prescott E, Roos-Hesselink JW, Graham Stuart A, Taylor RS, Thompson PD, Tiberi M, Vanhees L, Wilhelm M, . 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease. (2020)
22. Roach ES, Golomb MR, Adams R, Biller J, Daniels S, Deveber G, Ferriero D, Jones BV, Kirkham FJ, Scott RM, Smith ER, , . Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. (2008) 39(1524-4628):2644-91.
23. Thijssen CGE, Bons LR, Gökalp AL, Van Kimmenade RRJ, Mokhles MM, Pelliccia A, Takkenberg JJM, Roos-Hesselink JW. Exercise and sports participation in patients with thoracic aortic disease: a review. (2019) 17(1744-8344):251-266.
24. Mayer K, Kennerknecht I, Steinmann B. Clinical utility gene card for: Ehlers-Danlos syndrome types I-VII and variants - update 2012. Eur J Hum Genet. (2013) 21(1).
¤ Powered by BCM's Genboree.