Myhre syndrome: Clinical features and restrictive cardiopulmonary complications

Starr, Lois J.; Grange, Dorothy K.; Delaney, Jeffrey W.; Yetman, Anji T.; Hammel, James M.; Sanmann, Jennifer N.; Perry, Deborah; Schaefer, Gerald; Olney, Ann Haskins

doi:10.1002/ajmg.a.37273

Cited by 35 publications

(38 citation statements)

References 27 publications

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“…Pericardial disease (9, 17%) was usually a recurrent, chronic and occasionally lethal disease, with only one patient [Michot et al, ] reported as an “isolated episode.” Five (56%) of those with pericardial disease could be viewed as having LAPS. We classified the remaining nine patients as either as constrictive (4, 7%) or having chronic effusions (4, 7%), and for the sake of this discussion, include in this discussion the patient with epicarditis reported by Starr et al []. Seven (78%) of those affected were 18 years and younger.…”

Section: Resultsmentioning

confidence: 99%

“…A variety of cardiovascular abnormalities were noted in 54% of the patients in the largest series of 32 patients [Michot et al, ], which was followed by detailed reporting of pericardial disease [Picco et al, ], and possible treatment with losartan [Piccolo et al, ]. Recently, abnormal wound healing with an exuberant fibroproliferative response during operative procedures, including orthotopic heart transplantation for restrictive cardiomyopathy (RCM) [Starr et al, ], has been highlighted as an important management issue.…”

Section: Introductionmentioning

confidence: 99%

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

Lin

Michot

Cormier‐Daire

et al. 2016

American J of Med Genetics Pt A

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lin

Michot

Cormier‐Daire

et al. 2016

American J of Med Genetics Pt A

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“…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, ).…”

Section: Introductionmentioning

confidence: 99%

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

Alagia

Cappuccio

Pinelli

et al. 2017

American J of Med Genetics Pt A

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Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2‐year‐old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.

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“…[12] Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. [13] Cardiac manifestations in Myhre syndrome included PDA, septal defects, aortic coarctation, and pericarditis. [13] As both siblings in this report grew up normally (i.e., without mental, skeletal, or facial abnormalities), involvement of the aforementioned genetic syndromes is unlikely.…”

Section: Discussionmentioning

confidence: 99%

“…[13] Cardiac manifestations in Myhre syndrome included PDA, septal defects, aortic coarctation, and pericarditis. [13] As both siblings in this report grew up normally (i.e., without mental, skeletal, or facial abnormalities), involvement of the aforementioned genetic syndromes is unlikely.…”

Section: Discussionmentioning

confidence: 99%

Familial clustering of congenital deafness, patent ductus arteriosus, Eisenmenger complex, and differential cyanosis

et al. 2017

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Rationale:Few studies had reported syndromes that include patent ductus arteriosus (PDA) with Eisenmenger syndrome and congenital deafness clustered in male siblings without facial, skeletal, or mental abnormalities.Patient concerns:Two brothers, who were deaf and had PDA with Eisenmenger complex, were first seen at our Cardiology clinic at the ages of 25 and 41, respectively. They presented with progressive dyspnea on exertion. Upon physical examination, both brothers had clubbing and/or cyanotic toes, normal fingers, and without facial, skeletal, ophthalmological, or mental abnormalities.Diagnoses and interventions:Echocardiography and multidetector computed tomography revealed large PDAs in both brothers. Cardiac catheterization showed bidirectional shunting via the PDA.Outcomes and lessons:Familial clustering of Eisenmenger PDA and congenital deafness is rare. Further studies are warranted to define possible genetic links.

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Myhre syndrome: Clinical features and restrictive cardiopulmonary complications

Cited by 35 publications

References 27 publications

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

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

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

Familial clustering of congenital deafness, patent ductus arteriosus, Eisenmenger complex, and differential cyanosis

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