ルビンシュタイン・テイビ症候群

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).

Rubinstein-Taybi syndrome (RTS) is caused by germline loss-of-function variants of CREBBP or EP300, which function as histone acetyltransferases and act as tumor suppressors. Various benign or malignant tumors have been reported in RTS, suggesting tumor predisposition. To date, five patients with RTS complicated by neuroblastoma have been reported, and pathogenic germline variants were confirmed in two of the patients. We report a 2-year-old male with neuroblastoma and RTS harboring a germline CREBBP missense variant at the histone acetyltransferase (HAT) domain. Neuroblastoma was diagnosed at 4 months of age, and histological evaluation classified the tumor as low risk. The neuroblastoma was stable at 2 years of age. His dysmorphic features and developmental delay were consistent with phenotypes of RTS. Whole genome sequencing of both tumor and germline identified a de novo missense variant of CREBBP (NM_004380.3:c.4862T>A p.(Leu1621Gln)). No other contributing germline or somatic variants were identified, except for polyploidy involving chromosomes 7, 12, and 17. Our results suggest that germline loss-of-function of CREBBP may contribute to tumor predisposition factor since somatic variants of CREBBP and EP300 have been identified in neuroblastoma. Paired tumor-normal genome sequencing enabled comprehensive analysis of germline tumor predisposition, as well as genomic profiles of tumor tissue.

BACKGROUND: Rubinstein Taybi syndrome (RSTS), a rare congenital disease, is caused by mutations in lysine acetyl transferase type 3 (KAT3) genes, EP300 and CREBBP. Many of the tissues affected in RSTS are derived from the neural crest (NC). Hence, we proposed that NC development would be perturbed in RSTS. RESULTS: Zebrafish RSTS models generated by knocking down or mutating ep300a and crebbpa genes reveal defects in NC migration. This effect on migration is conserved in NC cells generated from human RSTS patient-derived induced pluripotent stem cells (iPSC) cells. The defects in NC migration can be partially reversed by HDAC inhibition in morphant embryos. KAT3 knockdown causes downregulation of snai1b and snai2 and upregulation of cdh6, important regulators of epithelial to mesenchymal transition (EMT). Snai2 is known to repress CDH6, also known as cadherin 6b, in chick NC cells facilitating their delamination from the neural tube and migration. CONCLUSIONS: We demonstrate for the first time that NC migration is defective in zebrafish and iPSC models of RSTS. We make a case for classifying RSTS as a neurocristopathy. We propose that KAT3 genes control NC migration through regulation of EMT genes snai2 and snai1b.

Rubinstein-Taybi syndrome (RSTS) and Menke-Hennekam syndrome (MKHK) are two rare Mendelian disorders presented with variable degrees of intellectual disability and different facial dysmorphism. They are caused by loss-of-function (LOF) variants or missense/inframe deletion variants in the exon 30 and 31 of the CREBBP gene respectively. This study aimed to refine the phenotype and provide characterization of genome-wide DNA methylation (DNAm) in RSTS and MKHK. We integrated and analyzed clinical data of 151 patients with RSTS and 36 patients with MKHK from this study and literatures. Meanwhile, genome-wide DNAm analysis were carried out on 51 blood samples (RSTS n = 9, MKHK n = 8, control n = 33), and 21 human induced pluripotent cell (hiPSC) samples (RSTS n = 5, MKHK n = 4, control n = 12). Phenotype analysis showed that patients with RSTS variants downstream the last 50 nt of the penultimate exon had atypical facial malformation and severer medical problems compared to the classical RSTS caused by LOF CREBBP variants. Individuals with MKHK variants in intrinsically disordered region (IDR) showed resemblant features. Meanwhile, DNAm analysis identified two specific blood DNA methylation patterns (episignatures): RSTS and MKHK_IDR compared to matched normal controls. Samples with MKHK variants outside the IDR did not obey the MKHK_IDR episignature. By interrogating DNAm in hiPSCs of patients with RSTS and MKHK, we observed differentially methylated genes play a role in embryonic development and organogenesis. In conclusion, our results suggest that phenotypic features and DNA methylation episignatures may differ for each genomic region.