Pathologic studies of Myhre syndrome (OMIM 139201) have provided modest insights into this ultra-rare multisystem disorder, with postmortem examinations being scarce. Morbidity is related to severe congenital heart defects, aortic hypoplasia, airway stenosis, constrictive pericarditis, and restrictive cardiomyopathy. We report two detailed autopsies: the first of an 8-year-old female who succumbed to congenital mitral valve disease and restrictive cardiopulmonary complications. Autopsy documented chronic pericarditis and fibrosing pleuritis, diffuse interstitial pulmonary fibrosis, extensive submucosal interstitial fibrosis of the bladder, and nodular medial hypertrophy of the aorta. The second patient was a 20-year-old female with progressive laryngo-tracheal stenosis, interstitial lung disease, pericardial and peritoneal adhesions, and dermal fibrosis. Both patients had ovarian fibrosis with reduced oocytes. Neuropathologic examination revealed brains below expected weight with hypoxic-ischemic injury. The first patient also had scattered intraparenchymal microcalcifications and a known Chiari I malformation, and the second had a thickened calvarium and dura mater and rounded cerebrum (shortened frontal and occipital lobes). These two patients demonstrate the value of postmortem examination to confirm suspected pathology and elucidate new features. The pleiotropy of Myhre syndrome was demonstrated by complex comorbidities and the devastating impact of indiscriminate fibrosis. Counseling regarding the role of postmortem examination should be considered in the palliative care of Myhre syndrome patients and their families.

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.

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 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.

Vascular anomalies represent a broad spectrum of disorders characterized by aberrant blood or lymphatic vessel development, which can lead to complex clinical phenotypes. Historically, vascular anomalies were classified solely on the basis of their clinical and histopathologic features. However, the last two decades have witnessed significant advances in our understanding of the genetic basis of these lesions. It is now recognized that many vascular anomalies arise from somatic pathogenic variants in key growth signaling pathways, including the PI3K-AKT-mTOR and RAS-MAPK pathways. These insights have catalyzed the development of targeted therapies designed to address the molecular underpinnings of disease. mTOR inhibitors, originally developed and widely used as anticancer agents, have also demonstrated significant efficacy in improving outcomes for patients with low-flow vascular malformations such as lymphatic malformations and venous malformations. Similarly, MEK inhibitors and other oncology drugs are being repurposed as promising therapeutic options for complex lymphatic anomalies and arteriovenous malformations, conditions that historically have had limited medical therapeutic options. Clinical trials for vascular anomalies are emerging, but questions remain about how to best measure response in these patients, as well as the optimal duration of treatment. This case-based review explores recent developments in precision medicine for vascular anomalies, highlighting a paradigm shift in the management of these complex and often therapeutically challenging disorders.

Neurofibromatosis type 1 (NF1) is a progressive multisystem condition that is characterized by a wide range of clinical manifestations and clinical variability. Individuals with NF1 can be significantly impacted by NF1-related complications, and targeted therapies are emerging. Currently, MEK inhibitors selumetinib and mirdametinib are the only FDA-approved targeted therapies for NF1-related symptomatic or progressive, inoperable plexiform neurofibromas. Several additional MEK inhibitors are being investigated in clinical trials for the treatment of plexiform neurofibromas. Additional therapies are currently under investigation for the treatment of malignant peripheral nerve sheath tumors, low-grade gliomas, skeletal manifestations, cutaneous neurofibromas, and other NF1-related complications.

Myhre syndrome (MIM #139210) is a rare multisystem disorder first described in 1981, characterized by short stature, neurodevelopmental delay, joint contractures, and cardiopulmonary complications. Its molecular basis, recurrent pathogenic variants in SMAD4, was not discovered until 2011. This narrative is based on a review of medical records, personal experiences in the care of a remarkable patient, and family interviews. It traces the life of a young man from rural Montana whose diagnosis was delayed for over two decades, despite early evaluations by renowned specialists. The absence of a unifying diagnosis profoundly shaped his and his family's experience-emotionally, medically, and socially. When the diagnosis of Myhre syndrome was finally established via whole exome sequencing in adulthood, it brought both clarity and new uncertainties. Through his story, we examine the psychosocial toll of diagnostic delay, the transformative potential of genomic medicine, and the resilience of individuals and families living with complex, undiagnosed conditions. The narrative also underscores the ongoing systemic barriers to care and inclusion for individuals with lifelong rare disorders. Lastly, this account offers a reflection on the philosophical framework of Maurice Merleau-Ponty, whose phenomenology of the lived body versus the body-object provides a lens to understand the subjective and embodied dimensions of living with an undiagnosed condition.

Myhre syndrome is a rare connective tissue disorder characterized by skeletal, cardiopulmonary, dermatologic, neurocognitive changes, and a predisposition to exaggerated fibrosis in response to mechanical stress. We report monozygotic male twins with Myhre syndrome caused by the recurrent SMAD4 gain-of-function variant c.1498A>G (p.Ile500Val), identified by targeted next-generation sequencing of peripheral blood. Proband 1 presented at age 37 years for evaluation of symptomatic aortic stenosis. Clinical recognition of Myhre syndrome prompted deferral of transesophageal echocardiography, and molecular diagnosis informed subsequent conservative management. His co-twin, Proband 2, underwent posterior pharyngeal flap surgery and right-heart catheterization with pulmonary artery stenting in childhood; later, he developed progressive pulmonary arterial hypertension and died at 31 years. We report on the differing outcomes of the twins and the possibility that invasive airway and cardiac procedures may have accelerated fibro-proliferative complications of Proband 2. Early recognition of Myhre syndrome allows selection of alternatives to high-risk procedures, longitudinal monitoring, and may reduce morbidity and mortality.

Myhre syndrome is a rare progressive genetic disorder characterized by hearing loss, cardiovascular and joint problems, neoplasia, and neuropsychologic disabilities. Parents of children with Myhre syndrome and adults themselves face unique challenges, stresses, and fears associated with this diagnosis. Reflective writing in the form of journaling can provide psychosocial support and help individuals cope with this diagnosis. Adult patients and parents whose children were evaluated at the Massachusetts General Hospital Myhre Syndrome Clinic were invited to participate in a three-month journaling intervention. Participation in the study required the completion of a series of surveys prior to starting and upon completion of the study. Data from these surveys were analyzed to assess for change in mental well-being. Eleven individuals participated, six of whom completed the three-month journaling intervention and post-journaling surveys. Three participants indicated that journaling had an impact on their mental well-being, and of these, two planned to continue journaling. However, there was no statistically significant difference in mental well-being scores pre- and post-journaling intervention. The very small size of the study limits interpretation, but we think it is reasonable to suggest that expressive writing through journaling may be a coping mechanism and means of improving well-being for some individuals in the Myhre syndrome community.

PDGFRB-related Penttinen syndrome is characterized by progressive progeroid features, acroosteolysis, and development of aneurysms, structural anomalies of the posterior fossa, variable myofibromatosis, and overgrowth. PDGFRB-related disorders, including Penttinen syndrome, Kosaki syndrome, and infantile myofibromatosis, have been successfully treated using imatinib. Here, we report a child diagnosed in infancy who initiated imatinib monotherapy at 8 months of age and has continued treatment for 4 years. At the time of diagnosis, he was known to have structural anomalies of the posterior fossa, sparse hair, joint stiffness, myofibromatosis, thin and fragile skin, decreased subcutaneous fat, and prominent vasculature. Imatinib has been well tolerated without apparent side effects. Within weeks to months after initiating imatinib, he grew thick curly hair, and the texture of his skin and joint stiffness had marked improvement. Over the past 4 years, he has not developed acroosteolysis and continues to have normal hair growth. Surveillance MRA has not identified aneurysms or vessel ectasia. Height decreased from 90th to 75th percentile. He has mild developmental delays and is awaiting formal evaluation for autism spectrum disorder. Overall, early imatinib treatment has been successful in ameliorating and preventing the development of some features of Penttinen syndrome.

This systematic review investigates factors influencing parental decision-making following a prenatal diagnosis (PND) of Turner syndrome (TS), aiming to enhance the foundation for tailored and supportive genetic counseling. A comprehensive literature search was conducted in the medical databases PubMed, Embase, and CINAHL. The selection of studies was guided by specific eligibility criteria. Extracted data was arranged in a review matrix, and study quality was assessed using a methodological quality score (MQS). Twenty-seven studies were selected for review, including 21 retrospective studies, five case reports, and one prospective study. The mean MQS across studies was 9.7 points (low to moderate). Across the included studies, nine categories of factors were investigated in association with parental decisions, including five pregnancy-related categories (ultrasound-detected abnormalities, karyotype, gestational age at diagnosis, time period of diagnosis, and prenatal counseling) and four categories related to expectant parents (age, reproductive history, expectations/concerns about the child's prognosis, and socio-demographic characteristics). Among these, ultrasound-detected abnormalities, karyotype, and counseling emerged as key factors influencing parental decisions. Parental decisions following a PND of TS are influenced by a complex interplay of medical, psychological, and socio-cultural factors. Addressing these determinants through patient-centered, non-directive counseling and equitable access to genetic expertise can support informed decision making.

Turner syndrome (TS) continues to present a diagnostic challenge to healthcare professionals. The diagnostic challenges associated with TS result in delayed treatment and clinical care. Here we provide an update of the physical appearance of girls and women with TS by presenting clinical photographs and detailed clinical descriptions of 25 Danish girls and women with TS. Our data highlight the wide variation in physical appearance and clinical phenotype seen in girls and women with TS.

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.

It is evident that Turner syndrome (TS) impacts almost all developmental stages of the fetal heart with congenital heart disease (CHD) being seen in 23%-50% of individuals. Although the spectrum of CHDs in TS is well-established, with left-sided lesions predominating, the influence of specific karyotypes on the prevalence and types of CHDs remains incompletely understood. The primary objective of this systematic review/meta-analysis was to quantitatively synthesize the existing evidence on the association between specific karyotypes in TS and the risk of various CHDs. A systematic literature search was conducted through December 2023 to identify studies reporting the prevalence of CHDs in relation to TS karyotype. The quality of the individual studies was assessed using the Joanna Briggs Institute critical appraisal tools for systematic reviews. The overall estimates were pooled using both fixed- and random-effects models. Sensitivity and subgroup analysis were performed. Twenty-five studies were included in the analysis. TS individuals with a 45,X karyotype showed a significantly higher likelihood of bicuspid aortic valve (BAV) (pooled OR, 3.14 [95% CI: 2.49-3.94]), aortic coarctation (CoA) (pooled OR, 4.16 [95% CI: 2.74-6.31]), and partial anomalous pulmonary venous return (PAPVR) (pooled OR, 4.86 [2.31-10.2]) compared with TS individuals with a non-45,X karyotype. In addition, TS individuals with a 45,X karyotype also showed a significantly higher likelihood of BAV (pooled OR, 2.72 [95% CI: 1.62-4.56]) when compared with TS individuals with 45,X/46,XX mosaicism. TS individuals with a 45,X karyotype showed a significantly higher risk of BAV (pooled OR, 2.13 [95% CI: 1.42-3.21]) and CoA (pooled OR, 4.52 [95% CI: 1.58-13.0]) when compared with TS individuals with an isochromosome Xq. A significantly higher likelihood of BAV was also found in 45,X compared to other karyotypes (e.g., 45,X/46,XY and TS karyotypes with ring X chromosome). Some heterogeneity was evident, but publication was low. This meta-analysis confirms a strong association between the 45,X karyotype and increased prevalence of BAV, CoA, and PAPVR in TS. While 45,X/46,XX mosaicism and karyotypes with an isochromosome Xq mitigate risk, the findings emphasize the need for large-scale studies to refine risk assessment and management strategies.

The effect of estrogen deficiency on bone health in Turner syndrome (TS) may be a concern even before adulthood. Previous guidelines have discussed hormone replacement therapy (HRT) in children with TS. However, some practical issues related to puberty induction in TS require clarification, such as how to implement HRT to achieve adequate bone health. It is generally assumed that earlier initiation of HRT will result in better bone health in young adults with TS and estrogen deficiency. The present study reviews pubertal development, bone health, and current pubertal induction therapies in TS, with a particular focus on patients without endogenous estrogen production. Current guidelines recommend using transdermal estradiol patches starting at the age of 11-12 years if necessary to mimic the gradual increase in circulating, physiological estradiol. Theoretically, earlier therapy combined with forecasting estrogen deficiency on the basis of increased FSH may allow a closer approximation to endogenous estradiol secretion in patients with TS without spontaneous puberty. This approach may lead to better long-term outcomes, such as the acquisition of normal bone mineral density. Further research is needed to assess how the achievement of normal bone density and bone quality relates to the timing of HRT in children and young adults with TS. The resulting improvements in transdermal estradiol therapy may help patients with TS achieve optimal bone health.

Usher syndrome, the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this autosomal recessive disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple Usher syndrome genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on the prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic Usher syndrome variants from three clinical databases and determined the occurrence of these pathogenic Usher syndrome variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of Usher syndrome variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all Usher syndrome subtypes is 1 in ~29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A.