Gain‐of‐function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome

Abstract

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.

A child with Myhre syndrome presenting with corectopia and tetralogy of Fallot

“… a Include 53 cases of the literature reviewed by Lin et al (), the additional cases by Erdem, Sahin, and Tatar () and Garavelli et al () published after Lin et al (), and the current case.…”

“…Myhre syndrome (MIM 139210) is a rare autosomal dominant disorder reported so far in over 60 individuals, mostly males diagnosed in childhood or adolescence (Caputo et al, ; Lin et al, ). Clinical features of this disorder include poor growth, variable degree of intellectual disability, distinctive dysmorphic features including short palpebral fissures, maxillary hypoplasia, small mouth with thin upper lip and short philtrum, prognathism, and thick skin.…”

“…Clinical features of this disorder include poor growth, variable degree of intellectual disability, distinctive dysmorphic features including short palpebral fissures, maxillary hypoplasia, small mouth with thin upper lip and short philtrum, prognathism, and thick skin. Restricted joint mobility and scarring abnormalities are striking features of the disorders (Caputo et al, ; Le Goff et al, ; Lin et al, ). Cardiovascular abnormalities include restrictive cardiomyopathy and pericardial disease although congenital heart defects have also been reported (Lin et al, ; Starr et al, ).…”

“…Restricted joint mobility and scarring abnormalities are striking features of the disorders (Caputo et al, ; Le Goff et al, ; Lin et al, ). Cardiovascular abnormalities include restrictive cardiomyopathy and pericardial disease although congenital heart defects have also been reported (Lin et al, ; Starr et al, ). Patients with Myhre syndrome might develop various long‐term and life‐threatening complications including systemic hypertension, cardiomyopathy, pericarditis, laryngo‐tracheal stenosis, and pulmonary insufficiency (Garavelli et al, ; Lin et al, ; Starr et al, ).…”

Optic disc swelling in acromicric and geleophysic dysplasia

“…Papilledema (Erdem, Sahin, & Tatar, 2018) and pseudopapilledema (Al Ageeli et al, 2012;Lin et al, 2016) have also been reported in Myhre syndrome (OMIM 139210), an another acromelic disorder characterized by connective tissue thickening. Unfortunately, the eye findings in these reports are not described in detail and it is thus unclear whether they represent papilledema or pseudopapilledema.…”