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Clinical Genetics Jun 2014Myhre syndrome (MS) is a developmental disorder characterized by typical facial dysmorphism, thickened skin, joint limitation and muscular pseudohypertrophy. Other... (Review)
Review
Myhre syndrome (MS) is a developmental disorder characterized by typical facial dysmorphism, thickened skin, joint limitation and muscular pseudohypertrophy. Other features include brachydactyly, short stature, intellectual deficiency with behavioral problems and deafness. We identified SMAD4 as the gene responsible for MS. The identification of SMAD4 mutations in Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature (LAPS) cases supports that LAPS and MS are a unique entity. The long-term follow up of patients shows that these conditions are progressive with life threatening complications. All mutations are de novo and changing in the majority of cases Ile500, located in the MH2 domain involved in transcriptional activation. We further showed an impairment of the transcriptional regulation via TGFβ target genes in patient fibroblasts. Finally, the absence of SMAD4 mutations in three MS cases may support genetic heterogeneity.
Topics: Adolescent; Adult; Child; Child, Preschool; Cryptorchidism; Disease Progression; Facies; Female; Fibroblasts; Follow-Up Studies; Genetic Heterogeneity; Genotype; Growth Disorders; Hand Deformities, Congenital; Humans; Hypertrophy; Intellectual Disability; Joint Diseases; Male; Mutation; Phenotype; Smad4 Protein; Transcriptional Activation; Transforming Growth Factor beta
PubMed: 24580733
DOI: 10.1111/cge.12365 -
Cardiology in the Young Nov 2023Myhre syndrome is a rare disease secondary to pathogenic variants in gene. It is a multisystem disease characterised by short stature, deafness, joint stiffness,...
Myhre syndrome is a rare disease secondary to pathogenic variants in gene. It is a multisystem disease characterised by short stature, deafness, joint stiffness, craniofacial dysmorphism, and potential cardiac manifestations. Herein, we report two new paediatric cases of Myhre syndrome who, additionally, presented with mid-aortic syndrome. This confirms and extends the scarce reports describing the association between these two entities.
Topics: Male; Humans; Child; Mutation; Intellectual Disability; Growth Disorders; Hand Deformities, Congenital
PubMed: 37325812
DOI: 10.1017/S1047951123001592 -
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 -
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 -
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 -
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 -
Clinical Dysmorphology Jul 2019
Review
Topics: Asian People; Child; Child, Preschool; China; Cryptorchidism; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Smad4 Protein
PubMed: 30921096
DOI: 10.1097/MCD.0000000000000271 -
Annals of Pediatric Endocrinology &... Sep 2021Myhre syndrome (MS) is a rare autosomal-dominant disorder characterized by short stature, intellectual disability, skeletal anomalies, restricted joint mobility,...
Myhre syndrome (MS) is a rare autosomal-dominant disorder characterized by short stature, intellectual disability, skeletal anomalies, restricted joint mobility, distinctive facial dysmorphism, and deafness. Early diagnosis of MS is difficult because its features progress and become noticeable at school age. Recently, the SMAD4 gene was identified as the major gene responsible for MS. Herein, we report the first Korean case of MS after identification of a SMAD4 mutation by clinical exome sequencing. The patient was born small for gestational age, and she had the typical clinical features of MS, including short stature, characteristic facial appearance, developmental delay, and selective mutism. She was diagnosed with central precocious puberty. Because of the patient's precocious puberty and short stature, we administered combined recombinant human growth hormone and gonadotropin-releasing hormone agonist treatments, which resulted in improved height. While there have been 79 cases of MS reported worldwide, to our knowledge, this is the first case of genetically-confirmed MS in Korea.
PubMed: 34015905
DOI: 10.6065/apem.2040214.107 -
Indian Journal of Psychiatry Oct 2023