Pediatric Grand Rounds (RECORDING) Leveraging Nature’s Success: Lessons from Modifiers of Marfan Syndrome and Related Aneurysm Conditions

This presentation is a recording of a Stanford Pediatric Grand Rounds Session.  World-renowned experts will present the latest research, practice guidelines, and treatment protocols to advance best practices in the care of pediatric patients. These online recordings will provide pediatricians and family physicians with up-to-date clinical information on a wide range of clinical issues encountered in daily pediatric practice. 

This talk highlights recent advances in the diagnosis and management of vascular connective tissue disorders including Marfan syndrome, Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome. It will emphasize the use of preclinical models of disease to elucidate pathogenetic mechanisms and to derive novel therapeutic strategies

  Release Date: April 15, 2022
  Expiration Date: April 14, 2023
  Estimated Time to Complete: 1.0 hours 
  Registration Fee: FREE
 *Originally recorded 01/21/2022. 

1. Apply the differential diagnosis of Marfan syndrome in clinical practice.
2. Use diagnosis-specific management principles in the care of patients with syndromic presentations of aortic aneurysm.
3. Understand the genetic and environmental determinants of disease severity and currentmechanisms for productive modification.
4. Appreciate research advances that have the potential to inform the diagnosis and management of patients with vascular connective tissue disorders.

In support of improving patient care, Stanford Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. 

Credit Designation 
American Medical Association (AMA) 
Stanford Medicine designates this Enduring Material for a maximum of 1.00 AMA PRA Category 1 Credits^TM.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Cultural and Linguistic Competency
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References/Bibliography
van Andel, M. M., et al. (2020). Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial. European Heart Journal. https://academic.oup.com/eurheartj/article/41/43/4181/5858321?login=true

Bowen, C. J., et al. (2019). Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome. Journal of Clinical Investigation. https://www.jci.org/articles/view/130730/sd/1

Brooke, B. S., Habashi, J. P., Judge, D. P., Patel, N., et al. (2008). Angiotensin II Blockage and Aortic-Root Dilation in Marfan’s Syndrome. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/nejmoa0706585

Cohn, R. D., van Erp, C., Habashi, J. P., Soleimani, A. A., Klein, E. C., Lisi, M. T., Gamradt, M., ap Rhys, C. M., Holm, T. M., Loeys, B. L., Ramirez, F., Judge, D. P., Ward, C. W., & Dietz, H. C. (2007). Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nature medicine, 13(2), 204–210. https://doi.org/10.1038/nm1536

Creamer, T. J., Bramel, E. E., & MacFarlane, E. G. (2021). Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies. Genes, 12(2), 183. https://doi.org/10.3390/genes12020183

Dietz, H., Cutting, C., Pyeritz, R. et al. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339. https://doi.org/10.1038/352337a0

Doyle, J. J. et al. (2015). A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife Sciences. https://elifesciences.org/articles/08648

Gallo, E. M. et al. (2013). Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. Journal of Clinical Investigation. https://www.jci.org/articles/view/69666

Habashi, J. P., Doyle, J. J., Holm, T. M., Aziz, H., Schoenhoff, F., Bedja, D., Chen, Y., Modiri, A. N., Judge, D. P., & Dietz, H. C. (2011). Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science (New York, N.Y.), 332(6027), 361–365. https://doi.org/10.1126/science.1192152

Habashi, J. P., Judge, D. P., Holm, T. M., Cohn, R. D., Loeys, B. L., Cooper, T. K., Myers, L., Klein, E. C., Liu, G., Calvi, C., Podowski, M., Neptune, E. R., Halushka, M. K., Bedja, D., Gabrielson, K., Rifkin, D. B., Carta, L., Ramirez, F., Huso, D. L., & Dietz, H. C. (2006). Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science (New York, N.Y.), 312(5770), 117–121. https://doi.org/10.1126/science.1124287

Habashi, J. P., MacFarlane, E. G., Bagirzadeh, R., Bowen, C., Huso, N., Chen, Y., Bedja, D., Creamer, T. J., Rykiel, G., Manning, M., Huso, D., & Dietz, H. C. (2019). Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome. Science translational medicine, 11(490), eaat4822. https://doi.org/10.1126/scitranslmed.aat4822

Holm, T. M., Habashi, J. P., Doyle, J. J., Bedja, D., Chen, Y., van Erp, C., Lindsay, M. E., Kim, D., Schoenhoff, F., Cohn, R. D., Loeys, B. L., Thomas, C. J., Patnaik, S., Marugan, J. J., Judge, D. P., & Dietz, H. C. (2011). Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science (New York, N.Y.), 332(6027), 358–361. https://doi.org/10.1126/science.1192149

Judge, D. P. et al. (2004). Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. Journal of Clinical Investigation. https://www.jci.org/articles/view/20641

Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., Spevak, P. J., Cameron, D. E., De Backer, J., Hellemans, J., Chen, Y., Davis, E. C., Webb, C. L., Kress, W., … Dietz, H. C. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature genetics, 37(3),275–281. https://doi.org/10.1038/ng1511

Loeys, B. L., Schwarze, U., Holm, T., Callewaert, B. L., et al. (2006). Aneurysm Syndromes Caused by Mutations in the TGF-β Receptor. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/nejmoa055695

Mullen, M., Jin, X. Y., Child, A., Stuart, A. G., Dodd, M., Aragon-Martin, J. A., Gaze, D., Kiotsekoglou, A., Yuan, L., Hu, J., Foley, C., Van Dyck, L., Knight, R., Clayton, T., Swan, L., Thomson, J., Erdem, G., Crossman, D., Flather, M., & AIMS Investigators (2019). Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomized trial. Lancet (London, England), 394(10216), 2263–2270. https://doi.org/10.1016/S0140-6736(19)32518-8

Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., Ramirez, F., Sakai, L. Y., & Dietz, H. C. (2003). Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nature genetics, 33(3), 407–411. https://doi.org/10.1038/ng1116

Ng, C. M. et al. (2004). TGF-β-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. Journal of Clinical Investigation. https://www.jci.org/articles/view/22715

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Mitigation of Relevant Financial Relationships

Stanford Medicine adheres to the Standards for Integrity and Independence in Accredited Continuing Education. 

There are no relevant financial relationships with ACCME-defined ineligible companies for anyone who was in control of the content of this activity, except those listed in the table below. All of the relevant financial relationships listed for these individuals have been mitigated.

Member Information

Role in activity

Nature of Relationship(s) / Name of Ineligible Company(s)

Alan R. Schroeder, MD
Clinical Professor
Stanford University

Course Director and Reviewer

Nothing to disclose

Harry (Hal) Dietz, MD
Professor
Johns Hopkins / HHMI

Faculty

Membership on Advisory Committees or Review Panels, Board Membership, etc.-Aytu BioPharma|Membership on Advisory Committees or Review Panels, Board Membership, etc.-Altius|Membership on Advisory Committees or Review Panels, Board Membership, etc.-GlaxoSmithKline|Consulting Fee-Blade Therapeutics

Debra Babcock, MD
Stanford Childrens (PCHA)

Planner

Nothing to disclose

Caitlin Billingham, MD, MPH
Chief Resident
Stanford Pediatrics

Planner

Nothing to disclose

Lisa Jo Chamberlain, MD
Professor of Pediatrics – General Pediatrics
Stanford Children's Health

Planner

Nothing to disclose

Olivera Marsenic Couloures, MD
LPCH

Planner

Nothing to disclose

Lane Donnelly, MD
University of North Carolina

Planner

Nothing to disclose

Baraka Dechelle Floyd, MD
Clinical Assistant Professor and Associate Chair for Diversity, Equity, and Inclusion
Stanford University School of Medicine

Planner

Nothing to disclose

Ingrid Garnica, Other
Stanford Pediatrics

Planner

Nothing to disclose

Charles Gawad, MD, PhD
Associate Professor
Stanford

Planner

Ownership-BioSkryb Genomics

Allison Guerin, EdD
Stanford

Planner

Nothing to disclose

Mary Beth Leonard, MD, MSCE
Arline and Pete Harman Professor and Chair, Department of Pediatrics
Stanford School of Medicine

Planner

Nothing to disclose

Stephen J Roth, MPH, MD
Attending, Cardiovascular ICU
Lucile Packard Children's Hospital Stanford

Planner

Nothing to disclose

Sarina Tom, BA
Education Operations Manager
Stanford Pediatrics

Planner

Nothing to disclose

Ke-You Zhang, MD
Stanford University

Planner

Nothing to disclose