Purpose Beckwith–Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM. Methods We looked for cases showing the clinical features of both BWS and long QT syndrome (LQTS), which is often associated with KCNQ1 variants. Pathogenic variants were identified by genomic analysis and targeted sequencing. Functional experiments were performed to link these pathogenic variants to the imprinting defect. Results We found three rare cases in which complete IC2 LOM is associated with maternal transmission of KCNQ1 variants, two of which were demonstrated to affect KCNQ1 transcription upstream of IC2. As a consequence of KCNQ1 haploinsufficiency, these variants also cause LQTS on both maternal and paternal transmission. Conclusion These results are consistent with the hypothesis that, similar to what has been demonstrated in mouse, lack of transcription across IC2 results in failure of methylation establishment in the female germline and BWS later in development, and also suggest a new link between LQTS and BWS that is important for genetic counseling.

Background: Beckwith-Wiedemann syndrome (BWS) phenotype usually mitigates with age and data on adulthood are limited. Our study aims at reporting phenotype evolution and health issues in adulthood.Methods: 34 patients (16 males), aged 18-58 years (mean 28.5) with BWS were enrolled.Results: 26 patients were molecularly confirmed, 5 tested negative, and 3 were not tested. Final tall stature was present in 44%. Four patients developed Wilms' Tumor (2, 3, 5, and 10 years, respectively); one hepatoblastoma (22 years); one acute lymphoblastic leukemia (21 years); one adrenal adenoma and testicular Sertoli cell tumor (22 and 24 years, respectively); and three benign tumors (hepatic haemangioma, uterine myoma, and mammary fibroepithelioma). Surgery for BWS-related features was required in 85%. Despite surgical correction several patients presented morbidity and sequelae of BWS pediatric issues: pronunciation/swallow difficulties (n = 9) due to macroglossia, painful scoliosis (n = 4) consistent with lateralized overgrowth, recurrent urolithiasis (n = 4), azoospermia (n = 4) likely consequent to cryptorchidism, severe intellectual disability (n = 2) likely related to neonatal asphyxia and diabetes mellitus (n = 1) due to subtotal pancreatectomy for intractable hyperinsulinism. Four patients (two males) had healthy children (three physiologically conceived and one through assisted reproductive technology).Conclusions: Adult health conditions in BWS are mostly consequent to pediatric issues, underlying the preventive role of follow-up strategies in childhood. Malignancy rate observed in early adulthood in this small cohort matches that observed in the first decade of life, cumulatively raising tumor rate in BWS to 20% during the observation period. Further studies are warranted in this direction.

The ability to identify our own body and its boundaries is crucial for survival. Ideally, the sooner we learn to discriminate external stimuli occurring close to our body from those occurring far from it, the better (and safer) we may interact with the sensory environment. However, when this mechanism emerges within ontogeny is unknown. Is it something acquired throughout infancy, or is it already present soon after birth? The presence of a spatial modulation of multisensory integration (MSI) is considered a hallmark of a functioning representation of the body position in space. Here, we investigated whether MSI is present and spatially organized in 18- to 92-h-old newborns. We compared electrophysiological responses to tactile stimulation when concurrent auditory events were delivered close to, as opposed to far from, the body in healthy newborns and in a control group of adult participants. In accordance with previous studies, adult controls showed a clear spatial modulation of MSI, with greater superadditive responses for multisensory stimuli close to the body. In newborns, we demonstrated the presence of a genuine electrophysiological pattern of MSI, with older newborns showing a larger MSI effect. Importantly, as for adults, multisensory superadditive responses were modulated by the proximity to the body. This finding may represent the electrophysiological mechanism responsible for a primitive coding of bodily self boundaries, thus suggesting that even just a few hours after birth, human newborns identify their own body as a distinct entity from the environment.

The pathogenic variants in the neuroblastoma‐amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole‐exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co‐occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). We revealed a recognizable facial profile (hypotelorism, thin lips, pointed chin, and “progeroid” appearance) determined by using DeepGestalt facial recognition technology, and we provide evidence for the occurrence of genotype–phenotype correlations. Notably, severe hepatic involvement was associated with variants affecting the NBAS‐Nter and Sec39 domains, whereas milder liver involvement and immunodeficiency were generally associated with variants located at the N‐terminus and C‐terminus of the protein. Remarkably, no patient was reported to carry two nonsense variants, suggesting lethality of complete NBAS loss‐of‐function.

Macrocephaly, defined as head circumference ≥ 2 SDs, is a cardinal feature of Sotos syndrome (SS) and generally persists in adulthood. Subdural fluid collection, typically associated with macrocephaly, is described in children due to anatomical conformation, and in adulthood due to brain atrophy and ex-vacuo hydrocephalus. On the other hand, a true, symptomatic, chronic subdural hematoma (CSH) is a previously unreported complication of SS in adulthood. Here we describe the first SS patient presenting symptomatic CSH, leading to frequent hospitalizations for surgical evacuations that consistently recurred. Middle meningeal artery (MMA) embolization and epidural blood patch (EBP) allowed to resolve the CSH with complete resolution of clinical signs and symptoms. We hypothesize that appearance and recurrences of CSH may be related to pathological biomechanics of brain, cerebro-spinal fluid and skull, secondary to anatomical features of SS. In this context, surgical evacuation may be less efficient than usual to cure CSH. Alternative treatment to avoid blood extravasation, as MMA embolization, or to cure concurrent causes of the pathology, as EBP, may be considered.