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Plexiform neurofibromas (PNFs) are benign nerve tumors driven by loss of the NF1 tumor suppressor in Schwann cells. PNFs are rich in immune cells, but whether immune cells are necessary for tumorigenesis is unknown. We show that inhibition of stimulator of interferon gene (STING) reduces plasma CXCL10, tumor T cell and dendritic cell (DC) recruitment, and tumor formation. Further, mice lacking XCR-1+ DCs showed reduced tumor-infiltrating T cells and PNF tumors. Antigen-presenting cells from tumor-bearing mice promoted CD8+ T cell proliferation in vitro, and PNF T cells expressed high levels of CCL5, implicating T cell activation. Notably, tumors and nerve-associated macrophages were absent in Rag1-/-; Nf1f/f; DhhCre mice and adoptive transfer of CD8+ T cells from tumor-bearing mice restored PNF initiation. In this setting, PNF shrunk upon subsequent T cell removal. Thus, STING pathway activation contributes to CD8+ T cell-dependent inflammatory responses required for PNF initiation and maintenance. [ABSTRACT FROM AUTHOR]

Background: Children with Neurofibromatosis 1 (NF1) show cognitive, behavioural and social differences compared to their peers. However, the age and sequence at which these differences begin to emerge is not fully understood. This prospective cohort study examines the cognitive, behavioural, ADHD trait and autism symptom development in infant and pre-school children with NF1 compared with typically developing (TD) children without a family history of neurodevelopmental conditions. Methods: Data from standardised tests was gathered at 5, 10, 14, 24 and 36 months of age (NF1 n = 35, TD n = 29). Developmental trajectories of cognitive (Mullen Scales of Early Learning, MSEL) and adaptive behavioural (Vineland Adaptive Behavior Scales, VABS) development from 5 to 36 months were analysed using linear mixed modelling. Measures of ADHD (Child Behavior Checklist) and autism traits (ADOS-2, BOSA-MV and ADI-R) were assessed at 24 and 36 months. Results: The developmental trajectory of cognitive skills (all domains of the MSEL) and behavioural skills (four domains of the VABS) differed significantly between NF1 and TD groups. Post-hoc tests demonstrated that the NF1 participants scored significantly lower than TD participants at 24 months on all MSEL and VABS domains. The NF1 cohort demonstrated higher mean autism and ADHD traits at 24 months and 14% of the NF1 cohort met a research diagnostic classification for autism at 36 months. Limitations: The study has a relatively small sample size due to variable retention and rolling recruitment. Due to limitations imposed by the COVID-19 pandemic, we utilised the Brief Observation of Symptoms of Autism for Minimally Verbal children (BOSA-MV) for some participants, which was administered online and may not gather as accurate a picture of traits as ADOS-2. The BOSA-MV was utilised for 41% of participants with NF1 at 36 months compared to 11% at 24 months. This may explain the reduction in the percentage of children with NF1 that met autism criteria at 36 months. Conclusions: By 24 months of age, the NF1 cohort show lower cognitive skills and adaptive behaviour and higher levels of autism and ADHD traits as compared to TD children. This has implications for developmental monitoring and referral for early interventions. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF-1) is commonly associated with a variety of rare tumors. However, no case of multiple gastric gastrointestinal stromal tumors (GISTs) or duodenal ampulla neuroendocrine tumors (NETs) with multiple liver metastases in a patient with NF-1 has yet been reported. Here, we describe a case of a 55-year-old female patient with NF-1 whose serum Pro-Gastrin-Releasing Peptide (pro-GRP) levels were elevated. Gastrointestinal endoscopy and biopsy showed duodenal papilla space-occupying mass, and the pathological diagnosis turned out to be neuroendocrine tumors (NETs). During surgical exploration, multiple tumors were found on the serosal surface of the stomach and numerous miliary metastases in the liver. Following histopathological examination, it was determined that the liver metastases were NF-1 and the tumors in the gastric wall were GISTs. The patient benefited from targeted therapy and had an uneventful hospital stay. In this case, we emphasize treating patients with neurofibromatosis type 1 who exhibit abdominal symptoms with a high degree of clinical suspicion and performing thorough evaluations to rule out multiple tumors. [ABSTRACT FROM AUTHOR]

Peripheral nerve sheath tumors encompass a spectrum of well-defined clinicopathologic entities, ranging from benign tumors, such as neurofibromas, to high grade malignant neoplasms termed malignant peripheral nerve sheath tumors. Morphologic variability of these tumors is wide, and they engender some of the most controversial, difficult differential diagnoses. Localized neurofibromas often involve a major nerve and result typically in fusiform expansion of the nerve trunk (intraneural subtype). We report a case of circumscribed solitary neurofibromas in a 14-year-old boy with NF1 who presented to our department with a left neck swelling. The neurofibromas lesion involved the anterior branch of the great auricular nerve. The sensory symptoms initially reported by the patient (paresthesia and hyperesthesia) in the lower preauricular region. Surgical treatment represents the therapeutic method of choice in the approach to neurofibromas, considering functional disorders and possible aesthetic deformities. The case described presented difficulties in surgical excision, based on risk of functional and aesthetic results. [ABSTRACT FROM AUTHOR]

Objective: Neurofibromatosis type 1 (NF1) is a genetic disorder presenting primary with variable patterns of skin pigmentation, neurofibromas and iris Lisch nodules. In addition, likely pathogenic/pathogenic mutations of the NF1 gene predispose to multiple tumors. Juvenile myelomonocytic leukemia (JMML) is also associated with NF1. Molecular diagnosis is important in patients with an atypical presentation, as well as in children who have not yet developed sufficient characteristic features or for providing prenatal diagnosis. The purpose of this study was to define NF1 gene mutations in the northeastern part of Türkiye and to contribute to the mutational spectrum of NF1. In addition, rare findings, such as cerebral vasculopathy and JMML, were discussed over the phenotypic findings. Methods: In this study, NF1 gene sequence analysis was performed using next-generation sequencing in 32 unrelated Turkish patients with a prediagnosis of NF1. Results: Disease-causing variants were found in 68.75% (n=22/32) of the patients, whereas two of them were novel. Our study was also important in the aspect of vasculopathy regarding the frequency which was 9.1% of in a relatively small patient group. Another aspect was the distinct distribution of malignant tumors. In contrast to central nervous system malignancies, which are the most common malignancies apart from malignant peripheral nerve sheath tumors in the literature, JMML was the most common in our study. Conclusion: The aim of this study is to draw attention to rare symptoms, such as vasculopathy and JMML, in NF1 in a small cohort. Although JMML is a rare childhood cancer, it is accompanied by RASopathies. It is important to investigate this association because JMLL treatment approaches change in the presence of germline mutations. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: The landscape of malignant peripheral nerve sheath tumours (MPNSTs) is usually challenging both in terms of recognition and management. Despite a low incidence in the general population (0.001%), MPNST is an important cause of mortality in the neurofibromatosis type 1 (NF1) population. It is essential for a multi-disciplinary collaboration to achieve the best possible outcome. The aim of our paper was to contribute with a comprehensive review from the literature of the best multi-modality ways that show improvements in terms of survival and address potential future treatment approaches based on the molecular alterations seen in these tumours. Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that have nerve sheath differentiation and can present at any anatomical site. They can arise from precursor neurofibroma in the context of neurofibromatosis type 1 (NF1) or as de novo and sporadic tumours in the absence of an underlying genetic predisposition. The primary therapeutic approach is most often radical surgery, with non-surgical modalities playing an important role, especially in locally advanced or metastatic cases. The aim of multimodality approaches is to optimize both local and systemic control while keeping to a minimum acute and late treatment morbidity. Advances in the understanding of the underlying biology of MPNSTs in both sporadic and NF-1-related contexts are essential for the management and implementation of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is associated with below average writing achievement. However, little is known about specific aspects of written language impacted by NF1, changes in writing over time, and associations between cognitive aspects of the NF1 phenotype and writing. At three timepoints over six years, children with NF1 and plexiform neurofibromas (PNs) completed Woodcock-Johnson tests of writing mechanics (Spelling, Punctuation & Capitalization, handwriting), written expression of ideas (Writing Samples), writing speed (Writing Fluency), and tests of general cognitive ability, executive function, memory, and attention. Children (N = 76, mean age = 12.8 ± 3.4 years) completed at least one baseline writing subtest. Overall writing scores were in the Average range (M = 93.4, SD = 17.4), but lower than population norms (p = 0.002). Scores were highest on Writing Samples (M = 95.2, SD = 17.3), and lowest for Punctuation & Capitalization (M = 87.9, SD = 18.8, p = 0.034). Writing scores were mostly stable over time. Nonverbal reasoning was related to some tests of writing mechanics and written expression of ideas. Short-term memory and inattention explained additional variance in Writing Samples and Spelling. Poor handwriting was associated with writing content beyond the impact of cognitive factors. Children with NF1 and PNs may benefit from early screening and writing support. Interventions should address the contribution of both cognitive and handwriting difficulties in written language. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is the most common human genetic disease. In these patients, the incidence of malignant peripheral nerve sheath tumors (MPNST) and gastrointestinal stromal tumors (GIST) is increased. A male patient in his forties with neurofibromatosis 1, presented with the coexistence of multiple GISTs located at intestinal and colonic mesentery, MPNST located at his leg and atypical neurofibromatous neoplasm with uncertain biologic potential located at colonic mesentery. By FISH, the MPNST harbored CDKN2A loss and recurred 1 year later. After reresection and radiotherapy, the patient is now disease-free without evidence of disease. Atypical neurofibromatous neoplasm with uncertain biologic potential is a newly defined entity, and it is important to discriminate it from low-grade MPNST, which requires more aggressive treatment methods. To the best of our knowledge, this is the first report describing synchronous GISTs, MPNST, and atypical neurofibromatous neoplasm with uncertain biologic potential developing in a single NF1 patient. [ABSTRACT FROM AUTHOR]

Background Selumetinib is the first approved treatment for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) in the EU and US, as well as in multiple other countries. Evidence for the management of selumetinib-associated adverse events (AEs) is mostly limited to clinical trials and expanded-access programs. We gathered a panel of European healthcare practitioners with clinical experience prescribing selumetinib and/or managing pediatric patients with NF1-PN to provide recommendations on the prevention and management of AEs. Methods A modified Delphi approach was used to develop the recommendations among the group of experts. Initial statements were developed from a literature review of current management recommendations and regulatory reports. The panel refined the statements and rated the extent to which they agreed with them in 2 sessions and a follow-up survey. The panel comprised 2 pediatric neuro-oncologists, 1 pediatric oncologist, 1 pediatrician, 1 neuropediatrician, 1 oncologist, 1 neurologist, 2 psychologists, and 1 dermatologist. Results The experts agreed on the relative frequency and impact of AEs potentially associated with selumetinib. Consensus-level agreement was reached for 36 statements regarding the prevention and management of AEs potentially associated with selumetinib. Experts recommended treatments for AEs based on their experience. Conclusions The development of a variety of consensus statements indicates expert agreement on best practices for the prevention and management of AEs potentially associated with selumetinib in pediatric patients with NF1-PN. These events are generally manageable and should be considered alongside treatment benefit. Information sharing is warranted as further experience is gained. [ABSTRACT FROM AUTHOR]

Hearing loss has not been thoroughly investigated as a comorbidity in larger cohorts with neurofibromatosis type 1 (NF1). Available audiometric data were reviewed from patients with NF1 seen at a tertiary pediatric hospital to assess prevalence and risk factors for hearing loss. Of 1172 patients with NF1 seen between 2010 and 2022, 90 had available audiometric data and 48 of 90 patients (53%) had one or more audiogram revealing hearing loss. Those not referred to audiology were presumed to have normal hearing, resulting in a conservative hearing loss estimate of 4% for children and young adults with NF1. Of 90 patients with audiograms, 29 (32%) had conductive loss (CHL), 15 (17%) had sensorineural loss (SNHL), and 3 (3%) had mixed hearing loss. Hearing loss type was undetermined for one patient. For children with CHL, six had permanent CHL secondary to plexiform neurofibroma, 19 CHL were transient due to active middle ear dysfunction, and four CHL cases were indeterminate in etiology. For three children with SNHL or mixed hearing loss, etiology included history of ototoxic chemotherapy and/or family history of SNHL. In the 16 patients with SNHL or mixed hearing loss with more than one audiogram over time, progressive hearing decline was noted in eight of 16, and 26 of 178 hearing thresholds (15%) progressed. Our findings suggest that audiometric evaluations should be considered for at least a subset of children with NF1, given the higher-than-expected rate of hearing loss in patients with NF1 compared with the general population. [ABSTRACT FROM AUTHOR]

Understanding drug behavior within the skin, especially for photosensitive compounds, is crucial for developing effective and safe topical therapies. This study employs Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) to investigate the skin permeation and photostability of selumetinib, a MEK inhibitor used in treating type 1 neurofibromatosis (NF1). The highest amounts of selumetinib in the skin sections were obtained when using the gel formulation, suggesting that it is to be preferred to cream formulations to achieve higher permeation of the drug. Our study also revealed that selumetinib is amenable to photodegradation in ex vivo skin explants, and yields one main degradation product, whose degradation is likely triggered by hydrogen abstraction. MALDI-MSI results showed selumetinib and its degradation product concentrate in skin appendages, indicating these structures might serve as drug reservoirs, potentially prolonging retention and efficacy. This study demonstrates that combining MALDI-MSI with LC/MS-MS can highly contribute to the characterization of the fate of photosensitive compounds in the skin, an essential prerequisite to the development of compound-specific photoprotective measures. It will also pave the way for innovative topical delivery strategies for NF1 treatment. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder that commonly involves skin, nerves, and skeletal system with increased neoplastic predisposition. This disease has been rarely associated with multiple congenital anomalies. Herein, we describe an Egyptian child with NF1 and coexistent bilateral congenital glaucoma, giant congenital melanocytic nevi (GCMN), alopecia, and hypospadias. Case presentation: A 2.5-year-old boy presented with developmental delay, back swelling, and multiple congenital anomalies. His father and two sisters were known to have NF1. The child was diagnosed with bilateral primary congenital glaucoma at the age of 3.5 months and underwent trabeculectomy with mitomycin C therapy. Examination at the age of 5 months revealed marked hypotonia, multiple GCMN, scanty café-au-lait macules, left upper eyelid plexiform neuroma and trichomegaly, hypertrichosis of left eyebrow, hypertelorism, depressed nasal bridge, left frontal scalp alopecia, and distal penile hypospadias. At the age of 8 months, brain imaging depicted a markedly dilated left lateral ventricle, and he underwent ventriculoperitoneal shunt surgery. The child developed back swelling at the age of 2.5 years, and a spinal magnetic resonance image showed bilateral multiple spinal neurofibromas in the paraspinal region with intraspinal extensions. A whole exome sequencing identified a heterozygous missense variant NM_001042492.3:c.1466A > G (NP_001035957.1:p.Tyr489Cys) in NF1 gene. Conclusions: The present case report adds to the knowledge of the phenotypic spectrum and variability of NF1 by reporting the association of multiple unusual congenital anomalies. Importantly, such congenital anomalies could be the first presenting features in patients with NF1 since cafe´-au-lait macules and other typical diagnostic criteria may not be apparent in the neonatal period and early infancy. Accordingly, NF1 should be considered in newborns with congenital glaucoma, GCMN, scalp alopecia, and hypospadias. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that caused by NF1 mutations. NF1 gene encodes neurofibromin (a GTPase‐activating protein) and plays a regulatory role in many signalling pathway such as the Ras/MAPK pathway, which is important for regulating cell growth, proliferation and neural development. Therefore, NF1 gene mutations causes the excessive activation of signalling pathways and uncontrolled cell growth. NF1 exhibits complete genetic penetrance and clinical heterogeneity. Glomerular disease has rarely been reported in patients with NF1, especially in children. Currently, the relationship between NF1 and nephrotic syndrome is unclear. Here, we present a case of NF1 with nephrotic syndrome and further explore the association between NF1 and glomerular diseases. It also reminds clinicians that NF1 has complex and highly variable clinical manifestations and that a comprehensive workup is essential for patients. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the leucine zipper-like transcriptional regulator 1 gene (LZTR1) have been identified in schwannomatosis and Noonan syndrome. Here, we expand the phenotype spectrum of LZTR1 variants. We identified four loss-of-function heterozygous LZTR1 variants in five children with multiple café au lait macules and one adult with multiple café au lait macules and axillar freckling, by applying gene panel analysis in four families. The three LZTR1 variants, namely, c.184del/p.Glu62Serfs*39, c.1927C < T/p.Gln643*, and c.857_858delinsT/p. Gly286Valfs*65, were novel, whereas the variant c.1018C > T/p.Arg340* had been previously reported in a patient with schwannomatosis. Similar to what is known from other LZTR1-associated conditions, penetrance of the skin manifestations was reduced in two carriers of the familial variants. Our study expands the LZTR1 phenotype to the presence of isolated café au lait macules with or without freckling. Thus, variants in the LZTR1 gene should be considered in patients with multiple café au lait macules. [ABSTRACT FROM AUTHOR]

This study compared the thickness of each intraretinal layer in patients with neurofibromatosis 1 (NF1) and controls to analyze the association between intraretinal layer thickness and visual function. The macular spectral-domain optical coherence tomography volumetric dataset obtained from 68 eyes (25 adult eyes, 43 pediatric eyes) with NF1 without optic glioma and 143 control eyes (100 adult eyes, 43 pediatric eyes) was used for image auto-segmentation. The intraretinal layers segmented from the volumetric data included the macular retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, outer plexiform layer, outer nuclear layer, and photoreceptor layer. Cases and controls were compared after adjusting for age, sex, refractive error, and binocular use. The association between retinal layer thickness and visual acuity was also analyzed. The GCIPL was significantly thinner in both adult and pediatric patients with NF1 compared with healthy controls. Average RNFL and GCIPL thicknesses were associated with visual acuity in adult patients with NF1. In pediatric patients, average GCIPL thickness was associated with visual acuity. These results suggest that changes in the inner retinal layer could be a biomarker of the structural and functional status of patients with NF1. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1), an autosomal dominant disorder, characterized by a spectrum of diverse neurocutaneous manifestations, is caused by heterozygous pathogenic variants in NF1 gene. While patients with NF1 often exhibit characteristic features, atypical phenotypes can arise, necessitating consideration of differential diagnoses or concurrent pathologies. Case presentation: A seven-year-old boy with suspected NF1 underwent clinical evaluation. He presented hallmark café-au-lait spots, axillary freckling, and neurofibromas. Neuroimaging revealed a cranial plexiform neurofibroma. Additionally, he exhibited attention-deficit hyperactivity disorder and developmental delay. Genetic testing identified an Alu insertion variant within the NF1 gene, and subsequent array comparative genomic hybridization detected a 16p13.11 duplication. Conclusions: This case underscores the intricate molecular bases of NF1 by identifying a rare Alu insertion variant. The patient's neurocognitive challenges and dysmorphic features prompted exploration of a potential overlapping genetic condition. Coexisting genetic disorders have been documented in NF1 patients, emphasizing the necessity of discerning atypical manifestations. The observed 16p13.11 duplication likely contributes to the patient's phenotype, enhancing the precision of diagnosis, prognosis, and genetic counseling. [ABSTRACT FROM AUTHOR]

Approximately 40% of pheochromocytoma and paraganglioma (PPGL) cases are familial, typically presenting earlier with more complex symptoms. This paper synthesizes literature and guidelines to inform on clinical characteristics and perioperative care for PPGL. Pheochromocytoma in von Hippel-Lindau (VHL) disease exhibits heightened secretion activity without significant perioperative hemodynamic changes. Tumors in multiple endocrine neoplasia type 2 (MEN2) have a stronger endocrine function, which may induce hemodynamic fluctuations during surgery. Therefore, pheochromocytoma screening is essential at all stages of MEN2. Neurofibromatosis type 1 (NF1) often presents multisystem lesions and can result in difficult airway. Pheochromocytoma should be evaluated when NF1 patients present hypertension. Pheochromocytoma and paraganglioma type 5 may present multiple lesions of pheochromocytoma or paraganglioma. In summary, hereditary PPGLs may present with severe lesions in other systems, beyond tumor function. A multi-disciplinary team (MDT) approach is often invaluable in perioperative management. [ABSTRACT FROM AUTHOR]

Background: Cutaneous neurofibromas (cNFs) are a major cause of disfigurement in patients with Neurofibromatosis Type 1 (NF1). However, clinical trials investigating cNF treatments lack standardised outcome measures to objectively evaluate changes in cNF size and appearance. 3D imaging has been proposed as an objective standardised outcome measure however various systems exist with different features that affect useability in clinical settings. The aim of this study was to compare the accuracy, precision, feasibility, reliability and accessibility of three imaging systems. Materials and methods: We compared the Vectra‐H1, LifeViz‐Micro and Cherry‐Imaging systems. A total of 58 cNFs from 13 participants with NF1 were selected for imaging and analysis. The primary endpoint was accuracy as measured by comparison of measurements between imaging systems. Secondary endpoints included reliability between two operators, precision as measured with the average coefficient of variation, feasibility as determined by time to capture and analyse an image and accessibility as determined by cost. Results: There was no significant difference in accuracy between the three devices for length or surface area measurements (p > 0.05), and reliability and precision were similar. Volume measurements demonstrated the most variability compared to other measurements; LifeViz‐Micro demonstrated the least measurement variability for surface area and image capture and analysis were fastest with LifeViz‐Micro. LifeViz‐Micro was better for imaging smaller number of cNFs (1–3), Vectra‐H1 better for larger areas and Cherry for uneven surfaces. Conclusions: All systems demonstrated excellent reliability but possess distinct advantages and limitations. Surface area is the most consistent and reliable parameter for measuring cNF size in clinical trials. [ABSTRACT FROM AUTHOR]

Backgrounds: Giant neurofibromas occurring in individuals diagnosed with neurofibromatosis type 1 (NF1) often result in considerable disfigurement, functional impairment, and diminished quality of life. Although debulking surgery poses inherent risks of complications, it remains the most efficacious approach to address these issues. The primary objective of this study was to share our surgical experience with giant neurofibromas in the extremities and trunk wall of NF1 patients which may help surgeons to minimize intraoperative bleeding and facilitate tumor excision. Methods: A retrospective review was conducted at a single center, encompassing 36 NF1 patients with giant neurofibromas in the extremities and trunk wall who underwent debulking surgery from July 2010 to July 2022. Results: Twenty‐one male and fifteen female NF1 patients who received one to four surgical interventions were evaluated. The average age at the time of surgery was 17.8 years. The median follow‐up time was 52 months. Our findings revealed relatively low rates of complications and recurrence. Notably, patients expressed satisfaction with both the aesthetic and functional results. Conclusions: Debulking surgery of giant neurofibromas in the extremities and trunk wall of NF1 patients can effectively reduce the tumor burden, leading to improvements in both the appearance and function. [ABSTRACT FROM AUTHOR]

Objective Elevated rates of social difficulties are evident for children and adolescents with neurofibromatosis type 1 (NF1) but the effects of social skills interventions have not been investigated for this population. The Program for the Education and Enrichment of Relational Skills (PEERS®), a widely established social skills intervention in autism spectrum disorders with expansion to other conditions, was recently modified to be offered virtually. This study examined the feasibility and acceptability of this telehealth intervention. Methods 27 adolescents with NF1 with social skills difficulties and at least 1 caregiver enrolled in the study. 19 of those participants (M age = 14.21 years, SD  =   1.63; 7 females; 79% White) completed PEERS® via telehealth in a single-arm pilot study. Dropout rates, attendance records, helpfulness of the curriculum topics and caregiver-reported acceptability, including ratings on the Treatment Acceptability Questionnaire, were examined. Results Low study drop out (30% of enrolled participants; 14% of participants who began the intervention) and high attendance rates were observed. Caregivers found sessions related to common, everyday interactions most helpful. Adolescents indicated sessions related to having get-togethers and social nuances (e.g. humor) as most helpful. Caregiver ratings indicated acceptability of the intervention. Conclusions This investigation supported the feasibility and acceptability of telehealth PEERS®, a social skills intervention program, among adolescents with NF1 and their caregivers based on attendance patterns as well as appraisal of the curriculum and telehealth modality. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the NF1 gene. Patients harboring these mutations are predisposed to a spectrum of peripheral nerve sheath tumors (PNSTs) originating from Schwann cells, of which malignant peripheral nerve sheath tumors (MPNSTs) are the deadliest, with limited treatment options. Therefore, an unmet need still exists for more effective therapies directed at these aggressive malignancies. Cold atmospheric plasma (CAP) is a reactive oxygen species (ROS) and reactive nitrogen species (RNS) generating ionized gas that has been proposed to be a potential therapeutic modality for cancer. In this study, we sought to determine the effects of CAP on NF1-associated PNSTs. Utilizing established mouse and human cell lines to interrogate the effects of CAP in both in vitro and in vivo settings, we found that NF1-associated PNSTs were highly sensitive to CAP exposure, resulting in cell death. To our knowledge, this is the first application of CAP to NF1-associated PNSTs and provides a unique opportunity to study the complex biology of NF1-associated tumors. [ABSTRACT FROM AUTHOR]

Background: An internal thoracic artery aneurysm (ITAA) is an exceedingly rare condition, with approximately two-thirds of reported cases being iatrogenic pseudoaneurysms. The remainder are attributed to various causes, including vasculitis, connective tissue disease, and neurofibromatosis type 1 (NF-1). NF-1 is an autosomal dominant disorder characterized by distinct clinical manifestations that occasionally include life-threatening vascular complications. Although NF-1 patients may develop various vascular abnormalities, ruptured ITAA is rarely reported, with only seven published cases. Case presentation: A 32-year-old man with NF-1 consulted for a three-day history of persistent left back and upper arm pain. Initial chest radiography indicated left pleural effusion and an opacity at the left lung apex. Computed tomography scan revealed a mass in the left upper mediastinum that was initially suspected to be a tumor. Subsequent contrast-enhanced computed tomography revealed the mass to be a subclavian artery aneurysm. Detailed contrast-enhanced computed tomography with 1-mm slices was performed for surgical planning, identifying the mass as a left ITAA with contained rupture. Given the risk of re-rupture, emergency angiography was performed, which confirmed rupture of the left ITAA without extravasation. The ITAA was successfully treated with multiple microcoils at the proximal and distal ends. The patient had an uneventful recovery and was discharged on the fourth postoperative day. Conclusions: This case highlights the importance of considering vascular lesions in NF-1 patients who present with pleural effusion. It also emphasizes the challenges in diagnosing ITAA and the effectiveness of thin-slice contrast-enhanced computed tomography scans and endovascular treatment. [ABSTRACT FROM AUTHOR]

Tunlametinib (科露平®) is an oral, selective, mitogen-activated protein kinase kinase 1 and 2 (MEK 1/2) inhibitor being developed by Shanghai KeChow Pharma, Inc. for the treatment of solid tumours with RAS and RAF mutations, including melanoma, non-small cell cancer (NSCLC), colorectal cancer (CRC) and neurofibromatosis type 1 (NF1) plexiform neurofibromas. In March 2024, tunlametinib was granted conditional approval in China (based on surrogate endpoints) for use in patients with NRAS-mutated advanced melanoma who have failed anti-PD-1/PD-L1 treatment. This article summarizes the milestones in the development of tunlametinib leading to this first approval for the treatment of solid tumours with RAS and RAF mutations. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen‐activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1‐deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1‐deficient Drosophila cells. When further investigating autophagy‐related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1‐deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1‐deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1‐deficient cell viability. In conclusion, NF1‐deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1‐associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors. [ABSTRACT FROM AUTHOR]

Neurofibromatosis Type 1 (NF1) is a complex genetic disorder characterized by the development of benign neurofibromas, which can cause significant morbidity in affected individuals. While the molecular mechanisms underlying NF1 pathogenesis have been extensively studied, the development of effective therapeutic strategies remains a challenge. This paper presents the development and validation of a novel biomaterial testing model to enhance our understanding of NF1 pathophysiology, disease mechanisms and evaluate potential therapeutic interventions. Our long-term goal is to develop an invitro model of NF1 to evaluate drug targets. We have developed an in vitro system to test the cellular behavior of NF1 patient derived cells on electroconductive aligned nanofibrous biomaterials with electrical stimulatory cues. We hypothesized that cells cultured on electroconductive biomaterial will undergo morphological changes and variations in cell proliferation that could be further enhanced with the combination of exogenous electrical stimulation (ES). In this study, we developed electrospun Hyaluronic Acid–Carbon Nanotube (HA-CNT) nanofiber scaffolds to mimic the axon's topographical and bioelectrical cues that influence neurofibroma growth and development. The cellular behavior was qualitatively and quantitively analyzed through immunofluorescent stains, Alamar blue assays and ELISA assays. Schwann cells from NF1 patients appear to have lost their ability to respond to electrical stimulation in the development and regeneration range, which was seen through changes in morphology, proliferation and NGF release. Without stimulation, the conductive material enhances NF1 SC behavior. Wild-type SC respond to electrical stimulation with increased cell proliferation and NGF release. Using this system, we can better understand the interaction between axons and SC that lead to tumor formation, homeostasis and regeneration. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis 1 is a form of phacomatosis or neurocutaneous disease inherited as an autosomal dominant disease. Thoracic involvement is rare and involves the lung parenchyma, mediastinum, and thoracic cage, including ribs and the spine. Lung parenchymal involvement includes airspace abnormalities like cysts, bullae, and emphysema with an upper lobe predominance and interstitial abnormality in the form of reticulations and fibrosis in the lower lobes. The structural abnormality of the lung resembles numerous other diseases. Hence, properly identifying and recognizing neurofibromatosis 1-associated diffuse lung disease (NF-1 DLD) is crucial in avoiding misdiagnosis. NF1-DLD is associated with many complications like pulmonary hypertension, lung malignancy, aspergilloma, secondary bacterial infections, and pneumothorax. Case presentation: An elderly male with neurofibromatosis type-1 presented with breathlessness, cough, and mucopurulent expectoration and was found to have diffuse involvement of the lung parenchyma involving cysts, bullae, emphysema, fibrosis, and traction bronchiectasis. He was managed conservatively, controlling infection and optimizing respiratory symptoms. Conclusion: Neurofibromatosis-associated diffuse lung disease is a rare disorder. There is no definitive treatment that can reverse the pulmonary lesions. However, early diagnosis will help plan effective preventive measures and avoid complications. We present this case to increase awareness regarding the various pulmonary manifestations of neurofibromatosis. [ABSTRACT FROM AUTHOR]

Introduction: Neurofibromatosis type 1 (NF type 1) is an autosomal dominant disease with typical clinical manifestations, such as skin lesions, Lisch nodules, optic pathway gliomas, and neurofibromas, caused by the mutation of the NF1 gene. Visual evoked potentials (VEP) present a measure of the electrophysiological response of visual cortex to a visual stimulus. The role of VEP in the pathophysiology of NF type 1 is very complex and requires additional research. The Aim: We examined the differences between NF type 1 patients with normal and altered VEP and analyzed the correlation between the prolongation of P100 latency and disease severity. Materials and Methods: Two groups were formed: a control group and a study group with NF type 1 patients. Based on the control group analysis, a threshold value for a normal VEP finding of 116 ms was obtained, and it was used to divide the study group into subgroups with normal and altered VEP. We proceeded with examining the differences in clinical manifestations of the disease between the subgroups, after which we checked if there is a correlation between the prolongation of the P100 latency and the severity of the clinical picture according to the Riccardi scale. Statistical analysis was performed using the Pearson chi-square test and the Spearman correlation test in the program SPSS 28.0, with levels of statistical significance p = 0.05 and p = 0.001. Results: In the group with the abnormal VEP we found a statistically significant more frequent occurrence of optic tract glioma (p = 0.008), tumors (p = 0.032), epilepsy (p = 0.043), and cognitive disorders (p = 0.028), while the other clinical signs had an equal prevalence in both groups. A moderately strong correlation (rs = 0.665) was observed between the prolongation of P100 latency and the severity of the clinical picture. Conclusion: Our results showed the important role of VEP in the description of clinical phenotypes of NF type 1. The authors of the study propose VEP to be included in the diagnostic algorithms designed for patients with NF type 1. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor. Individuals with neurofibromatosis type 1 (NF1) have an increased risk of developing GBM. We present a case report of a 44-year-old male with NF1 who developed GBM. NF1-associated GBM presents distinct molecular features and younger age at diagnosis compared to sporadic cases. Treatment typically follows standard protocols for GBM. Despite advancements in neuro-oncology, gaps in knowledge persist regarding NF1-associated GBM, including its prevalence, molecular mechanisms, and optimal treatment strategies. Larger studies and collaborative efforts are needed to address these gaps and enhance patient care. [ABSTRACT FROM AUTHOR]

Plexiform neurofibroma (PF) is a rare benign variant belonging to a subtype of neurofibromatosis type 1 that forms bulging or deforming masses arising from the peripheral nerve sheath. These masses involve surrounding connective tissue or dermal layers, leading to multiple cutaneous changes and certain characteristic appearances. It is these appearances that aid in the diagnosis of PF. We have encountered two distinct patients diagnosed with this disorder. While one patient was clinically and pathologically confirmed for PF, the other had no characteristic cutaneous changes. The diagnosis was made with postoperative histopathology and confirmed with an immunohistochemical examination. There are various modalities in the management of PFs, with surgery being a mainstay in the treatment of disfiguring large PFs, especially in resource-restrained settings. In view of high recurrence rates, postoperative clinical follow-up is a must. This paper describes these patients' typical and atypical clinical presentation and subsequent management. [ABSTRACT FROM AUTHOR]