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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 -
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 -
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 -
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 -
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 -
GeroScience Apr 2021
Topics: Cellular Senescence; Cryptorchidism; DNA Damage; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Mutation; Smad4 Protein; Syndrome; Transforming Growth Factor beta
PubMed: 33630210
DOI: 10.1007/s11357-021-00337-x -
GeroScience Jun 2021SMAD4 encodes a member of the SMAD family of proteins involved in the TGF-β signaling pathway. Potentially heritable, autosomal dominant, gain-of-function heterozygous...
SMAD4 mutations and cross-talk between TGF-β/IFNγ signaling accelerate rates of DNA damage and cellular senescence, resulting in a segmental progeroid syndrome-the Myhre syndrome.
SMAD4 encodes a member of the SMAD family of proteins involved in the TGF-β signaling pathway. Potentially heritable, autosomal dominant, gain-of-function heterozygous variants of SMAD4 cause a rare developmental disorder, the Myhre syndrome, which is associated with a wide range of developmental and post-developmental phenotypes that we now characterize as a novel segmental progeroid syndrome. Whole-exome sequencing of a patient referred to our International Registry of Werner Syndrome revealed a heterozygous p.Arg496Cys variant of the SMAD4 gene. To investigate the role of SMAD4 mutations in accelerated senescence, we generated cellular models overexpressing either wild-type SMAD4 or mutant SMAD4-R496C in normal skin fibroblasts. We found that cells expressing the SMAD4-R496C mutant exhibited decreased proliferation and elevated expression of cellular senescence and inflammatory markers, including IL-6, IFNγ, and a TGF-β target gene, PAI-1. Here we show that transient exposure to TGF-β, an inflammatory cytokine, followed by chronic IFNγ stimulation, accelerated rates of senescence that were associated with increased DNA damage foci and SMAD4 expression. TGF-β, IFNγ, or combinations of both were not sufficient to reduce proliferation rates of fibroblasts. In contrast, TGF-β alone was able to induce preadipocyte senescence via induction of the mTOR protein. The mTOR inhibitor rapamycin mitigated TGF-β-induced expression of p21, p16, and DNA damage foci and improved replicative potential of preadipocytes, supporting the cell-specific response to this cytokine. These findings collectively suggest that persistent DNA damage and cross-talk between TGF-β/IFNγ pathways contribute to a series of molecular events leading to cellular senescence and a segmental progeroid syndrome.
Topics: Cellular Senescence; Cryptorchidism; DNA Damage; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Mutation; Smad4 Protein; Transforming Growth Factor beta
PubMed: 33428109
DOI: 10.1007/s11357-020-00318-6 -
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 Rheumatology Online Journal Sep 2020Myhre syndrome is a genetic disorder caused by gain of function mutations in the SMAD Family Member 4 (SMAD4) gene, resulting in progressive, proliferative skin and...
BACKGROUND
Myhre syndrome is a genetic disorder caused by gain of function mutations in the SMAD Family Member 4 (SMAD4) gene, resulting in progressive, proliferative skin and organ fibrosis. Skin thickening and joint contractures are often the main presenting features of the disease and may be mistaken for juvenile scleroderma.
CASE PRESENTATION
We report a case of a 13 year-old female presenting with widespread skin thickening and joint contractures from infancy. She was diagnosed with diffuse cutaneous systemic sclerosis, and treatment with corticosteroids and subcutaneous methotrexate recommended. There was however disease progression prompting genetic testing. This identified a rare heterozygous pathogenic variant c.1499 T > C (p.Ile500Thr) in the SMAD4 gene, suggesting a diagnosis of Myhre syndrome. Securing a molecular diagnosis in this case allowed the cessation of immunosuppression, thus reducing the burden of unnecessary and potentially harmful treatment, and allowing genetic counselling.
CONCLUSION
Myhre Syndrome is a rare genetic mimic of scleroderma that should be considered alongside several other monogenic diseases presenting with pathological fibrosis from early in life. We highlight this case to provide an overview of these genetic mimics of scleroderma, and highlight the molecular pathways that can lead to pathological fibrosis. This may provide clues to the pathogenesis of sporadic juvenile scleroderma, and could suggest novel therapeutic targets.
Topics: Adolescent; Cryptorchidism; Diagnosis, Differential; Facies; Female; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Microscopic Angioscopy; Scleroderma, Localized; Scleroderma, Systemic; Skin; Smad4 Protein
PubMed: 32917212
DOI: 10.1186/s12969-020-00466-1 -
Annals of the New York Academy of... Apr 2021Acromelic dysplasias are a group of rare musculoskeletal disorders that collectively present with short stature, pseudomuscular build, stiff joints, and tight skin....
Acromelic dysplasias are a group of rare musculoskeletal disorders that collectively present with short stature, pseudomuscular build, stiff joints, and tight skin. Acromelic dysplasias are caused by mutations in genes (FBN1, ADAMTSL2, ADAMTS10, ADAMTS17, LTBP2, and LTBP3) that encode secreted extracellular matrix proteins, and in SMAD4, an intracellular coregulator of transforming growth factor-β (TGF-β) signaling. The shared musculoskeletal presentations in acromelic dysplasias suggest that these proteins cooperate in a biological pathway, but also fulfill distinct roles in specific tissues that are affected in individual disorders of the acromelic dysplasia group. In addition, most of the affected proteins directly interact with fibrillin microfibrils in the extracellular matrix and have been linked to the regulation of TGF-β signaling. Together with recently developed knockout mouse models targeting the affected genes, novel insights into molecular mechanisms of how these proteins regulate musculoskeletal development and homeostasis have emerged. Here, we summarize the current knowledge highlighting pathogenic mechanisms of the different disorders that compose acromelic dysplasias and provide an overview of the emerging biological roles of the individual proteins that are compromised. Finally, we develop a conceptual model of how these proteins may interact and form an "acromelic dysplasia complex" on fibrillin microfibrils in connective tissues of the musculoskeletal system.
Topics: Animals; Bone Diseases, Developmental; Cryptorchidism; Disease Models, Animal; Dwarfism; Facies; Fibrillins; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Joints; Limb Deformities, Congenital; Mice; Mice, Knockout; Microfibrils; Musculoskeletal Abnormalities; Skin Abnormalities; Smad4 Protein; Transforming Growth Factor beta; Weill-Marchesani Syndrome
PubMed: 32880985
DOI: 10.1111/nyas.14465