Descriptive Epidemiology From the Myhre Syndrome Foundation Registry: The Value of Self-Reported Data.

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. 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. 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%). 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.

Background Myhre syndrome is an autosomal dominant condition caused by pathogenic variants in the transcriptional co-regulator SMAD4. Myhre syndrome is characterized by distinctive facial features, short stature, musculoskeletal abnormalities, and intellectual disability. Reported ocular abnormalities include refractive errors, corectopia, cataract, strabismus, and pseudo) papilledema. Case report We describe an 8-year-old boy with Myhre syndrome due to a c.1498A > G; p.I500V pathogenic variant in SMAD4. Ocular examination revealed bilateral emmetropia, mild visual acuity reduction in the right eye (20/25), grade 1b foveal hypoplasia in both eyes and small optic discs with pseudopapilledema. Conclusion This report marks the first reported case of foveal hypoplasia in Myhre syndrome, a potentially underreported finding, given the relative lack of OCT assessment in patients with Myhre syndrome. We discuss pathophysiological link between foveal hypoplasia and gain-of-function variants in SMAD4.

ObjectivesMyhre Syndrome is a complex multi-system disorder that frequently presents in childhood with developmental delay and failure to thrive.1 It is caused by specific heterozygous missense variants in SMAD4, a...

The Impact of COVID-19 on Individuals With Intellectual and Developmental Disabilities: Clinical and Scientific Priorities.

Advocacy support groups grow into national and international organizations, but they all begin with personal experiences. As the parents to a newly diagnosed two-year-old son with Myhre syndrome, my husband and I were overwhelmed with the journey ahead. Thanks to networking, primarily through social media, we located other families living with Myhre syndrome and were quickly immersed in the challenges and joy of this community. Myhre syndrome, caused by pathogenic missense variants in SMAD4, is a rare connective tissue disease characterized by short stature, hearing loss, neurodevelopmental challenges, and fibroproliferation.This personal essay, written with physician partners, describes the development of a global advocacy group for patients with Myhre syndrome. I have the honor of serving as the founding Executive Director and reflect proudly on the great strides that our marvelous support group has made. We empower the global community impacted by this rare condition by providing meaningful and accessible data, educational opportunities, and connections with others going through similar experiences. Utilizing the expertise of our Board of Directors and my corporate expertise, we discuss how we have been able to elevate our ultra-rare community into a broader, more comprehensive network.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.

Myhre syndrome is a rare genetic disease caused by recurrent gain-of-function variants in SMAD4 (Ile500Thr, Ile500Val, Arg496Cys, and Ile500Met) characterized by postnatal short stature with pseudo-muscular build, joint stiffness, variable intellectual disability, hearing loss, and a distinctive pattern of dysmorphic facial features. The course can be severe in some cases, with life-threatening cardiac and pulmonary complications caused by connective tissue involvement. These progressive features over time make early clinical diagnosis difficult but possible by astute clinicians who evaluate young children with autism or short stature and unusual appearance. Only two cases of Myhre syndrome diagnosed during the prenatal period have been reported. Here, we present a detailed description of two unrelated fetuses with Myhre syndrome, each molecularly confirmed by genome or exome sequencing, who underwent fetal examination after termination of pregnancy. One had severe intrauterine growth retardation associated with crossed fused renal ectopia, and the other one had pulmonary atresia with ventricular septal defect (a form of tetralogy of Fallot). Both had mild dysmorphic features with a wide nasofrontal angle. Our results and a systematic prenatal literature review add insight into the early natural history of Myhre syndrome and highlight the contribution of prenatal next-generation sequencing in prenatal diagnosis and the importance of fetal autopsy in Myhre syndrome.

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.

Myhre syndrome (MIM 139210) is a rare autosomal‐dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life‐threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011, SMAD4 (SMAD family member 4) has been identified as the disease‐causing gene. All mutations identified so far are de novo heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF‐β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of SMAD4 mutations during development will decipher new regulatory network related to TGF‐β/BMP signalling. Key Concepts Myhre syndrome is a rare genetic condition of autosomal‐dominant inheritance due to SMAD4 mutations affecting Arg496 or Ile500 residues. Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Myhre syndrome is associated to a risk of early death due to possibly life‐threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis). Similar to mothers against decapentaplegic family member 4 ( SMAD4 ) encodes the common partner SMAD of the eight‐member family of SMAD proteins. SMAD4 aggregates into heterotrimer with the receptor‐regulated SMADs (R‐SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF‐β, activin or BMP receptor pathways. The SMAD4 mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes. Germline heterozygous mutations in SMAD4 are known to cause juvenile polyposis syndrome (JPS) and JPS‐hereditary hemorrhagic telangiectasia. The SMAD4 mutations observed in JPS and JPS‐HHT include nonsense, missense, splice‐site changes and deletions, consistent with a loss‐of‐function mechanism. Increased tumoural risk has not been observed so far in Myhre syndrome. The development of tissue‐specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes.

Myhre syndrome (MS) is a rare genetic connective tissue disorder characterized by intellectual disability, growth deficiency, muscular pseudohypertrophy, hearing loss, restricted joint mobility, laryngotracheal stenosis, choanal stenosis, and facial deformities. We encountered a case of difficult endotracheal intubation in a patient with MS. A 17-year-old girl with trismus, macroglossia, and difficulty with neck flexion was scheduled to undergo general anesthesia for dental treatment. Because of these characteristic clinical manifestations, endotracheal intubation was performed with a flexible fiber-optic bronchoscope. When providing general anesthesia for patients with MS, preoperative evaluation of the airway and preparation for potentially difficult tracheal intubation are required.

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.

Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2‐year‐old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.

Background: Myhre syndrome, caused by pathogenic variants in SMAD4, is characterized by compact body habitus with short stature, distinctive craniofacial appearance, stiff skin, cardiovascular abnormalities (valve stenosis, coarctation, hypoplasia, or stenosis of aorta), effusions of potential spaces (pericardium, pleura, peritoneum), restricted movement of the joints (including thorax), and hearing loss. Lung and airway disease has been reported, but not always well-defined, to include interstitial lung disease, large airway obstruction, and pulmonary arterial hypertension. Excessive fibroproliferation of tissues especially following trauma or surgical instrumentation has been recognized, although these may also present spontaneously. Method: We report the pathologic features of 1 new patient with progressive choanal stenosis, and 22 literature cases, including the expanded history of 5 patients (3 who died). Results: Examination of patient tissues documents cellular fibroproliferation and deposition of excessive extracellular matrix explaining some of the observed clinical features of Myhre syndrome. Conclusion: Excessive fibrosis is noted in multiple tissues, especially heart, lung, and upper and lower airways. Our research provides the first systematic review to provide a knowledge base of gross and pathologic findings in Myhre syndrome.

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.

Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.