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-ß 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-ß, 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.
Subject(s)
Cardiovascular Abnormalities/diagnosis , Cardiovascular Abnormalities/genetics , Cryptorchidism/diagnosis , Cryptorchidism/genetics , Growth Disorders/diagnosis , Growth Disorders/genetics , Hand Deformities, Congenital/diagnosis , Hand Deformities, Congenital/genetics , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Mutation , Phenotype , Smad4 Protein/genetics , Adolescent , Adult , Cardiovascular Abnormalities/therapy , Child , Cryptorchidism/therapy , Echocardiography , Exons , Facies , Female , Genetic Association Studies , Growth Disorders/therapy , Hand Deformities, Congenital/therapy , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Intellectual Disability/therapy , Magnetic Resonance Imaging , Male , Tomography, X-Ray Computed , Treatment Outcome , Ultrasonography , Young AdultABSTRACT
This study assessed attitudes and beliefs regarding the importance of a genetic versus non-genetic diagnosis within the mitochondrial disease community. Survey respondents were categorized into two groups - those with a genetic diagnosis, and those with a non-genetic diagnosis of mitochondrial disease. We found that while both groups perceive problems with the support available to adult mitochondrial disease patients, the non-genetic group experiences less medical and social support due to lack of a definitive diagnosis. Understanding the efficacy of existing resources for mitochondrial disease sub-groups will allow for the development or improvement of resources designed to meet patient needs.