Gain‐of‐function mutations in <i>SMAD4</i> cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome
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- Angela E. Lin
- Genetics Unit Massachusetts General Hospital MassGeneral Hospital for Children Harvard Medical School Boston Massachusetts
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- Caroline Michot
- INSERM UMR1163 Unit Department of Genetics Institut Imagine Paris Descartes University‐Sorbonne Paris Cité Necker Enfants‐Malades Hospital Paris France
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- Valerie Cormier‐Daire
- INSERM UMR1163 Unit Department of Genetics Institut Imagine Paris Descartes University‐Sorbonne Paris Cité Necker Enfants‐Malades Hospital Paris France
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- Thomas J. L'Ecuyer
- Division of Cardiology Department of Pediatrics University of Virginia Children's Hospital Charlottesville Virginia
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- G. Paul Matherne
- Division of Cardiology Department of Pediatrics University of Virginia Children's Hospital Charlottesville Virginia
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- Barrett H. Barnes
- Division of Gastroenterology Department of Pediatrics University of Virginia Children's Hospital Charlottesville Virginia
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- Jennifer B. Humberson
- Division of Genetics Department of Pediatrics University of Virginia Children's Hospital Charlottesville Virginia
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- Andrew C. Edmondson
- Division of Human Genetics The Children's Hospital of Philadelphia Philadelphia Pennsylvania
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- Elaine Zackai
- Division of Human Genetics The Children's Hospital of Philadelphia Philadelphia Pennsylvania
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- Matthew J. O'Connor
- Division of Cardiology The Children's Hospital of Philadelphia Philadelphia Pennsylvania
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- Julie D. Kaplan
- Division of Medical Genetics Department of Pediatrics University of Mississippi Medical Center Jackson Mississippi
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- Makram R. Ebeid
- Division of Cardiology Department of Pediatrics University of Mississippi Medical Center Jackson Mississippi
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- Joel Krier
- Division of Genetics Brigham and Women's Hospital Harvard Medical School Boston Massachusetts
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- Elizabeth Krieg
- Division of Genetics Brigham and Women's Hospital Harvard Medical School Boston Massachusetts
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- Brian Ghoshhajra
- Thoracic Aortic Center Massachusetts General Hospital Harvard Medical School Boston Massachusetts
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- Mark E. Lindsay
- Thoracic Aortic Center Massachusetts General Hospital Harvard Medical School Boston Massachusetts
説明
<jats:sec><jats:label /><jats:p>Myhre syndrome is a rare, distinctive syndrome due to specific gain‐of‐function mutations in <jats:italic>SMAD4</jats:italic>. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a <jats:italic>SMAD4</jats:italic> mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF‐β signaling cascade (Marfan, Loeys–Dietz, or Shprintzen–Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the <jats:italic>SMAD4</jats:italic> protein to integrate diverse signaling pathways, including canonical TGF‐β, BMP, and Activin signaling. The co‐occurrence of congenital and acquired phenotypes demonstrates that the gene product of <jats:italic>SMAD4</jats:italic> is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.</jats:p></jats:sec>
収録刊行物
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- American Journal of Medical Genetics Part A
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American Journal of Medical Genetics Part A 170 (10), 2617-2631, 2016-06-14
Wiley