American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献

Myhre syndrome (MYHRS) is an ultra-rare, progressive multisystem disorder caused by recurrent heterozygous missense variants in the SMAD4 gene, a central mediator of TGF-β and BMP signaling. Skeletal abnormalities-including postnatal short stature, brachydactyly, thickened calvarium, and craniofacial dysmorphism-are cardinal features, often accompanied by joint contractures and progressive soft tissue fibrosis. Extensive cellular and genetic evidence supports a gain-of-function (GoF) mechanism wherein mutant SMAD4 displays increased protein stability and prolonged nuclear localization, enhancing canonical SMAD signaling and driving overexpression of profibrotic and extracellular matrix (ECM) genes. Although a dominant-negative (DN) effect was recently proposed for some variants, GoF remains the prevailing and best-supported model. The underlying skeletal pathophysiology likely reflects both primary disruption of mesenchymal differentiation affecting bone and cartilage, and secondary progressive fibrosis that amplifies contractures and skeletal rigidity over time, though direct mechanistic studies in bone tissue remain limited. Therapeutically, TGF-β pathway inhibitors such as losartan exhibit promising in vitro and early clinical benefits, while advanced strategies-spanning targeted small molecules, anti-fibrotic agents, and emerging gene-editing approaches-are prospective direction for therapies. The integration of patient-derived iPSC models engineered animal systems, multi-modal technologies, and artificial intelligence (AI) holds significant promise for precision medicine in Myhre syndrome.

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.

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.

From Stochholm et al. 2025. “Vizualizing Turner Syndrome.” American Journal of Medical Genetics Part C: Seminars in Medical Genetics: e32144. doi:10.1002/ajmg.c.32144. Photographs of individuals with Turner syndrome. Reproduced with permission from the patients and, where applicable, their legal guardians.

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.