Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.
Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. 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 SMAD4 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 SMAD4 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 SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. © 2016 Wiley Periodicals, Inc.
Genetics Unit, Massachusetts General Hospital, MassGeneral Hospital for Children, Harvard Medical School, Boston, Massachusetts. lin.angela@mgh.harvard.edu.
Angela E
AE
Lin
INSERM UMR1163 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
Caroline
C
Michot
INSERM UMR1163 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
Valerie
V
Cormier-Daire
Division of Cardiology, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, Virginia.
Thomas J
TJ
L'Ecuyer
Division of Cardiology, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, Virginia.
G Paul
GP
Matherne
Division of Gastroenterology, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, Virginia.
Barrett H
BH
Barnes
Division of Genetics, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, Virginia.
Jennifer B
JB
Humberson
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Andrew C
AC
Edmondson
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Elaine
E
Zackai
Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Matthew J
MJ
O'Connor
Division of Medical Genetics, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi.
Julie D
JD
Kaplan
Division of Cardiology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi.
Makram R
MR
Ebeid
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Joel
J
Krier
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Elizabeth
E
Krieg
Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Brian
B
Ghoshhajra
Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Pediatric Cardiology, Department of Pediatrics, MassGeneral Hospital for Children, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.|Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Mark E
ME
Lindsay
D000293:Adolescent; D000328:Adult; D018376:Cardiovascular Abnormalities / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D002648:Child; D003456:Cryptorchidism / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D004452:Echocardiography; D005091:Exons; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006130:Growth Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D006228:Hand Deformities, Congenital / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010641:Phenotype; D051901:Smad4 Protein / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography; D055815:Young Adult
D051901:Smad4 Protein
SMAD4 mutations; TGF-β signaling; cardiovascular malformation; coarctation; congenital heart defect; pericardial effusion; pericarditis; restrictive cardiomyopathy