-
Differentiation; Research in Biological... 2022Myhre syndrome is a connective tissue disorder characterized by congenital cardiovascular, craniofacial, respiratory, skeletal, and cutaneous anomalies as well as...
Myhre syndrome is a connective tissue disorder characterized by congenital cardiovascular, craniofacial, respiratory, skeletal, and cutaneous anomalies as well as intellectual disability and progressive fibrosis. It is caused by germline variants in the transcriptional co-regulator SMAD4 that localize at two positions within the SMAD4 protein, I500 and R496, with I500 V/T/M variants more commonly identified in individuals with Myhre syndrome. Here we assess the functional impact of SMAD4-I500V variant, identified in two previously unpublished individuals with Myhre syndrome, and provide novel insights into the molecular mechanism of SMAD4-I500V dysfunction. We show that SMAD4-I500V can dimerize, but its transcriptional activity is severely compromised. Our data show that SMAD4-I500V acts dominant-negatively on SMAD4 and on receptor-regulated SMADs, affecting transcription of target genes. Furthermore, SMAD4-I500V impacts the transcription and function of crucial developmental transcription regulator, NKX2-5. Overall, our data reveal a dominant-negative model of disease for SMAD4-I500V where the function of SMAD4 encoded on the remaining allele, and of co-factors, are perturbed by the continued heterodimerization of the variant, leading to dysregulation of TGF and BMP signaling. Our findings not only provide novel insights into the mechanism of Myhre syndrome pathogenesis but also extend the current knowledge of how pathogenic variants in SMAD proteins cause disease.
Topics: Humans; Intellectual Disability; Smad4 Protein; Mutation; Hand Deformities, Congenital; Transforming Growth Factor beta
PubMed: 36194927
DOI: 10.1016/j.diff.2022.09.002 -
Orphanet Journal of Rare Diseases Jul 2022Myhre syndrome (MS) is a rare genetic disease characterized by skeletal disorders, facial features and joint limitation, caused by a gain of function mutation in SMAD4...
BACKGROUND
Myhre syndrome (MS) is a rare genetic disease characterized by skeletal disorders, facial features and joint limitation, caused by a gain of function mutation in SMAD4 gene. The natural history of MS remains incompletely understood.
METHODS
We recruited in a longitudinal retrospective study patients with molecular confirmed MS from the French reference center for rare skeletal dysplasia. We described natural history by chaining data from medical reports, clinical data warehouse, medical imaging and photographies.
RESULTS
We included 12 patients. The median age was 22 years old (y/o). Intrauterine and postnatal growth retardation were consistently reported. In preschool age, neurodevelopment disorders were reported in 80% of children. Specifics facial and skeletal features, thickened skin and joint limitation occured mainly in school age children. The adolescence was marked by the occurrence of pulmonary arterial hypertension (PAH) and vascular stenosis. We reported for the first time recurrent strokes from the age of 26 y/o, caused by a moyamoya syndrome in one patient. Two patients died at late adolescence and in their 20 s respectively from PAH crises and mesenteric ischemia.
CONCLUSION
Myhre syndrome is a progressive disease with severe multisystemic impairement and life-threathning complication requiring multidisciplinary monitoring.
Topics: Adolescent; Adult; Child; Child, Preschool; Cryptorchidism; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Retrospective Studies; Smad4 Protein; Young Adult
PubMed: 35907855
DOI: 10.1186/s13023-022-02447-x -
Brazilian Journal of Cardiovascular... Oct 2021A 32-month-old girl with patent ductus arteriosus, false tendon of left ventricle, mild pulmonary hypertension, and chronic cardiac insufficiency (cardiac function level...
A 32-month-old girl with patent ductus arteriosus, false tendon of left ventricle, mild pulmonary hypertension, and chronic cardiac insufficiency (cardiac function level I-II) was misdiagnosed with Marfan Syndrome and there was no improvement in her physical growth after operation for this disease. The preterm baby was finally diagnosed with Myhre Syndrome by clinical phenotypes and mutation of SMAD4 gene.
Topics: Child, Preschool; Cryptorchidism; Diagnostic Errors; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Marfan Syndrome; Smad4 Protein
PubMed: 34236823
DOI: 10.21470/1678-9741-2020-0592 -
European Journal of Human Genetics :... Nov 2014Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4...
Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.
Topics: Adolescent; Adult; Child; Cryptorchidism; Facies; Female; Follow-Up Studies; Growth Disorders; Hand Deformities, Congenital; Heterozygote; Humans; Hypertrophy; Intellectual Disability; Joint Diseases; Male; Middle Aged; Mutation; Sequence Analysis, DNA; Smad4 Protein; Young Adult
PubMed: 24424121
DOI: 10.1038/ejhg.2013.288 -
Molecular Genetics & Genomic Medicine Mar 2023Myhre syndrome is a rare multisystem genetic disorder that is caused by de novo heterozygous gain-of-function variants in SMAD4. Patients with Myhre syndrome exhibit... (Review)
Review
BACKGROUND
Myhre syndrome is a rare multisystem genetic disorder that is caused by de novo heterozygous gain-of-function variants in SMAD4. Patients with Myhre syndrome exhibit several phenotypes at different ages such as small size, autism, developmental delay, left-sided heart defects, and hearing loss and often have a characteristic facial appearance. The early clinical diagnosis of Myhre syndrome remains a major challenge, particularly in the first year of life.
METHODS
A Chinese male infant with syndactyly of fingers, hypertelorism, short palpebral fissures, and short philtrum was enrolled into the ENT department of the Chinese PLA General Hospital. Whole exome sequencing analysis was used to detect the disease-causing variant. A literature review of Myhre syndrome was also performed.
RESULTS
A recurrent de novo missense variant c.1498A > G p.I500V(p. Ile500Val) in SMAD4 was detected confirming the clinical diagnosis of Myhre syndrome at the age of 38 days. The infant appears to be the youngest reported case of Myhre syndrome. At 23-month follow-up, the affected infant has dysmorphic facial features, growth retardation, and previously undescribed complete syndactyly. Review the literatures noted several common features in Myhre syndrome patients including hearing loss (72.7%), characteristic facial features (26.0%-54.5%), finger and toe abnormalities (3.9%-48.1%), short stature (45.5%), and respiratory (30.0%) and cardiovascular problems (65.0%).
CONCLUSIONS
Clinicians should have a low threshold to perform genetic testing on patients with features suggesting Myhre syndrome even in the first year of life. Although some individuals with Myhre syndrome have normal hearing, early onset or progressive hearing loss usually occur in one or both ears in most patients, with remarkable phenotypic heterogeneity. Syndactyly may be minor such as typical 2-3 toe involvement, or more complicated as was observed in our patient.
Topics: Humans; Male; Deafness; Growth Disorders; Hearing Loss; Intellectual Disability; Syndactyly; Infant, Newborn
PubMed: 36373990
DOI: 10.1002/mgg3.2103 -
Frontiers in Pediatrics 2020Myhre syndrome is a rare condition caused by a mutation in the gene, which leads to a defective TGF-β/BMP signaling, resulting in the proliferation of abnormal fibrous...
Myhre syndrome is a rare condition caused by a mutation in the gene, which leads to a defective TGF-β/BMP signaling, resulting in the proliferation of abnormal fibrous tissues. Clinically, patients with Myhre syndrome manifest with defects of connective tissue (skin, muscles, joints), and cardiovascular and neurological impairment. In our report, we present a case of a 16-year-old female with skeletal abnormalities, reduced articular mobility, skin, and muscular hypertrophy and cardiovascular defects characteristic of Myhre syndrome. Long-term pulmonary hypertension and arterial hypertension were persistent in spite of antihypertensive treatment. Our patient was also diagnosed with chronic kidney disease and Dunbar syndrome, which is an external compression of the coeliac trunk or coeliac artery by the surrounding tissues. Until now, only a few cases of renal complications in Myhre syndrome have been published. We describe for the first time a female patient with genetically confirmed Myhre syndrome caused by the p.Ile500Val mutation presenting with an unusual occurrence of congenital vesicoureteral reflux, proteinuria with a decreased renal function, and a condition recognized as Dunbar syndrome.
PubMed: 32175297
DOI: 10.3389/fped.2020.00072 -
Experimental and Therapeutic Medicine May 2022Myhre syndrome is a rare genetic autosomal dominant connective tissue disorder, characterized by developmental delay, characteristic facial features, various bone and...
Myhre syndrome is a rare genetic autosomal dominant connective tissue disorder, characterized by developmental delay, characteristic facial features, various bone and joint abnormalities, distinctive cardiovascular, ophthalmological and ear, nose and throat (ENT) manifestations, in association with mild to moderate intellectual disability and autism or autism spectrum disorder-like behaviour. The diagnosis of Myhre syndrome is established corroborating the clinical findings with heterozygous mutation identified in the majority of the patients. gene mutations result in abnormal TGF-β signalling in several cell types, which affects the development of several body systems and leads to the specific phenotype of Myhre syndrome. We herein report the case of an 18-year-old female patient who was diagnosed at the age of 17 years with Myhre syndrome, the first documented case of this syndrome in Romania. Sequence analysis of protein-coding genes using whole-exome analysis identified a '', heterozygous missense variant of , c.1498A>G, p. (Ile500Val), which is pathogenic for Myhre syndrome. Although this condition is rare, a series of particularities were identified in the present case, consisting of severe allergic reactions, recurrent ENT tumour development and delayed dental eruption, which have not been described in Myhre syndrome to date, to the best of the authors' knowledge.
PubMed: 35386616
DOI: 10.3892/etm.2022.11252 -
Molecular Syndromology Jan 2020Myhre syndrome is a rare autosomal dominant multisystemic disorder. Typical features of this disorder include distinctive facial appearance, deafness, intellectual...
Myhre syndrome is a rare autosomal dominant multisystemic disorder. Typical features of this disorder include distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, brachydactyly, and skeletal anomalies. Gain-of-function mutations in the gene are responsible for this syndrome. Herein, we present a 9.6-year-old Turkish girl with molecularly confirmed Myhre syndrome who had novel findings including bilateral Axenfield Rieger anomaly with secondary glaucoma and bilateral enlarged vestibular aqueducts.
PubMed: 32021609
DOI: 10.1159/000504829