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

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.

A Second Family with Myhre Syndrome Caused by the Same Recurrent SMAD4 Pathogenic Variation (p.Arg496Cys)

“…Only four distinct SMAD4 missense pathogenic variants affecting the 496 and 500 residues located in MH2 domains have been detected in MS cases [Caputo et al, 2012;Le Goff and Cormier-Daire, 2012;Caputo et al, 2014;Meerschaut et al, 2019]. Fewer than 100 affected individuals with molecularly confirmed diagnosis have been reported [Starr et al, 1993;Titomanlio et al, 2001;Le Goff et al, 2014;Dolivo et al, 2017;Nomura et al, 2017;Alagia et al, 2018;Erdem et al, 2018;Meerschaut et al, 2019;Yu et al, 2019;Alape et al, 2020;Gürsoy et al, 2020;Lin et al, 2020;Cappuccio et al, 2022;Yang et al, 2022]. This study reports the second family demonstrating MS cases.…”

A newborn male with Myhre syndrome, hearing loss, and complete syndactyly of fingers 3–4

“…Cardiovascular abnormalities affect about 70% of patients and include restrictive cardiomyopathy and pericardial disease. In addition, congenital heart defects and tetralogy of Fallot have also been reported (Alagia et al, 2018;Cappuccio et al, 2022;Lin et al, 2016Lin et al, , 2020Starr et al, 2015). Respiratory involvement consists of choanal stenosis and laryngotracheal proliferative fibrosis manifested as progressive tachypnea, exertional dyspnea, and respiratory distress.…”