Navigating Drug Discovery for Myhre Syndrome: The Complexity of a Multisystemic Rare Disease.

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 SMAD4 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 SMAD4 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 SMAD4 variations and also evaluate the parents of the Myhre cases.

Myhre syndrome is a rare condition caused by a mutation in the SMAD4 gene, which leads to a defective TGF-β/BMP signaling, resulting in the proliferation of abnormal fibrous tissues. Clinically, patients with Myhre syndrome manifest with defects of connective tissue (skin, muscles, joints), and cardiovascular and neurological impairment. In our report, we present a case of a 16-year-old female with skeletal abnormalities, reduced articular mobility, skin, and muscular hypertrophy and cardiovascular defects characteristic of Myhre syndrome. Long-term pulmonary hypertension and arterial hypertension were persistent in spite of antihypertensive treatment. Our patient was also diagnosed with chronic kidney disease and Dunbar syndrome, which is an external compression of the coeliac trunk or coeliac artery by the surrounding tissues. Until now, only a few cases of renal complications in Myhre syndrome have been published. We describe for the first time a female patient with genetically confirmed Myhre syndrome caused by the p.Ile500Val SMAD4 mutation presenting with an unusual occurrence of congenital vesicoureteral reflux, proteinuria with a decreased renal function, and a condition recognized as Dunbar syndrome.

Retinal involvement in two unrelated patients with Myhre syndrome

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 is a rare connective tissue disorder caused by heterozygous pathogenic variants in the SMAD4 gene. Although recognizing Myhre syndrome in early childhood is challenging, it is important to manage airway stenosis in patients with Myhre syndrome. Case Presentation: 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 SMAD4 was identified through exome sequencing. Tracheostomy was performed, and the patient has maintained stable respiration through a customized tracheostomy tube with a home ventilator. Conclusions: 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.

Myhre syndrome is an ultrarare genetic disease characterized by short stature, distinct craniofacial features, cardiovascular and respiratory fibrosis and stenosis, neurodevelopmental delays, autism, intellectual disability, and hearing loss. The natural history of Myhre syndrome is still not fully understood due to a small patient population with a heterogeneity of symptoms. Myhre Syndrome Foundation created the Myhre Syndrome Patient Registry with Coordination of Rare Diseases at Sanford to capture disease symptoms and quality of life data of the global Myhre syndrome community. Here we describe the self-reported questionnaire data from 105 people with Myhre syndrome from 24 countries. This data expands the knowledge of Myhre syndrome manifestations and documents patient and caregiver concerns.

Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients. Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity. • The clinical and radiological signs of the disease in children older than 7-8years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.

Myhre syndrome is a rare disorder caused by a heterozygous mutation in the SMAD4 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.

Myhre syndrome is a rare disorder caused by pathogenic gain-of-function variants in the SMAD4 gene. Most of the patients have had de novo variants. There are several instances of autosomal dominant inheritance, and penetrance appears to be complete. We describe seven Brazilian patients, three of whom are siblings carrying the recurrent c.1486C>T p.(Arg496Cys) variant in SMAD4 inherited from the father. The other three patients are unrelated simplex cases. All affected individuals have clinical features commonly found in Myhre syndrome, including typical dysmorphic facial features, with intra- and interfamilial clinical heterogeneity. Five of the patients have developmental delay and/or clinical signs of intellectual disability. However, only one had neuropsychological testing. Only one patient had a diagnosis of autism spectrum disorder. As in previously reported families, this new family has the same c.1486C>T p.(Arg496Cys) variant. This is the first study describing Brazilian patients with Myhre syndrome, highlighting the clinical variability of this rare disease. We reinforce the need to investigate the parents to provide appropriate genetic counseling.

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.

Myhre syndrome is a rare autosomal dominant multisystemic disorder. Typical features of this disorder include distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, brachydactyly, and skeletal anomalies. Gain-of-function mutations in the SMAD4 gene are responsible for this syndrome. Herein, we present a 9.6-year-old Turkish girl with molecularly confirmed Myhre syndrome who had novel findings including bilateral Axenfield Rieger anomaly with secondary glaucoma and bilateral enlarged vestibular aqueducts.

* Abbreviation: PPC — : pediatric palliative care Myhre syndrome is a rare connective tissue disorder. Signs and symptoms include fibrosis of the skin and internal organs (heart, lungs, gastrointestinal system), intellectual disability, distinctive facial features, and skeletal abnormalities.1,2 Myhre syndrome is caused by a mutation in the SMAD4 gene. It typically occurs for the first time in an affected person.1 A clinical case is described in a child whose family received a diagnosis of Myhre syndrome after he died. Although for some families the specific diagnosis is important, this mother did not feel that the information would have changed the course of her child’s life. We outline the benefits of palliative care supporting the child and family with attention to individualized symptom management, improved communication, and support making difficult decisions. My son Connor had an undiagnosed condition affecting several body systems including his airway, his heart, and his development. He also had subtle features including small hands and feet and skin that appeared thicker or fluid-filled. Although he was managed by an excellent pediatrician, the silos of medical care in our community at the time meant that crises were addressed by multiple different people on different teams, each of whom had an incomplete knowledge of Connor’s specific medical issues. The research program (Care4Rare)3 at the Children’s Hospital of Eastern Ontario in Ottawa, Canada, performed whole exome sequencing of Connor’s DNA. They identified a mutation in the gene SMAD4 . This specific change (c. 1499>C, p.Ile500Thr) has been seen in other children with a multisystem condition known as Myhre syndrome; from a genetic standpoint, this was molecularly confirmed … Address correspondence to Christina Vadeboncoeur, MD, FRCPC, Children’s Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa, ON K1H 8L1, Canada. E-mail: vadeboncoeur{at}cheo.on.ca

Myhre syndrome is a rare disease secondary to pathogenic variants in SMAD4 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.

Myhre syndrome is a rare disorder characterised by short stature, skeletal anomalies, facial dysmorphism and hearing loss (HL), resulting from heterozygous mutations of the SMAD4 gene. We describe the benefits...

Myhre syndrome is a rare genetic autosomal dominant connective tissue disorder, characterized by developmental delay, characteristic facial features, various bone and joint abnormalities, distinctive cardiovascular, ophthalmological and ear, nose and throat (ENT) manifestations, in association with mild to moderate intellectual disability and autism or autism spectrum disorder-like behaviour. The diagnosis of Myhre syndrome is established corroborating the clinical findings with SMAD4 heterozygous mutation identified in the majority of the patients. SMAD4 gene mutations result in abnormal TGF-β signalling in several cell types, which affects the development of several body systems and leads to the specific phenotype of Myhre syndrome. We herein report the case of an 18-year-old female patient who was diagnosed at the age of 17 years with Myhre syndrome, the first documented case of this syndrome in Romania. Sequence analysis of protein-coding genes using whole-exome analysis identified a ‘de novo’, heterozygous missense variant of SMAD4, c.1498A>G, p. (Ile500Val), which is pathogenic for Myhre syndrome. Although this condition is rare, a series of particularities were identified in the present case, consisting of severe allergic reactions, recurrent ENT tumour development and delayed dental eruption, which have not been described in Myhre syndrome to date, to the best of the authors' knowledge.