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Pediatrics Jun 2018
Topics: Child, Preschool; Cryptorchidism; Decision Making; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Palliative Care; Parents; Patient Care Team; Physician's Role; Rare Diseases; Referral and Consultation; Time Factors
PubMed: 29720536
DOI: 10.1542/peds.2017-3417 -
Pediatrics International : Official... Nov 2017
Topics: Age Factors; Child; Child, Preschool; Cryptorchidism; Disease Progression; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Phenotype
PubMed: 29359479
DOI: 10.1111/ped.13413 -
American Journal of Medical Genetics.... Feb 2018Myhre 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...
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.
Topics: Abnormalities, Multiple; Child, Preschool; Cryptorchidism; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Mutation; Phenotype; Pupil Disorders; Smad4 Protein; Tetralogy of Fallot; Exome Sequencing
PubMed: 29230941
DOI: 10.1002/ajmg.a.38560 -
Clinical Dysmorphology Jan 2018
Topics: Adenoids; Adolescent; Brachydactyly; Breast Diseases; Cataract; Cryptorchidism; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Hypertrophy; Intellectual Disability; Male; Nipples; Papilledema; Smad4 Protein
PubMed: 28562390
DOI: 10.1097/MCD.0000000000000188 -
Biology Open Mar 2017Smad4 is an intracellular effector of the TGFβ family that has been implicated in Myhre syndrome, a skeletal dysplasia characterized by short stature, brachydactyly and...
Smad4 is an intracellular effector of the TGFβ family that has been implicated in Myhre syndrome, a skeletal dysplasia characterized by short stature, brachydactyly and stiff joints. The TGFβ pathway also plays a critical role in the development, organization and proliferation of the growth plate, although the exact mechanisms remain unclear. Skeletal phenotypes in Myhre syndrome overlap with processes regulated by the TGFβ pathway, including organization and proliferation of the growth plate and polarity of the chondrocyte. We used and models of Smad4 deficiency in chondrocytes to test the hypothesis that deregulated TGFβ signaling leads to aberrant extracellular matrix production and loss of chondrocyte polarity. Specifically, we evaluated growth plate chondrocyte polarity in tibiae of Col2-Cre;Smad4 mice and in chondrocyte pellet cultures. and , Smad4 deficiency decreased aggrecan expression and increased MMP13 expression. Smad4 deficiency disrupted the balance of cartilage matrix synthesis and degradation, even though the sequential expression of growth plate chondrocyte markers was intact. Chondrocytes in Smad4-deficient growth plates also showed evidence of polarity defects, with impaired proliferation and ability to undergo the characteristic changes in shape, size and orientation as they differentiated from resting to hypertrophic chondrocytes. Therefore, we show that Smad4 controls chondrocyte proliferation, orientation, and hypertrophy and is important in regulating the extracellular matrix composition of the growth plate.
PubMed: 28167493
DOI: 10.1242/bio.021436 -
European Journal of Pediatrics Oct 2016Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4...
UNLABELLED
Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients.
CONCLUSION
Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity.
WHAT IS KNOWN
• The clinical and radiological signs of the disease in children older than 7-8 years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.
Topics: Brachydactyly; Child; Cryptorchidism; Facies; Fingers; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Mutation, Missense; Nails, Malformed; Pericarditis; Phenotype; Radiography; Retrospective Studies; Smad4 Protein
PubMed: 27562837
DOI: 10.1007/s00431-016-2761-3 -
American Journal of Medical Genetics.... Oct 2016Myhre syndrome is a rare, distinctive syndrome due to specific gain-of-function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic... (Review)
Review
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.
Topics: Adolescent; Adult; Cardiovascular Abnormalities; Child; Cryptorchidism; Echocardiography; Exons; Facies; Female; Genetic Association Studies; Growth Disorders; Hand Deformities, Congenital; High-Throughput Nucleotide Sequencing; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Magnetic Resonance Imaging; Male; Mutation; Phenotype; Smad4 Protein; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography; Young Adult
PubMed: 27302097
DOI: 10.1002/ajmg.a.37739 -
Journal of Medical Genetics Jul 2016Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric...
BACKGROUND
Acromelic dysplasias are a group of disorders characterised by short stature, brachydactyly, limited joint extension and thickened skin and comprises acromicric dysplasia (AD), geleophysic dysplasia (GD), Myhre syndrome and Weill-Marchesani syndrome. Mutations in several genes have been identified for these disorders (including latent transforming growth factor β (TGF-β)-binding protein-2 (LTBP2), ADAMTS10, ADAMSTS17 and fibrillin-1 (FBN1) for Weill-Marchesani syndrome, ADAMTSL2 for recessive GD and FBN1 for AD and dominant GD), encoding proteins involved in the microfibrillar network. However, not all cases have mutations in these genes.
METHODS
Individuals negative for mutations in known acromelic dysplasia genes underwent whole exome sequencing.
RESULTS
A heterozygous missense mutation (exon 14: c.2087C>G: p.Ser696Cys) in latent transforming growth factor β (TGF-β)-binding protein-3 (LTBP3) was identified in a dominant AD family. Two distinct de novo heterozygous LTPB3 mutations were also identified in two unrelated GD individuals who had died in early childhood from respiratory failure-a donor splice site mutation (exon 12 c.1846+5G>A) and a stop-loss mutation (exon 28: c.3912A>T: p.1304*Cysext*12).
CONCLUSIONS
The constellation of features in these AD and GD cases, including postnatal growth retardation of long bones and lung involvement, is reminiscent of the null ltbp3 mice phenotype. We conclude that LTBP3 is a novel component of the microfibrillar network involved in the acromelic dysplasia spectrum.
Topics: Bone Diseases, Developmental; Exome; Exons; Fibrillin-1; Heterozygote; Humans; Latent TGF-beta Binding Proteins; Limb Deformities, Congenital; Microfilament Proteins; Mutation; Mutation, Missense; Phenotype; Transforming Growth Factor beta; Weill-Marchesani Syndrome
PubMed: 27068007
DOI: 10.1136/jmedgenet-2015-103647 -
Clinical Dysmorphology Apr 2016Myhre syndrome is a rare autosomal dominant genetic condition characterized by short stature, distinctive facial dysmorphisms, generalized muscle hypertrophy, skeletal...
Myhre syndrome is a rare autosomal dominant genetic condition characterized by short stature, distinctive facial dysmorphisms, generalized muscle hypertrophy, skeletal abnormalities, decreased joint motility, developmental delay, deafness and cardiac defects. Myhre syndrome and the allelic laryngeal stenosis, arthropathy, prognathism and short stature syndrome are caused by a missense mutation of SMAD4, resulting in altered expression of transforming growth factor β and bone morphogenic protein, affecting cell growth and differentiation. Here, we report on the case of a 7-year-old girl showing symptoms of Myhre syndrome and with a known SMAD4 mutation presenting with the novel symptom of severe constipation.
Topics: Constipation; Cryptorchidism; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Mutation; Phenotype; Smad4 Protein; Treatment Outcome
PubMed: 26636501
DOI: 10.1097/MCD.0000000000000109 -
American Journal of Medical Genetics.... Dec 2015Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal...
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. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.
Topics: Child; Cryptorchidism; Electrocardiography; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Heart Diseases; Heart Transplantation; Humans; Intellectual Disability; Male; Mutation; Pregnancy; Smad4 Protein; Young Adult
PubMed: 26420300
DOI: 10.1002/ajmg.a.37273