歌舞伎症候群

Kabuki syndrome (KS) is a rare, multisystemic congenital disorder characterized by distinct craniofacial features, musculoskeletal abnormalities, and varying degrees of intellectual disability. While diagnosis is primarily clinical, the underlying molecular variability often leads to delayed identification. Given that orodental anomalies are among the earliest quantifiable markers of the syndrome, the dental professional occupies a critical position in the diagnostic pathway. This report describes a female patient presenting with pathognomonic craniofacial traits, including arched supraorbital ridges, a prominent nose, broad nasal bridge with a flattened tip, thick eyebrows and eyelashes, large low-set ears, and prominent lips with an elongated philtrum. Intraoral examination revealed significant dental manifestations, specifically an anterior open bite, retained primary teeth, and anomalies such as missing teeth and impacted teeth. These findings served as the primary clinical indicators that facilitated a multidisciplinary referral and subsequent genetic confirmation. The high prevalence of specific dental findings - estimated to affect over 70% of KS patients - underscores the pivotal role of the dentist in early recognition. By identifying these oral phenotypes during routine examinations, dental practitioners can bridge the diagnostic gap, ensuring timely genetic testing and the initiation of comprehensive, coordinated management.

OBJECTIVE: Wiedemann-Steiner syndrome (WSS) is a neurodevelopmental disorder caused by pathogenic KMT2A variants and characterized by intellectual disability, behavioral challenges, and executive dysfunction. KMT2A loss has been linked to atypical neurogenesis in hippocampal and prefrontal regions, potentially contributing to dysregulated behaviors. Endocrinological abnormalities have also been found among those with WSS, which in turn may impact their stress biology. This study examines the associations between chronic stress, measured by hair cortisol concentration (HCC), and cognitive and behavioral functioning in WSS. METHOD: Twenty White individuals with WSS (14 female; Mage = 14.85 years, SD = 6.14) completed standardized tests of executive functioning. Caregivers completed the Behavior Rating Inventory of Executive Function and the Child/Adult Behavior Checklist to index daily behavior functioning. Hair samples were collected from participants and their parents to derive HCC. RESULTS: Mean HCC levels in the subset of children with WSS did not differ from normative reference values. In our whole cohort, higher HCC was associated with poorer performance scores on tests of cognitive flexibility. Regression models showed that higher HCC predicted poorer cognitive flexibility, explaining 36%-42% of the variance. CONCLUSIONS: These findings provide preliminary evidence that long-term cortisol levels are related to performance-based executive functioning difficulties in WSS. Results within the context of extant literature on WSS suggest that altered stress physiology, such as chronic exposure to stress hormone production, may contribute to their executive and behavioral dysfunction, potentially reflecting the downstream impact of disrupted KMT2A epigenetic function on later functional development of the prefrontal lobe network. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Neurodevelopment is a highly ordered, precisely regulated process that establishes the neurobiological foundations of cognition, thought, emotion, and behavior. Neurodevelopmental disorders (NDDs) display marked phenotypic and genetic heterogeneity and variably impair learning, daily functioning, and social adaptation. As a key epigenetic mechanism, histone lysine methylation shapes chromatin accessibility and transcriptional programs, exerting central roles in neural stem cell fate decisions, neuronal migration and circuit assembly, as well as synaptic plasticity and learning and memory. Focusing on the activating histone H3 lysine 4 (H3K4) methylation marks (H3K4me1/2/3), this review synthesizes evidence for the bidirectional regulation mediated by "writers" (the KMT2/SET/DOT1) and "erasers" (the KDM/LSD and KDM5) in NDDs, including Kabuki syndrome, Wiedemann-Steiner syndrome, autism spectrum disorder, and schizophrenia. We further outline how animal models, patient-derived brain organoids, and multi-omics atlases enhance mechanistic insight, and we discuss the translational potential of small-molecule interventions, and metabolic modulation. Together, we summarize how the precise balance of methylation writing and erasure-and its crosstalk with DNA methylation and histone acetylation-forms an epigenetic network that drives neurodevelopmental programs. Targeting this network offers testable therapeutic avenues for NDDs.

INTRODUCTION: Nonimmune hydrops fetalis (NIHF) has numerous etiologies, the most common of which are cardiac anomalies and fetal infection. However, genetic disorders are also being increasingly recognized as a cause of NIHF. Here, we report a case of a neonate presenting with polyhydramnios, NIHF, structural heart disease, and diaphragmatic defect who was found to have a previously unreported mutation in the KMT2D gene. CASE PRESENTATION: A female neonate with antenatally detected NIHF was born at 35 weeks of gestation via cesarean section. At birth, she was noted to have dysmorphic features, scoliosis, and a single umbilical artery. Further investigations revealed a left-sided obstructive cardiac lesion and a right-sided Morgagni hernia. She required invasive ventilation, inotropes, and prostaglandin E1 for preductal coarctation of the aorta with hypoplastic left heart syndrome. Genetic analysis was warranted due to multiple anomalies in the neonate. Whole exome sequencing (WES) showed a previously unreported truncating mutation in the KM2TD gene, confirming the diagnosis of Kabuki syndrome type 1. CONCLUSION: Kabuki syndrome is rare, and its presentation with hydrops is extremely rare. Our case presented with polyhydramnios, antenatal hydrops, hypoplastic left heart, right-sided Morgagni hernia, and scoliosis with a novel mutation, thus potentially expanding the genotype-phenotype spectrum of this syndrome. This case highlights that a pediatrician should have a high index of suspicion for inherited genetic syndromes in a case of nonimmune hydrops with multiple congenital anomalies. Genetic tests are valuable for identifying rare syndromes and novel mutations.

Episignatures are increasingly valuable for variant interpretation in rare neurodevelopmental disorders, especially when optimized to capture the impact of specific variant types and locations across a gene. Here, we generated a next-generation DNA methylation (DNAm) episignature for Kabuki syndrome type 1 (KS1) using the largest cohort studied to date, aiming to clarify the epigenomic and phenotypic effects of diverse KMT2D variant types and positions. Genome-wide DNAm profiles were obtained for 110 individuals with KMT2D variants and 854 controls using microarrays and long-read sequencing (LRS). Differentially methylated loci were enriched in genes involved in embryonic and nervous system development and were leveraged to construct a support-vector machine classifier for detecting pathogenic KMT2D variants. The classifier achieved 97% sensitivity and 100% specificity in validation cohorts and outperformed in silico tools, demonstrating stronger concordance with clinical presentation. Missense variants in the C-terminal region (exon 48) of KMT2D and the N-terminal plant homeodomain (PHD)-type zinc fingers were predominantly classified as pathogenic, highlighting regions enriched for pathogenic variants. Missense variants in the central region (exons 31-39) were more often predicted benign for KS1, consistent with potential association with a different syndrome, highlighting the classifier's specificity for KS1. Test performance was consistent across array and LRS platforms, and classifier scores reflected levels of mosaicism detected by LRS. The KS1 episignature also positively classified pathogenic KDM6A variants associated with KS2. These findings represent a significant advance in the evolution of episignature development, demonstrating diagnostic and interpretive value of a KS1 signature in resolving uncertain or complex cases.