Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.

Gerarda Cappuccio; Nicola Brunetti-Pierri; Paul Clift; Christopher Learn; John C Dykes; Catherine L Mercer; Bert Callewaert; Ilse Meerschaut; Alessandro Mauro Spinelli; Irene Bruno; Matthew J Gillespie; Aaron T Dorfman; Adda Grimberg; Mark E Lindsay; Angela E Lin

doi:10.1002/ajmg.a.62645

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Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.

Authors

Cappuccio, Gerarda^{1, 2}
Brunetti-Pierri, Nicola^{1, 2}
Clift, Paul³
Learn, Christopher⁴
Dykes, John C⁵
Mercer, Catherine L⁶
Callewaert, Bert^{7, 8}
Meerschaut, Ilse^{8, 9}
Spinelli, Alessandro Mauro¹⁰
Bruno, Irene¹⁰
Gillespie, Matthew J¹¹
Dorfman, Aaron T¹¹
Grimberg, Adda^{12, 13}
Lindsay, Mark E^{14, 15}
Lin, Angela E¹⁶

¹ Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy. , (Italy)
² Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy. , (Italy)
³ Adult Congenital Heart Disease Unit, University Hospitals Birmingham, Birmingham, UK.
⁴ Adult Congenital Heart Disease Program, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Departments of Pediatrics, Stanford, California, USA.
⁶ Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Princess Anne Hospital, Southampton, UK.
⁷ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. , (Belgium)
⁸ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. , (Belgium)
⁹ Department of Pediatrics, Ghent University Hospital, Ghent, Belgium. , (Belgium)
¹⁰ Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. , (Italy)
¹¹ Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹² Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Pediatrics, Division of Pediatric Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁵ Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁶ Genetics Unit, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts, USA.

Type

Published Article

Journal

American Journal of Medical Genetics Part A

Publisher

Wiley (John Wiley & Sons)

Publication Date

May 01, 2022

Volume

188

Issue

5

Pages

1384–1395

Identifiers

DOI: 10.1002/ajmg.a.62645

PMID: 35025139

Source

Medline

Keywords

Language

English

License

Unknown

Abstract

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology. © 2022 Wiley Periodicals LLC.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 06/06/2022 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/35025139

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