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Purpose: Despite ever-increasing knowledge of the genetic etiologies of neurodevelopmental disorders, approximately half remain undiagnosed after exome or genome sequencing. Here, we provide a deep clinical characterization of 11 previously unreported patients with a recently described neurodevelopmental disorder (NDD) due to pathogenic variants in RNU4-2., Methods: The 11 patients were identified in a pool of 70 patients selected for targeted RNU4-2 sequencing on the basis of their clinical phenotypes from a cohort of 1032 individuals with a NDD and without a prior genetic diagnosis., Results: The 11 patients were aged between 13 months and 36 years. All patients showed moderate to severe developmental delay and/or intellectual disability. Height and weight were below 10th percentile and most showed microcephaly. In almost 50% of the patients, intrauterine growth retardation was detected. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelid and epicanthus, full cheeks, tented philtrum, mouth constantly slightly open with an everted lower lip vermilion, high palate, and profuse drooling. Of 11 patients, 64% also presented with ophthalmological problems (mainly strabismus, nystagmus, and refraction errors) and 64% had musculoskeletal features (joint hypermobility, mild scoliosis, and easy fractures)., Conclusion: This work provides an improved characterization of the phenotypic spectrum of RNU4-2 syndrome across different age groups and demonstrates that thorough clinical assessment of patients with an NDD can be enhanced significantly for this novel syndrome., Competing Interests: Conflict of Interest The enclosed manuscript has been revised and approved by all the authors and they have taken care to ensure the integrity of the work. The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Noonan syndrome and related disorders are a group of well-known genetic conditions caused by dysregulation of the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway. Because of the overlap of clinical and molecular features, they are now called RASopathies. In this study, we retrospectively analyzed the clinical data of 121 patients with a molecularly confirmed diagnosis of RASopathy, describing frequencies for clinical features in all organ systems as well as molecular data. The most common clinical diagnosis was Noonan Syndrome and the most frequently affected gene was PTPN11 followed by SOS1, RAF1, LZTR1, and RIT1. All patients had distinctive craniofacial features indicative of the RASopathy spectrum but we report some atypical features regarding craniofacial shape, such as craniosynostosis and microcephaly. We also describe uncommon clinical characteristics such as aortic dilation, multivalvular heart disease, abnormalities of the posterior fossa, and uterine congenital anomalies in female patients. Furthermore, the presence of multiple giant cell granulomas was observed specifically in patients with SOS1 variants. This comprehensive evaluation allows broadening the phenotypic spectrum of our population and their correlation with the genotype, which are essential to improve the recognition and the follow up of RASopathies as a multisystemic disease., (© 2024 Wiley Periodicals LLC.)

The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

According to the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS), diffuse midline glioma H3 K27-altered is a grade 4 infiltrative glioma that arises from midline anatomical structures and is characterized by the loss of H3 K27me3 and co-occurring H3 K27M mutation or EZHIP overexpression. However, the H3 K27M mutation has also been observed in circumscribed gliomas and glioneuronal tumors arising in midline anatomical structures, which may result in diagnostic pitfalls.Rosette-forming glioneuronal tumor (RGNT) is a CNS WHO grade 1 neoplasm that histologically features neurocytic and glial components and originates in midline anatomical structures.This study aimed to assess whether RGNTs, similar to other midline tumors, may exhibit immunohistochemical loss of H3 K27me3 and harbor the H3 K27M mutation.All seven analyzed RGNTs displayed immunohistochemical loss of H3 K27me3 in all tumor cells or H3 K27me3 mosaic immunostaining. In one case, H3 K27me3 loss was associated with the H3 K27M mutation, whereas the other six cases did not exhibit any H3 mutations or EZHIP overexpression. During a follow-up period of 23 months, the H3 K27M-mutant case remained unchanged in size despite partial resection, indicating that the H3 mutation may not confer higher biological aggressiveness to RGNT.The immunohistochemical loss of H3 K27me3 co-occurring with the H3 K27M mutation may result in the potential misdiagnosis of RGNT, especially in cases of small biopsy specimens consisting of only the glial component., (© 2024. The Author(s).)

The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors introduced the new tumor type CNS tumor with BCOR internal tandem duplication (ITD), characterized by a distinct DNA methylation profile and peculiar histopathological features, including a circumscribed growth pattern, ependymoma-like perivascular pseudorosettes, microcystic pattern, absent or focal GFAP immunostaining, OLIG2 positivity, and BCOR immunoreactivity. We describe a rare case of a CNS tumor in a 45-year-old man with histopathological and immunohistochemical features overlapping the CNS tumor with BCOR internal tandem duplication (ITD) but lacking BCOR immunostaining and BCOR ITD. Instead, the tumor showed CREBBP::BCORL1 fusion and pathogenic mutations in BCOR and CREBBP, along with a DNA methylation profile matching the "CNS tumor with EP300:BCOR(L1) fusion" methylation class. Two CNS tumors with fusions between CREBBP, or its paralog EP300, and BCORL1, and approximately twenty CNS tumors with CREBBP/EP300::BCOR fusions have been reported to date. They exhibited similar ependymoma-like features or a microcystic pattern, along with focal or absent GFAP immunostaining, and shared the same DNA methylation profile. Given their morphological and epigenetic similarities, circumscribed CNS tumors with EP300/CREBBP::BCOR(L1) fusions and CNS tumors with BCOR ITD may represent variants of the same tumor type. The ependymoma-like aspect coupled with the lack of diffuse GFAP immunostaining and the presence of OLIG2 positivity are useful clues for recognizing these tumors in histopathological practice. The diagnosis should be confirmed after testing for BCOR(L1) gene fusions and BCOR ITD., (© 2024. The Author(s).)

Coffin-Siris syndrome (CSS) is a rare neurodevelopmental and multisystemic disorder with wide genetic heterogeneity and phenotypic variability caused by pathogenic variants in the BAF complex with 341 cases enrolled in the CSS/BAF-related disorders registry by 2021. Pathogenic variants of ARID1A account for 7-8% of cases with CSS phenotype. Malignancy has been previously reported in six individuals with CSS associated with BAF mutations. Two of these malignancies including one acute lymphoid leukemia and one hepatoblastoma were reported in ARID1A-associated CSS (ARID1A-CSS). Alterations in ARID1A are among the most common molecular aberrations in human cancer. Somatic deletion of 1p and specifically of 1p36.11 containing ARID1A is frequently seen in hepatoblastoma and has been associated with high-risk features. Here we report a child with CSS Phenotype and a novel de novo variant of ARID1A with hepatoblastoma. Because hepatoblastoma has an incidence of 1 per million children, the presence of hepatoblastoma in 2 of 30 known cases of ARID1A-CSS is significant. ARID1A-CSS should be included among the cancer predisposition syndromes associated with an increased risk of hepatoblastoma and tumour surveillance considered for these patients. The role of ARID1A in the pathogenesis and outcome of hepatoblastoma deserves further investigation., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Main Goals: To analyze how and when the endoscope is used in vestibular schwannoma surgery and identify the benefits of using endoscopy in this type of surgery., Background: It is currently unclear if there is any benefit from using an endoscope in vestibular schwannoma surgery so this retrospective analysis set out to study this., Methods: All the patients who underwent vestibular schwannoma surgery at our clinic were included for all the vestibular schwannoma approaches taken. We studied when endoscopy was used during surgery and the goal of using endoscopy. Several pre- and postoperative factors were assessed such as complications, facial function, and hearing function in the case of techniques that allow hearing preservation., Results: From January 2015 to September 2018, 280 patients underwent lateral skull base surgery. Of these, 112 were included in this study. The endoscope was used in all 112 patients, and in eight cases it was possible to identify residual disease using the endoscope to check the surgical field, and then to remove the disease under endoscopic view. Moreover, in two other cases, the endoscope was used to resolve a vasculoneural conflict between the anterior inferior cerebellar artery (AICA) loop and facial nerve in one case, and for deafferentation of the superior and inferior vestibular nerves in the second case. No major intraoperative complications occurred in our series. There was no statistically significant difference in postoperative facial nerve function between patients in whom the endoscope was used as a diagnostic tool and patients in whom it was used as an operative tool (p = 0.3152)., Conclusions: The endoscope may be useful, especially in surgical techniques where there is poor control of the internal auditory canal (IAC). An endoscopic support technique is strongly recommended to avoid residual disease, particularly in retrosigmoid and retrolabyrinthine approaches. Moreover, the recent introduction of the transcanal transpromontorial approach allows the endoscope to be used during all the procedures in patients affected by a vestibular schwannoma limited to the IAC or to support surgical procedures during an enlarged microscopic approach.

Objective: Hearing restoration has always been a dream in vestibular schwannoma (VS) surgery. The aim of this study is to describe an endoscopic assisted transcanal retrocochlear approach to the internal auditory canal (IAC) with total removal of the VS; simultaneously we assessed the anatomical and functional aspects of hearing restoration with cochlear implant (CI)., Study Design: A retrospective case series., Setting: Tertiary referral center., Patients: Six patients affected by VS involving the fundus of the IAC (Koos stage I-II) were included in this study. The patients already demonstrated symptoms of IAC involvement by the neuroma, with severe to profound hearing loss., Interventions: Transcanal microscopic, endoscopic assisted, approach was chosen for total tumor removal. Preoperative and intraoperative electrophysiological monitoring was performed using electrically evoked auditory brainstem responses (EABR) to evaluate preservation of cochlear function., Main Outcome and Measures: A retrospective evaluation of electrophysiological data collected during surgeries has been conducted; clinical outcomes, surgical complications, and postoperative radiological evaluations were also considered., Results: Total tumor removal was achieved in all patients with no major complications. One patient showed temporary facial palsy (HB stage II). We were able to preserve cochlear function in five out of six patients. In those patients intraoperative monitoring with EABR was performed after tumor removal with good responses., Conclusions: Transcanal retrocochlear approach for VS removal allows preservation of cochlea and cochlear nerve function. This is the first step towards developing an effective surgical technique for VS removal and hearing rehabilitation with CI.

Objective Vestibular schwannoma (VS) is a benign tumor of the lateral skull base. Different microscopic surgical techniques are described in literature: the retrosigmoid and translabyrinthine approaches are used to treat big tumors located in the cerebellopontine angle, and the middle cranial fossa approach is utilized for small tumors with good hearing preservation. The expanded transcanal transpromontorial (ExpTT) approach is a combined microscopic-endoscopic technique previously indicated for Koos stage I and II VS and now proposed for larger VS, up to 3 cm in diameter, with linear progression into the cerebellopontine angle and touching the brainstem. Study Design The study was a retrospective case series of patients who underwent ExpTT surgery for VS in our ear, nose, and throat department. Setting We reviewed the surgical videos and electrophysiologic data recorded during the surgical operations. Subjects and Methods From January 2015 to January 2017, 20 patients affected by Koos stage II and III VS underwent surgery in our department with the ExpTT approach. This novel technique is described step by step, with a focus on the surgical procedure and anatomic landmarks; outcomes are detailed in terms of early and late complications. The mean follow-up was 15 months. Results The ExpTT approach permitted, in all patients, gross total resection of the tumor without any complication and with preservation of facial nerve function. All patients had a good postoperative recovery. Conclusion The ExpTT technique is a new approach that combines the advantages of a microscopic technique with the ones offered by the endoscope in removal of VS.

Background: Recently, the transcanal approach for the removal of acoustic neuromas has been introduced. Facial nerve (FN) preservation is one of the main challenges of this kind of surgery., Objective: To describe our experience in the surgical treatment of acoustic neuromas, focusing on the functional results of FN preservation after a transcanal approach., Methods: A retrospective chart review was carried out on clinical data and videos from operations on 49 patients who underwent surgery with a totally transcanal exclusive endoscopic approach for Koos stage I-II lesions, or an enlarged transcanal transpromontorial approach for Koos stage II-III tumors, between March 2012 and February 2017. Patients and tumor characteristics, clinical manifestations, radiologic features, audiological results, FN outcomes (according to the House-Brackmann [HB] grading system) and complications were evaluated. Tumors were classified according to the Koos grading system., Results: The age of the patients (34 females and 15 males) ranged from 27 to 77 years (mean age: 54.9 yr). Preoperative diagnosis was "vestibular schwannoma" in all patients. At the last follow-up (range 1-60 mo, mean 13.9 mo), 42 of 49 showed grade I HB FN function, 5 of 49 grade II HB, and 2 of 49 grade III HB. Overall, in 95.9%, FN function was preserved (grade I-II HB) with stable results at follow-up; in 4.1% of cases, FN function was reduced, but not worse than grade III., Conclusion: The transcanal approach represents a feasible, minimally invasive, and conservative technique for the management of acoustic neuromas of the internal auditory canal.

The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder. This microdeletion is associated with variable clinical outcome, the phenotypical spectrum ranges from intellectual disability and/or multiple congenital anomalies, autism, learning and speech problems, to a normal Microdeleción 16p11.2: primeros casos reportados en Argentina 16p11.2 Microdeletion: first report in Argentina phenotype. Genomic testing that determines copy number of sequences, such as chromosomal microarray, is used to identify this microdeletion. However, the prediction of the individual phenotype of a patient based only on the location of such deletion remains a challenge, regarding the existence of many genomic variants that might hinder the interpretation of possible functional effects between most of the contributing genes to that region. We describe the clinical findings in two subjects with heterozygous microdeletions at 16p11.2, highlighting the phenotypic and behavioural findings that conditioned the diagnostic strategy. We also discuss the implications of diagnosis, in practical counselling situations., (Sociedad Argentina de Pediatría.)

Objectives/hypothesis: The aim of this study was to describe and evaluate the feasibility of an expanded transcanal transpromontorial approach, developed from the exclusive endoscopic transcanal transpromontorial approach., Study Design: Retrospective case series., Methods: Retrospective chart review of 10 patients operated by an expanded transcanal transpromontorial approach in two tertiary referral centers (University Hospital of Modena, Italy and University Hospital of Verona, Italy). Data from charts and video documentation were collected and analyzed., Results: Between April 2015 and January 2016, 10 patients underwent an expanded transcanal transpromontorial approach for vestibular schwannoma Koos stage I or II and were enrolled in the study. The size of the tumors ranged from 7 to 19 mm in maximum diameter. A gross total resection was achieved in all cases. One subject experienced postoperative cerebrospinal fluid otorhinorrhea and three subjects experienced temporary postoperative facial weakness, all of which completely resolved. The mean follow-up was 5 months., Conclusions: The expanded transcanal transpromontorial approach allowed bimanual dissection using a microscopic technique for the treatment of pathologies of the internal auditory canal and cerebellopontine angle. This novel approach resulted in minimal morbidity and comparable facial nerve preservation rates to the traditional approaches to the internal auditory canal. The expanded transpromontorial approach to the internal auditory canal holds promise for addressing pathology in this region of the temporal bone from the external auditory canal., Level of Evidence: 4. Laryngoscope, 127:2608-2614, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

OBJECTIVE The aim of this study was to describe the first case series in which an exclusive endoscopic transcanal transpromontorial approach (EETTA) was used to treat small vestibular schwannomas (VSs) and meningiomas of the internal auditory canal (IAC). METHODS The authors performed a retrospective review of patients who had undergone surgery using an EETTA to the IAC at 2 university tertiary care referral centers during the period from November 2011 to January 2015. RESULTS Ten patients underwent surgery via an EETTA for the treatment of VS in the IAC at the University Hospital of Modena or the University Hospital of Verona. The patients had Koos Grade I or II tumors and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Class D hearing status preoperatively. Gross-total resection was achieved in all patients. No major complications such as cerebrospinal fluid leakage or hemorrhage were reported. In 7 of 10 (70%) patients, facial nerve function was normal immediately after surgery (Rough Grading System [RGS] Grade I). Two patients presented with a transitory facial palsy immediately after surgery (RGS Grade II-III) but experienced complete recovery during the follow-up period. The mean follow-up was 10 months. CONCLUSIONS The EETTA proved to be successful for the removal of VS or meningioma involving the cochlea, fundus, and IAC, with possible lower complication rates and less invasive procedures than those for traditional microscopic approaches. The potential for the extensive and routine use of this approach in lateral and posterior skull base surgery will depend on the development of technology and surgical refinements and on the diffusion of skull base endoscopic skills among the otolaryngological and neurosurgical communities.

Surgical approaches to vestibular schwannomas (VS) are widely known and extensively recorded. For the first time, an exclusive endoscopic approach to the internal acoustic canal (IAC) was described and used to safely remove a cochlear schwannoma involving IAC in March 2012. The aim of this article was to summarize indications and technique to treat intracanalicular VS by transcanal/transpromontorial endoscopic approach. Because management of intracanalicular VSs is complex and strongly debated, this kind of therapeutic option in the appropriate and selected cases could modify classic concepts of the management of this pathology., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Medulloblastoma is the most common central nervous system tumor in children, while it is extremely rare in adults. Multimodal treatment involving surgery, radiotherapy and chemotherapy can improve the prognosis of this disease, and recent advances in molecular biology have allowed the identification of molecular subgroups (WNT, SHH, Groups 3 and 4), each of which have different cytogenetic, mutational and gene expression signatures, demographics, histology and prognosis. The present review focuses on the state of the art for adult medulloblastoma treatment and on novel molecular advances and their future implications in the treatment of this disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Foramen magnum meningioma poses a challenge for neurosurgeons. Prognosis has generally improved with diagnostic and surgical advances over the past two decades; however, it may ultimately depend more on the surgeon's ability to tailor the approach and interpret intraoperative risks in single cases. The series comprised 64 patients operated on for ventral and ventrolateral foramen magnum meningioma. All patients underwent preoperative magnetic resonance imaging and received surgery via the dorsolateral route, rendering the series homogeneous in neuroradiological workup and surgical treatment. Particular to this series was that the majority of patients were of advanced age (n = 29; age, >65 years), had serious functional impairment (n = 30, Karnofski score <70), and large tumors (mean diameter, 3.5 cm). Total tumor removal was achieved in 52 (81 %) patients; operative mortality was nil. Early outcome varied depending on difficulties encountered at surgery (cranial nerve position and type of involvement in particular) and type of preoperative dysfunction. Long-tract signs and cerebellar deficits improved in 74 and 77 % of cases, respectively, but only 27 % of cranial nerve deficits did so. Surgical complications most often involved the cranial nerves: cranial nerve impairment, especially of the 9th through the 12th cranial nerves, due to stretching or encasement was noted in 44 cases. At final outcome assessment, two thirds of the cranial nerve deficits cleared, and all but two patients returned to a normal productive life. One patient was reoperated on during the follow-up period. Foramen magnum meningiomas behave like clival or spinal tumors depending on their prevalent extension. A dorsolateral approach tailored to tumor position and extension and meticulous surgical technique allow for definitive control of surgical complications. Scrupulous postoperative care may prevent dysphagia, a major persistent complication of surgery. Long-term observation of indolent tumor behavior at follow-up suggests that incomplete resection may be a viable surgical treatment option.

Leptomeningeal dissemination of low-grade gliomas is an uncommon event. A 43-year old male presented with dizziness, gait ataxia, and diplopia. A nonenhancing lesion in the right cerebellar peduncle was identified, subtotally resected, and diagnosed as a grade II astrocytoma. After one year a nodular spread in the brain and leptomeninges was diagnosed, so the patient started chemotherapy with temozolomide and liposomal cytarabine. Complete remission was achieved after 12 months of treatment and the patient is still free from the disease after a follow-up of 24 months. We suggest that this combination may be a valuable treatment option.

Hypothesis: Electrical stimulation of the inferior colliculus in the midbrain can provide a safe and efficacious alternative to auditory brainstem implants (ABIs)., Background: Patients with neurofibromatosis type 2 (NF2) receive limited speech recognition with ABIs. Some ABI patients without NF2 can achieve excellent speech understanding, suggesting that the limited NF2 performance is due to brainstem damage from the tumor and its removal., Methods: An array of electrodes (Med-El ABI) was placed on the dorsal surface of the inferior colliculus in the midbrain of a human volunteer as an auditory prosthesis via an infratentorial supracerebellar median surgical approach. Electrophysiological responses, psychophysical responses, and speech recognition were measured., Results: Electrical stimulation produced auditory sensations on all 12 electrodes with no nonauditory sensations. Auditory threshold levels indicated the stability of the electrode array over time. Electrophysiological measures showed activation in the contralateral auditory cortex but none in ipsilateral cortex. All electrodes demonstrated a full range of loudness sensation and electrode-specific pitch sensations. Speech recognition was significant, but limited in the first month after surgery., Conclusion: This approach may provide advantages for patients with brainstem damage.

The ability of resident cells to induce apoptosis of invading immune cells is a major regulatory factor operating in immune-privileged tissues, including the nervous system. We investigated the cellular and molecular factors participating in modulation of immune response in peripheral nerves, focusing on two cytotoxic pathways: fas ligand (fasL) and perforin. fasL and perforin expression was found by immunochemistry on Schwann cells (Sc) in nerve biopsies from patients with chronic inflammatory demyelinating polyneuritis and on human Sc cultures. Treatment of Sc with tumor necrosis factor (TNF) alpha and interferon (IFN) gamma upregulated the expression of both molecules. In a coculture model, Sc exposed to TNFalpha or IFN gamma were able to induce both apoptotic and lytic injury of T-lymphocytes. Inactivation of fasL with the neutralizing antibody NOK-2 abolished T-cell apoptosis induced by Sc treated with TNFalpha, but not by Sc treated with IFN gamma. Conversely, T-cell lysis was significantly decreased when IFN gamma-activated Sc were treated with concanamycin A, which inhibited perforin release. At variance with T-lymphocytes, B-cells were less sensitive to cytokine-treated Sc toxicity. Thus, Sc exposed to inflammatory cytokines have the capacity of inducing selective damage of T-lymphocytes and have the potential of regulating the immune response in the peripheral nervous system., (Copyright 2003 Wiley-Liss, Inc.)