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Indian Journal of Psychiatry Oct 2023
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North American Journal of Medical... May 2015The cell cycle (or cell-division cycle) is a series of events that take place in a cell, leading to its division and duplication. Cell division requires cell cycle... (Review)
Review
The cell cycle (or cell-division cycle) is a series of events that take place in a cell, leading to its division and duplication. Cell division requires cell cycle checkpoints (CPs) that are used by the cell to both monitor and regulate the progress of the cell cycle. Tumor-suppressor genes (TSGs) or antioncogenes are genes that protect the cell from a single event or multiple events leading to cancer. When these genes mutate, the cell can progress to a cancerous state. We aimed to perform a narrative review, based on evaluation of the manuscripts published in MEDLINE-indexed journals using the Medical Subject Headings (MeSH) terms "tumor suppressor's genes," "skin," and "cell cycle regulatory checkpoints." We aimed to review the current concepts regarding TSGs, CPs, and their association with selected cutaneous diseases. It is important to take into account that in some cell cycle disorders, multiple genetic abnormalities may occur simultaneously. These abnormalities may include intrachromosomal insertions, unbalanced division products, recombinations, reciprocal deletions, and/or duplication of the inserted segments or genes; thus, these presentations usually involve several genes. Due to their complexity, these disorders require specialized expertise for proper diagnosis, counseling, personal and family support, and genetic studies. Alterations in the TSGs or CP regulators may occur in many benign skin proliferative disorders, neoplastic processes, and genodermatoses.
PubMed: 26110128
DOI: 10.4103/1947-2714.157476 -
American Journal of Medical Genetics.... May 2024Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty...
Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
PubMed: 38779990
DOI: 10.1002/ajmg.a.63638 -
Cranio : the Journal of... Oct 2014Myhre syndrome is a rare disorder characterized by abnormal growth of the skeleton, muscles, and joints. The relationship of this syndrome to craniofacial growth and...
AIMS
Myhre syndrome is a rare disorder characterized by abnormal growth of the skeleton, muscles, and joints. The relationship of this syndrome to craniofacial growth and development is unknown. To the authors' knowledge, this is the first Japanese case ever studied.
METHODOLOGY
At 10 years and 7 months of age, the patient was referred to the Department of Pediatric Dentistry in the authors' hospital, complaining of a dental problem.
RESULTS
The craniofacial region exhibited a long lower face, high and narrowed palate with submucous cleft palate, maxillary constriction, prognathism, open bite, and crowding of the dental arch. Some of these morphological disorders could be affected by the functional manifestations of muscular hypertrophy of the cheek region, muscle tenseness, or the low position of the tongue. General disorders of muscular hypertrophy, thickened bones, and limited joint mobility are consistent with craniofacial findings of muscle tension in the cheek region, thickened calvarium, and limitation of temporomandibular joint movement. The submucous cleft palate and crown deformation of the mandibular central incisor may be affected by dysfunctions of SMAD4 signaling.
CONCLUSIONS
Craniofacial growth and development is affected by the general characteristics of Myhre syndrome, and could be important in its diagnosis.
Topics: Child; Cryptorchidism; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Japan; Phenotype
PubMed: 25252769
DOI: 10.1179/0886963413Z.00000000024 -
A Second Family with Myhre Syndrome Caused by the Same Recurrent Pathogenic Variation (p.Arg496Cys).Molecular Syndromology Apr 2023Myhre syndrome (MS; OMIM #139210) is a rare connective tissue disorder presenting with cardiovascular, respiratory, gastrointestinal, and skeletal system findings. Fewer...
INTRODUCTION
Myhre syndrome (MS; OMIM #139210) is a rare connective tissue disorder presenting with cardiovascular, respiratory, gastrointestinal, and skeletal system findings. Fewer than 100 patients were reported until recently, and all molecularly confirmed cases had de novo heterozygous gain-of-function mutations in the gene. Dysregulation of the TGF-beta signaling pathway leads to axial and appendicular skeleton, connective tissue, cardiovascular system, and central nervous system abnormalities.
CASE PRESENTATION
Two siblings, 12 and 9 years old, were referred to us because of intellectual disability, neurodevelopmental delay, and dysmorphic facial features. Physical examination revealed hypertelorism, strabismus, small mouth, prognathism, short neck, stiff skin, and brachydactyly.
DISCUSSION
With a clinical diagnosis of MS, the gene was analyzed via Sanger sequencing, and a heterozygous c.1486C>T (p.Arg496Cys) pathogenic variation was detected in both of the siblings. The segregation analysis revealed that the mutation was inherited from the father who displayed a milder phenotype. Among the 90 patients in the literature, one family was reported in which two siblings carried the same variation (p.Arg496Cys), inherited from the severely affected mother. We are reporting the second family which has three affected family members, a father and two children. We report this study to remind the clinicians to be aware of the parental transmission of variations and also evaluate the parents of the Myhre cases.
PubMed: 37064342
DOI: 10.1159/000527149 -
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.... Mar 2021Myhre syndrome (MS) is an ultra-rare disorder due to pathogenic variants in the SMAD4 gene that encodes a protein regulating the TGF-β pathway and extra-cellular matrix... (Clinical Trial)
Clinical Trial
INTRODUCTION
Myhre syndrome (MS) is an ultra-rare disorder due to pathogenic variants in the SMAD4 gene that encodes a protein regulating the TGF-β pathway and extra-cellular matrix (ECM) homeostasis. Main clinical features of MS include thickening of skin and joint stiffness. Previous studies showed that losartan improved ECM deposition in MS fibroblasts.
MATERIALS AND METHODS
Four molecularly confirmed MS subjects (mean age 23.8 ± 17 years) were evaluated for: (a) skin thickness by Rodnan score, (b) joint range of motion (ROM) by goniometry, and (c) speckle-tracking echocardiogram. Following baseline evaluations, three MS individuals received losartan for 12 months and pre-defined endpoints were monitored after 6 and 12 months of treatment.
RESULTS
At baseline, Rodnan scores were increased, joint ROM was reduced, and speckle-tracking echocardiogram revealed reduced myocardial strain. In three MS subjects, improvements in skin thickness, joint ROM and to a lesser extent of myocardial strain, were observed after 6 and 12 months of losartan treatment.
CONCLUSIONS
Although further long-term controlled clinical trials with a larger number of affected individuals are needed, the present study suggests that losartan might improve skin, joint and heart abnormalities of MS.
Topics: Adolescent; Adult; Angiotensin II Type 1 Receptor Blockers; Child; Child, Preschool; Cryptorchidism; Facies; Female; Follow-Up Studies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Losartan; Male; Pilot Projects; Prognosis; Young Adult
PubMed: 33369056
DOI: 10.1002/ajmg.a.62019 -
Pediatric Allergy, Immunology, and... Jun 2021Myhre syndrome is a rare connective tissue disorder caused by heterozygous pathogenic variants in the gene. Although recognizing Myhre syndrome in early childhood is...
Myhre syndrome is a rare connective tissue disorder caused by heterozygous pathogenic variants in the gene. Although recognizing Myhre syndrome in early childhood is challenging, it is important to manage airway stenosis in patients with Myhre syndrome. We report the case of a 2-month-old boy who initially presented with severe multilevel airway stenosis, dysmorphic face, and multiple abnormalities. Lung fibrosis and mild aortic valve stenosis were additionally observed on follow-up examinations. A heterozygous missense variant, c.1499T>C (p.Ile500Thr), in was identified through exome sequencing. Tracheostomy was performed, and the patient has maintained stable respiration through a customized tracheostomy tube with a home ventilator. Patients who have dysmorphic face, airway stenosis, and cardiovascular anomalies that do not fit the diagnosis of common syndromes should be evaluated for rare diseases, including Myhre syndrome. Since respiratory complications can be life threatening, early diagnosis and suitable intervention are necessary.
Topics: Child, Preschool; Constriction, Pathologic; Cryptorchidism; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Tracheostomy
PubMed: 34143683
DOI: 10.1089/ped.2021.0029 -
Frontiers in Pediatrics 2021Myhre syndrome is a rare disorder caused by a heterozygous mutation in the gene. Affected patients may exhibit dysmorphic facial features, intrauterine growth...
Myhre syndrome is a rare disorder caused by a heterozygous mutation in the gene. Affected patients may exhibit dysmorphic facial features, intrauterine growth retardation, short stature, obesity, muscle hypertrophy, thickened skin, limited joint movement, hearing impairment, and varying degrees of psychomotor developmental disorder. Serious complications of the cardiovascular and respiratory system may be seen later in life. We report the case of a Chinese boy with Myhre syndrome presenting with a novel symptom of giant testicles where treatment with growth hormone combined with letrozole successfully improved his short stature. This case shows that letrozole combined with growth hormone can improve height in children with Myhre syndrome without adverse effects.
PubMed: 34395338
DOI: 10.3389/fped.2021.675934 -
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