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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 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 -
Journal of Cardiovascular Development... Jan 2022Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely... (Review)
Review
Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.
PubMed: 35200700
DOI: 10.3390/jcdd9020047 -
American Journal of Medical Genetics.... Feb 2020Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype...
Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3/34, mean age 40 years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring.
Topics: Adult; Cryptorchidism; Endometrial Neoplasms; Facies; Female; Gain of Function Mutation; Growth Disorders; Hand Deformities, Congenital; Heterozygote; Humans; Intellectual Disability; Male; Middle Aged; Mutation; Neoplasms; Phenotype; Smad4 Protein; Transforming Growth Factor beta; Exome Sequencing
PubMed: 31837202
DOI: 10.1002/ajmg.a.61430 -
American Journal of Otolaryngology 2015Myhre-LAPS syndrome is a recently recognized disease caused by a mutation in the SMAD4 gene. This results in a range of pathology including laryngotracheal stenosis,...
OBJECTIVES
Myhre-LAPS syndrome is a recently recognized disease caused by a mutation in the SMAD4 gene. This results in a range of pathology including laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome. We aim to delineate the role of intubation in development of airway stenosis in these patients as well as provide insight into diagnosis and management of this syndrome. Herein we present four patients with Myhre-LAPS syndrome complicated by airway stenosis and perform a systematic review of all cases of Myhre-LAPS syndrome with reported airway pathology.
STUDY DESIGN
Retrospective review
METHODS
All patients diagnosed with Myhre-LAPS syndrome and airway stenosis at a single institution from 1981 to 2014 were reviewed.
RESULTS
Four patients (4F, median age 42) were identified that met inclusion criteria. Initial presenting signs included progressive shortness of breath, dyspnea on exertion and respiratory distress. All four (100%) patients had multi-level airway stenosis most commonly in the subglottic and glottic regions and all patients had undergone at least one endotracheal intubation prior to presentation. One patient with a history of nasal tracheal intubation presented with nasal obstruction and was found to have choanal as well as subglottic stenosis. Two of the four (50%) patients are tracheostomy tube dependent, 1/4 (25%) died of a fatal cardiac arrhythmia and 1/4 (25%) has had 6 endoscopic treatments for subglottic stenosis in 4 years with rapid symptom recurrence.
CONCLUSIONS
Myhre-LAPS syndrome is characterized by progressive systemic fibrosis and patients are diagnosed by characteristic findings of prognathism, short stature, abnormal facies, and thick skin among other abnormalities. Airway management is complicated by recurrent, refractory subglottic stenosis often preceded by elective intubation as well as maxillary hypoplasia, trismus, and limited neck extension. Endotracheal intubation and surgical intervention should be approached with caution in these patients and multidisciplinary care teams are necessary to address all manifestations of this syndrome.
Topics: Adult; Airway Obstruction; Cryptorchidism; Facies; Female; Follow-Up Studies; Genetic Testing; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Intubation, Intratracheal; Laryngoscopy; Male; Middle Aged; Retrospective Studies; Tracheostomy
PubMed: 25940662
DOI: 10.1016/j.amjoto.2015.04.005 -
Clinical Dysmorphology Jan 2022
Topics: Cryptorchidism; Facies; Glucose Intolerance; Growth Disorders; Hand Deformities, Congenital; Humans; Hyperinsulinism; Intellectual Disability; Male
PubMed: 34620752
DOI: 10.1097/MCD.0000000000000396 -
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 -
Clinica Chimica Acta; International... Jan 2020Myhre syndrome is a rare autosomal dominant multi-organ disorder characterized by growth retardation, skeletal anomalies, muscular hypertrophy, joint stiffness, facial...
Myhre syndrome is a rare autosomal dominant multi-organ disorder characterized by growth retardation, skeletal anomalies, muscular hypertrophy, joint stiffness, facial dysmorphism, deafness, cardiovascular disease, and abnormal sexual development. Here we described the first two Chinese Myhre syndrome patients diagnosed by whole-exome sequencing. They both had de novo c.1498A > G (p.Ile500Val) variant in SMAD4 and presented with key characteristics of Myhre syndrome but also revealed uncommon features (polydactyly in the girl and precocious puberty in the boy). We performed functional analysis on four previously reported SMAD4 pathogenic variants in Myhre syndrome patients using dual-luciferase assay. Our results revealed that the pathogenic variants resulted in a variable degree of increased transcription activity of target genes that contain the minimal SMAD binding elements in their promoter regions. The boy responded to the recombinant human growth hormone treatment with improved height but also led to hyperinsulinemia and advanced bone age. Because of his precocious puberty, we subsequently combined the recombinant human growth hormone and gonadotrophin-releasing hormone agonist treatments, which resulted in overall improved height. We reviewed the sexual features of reported Myhre syndrome cases and discussed the possible mechanism of SMAD4 variants in Myhre syndrome that lead to the abnormal hypothalamic-pituitary-gonadal axis.
Topics: Base Sequence; Child, Preschool; China; Cryptorchidism; Facies; Female; Genetic Variation; Growth Disorders; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Pregnancy; Smad4 Protein
PubMed: 31654632
DOI: 10.1016/j.cca.2019.10.006 -
Clinical Dysmorphology Oct 2021
Topics: Cryptorchidism; Facies; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Schizophrenia
PubMed: 34456243
DOI: 10.1097/MCD.0000000000000386