The 1,4,5-trisphosphate receptor type 1 (ITPR1) gene encodes an endoplasmic reticulum calcium release channel, in which loss-of-function mutations have been associated with spinocerebellar ataxias and related neurological phenotypes. Only one gain-of-function mutation in the highly conserved suppressor domain of ITPR1 has been previously reported. We report a novel de novo ITPR1 variant (p.(Tyr131His)) detected by whole genome sequencing in a child with an unexplained movement disorder, characterized by tremor and dystonia, concurrent with a second diagnosis of Myhre syndrome. The proband's movement disorder characteristics share much overlap with previously reported individuals with suppressor domain variants; however, she does not have ataxia. We provide functional evidence of this variant's gain-of-function consequence via invitro experiments of inositol 1,4,5-triphosphate-mediated calcium release. Our findings deepen the knowledge of ITPR1-mediated movement disorders, expanding the phenotypic spectrum to include movement disorders without ataxia.

Myhre syndrome is a rare disorder that typically results from a de novo SMAD4 variant. De novo SMAD4 variants have recently been shown to be associated with 'selfish selection' in the male germline, explaining their exclusive paternal origin and the paternal age effect reported for Myhre syndrome. Over recent years, there has been a steady increase in the number of families reported with an affected parent and child. We expand the literature of families with Myhre syndrome reporting a mildly affected 38-year-old mother and her 4-year-old son who carry the SMAD4 p.Arg496Cys variant, consistent with all other reports of inherited Myhre syndrome. To better delineate the phenotypic spectrum, we developed a clinical severity score and compared familial cases to sporadic cases, revealing a milder phenotype in familial cases. Affected mothers with Myhre syndrome may be at increased risk of infertility and pregnancy loss. Since identification of the mode of transmission is essential for accurate reproductive counseling and appropriate clinical surveillance, we propose a nuanced reproductive and genetic counseling strategy that emphasizes awareness of potential autosomal dominant transmission, paternal age-related risk, and obstetric complications.

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 associated with a recognizable pattern of facial differences that develop after early childhood. Patients typically have midface hypoplasia, mandibular prognathism, narrow oral commissures with a short philtrum and thin upper lip vermillion. Other characteristics include deeply set eyes with short palpebral fissures, and small, widely spaced teeth. The aim of this study is to review the concept of prognathism in Myhre syndrome, describe the oral and maxillofacial surgery (OMS) evaluation of three females, and provide some preliminary data to propose more objective guidelines and diagnostic tools for facial evaluation in other patients. In addition to the dysmorphologic examination, maxillofacial imaging is recommended in many patients to evaluate the dentition, midface and mandibular anatomy. An orthopantomogram is useful to visualize the dentition, alveolar portion of the maxilla and the mandible. A lateral cephalogram can assess jaw relationships and allow cephalometric analyses to compare to published norms. With the common characteristics visualized, a checklist has been developed to serve as a guide when evaluating patients. OMS consultation can enhance the care provided by the medical geneticists who usually manage these individuals.

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 is a rare, multisystemic disorder caused by gain-of-function mutations in the SMAD4 gene, a key component of the TGF-β signaling pathway. These mutations lead to manifestations affecting neurodevelopment, bone and joint development, fibrosis and stenosis, immune responses, reproductive health, and cardiac function. The Myhre Syndrome Foundation (MSF) is a patient-centered organization focused on accelerating drug discovery while supporting patients, prioritizing research targeting fibrosis/stenosis and autism/intellectual and developmental disabilities, the most significant burdens reported by patients. Their short-term strategy involves: (1) Creating and running a preclinical platform to screen potential treatments using patient-derived and animal models. (2) Clinical readiness, addressing challenges associated with low disease incidence and heterogeneity in clinical trial design, by developing multi-domain endpoints, responder index, and biobanks/biomarkers. (3) Target identification investigating SMAD4 pathogenic variants rewiring protein-protein interactions in key signaling pathways. (4) Fostering partnerships with regulatory authorities, industries, and other patient research organizations. The MSF portfolio includes targeting fibrosis with immunotherapy using FAP-CAR-T cells, and a precision medicine approach aimed at restoring normal SMAD4 function through gene editing and small molecules. MSF aims to develop therapies that address both acute and chronic manifestations of this complex disease, improving the quality of life for affected individuals.

A proposed nosology of inherited disorders of the extracellular matrix (ECM): Insights from the IEMbase and dyadic classification.

This research review of Myhre syndrome is a summary of published articles which provide a valuable resource for readers, researchers, and future authors. It traces the evolution of the Laryngotracheal-Arthropathy-Prognathism-Short Stature (LAPS) syndrome to the current eponym of Myhre syndrome. These allelic disorders are caused by pathogenic variants in SMAD4. After the initial report over 40 years ago, the steady publication of case reports and small series was accelerated following the discovery of the pathogenic variants in SMAD4. The articles in this review include numerous case reports and small series, reports about basic science, the discovery of the causative gene, the emergence of the natural history in larger studies, and articles about specific features, especially the cardiovascular system and airways. We hope this analysis provides a foundation for future research that may extend symptom-based treatment to genetic-based therapy.

Myhre syndrome - it is never too late

Myhre syndrome: Endoscopic airway presentation.

Pulmonary, Airway, and Sleep Features in Myhre Syndrome: A Cohort Study

Background Cytokines play an important role in Th1 and Th2 inflammation. Both Th1 and Th2 cytokines can be utilized for evaluation and treatment response in many different disorders, including inborn errors of immunity. The role of broad cytokine panel testing in inborn errors of immunity is not well described. Objective To analyze broad cytokine panel testing in clinical practice. Methods A retrospective review of cytokine panel testing performed at Mayo Clinic was performed. Data were collected from patients at Mayo Clinic Rochester, Mayo Clinic Jacksonville, and Mayo Clinic Health System. Serum cytokine panel testing included the following cytokines: tumor necrosis factor (TNF), IL-6, IFN-β, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1β, IFN-γ, macrophage inflammatory protein-1 alpha (MIP-1α), granulocyte-monocyte colony-stimulating factor (GM-CSF), IL-2 receptor α soluble, IFN-α, and IL-18. Data collection ranged from 03/2021 to 09/2024. The study was funded by Mayo CCaTS grant number UL1TR002377. Results A total of 88 cytokine panel tests were performed during the study period on 80 total patients. There was at least 1 elevated cytokine level in 70/88 (80%) tests performed. There was elevation in each individual cytokine level as follows: TNF (49), IL-2 receptor α soluble (40), IFN-α (0), IL-18 (26), IL-6 (33), IFN-β (4), IL-10 (13), MCP-1 (18), IL-1β, IFN-γ (11), MIP-1α (12), and GM-CSF (6). 18 patients that underwent cytokine panel testing had common variable immune deficiency (CVID), and 10 of those patients had granulomatous lymphocytic interstitial lung disease. 6 patients with early onset inflammatory bowel disease, 5 patients with autoimmune lymphoproliferative syndrome, 2 patients with Myhre syndrome, 2 patients with Hyper IgE syndrome, 1 patient with hypereosinophilic syndrome, 1 patient with autoimmune polyglandular syndrome type 1, 1 patient with XIAP deficiency, 1 patient with X-linked chronic granulomatous disease, and 1 patient with STAT 1 gain of function were tested. Other patients tested had other medical diagnoses or were undergoing immunodeficiency evaluation. There was no significant increase noted in any individual cytokine level when compared with the whole cohort. Conclusion Cytokine panel testing could be a potential diagnostic tool in evaluation of inborn errors of immunity. Further research is needed to better characterize the importance of cytokine panel testing in inborn errors of immunity.

Myhre syndrome: Case report

Myhre syndrome is an extremely rare genetic disease of connective tissue characterized by multisystem lesion, progressive and proliferative fibrosis, mental retardation. The pathogenesis is based on a mutation of the SMAD4 gene, which leads to the proliferation of abnormal fibrous tissues. The main manifestations of pathology are growth deficiency, peculiar facial features (short eye slits, hypoplasia of the middle third, prognathism), mental retardation, lesions of the musculoskeletal system, ophthalmological disorders, sclerodermic manifestations, hearing loss, pathology of the cardiovascular, respiratory system and other organs and systems. Etiotropic and pathogenetic therapy has not been developed at the moment, treatment is exclusively symptomatic. The presented clinical case of a patient with Myhre syndrome clearly demonstrates the need for an interdisciplinary approach to the diagnosis and treatment of this disease. It should also be noted the importance of spreading knowledge about rare hereditary pathology among doctors of various specialties for timely diagnosis and selection of symptomatic therapy.

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.

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed invitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.

Myhre syndrome (MS) is a rare genetic condition that presents with multiple genetic anomalies including cleft lip and palate and Eustachian tube dysfunction. These patients are at a high risk for airway scarring from intubation and mucosal inflammation. Hearing loss (conductive or mixed, of varying severity) is a common comorbidity in these patients, the exact etiology of which is still unclear. We present the cases of 2 unrelated children with MS who suffered progressive mixed hearing loss from fibrosis and obliteration of the middle ear spaces. Both patients had multiple sets of ear tubes that demonstrated early extrusion. The older patient underwent bone conduction implantation at age 11 which resulted in dramatic improvement of speech recognition and interactive skills. The other younger patient demonstrates a similar trajectory but has not yet undergone implantation. Otolaryngologists should take a cautious approach to surgery of the eardrum and middle ear to avoid unnecessary induction of fibrosis in this susceptible patient population. These cases highlight a newly described etiology for hearing loss and suggest a benefit to bone conduction implantation.

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.

Psychiatric manifestations of Myhre syndrome: A case report.