Intramedullary Spinal Cord Tumors Associated with the Neurofibromatoses.

Cochlear implantation (CI) following vestibular schwannoma (VS) resection, traditionally controversial, is increasingly accepted due to advances in surgical techniques. Current evidence is limited to small, short-term studies. This report presents the largest consecutive single-center cohort and offers long-term audiological outcomes. This retrospective study analyzed 73 consecutive patients who underwent VS resection with either simultaneous (97%) or delayed (3%) CI at the Gruppo Otologico between 1985 and 2025, among more than 4000 patients who underwent VS removal during the same period. Sixty-three patients (86%) had sporadic VS, and 10 (14%) had neurofibromatosis type 2 (NF2). Tumor removal was performed using the enlarged translabyrinthine approach (ETLA). Outcomes were assessed through pure-tone average (PTA), speech discrimination scores (SDS), and open-set speech recognition. After a median 35-month follow-up, 48 patients (66%) were active CI users; 20 (27%) were nonusers or nonresponders. Five patients were "removed/non activated" (never activated due to postoperative complications or device malfunction or later explanted despite initial benefit) and were therefore not included in postoperative audiological outcome tables. Due to complications requiring explantation. Among users, the median postoperative PTA was 45.0dB HL (IQR: 40.0-61.3), and the median SDS was 60.0% (IQR: 20.0-70.0). Open-set performance demonstrated high-to-median scores across word, sentence, and comprehension tests. Performance group analysis revealed that 52% of patients achieved intermediate-to-high outcomes, including 75% of NF2 patients. Performing CI immediately after VS resection is feasible and offers long-term functional benefits for most patients, including carefully selected NF2 cases. Although results can vary, more than half of the patients attain meaningful speech perception. This extensive, long-term, single-center experience strongly supports the feasibility of CI in this context, emphasizing the importance of surgical technique, nerve preservation, and precise patient selection.

Differences in Optic Pathway Glioma Prevalence Among Children with Neurofibromatosis Type 1.

The scope of preimplantation genetic testing for monogenic disorders (PGT-M) in Japan, initially limited to severe childhood-onset diseases, appears to be expanding following the 2022 revision of the Japan Society of Obstetrics and Gynecology's definition of "severity." This study examines the impact of this definitional change on the acceptability of PGT-M by comparing attitudes of Japanese genetic professionals before and after the revision, focusing on three childhood-onset cancer predisposition syndromes: Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and neurofibromatosis type 1 (NF1). A two-phase survey was conducted in 2019-2020 and 2024 among clinical genetic specialists supervisors and certified genetic counselors. The survey explored views on PGT-M acceptability, the concept of "selection of life," awareness of the revised severity definition, and background factors influencing opinions. Among 382 respondents, LFS was most frequently judged acceptable for PGT-M, followed by FAP and NF1. Between the two phases, "unacceptable" responses declined, while "neither" increased. Those viewing PGT-M as "selection of life" were more likely to oppose it (r=-.293, p<.01). Genetic professionals in the pediatric field were more likely to consider PGT-M unacceptable (r=-.22, p<.01). These findings suggest that clinical experience, ethical perceptions, and institutional guidelines shape professional attitudes toward PGT-M. These findings have implications for genetic counseling practice and policy discussions surrounding the evolving scope of PGT-M. Ongoing dialogue and education are essential as eligibility criteria and societal values continue to evolve.

Severe pneumonia in children typically presents with the most prominent early lesion being damage to the bronchial mucosa. To explore the diagnostic value of hsa_circ_0077658 in pediatric severe pneumonia and its possible mechanism of action. 116 children with severe pneumonia, 87 children with pneumonia, and 60 healthy children were included. Lipopolysaccharide (LPS) was used to stimulate BEAS-2B cells to establish a pneumonia cell model. Reverse Transcription quantitative PCR (RT-qPCR) was performed to detect the expression levels of hsa_circ_0077658, miR-15a-5p and Neurofibromatosis type 1(NF1). The Enzyme-Linked Immunosorbent Assay (ELISA) method was performed to detect the levels of oxidative stress markers and inflammatory factors. The Annexin V/PI and Cell Counting Kit-8 (CCK-8) kits were used to assess the apoptosis and proliferation levels of BEAS-2B cells, respectively. Person's correlation analysis, dual luciferase assays and RNA Binding Protein Immunoprecipitation (RIP) experiments were performed to demonstrate the relationship between genes. Hsa_circ_0077658 and NF1 were downregulated in patients with pneumonia and in LPS-induced BEAS-2B cells, while miR-15a-5p was upregulated. Hsa_circ_0077658 showed excellent diagnostic performance, with an AUC of 0.820 (95% CI: 0.749-0.890) in healthy vs. pneumonia children comparison and 0.931 (95% CI: 0.894-0.966) for distinguishing pneumonia children from severe pneumonia children. Following exposure to LPS, BEAS-2B cells exhibited heightened oxidative stress, apoptosis, and inflammatory responses, while cellular proliferation was suppressed. Hsa_circ_0077658 targets miR-15a-5p, and NF1 is the downstream effect target of miR-15a-5p. Overexpression of hsa_circ_0077658 can alleviate the oxidative stress, apoptosis and inflammatory response in LPS-BEAS-2B cells, thereby promoting proliferation. This effect was reversed by overexpression of miR-15a-5p. Furthermore, overexpression of NF1 can reverse the exacerbating effect of miR-15a-5p overexpression on the damage caused by LPS to BEAS-2B cells. Hsa_circ_0077658 may be a biomarker for pediatric severe pneumonia, potentially influencing disease progression via the miR-15a-5p/NF1 axis.

Neurofibromatosis type 1 (NF1) is a progressive rare genetic disorder that frequently involves the development of plexiform neurofibromas (PN). Until recently, there was no approved pharmacological treatment for adults with NF1-PN, and the disease burden is not well understood. This real-world retrospective study aimed to describe treatment patterns, healthcare resource utilization (HRU), and costs among adults with NF1-PN in the US. Data were obtained from the Merative™ MarketScan® Commercial and Medicare Databases (01/01/2016-12/31/2022). Adults diagnosed with NF1 and PN were matched to controls without NF1-PN on sociodemographic characteristics (1:5 ratio). Continuous enrollment for ≥ 12 months before and ≥ 3 months after the index diagnosis (defined as the latter of NF1 or PN diagnosis by ICD-10-CM codes) was required for all patients. Treatment patterns, all-cause, and NF1/PN-specific HRU and costs were characterized during the follow-up period. A generalized linear model with Poisson or Tweedie distribution was used to compare all-cause HRU and costs, respectively, between patients and controls. This study included 944 patients with NF1-PN and 4,720 controls. The mean age was 39.6 (standard deviation: 15.6) years and 59.6% were female. Over a mean follow-up of 25.8 months, the most common treatment among patients with NF1-PN was prescription pain medication (69.5%), followed by debulking surgeries (22.9%), cytotoxic chemotherapy (7.0%), radiotherapy (4.8%), and targeted therapies (e.g., MEK inhibitors) (4.7%). All-cause HRU was significantly higher among patients than controls across all settings (1.6 vs. 0.27 inpatient days per patient per year [PPPY], 18.8 vs. 9.1 outpatient visits PPPY, 0.80 vs. 0.53 emergency department visits PPPY), with adjusted incidence rate ratios of 1.4 to 4.2 (all p < 0.001). Among patients with NF1-PN, 53% and 18% of all-cause inpatient days and outpatient visits, respectively, were attributable to an NF1 or PN diagnosis. The adjusted mean total healthcare costs were $23,516 PPPY higher among the NF1-PN ($34,398 PPPY) versus matched control ($6,149 PPPY) cohort, with a cost ratio of 4.3 (p < 0.001). This real-world study identified a substantially higher HRU and economic burden among adult patients with versus without NF1-PN across all settings, highlighting the need for new treatments to manage NF1-PN among this population.

Population-based evidence on cancer survival in individuals with neurofibromatosis 1 (NF1) remains limited. We compared survival following a first neoplasm in individuals with NF1 to that of the general Danish population and stratified on age, sex, and potential survival-related factors, including cancer stage and comorbidity. Using the Danish Cancer Registry, we identified 428 individuals with NF1 and 392,885 without NF1, all diagnosed with a first neoplasm (1977-2022). We estimated survival using Kaplan-Meier methods, assessed neoplastic and nonneoplastic mortality, and evaluated prior inpatient disease burden in adults (aged 20-69 years) based on hospital diagnoses 10 years to 6 months before neoplasm diagnosis. Among children (aged 1-19 years), NF1 was overall associated with better 5-year survival (NF1: 87.3% [81.1%-93.5%], non-NF1: 78.7% [77.9%-79.6%]), due to better survival following central nervous system (CNS) neoplasms. In adults, 5-year survival was lower in NF1 compared to the general population (57.0% [51.3%-62.6%] vs. 69.2% [69.0%-69.3%]). NF1 adults more often presented with stage IV breast (17.2% vs. 6.3%) and gastrointestinal cancers (52.5% vs. 37.7%). Among adults with no prior inpatient diagnoses, 5-year survival was poorer in NF1 (60.1% [51.3%-68.9%] vs. 72.1% [71.9%-72.3%]). Five-year neoplastic mortality was higher in NF1 adults (39.4% [33.8%-45.0%] vs. 27.7% [27.6%-27.9%]). In conclusion, individuals with NF1, particularly adults, have poorer cancer survival than the general population. Differences in cancer type and stage at diagnosis contribute but do not fully explain the excess mortality, indicating that factors beyond general health status may play a role.

Malignant peripheral nerve sheath tumour (MPNST) is a rare, aggressive sarcoma with high mortality. MPNST can develop sporadically, after radiation therapy or in association with neurofibromatosis type 1 (NF1). The treatment is challenging especially if surgical removal is not possible. NF1 is an autosomal-dominant genetic disorder most often caused by a germline pathogenic variant in the NF1 gene and in rare cases a deletion of the NF1 gene. Patients with NF1 have a higher risk of developing several different cancers, of which MPNST is one of the most frequent. MPNST in individuals with NF1 often presents with large MPNST which are often not accessible for surgery. Several studies have shown that patients with NF1-associated MPNST (nfMPNST) have an overall inferior survival than those with sporadic MPNST (sMPNST). Despite this, NF1 status alone may not be a causative factor for poor prognosis, which might rather be due to the incidence of larger tumours, which are more challenging to resect in toto. A systematic research protocol was made using the PRISMA-P model and the review question and inclusion and exclusion criteria were defined using the PICO model. The study characteristics defined by PICO include patients with NF1 as the population of interest. The development of MPNST was considered as the intervention, patients with sMPNST were chosen for comparison and the primary outcome of interest was survival. The literature search was performed on 12 October 2024 and 4,394 studies were eligible for screening, of which 36 studies were included in this study. Meta-analysis of eight studies found NF1 status to be a risk factor for the survival of MPNST. The reported survival rates varied between studies, but the 5-year overall survival (OS) remained poor in general, Awith 15 studies showing a significantly inferior survival for nfMPNST. Only four studies have a worse survival for sMPNST, but none with a significant difference. The findings in this systematic review and meta-analysis of 36 studies indicates that patients with nfMPNST have a worse survival compared to sMPNST.

Neurofibromatosis Type 1 (NF1) predisposes to peripheral nerve tumor development. The progression from a benign plexiform neurofibroma (PNF) towards a deadly malignant peripheral nerve sheath tumor (MPNST) is not completely understood but commonly involves the sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Here we use an iPSC-derived neural crest (NC) model to reproduce this malignant transformation through gene editing. NF1-CDKN2A double-knockout (2KO) NCs form neurofibroma-like tumors in vivo, requiring inactivation of p14ARF and p16INK4a. Additional PRC2 loss (3KO) disrupts pluripotency and induces mesenchymal stem cell-like features. 3KO NCs undergo global chromatin reorganization that prevents gliogenesis by SOX10 silencing and activates neuro-mesenchymal transcriptional programs recapitulating PNF-ANNUBP-MPNST progression. Upon nerve engraftment, 3KO NC spheres form MPNST-like tumors in vivo, mimicking an early-stage MPNST. Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model.

IntroductionTo date, there is no proven licensed systemic treatment for neurofibromatosis type 2 (NF2)-related schwannomatosis patients. There is a need for more effective, less toxic treatments and, as a rare disease, NF2 is often overlooked in targeted drug development. Subcutaneous schwannomas of the skin (CS) are common in the NF2 population.This trial involves the repurposing of medications already licensed for HIV—ritonavir and lopinavir (Kaletra and Norvir)—that have been shown to reduce tumour growth by reducing cell proliferation in human schwannoma and meningioma tumour cell cultures. The safety and tolerability of these drugs are already known, so they are safe candidates to trial in NF2 patients.Methods and analysisThis trial is an open-label, phase 0 design. A maximum of 16 participants diagnosed with NF2-related schwannomatosis will be enrolled in this study. Treatment duration is 30 days, with a 30-day follow-up. Biopsies and blood samples will be collected to assess whether the drugs reach the tumours and to analyse the tumour-cell response. The primary outcome is pharmacodynamic response, defined as a statistically significant decrease in biomarker activity in CS biopsy samples at day 30. The sample size calculation is based on the tissue biomarker response.Ethics and disseminationThe study was approved by an Ethics Committee (West of Scotland Research Ethics Service (23/WS/0178)), the Health Research Authority (HRA), the Medicines and Healthcare products Regulatory Authority (MHRA) and each of the participating NHS Trust’s Research and Development departments. Following analysis of trial data, the trial results will be written up for publication in a peer-reviewed scientific journal and will be disseminated at conferences.Trial registration numberISRCTN10422213.

Neurofibromatosis type1 (NF1) is amultisystem disorder with wide-ranging clinical presentations. Patients with NF1 may manifest with macrocephaly, strokes, and cognitive deficits, abnormal neural development, and other neurologic symptoms. This study used an atlas-based approach to quantitatively examine structural and physiologic changes of the brain in children with NF1. Children evaluated for NF1 over a9-year period at achildren's hospital were retrospectively reviewed (n = 34). Children with intracranial tumors or prior strokes were excluded. Patients received diffusion-weighted imaging (DWI) and arterial spin labeling (ASL) perfusion imaging on a3T MRI scanner. Using an atlas-based approach, quantitative assessment of regional brain volumes, median apparent diffusion coefficient (ADC), and cerebral blood flow (CBF) was performed for the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brainstem, and cerebral white matter. Differences were tested between NF1 patients and 100 typically developing controls. Compared to controls, children with NF1 demonstrated significantly increased volume measurements in all brain regions (p < 0.001), significantly higher median ADC values in all structures except for the putamen and nucleus accumbens (p < 0.001), and significantly lower median CBF most notable in the cerebral white matter (p < 0.001), globus pallidus (p < 0.001), hippocampus (p < 0.001), amygdala (p < 0.001), and brainstem (p = 0.001). This study measured microstructural and physiologic brain changes in children with NF1 compared to typically developing children. Further studies are needed to elucidate the cellular and molecular basis for these differences. With further refinement, atlas-based quantitative MRI brain signatures may serve as useful biomarkers of neural development, cognitive dysfunction, and risks for vasculopathy-related strokes in children with NF1.

Neurofibromatosis type 1 (NF1) is a rare genetic condition characterised by visible symptoms, clinical uncertainty, and psychosocial complexity. The experience of diagnosis often represents a key turning point that shapes personal identity, relationships, and perceptions of the body. However, little is known about how individuals make sense of and emotionally respond to receiving an NF1 diagnosis. This study aimed to explore the cognitive, emotional, and identity-related dimensions of the diagnostic experience among people living with NF1 in Poland. A qualitative study was conducted using semi-structured, in-depth interviews with 93 adults diagnosed with NF1, and the data were analysed using Reflexive Thematic Analysis. The findings indicate that receiving an NF1 diagnosis is not a single clinical event but an evolving identity process shaped by time, personal history, and social context. Participants' reactions to diagnosis varied depending on the diagnostic context and communication process. Four main patterns of response were generated: (1) lack of emotional reaction, relief, and acceptance of the diagnosis; (2) search for knowledge and active engagement with information; (3) denial, minimisation, and emotional distance; and (4) emotional crisis, somatic anxiety, and existential disorientation. The diagnosis also acted as a catalyst for redefining life, the body, and everyday experience, expressed through heightened bodily awareness and a reordering of life priorities, values, and relationships. Together, these themes demonstrate that the NF1 diagnosis functions both as a crisis and a transformative opportunity. It simultaneously confirms embodied experiences and challenges established self-concepts, prompting reflection, self-awareness, and biographical reorientation. The study highlights the importance of timely psychosocial support, empathetic and clear communication, and family-centred care in the diagnostic process. Understanding the emotional and identity-related responses to diagnosis may inform more holistic clinical practices and improve the quality of care for individuals and families affected by NF1.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1). While smaller gliomas may be only monitored, the current standard of care for symptomatic ones relies on chemotherapy, most commonly carboplatin and vincristine. These drugs can achieve tumour control but are associated with significant toxicity and do not generally restore visual function. Selumetinib, a selective MEK inhibitor, has shown efficacy in reducing NF1-related plexiform neurofibromas and has emerged as a promising targeted therapy for NF1-associated low-grade gliomas. To retrospectively evaluate the efficacy and safety of selumetinib in children with NF1-associated progressive OPGs, with attention to radiological and functional visual outcomes. We reviewed three paediatric patients with NF1 and progressive OPGs treated with selumetinib at 25 mg/m2/day. In one case, selumetinib was initiated as second-line after tumour regrowth following chemotherapy; in the other two, it was administered as first-line under compassionate use. Tumour response was assessed by MRI, visual function with serial ophthalmological evaluations. All patients showed radiological tumour shrinkage or stabilization with clinically meaningful improvements in visual acuity. One child achieved near-complete recovery of vision. Treatment was well tolerated: adverse events were mild, predominantly dermatological. No severe systemic toxicities were observed. While rigorous clinical trial data is still emerging, these preliminary cases suggest selumetinib may be a safe and effective therapeutic option for NF1-related OPGs, offering significant tumour control with a favourable toxicity profile compared to chemotherapy. Beyond stabilization, its potential to restore visual function represents a major advance, supporting the potential role of MEK inhibition as a first- and second-line treatment strategy.

This study examined age-specific associations between parent-reported executive function (EF) difficulties and internalizing/externalizing symptoms in children with neurofibromatosis type 1 (NF1), a genetic condition underrepresented in psychiatric research. Cross-sectional data of 1,049 observations from 803 children with NF1 (Mage = 10.58 years, SD = 3.84, range = 3-18; 47.5% female; 67.5% from higher-education households; 36.6% with familial NF1) across nine U.S. and Australian institutions were integrated. Parents rated EF difficulties using the Behavior Rating Inventory of Executive Function and internalizing/externalizing symptoms using the Child Behavior Checklist and the Behavior Assessment System for Children. Time-varying effect modeling estimated age-specific associations between EF and internalizing/externalizing symptoms and tested moderation by sex and parental education. Poorer functioning in all EF domains was associated with greater internalizing and externalizing symptoms from ages 3 to 18. The associations were largely consistent across ages as well as sex and parental education subgroups with a few differences: (1) emotional control and cognitive flexibility problems were more strongly associated with internalizing symptoms during middle and late adolescence; (2) inhibitory control was more strongly linked to externalizing symptoms in childhood; (3) stronger associations between EF and internalizing symptoms were observed among males in early adolescence. Parental complaints of EF difficulties are robustly linked to internalizing and externalizing problems from early childhood to late adolescence in children with NF1. Further longitudinal and experimental studies are needed to determine the directionality of these associations and whether EF represents a viable target for intervention.

Malignant melanoma (MM) uncommonly presents as a solid-cystic soft tissue mass, posing a significant diagnostic challenge. We report a rare case in a 63-year-old woman with neurofibromatosis type 1 (NF-1) who presented with a painful, rapidly progressive swelling on the posterior aspect of her right lower thigh. Imaging revealed a large, well-defined solid-cystic lesion suggestive of a soft tissue sarcoma or malignant peripheral nerve sheath tumor. Initial fine-needle aspiration cytology was nondiagnostic. Definitive diagnosis was achieved following wide surgical excision, with histopathological and immunohistochemical analysis confirming MM (strongly positive for S100, Melan-A, and SOX10). This case highlights that MM must be considered in the differential diagnosis of atypical cystic soft tissue lesions, even in anatomically unexpected locations, especially in patients with predisposing conditions such as NF-1 and affirms the indispensable integration of multimodality imaging with histopathological and immunohistochemical correlation in resolving diagnostically challenging soft tissue masses.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by pigmented lesions, cutaneous neurofibromas, and brain and peripheral nerve tumors. Plexiform neurofibromas (PNs) are congenital tumors whose growth tends to accelerate in the pediatric age. Selumetinib, a MEK1/2 inhibitor, is the first pharmacological treatment that has shown efficacy in reducing the size of PNs by inhibiting their key pathway, with few and moderate adverse events. The purpose of this study is to describe the effect of selumetinib in a large cohort of patients with NF1. This is a prospective case series that describes the patients affected by NF1 with inoperable, symptomatic, or disfiguring PNs treated with selumetinib at the Institute for Maternal and Child Health IRCCS "Burlo Garofolo" in Trieste, from January 2017 to June 2023. To determine the patients' response to selumetinib, we compared the MRI volume of the PN before the beginning of the treatment with the last one available. Twenty-three patients with PNs were treated with selumetinib. During the follow-up period (mean time 1085 days), a tumor reduction above 20% was observed in 13 patients (57%), while 7 subjects (30%) had a tumor stabilization and 3 (13%) had a tumor growth. The median volumetric reduction was 23%. No significant correlations were found between the patients' response to treatment and the other variables considered. No severe adverse events were recorded. In this prospective case series selumetinib appeared to be a useful drug for the treatment of PNs.

Giant skull base collision tumors in neurofibromatosis type 2-related schwannomatosis (NF2-SWN) pose a complex surgical challenge in young patients with lifelong tumor burden. Gross total resection is often impossible without severe neurological morbidity, and data on operative timing and durability are limited. We assessed long-term outcomes of planned, selective resection prioritizing neurological preservation. We queried a prospective institutional database for NF2-SWN patients undergoing surgery for giant (≥ 4.0cm) intracranial skull base collision tumors (≥ 2 neoplasms forming one mass) from January 2009 to December 2025. Surgery targeted symptomatic or high-risk components, accepting residual disease. Outcomes included time to reoperation, overall survival, and functional status. Thirteen patients underwent 31 skull base operations. Mean age at first surgery was 27 years (range 19-42), with mean tumor diameter 5.0cm (range 4.0-7.7cm). Most (69%) had prior surgery and/or radiotherapy. Gross total resection was never achieved. Over mean 9.4-year follow-up, Kaplan-Meier analysis demonstrated reoperation-free survival of 61.5% at 5 years (95% CI, 26.6-83.7%), with a median reoperation-free survival of 6.1 years. The mean interval between reoperations was 4.8 years (median, 3.9 years; IQR, 2.7-5.7; range, 0.8-14.6). Overall survival was 100% at 5 years and 88% at 10 years. At last follow-up, median Karnofsky Performance Status was 70. Planned, selective resection of giant NF2-related skull base collision tumors yielded a median reoperation-free interval of 6.1 years and maintained functional independence in a young, heavily pretreated population, supporting its feasibility as a longitudinal management strategy.

Neurofibromatosis (NF) comprises genetic disorders mainly caused by pathogenic variants, yet its phenotypic and genotypic heterogeneity complicates diagnosis. We analyzed clinical and genomic data from 97 NF patients using targeted panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS) from June 2020 to October 2024. Variants were classified according to established guidelines, and their distribution across protein domains was evaluated using Bayesian multinomial logistic regression. Deep-learning prediction tools and minigene splicing assays were applied to assess variants of uncertain significance (VUS). Sixty-nine variants were identified in NF1, NF2, and LZTR1, including 22 novel ones. In NF1, pathogenic deletions were enriched in non-domain regions, while substitutions predominated in domain regions, though without phenotype-specific associations. Two of three VUS were predicted and experimentally confirmed as pathogenic. One case achieved molecular diagnosis only through WGS after negative WES results. This study expands the mutational landscape of NF genes, underscores the diagnostic advantage of WGS, and demonstrates the effectiveness of advanced predictive and functional tools for VUS interpretation.

The panoramic radiographs (PRs) of 182 patients with confirmed NF1 were examined for MF's position and compared with PRs from 182 healthy individuals who were matched for gender and age (age (years): min: 13; max.: 73; mean: 35; male/female = 79/103). In most cases, the MF was located between the roots of the premolars or below the second premolar in both groups. The distribution pattern of the foramina did not differ between the NF1 groups. There was no tumor effect (PNF) on the topography of the foramen. Most of the PNF-associated mandibular dysplasia probably develop only after perineural ossification of the mandible at the MF and peri-foraminal arrangement of primary tooth germs and precursors of permanent dentition. The PNF-associated, often bizarre deformities of the lower jaw usually manifest distally to the premolar region, where they influence postnatal bone development.

Association of ketotifen use with cutaneous and neural tumor diagnoses in neurofibromatosis type 1.