Fetal central nervous system (CNS) anomalies are among the most common congenital malformations, yet the overall prenatal diagnostic yield of current genetic testing remains below 40%. Variants in RNU4-2, a non-coding gene encoding the U4 small nuclear RNA (snRNA), have recently been linked to a novel highly recurrent dominant neurodevelopmental disorder termed ReNU syndrome. While its postnatal phenotype has been well characterized, the contribution of RNU4-2 to fetal CNS anomalies remains unexplored. In this study, we retrospectively analyzed 148 fetuses with CNS anomalies who had non-diagnostic results from karyotyping, chromosomal microarray analysis, and exome sequencing. Targeted Sanger sequencing of RNU4-2 was performed to identify pathogenic variants. Two fetuses harbored the same de novo recurrent variant, n.64_65insT, corresponding to a diagnostic yield of 1.35%. Both cases presented with microcephaly, suggesting that it is a key prenatal feature of ReNU syndrome. Furthermore, molecular confirmation of RNU4-2 resolved a decade-long diagnostic odyssey in one family by excluding an inherited Xp22.13 duplication of uncertain significance as the causal variant. In conclusion, this study provides the first systematic prenatal evaluation of RNU4-2 in fetuses with CNS anomalies, thereby expanding the prenatal phenotypic spectrum of ReNU syndrome. Incorporating RNU4-2 testing into prenatal genetic workflows may enhance diagnostic yield, enable precise genetic counseling, and support informed reproductive decision-making.

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.

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.

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.

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.

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.