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Journal of Autism and Developmental... Jul 2019Myhre syndrome (MS) is a connective tissue disorder with multisystem involvement with or without intellectual disability. In most cases SMAD4 mutations are reported. To...
Myhre syndrome (MS) is a connective tissue disorder with multisystem involvement with or without intellectual disability. In most cases SMAD4 mutations are reported. To date, 55 individuals have been molecularly confirmed. Autism has been proposed among associate clinical features of MS but no standardized diagnosis was available in previous cases. We report a case of a 25-year-old man with a pathogenic heterozygous SMAD4 missense mutation affecting residue Arg (SMAD4:p.Arg496Cys). Clinical findings are consistent with MS, commorbid with affective disorder and High Functioning Autism Spectrum Disorder confirmed by a standardized assessment procedure. The thorough clinical assessment of cases with syndromes such as MS can extend our knowledge on both the phenotypic characteristics of the syndrome and the genetic basis of autism.
Topics: Adult; Autism Spectrum Disorder; Comorbidity; Cryptorchidism; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Mutation; Smad4 Protein
PubMed: 30968316
DOI: 10.1007/s10803-019-04015-y -
European Journal of Human Genetics :... Aug 2014Myhre syndrome (MS, MIM 139210) is a connective tissue disorder that presents with short stature, short hands and feet, facial dysmorphic features, muscle hypertrophy,...
Myhre syndrome (MS, MIM 139210) is a connective tissue disorder that presents with short stature, short hands and feet, facial dysmorphic features, muscle hypertrophy, thickened skin, and deafness. Recurrent missense mutations in SMAD4 encoding for a transducer mediating transforming growth factor β (TGF-β) signaling are responsible for MS. We found that MS fibroblasts showed increased SMAD4 protein levels, impaired matrix deposition, and altered expression of genes encoding matrix metalloproteinases and related inhibitors. Increased TGF-β signaling and progression of aortic root dilation in Marfan syndrome can be prevented by the antihypertensive drug losartan, a TGF-β antagonists and angiotensin-II type 1 receptor blocker. Herein, we showed that losartan normalizes metalloproteinase and related inhibitor transcript levels and corrects the extracellular matrix deposition defect in fibroblasts from MS patients. The results of this study may pave the way toward therapeutic applications of losartan in MS.
Topics: Adolescent; Adult; Child; Cryptorchidism; Extracellular Matrix; Facies; Female; Fibroblasts; Growth Disorders; Hand Deformities, Congenital; Humans; Hypertrophy; Intellectual Disability; Joint Diseases; Losartan; Metalloendopeptidases; Microfibrils; Mutation; Phosphorylation; Signal Transduction; Smad2 Protein; Smad4 Protein; Transforming Growth Factor beta; Young Adult
PubMed: 24398790
DOI: 10.1038/ejhg.2013.283 -
BMJ Case Reports Aug 2021Myhre syndrome is a rare disorder characterised by short stature, skeletal anomalies, facial dysmorphism and hearing loss (HL), resulting from heterozygous mutations of...
Myhre syndrome is a rare disorder characterised by short stature, skeletal anomalies, facial dysmorphism and hearing loss (HL), resulting from heterozygous mutations of the gene. We describe the benefits of cochlear implant (CI) in a patient with sensorineural HL carrying a mutation (NM_005359.6: c.1498A>G; p.lle500Val) within the gene, detected by whole-exome sequencing. The CI was inserted through the round window despite otospongiotic abnormalities. Pure-tone audiometry improved up to 20 dBHL. Speech perception in noise (Simplified Noise Reduction - SNR +10) increased from 0% pre implantation with hearing aids to 50% post implantation. The postoperative setting of the electrical stimulation limits yielded an asymmetric map, with lower levels for central electrodes and higher levels for lateral ones. Action potential could not be evoked via medial electrodes, suggesting a cochlear nerve dysfunction. Outcomes related to quality of life and cognitive impairment improved. CI was shown to be an effective auditory rehabilitation strategy.
Topics: Cochlear Implantation; Cryptorchidism; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Middle Aged; Quality of Life
PubMed: 34433528
DOI: 10.1136/bcr-2021-243164 -
Prenatal Diagnosis Sep 2023Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and...
Prenatal testing was performed in a 39-year-old Chinese pregnant woman referred for increased nuchal translucency measuring 5.7 mm. Non-invasive prenatal testing and SNP array study on amniotic fluid samples were normal. Whole exome sequencing (WES) was initiated further as the fetus had pericardial effusion of 1.2 mm, thickened myocardium over the right ventricular lateral wall and aberrant right subclavian artery. A detailed fetal echocardiogram also revealed persistent left superior vena cava and dilated coronary sinus at 20 weeks. From whole exome sequencing of the trio, a de novo heterozygous variant NM_005359.5(SMAD4): c.1499T>C (p.Ile500Thr) was detected. This pathogenic variant has been reported in the postnatal case cohort of Myhre syndrome. This condition is characterized by facial dysmorphism, intellectual disability, hearing loss, skeletal abnormalities and potential life threatening respiratory or cardiovascular manifestations. Termination of pregnancy was performed at 23 weeks. Small chins, pre-axial polydactyly, brachydactyly and clinodactyly were noted in the abortus. Ultrasound findings of increased nuchal translucency, thickened myocardium and pericardial effusion prompted further genetic evaluation for the prenatal diagnosis of Myhre syndrome by whole exome sequencing.
Topics: Pregnancy; Female; Humans; Adult; Intellectual Disability; Nuchal Translucency Measurement; Pericardial Effusion; Vena Cava, Superior; Prenatal Diagnosis; Heart Defects, Congenital; Ultrasonography, Prenatal; Smad4 Protein
PubMed: 37529930
DOI: 10.1002/pd.6414 -
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 -
Clinical Dysmorphology Apr 2015
Topics: Child, Preschool; Cryptorchidism; Facial Paralysis; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Hypertrophy; Infant, Newborn; Intellectual Disability; Joint Diseases; Pulmonary Valve Stenosis; Smad4 Protein
PubMed: 25486016
DOI: 10.1097/MCD.0000000000000068 -
Ear, Nose, & Throat Journal Jun 2024Myhre syndrome (MS) is a rare genetic condition that presents with multiple genetic anomalies including cleft lip and palate and Eustachian tube dysfunction. These...
Myhre syndrome (MS) is a rare genetic condition that presents with multiple genetic anomalies including cleft lip and palate and Eustachian tube dysfunction. These patients are at a high risk for airway scarring from intubation and mucosal inflammation. Hearing loss (conductive or mixed, of varying severity) is a common comorbidity in these patients, the exact etiology of which is still unclear. We present the cases of 2 unrelated children with MS who suffered progressive mixed hearing loss from fibrosis and obliteration of the middle ear spaces. Both patients had multiple sets of ear tubes that demonstrated early extrusion. The older patient underwent bone conduction implantation at age 11 which resulted in dramatic improvement of speech recognition and interactive skills. The other younger patient demonstrates a similar trajectory but has not yet undergone implantation. Otolaryngologists should take a cautious approach to surgery of the eardrum and middle ear to avoid unnecessary induction of fibrosis in this susceptible patient population. These cases highlight a newly described etiology for hearing loss and suggest a benefit to bone conduction implantation.
PubMed: 38907583
DOI: 10.1177/01455613241256474 -
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 -
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 -
American Journal of Medical Genetics.... Oct 2022Loss-of-function pathogenic variants in somatic and germline cells in SMAD4 may cause cancer and juvenile polyposis-Hereditary Hemorrhagic Telangiectasia (SMAD4-JP-HHT),...
An additional patient with SMAD4-Juvenile Polyposis-Hereditary hemorrhagic telangiectasia and connective tissue abnormalities: SMAD4 loss-of-function and gain-of-function pathogenic variants result in contrasting phenotypes.
Loss-of-function pathogenic variants in somatic and germline cells in SMAD4 may cause cancer and juvenile polyposis-Hereditary Hemorrhagic Telangiectasia (SMAD4-JP-HHT), respectively. In a similar manner, gain-of-function somatic and germline pathogenic variants in SMAD4 can cause various forms of cancer as well as Myhre syndrome. The different SMAD4 molecular mechanisms result in contrasting clinical phenotypes demonstrated by SMAD4-JP-HHT and Myhre syndrome. We report an additional patient with SMAD4-JP-HHT and aortopathy, and expand the phenotype to include severe valvulopathy, cutaneous, ophthalmologic, and musculoskeletal features consistent with an inherited disorder of connective tissue. We compared this 70-year-old man with SMAD4-JP-HHT to 18 additional literature cases, and also compared patients with SMAD4-JP-HHT to those with Myhre syndrome. In contrast to aorta dilation, hypermobility, and loose skin in SMAD4-JP-HHT, Myhre syndrome has aorta hypoplasia, stiff joints, and firm skin representing an intriguing phenotypic contrast, which can be attributed to different molecular mechanisms involving SMAD4. We remind clinicians about the possibility of significant cardiac valvulopathy and aortopathy, as well as connective tissue disease in SMAD4-JP-HHT. Additional patients and longer follow-up will help determine if more intensive surveillance improves care amongst these patients.
Topics: Connective Tissue; Cryptorchidism; Facies; Gain of Function Mutation; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Intestinal Polyposis; Mutation; Neoplastic Syndromes, Hereditary; Phenotype; Smad4 Protein; Telangiectasia, Hereditary Hemorrhagic
PubMed: 35869926
DOI: 10.1002/ajmg.a.62915