A successful combined spinal-epidural anesthesia for cesarean section in a patient with neurofibromatosis type 1-associated dural ectasia.

BACKGROUND: Dural ectasia is a common manifestation of neurofibromatosis type 1. Although there have been reports of unsuccessful spinal anesthesia due to dual ectasia in Marfan syndrome, reports describing similar unsuccessful spinal anesthesia in neurofibromatosis type 1 are lacking. CASE PRESENTATION: A parturient with neurofibromatosis type 1 was scheduled for a repeat cesarean section. During a previous cesarean section, she had experienced a failed spinal anesthesia, which resulted in a conversion to general anesthesia. Preoperative lumbar magnetic resonance imaging revealed dural ectasia, which was speculated to be the cause of the previous spinal anesthesia failure. Therefore, combined spinal-epidural anesthesia was implemented. Because the block level of spinal anesthesia was insufficient as predicted, supplemental administration of epidural anesthesia successfully provided adequate analgesia for the surgery. CONCLUSIONS: Combined spinal-epidural anesthesia can be useful for the management of cesarean sections in patients with neurofibromatosis type 1-associated dural ectasia.

Recurrence of spinal schwannomas in a patient with neurofibromatosis type 1: a case report.

Introduction and importance: Spinal schwannomas are benign tumors usually attached to peripheral nerves, consisting of a clonal population of Schwann cells. Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder that predominantly affects the skin, bone and nervous system. Neurofibromatosis type 1 is a clinically and genetically distinct from neurofibromatosis type 2. This case report highlights the rare association between spinal schwannoma and neurofibromatosis type 1. Case presentation: The patient with a past medical history of spinal schwannoma, operated 1 year back, presented with back pain, weakness of lower limbs and urge incontinence. On examination, she had cutaneous features suggestive of neurofibromatosis type 1 and there was impairment of all sensory modalities below hip region. MRI revealed spinal schwannoma at D9 level for which laminectomy with removal of schwannoma was performed. Clinical discussion: The occurrence and recurrence of spinal schwannoma in neurofibromatosis type 2 is a common finding. But such an association has not been established between spinal schwannoma and neurofibromatosis type 1. In this case, the recurrence of spinal schwannoma has been linked to neurofibromatosis type 1 in the absence of other well-defined etiologies. Conclusion: The occurrence of spinal schwannoma can be genetic or sporadic. The recurrence is usually associated with familial tumor syndrome. The available literature has not established association between neurofibromatosis type 1 and spinal schwannoma, thus, emphasizing the need of more focused studies.

A Rare Case of Malignant Triton Tumor Without Associated Neurofibromatosis.

This paper describes a rare case of malignant triton tumor (MTT), a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, that occurred in a 21-year-old male with no concomitant clinical signs of neurofibromatosis. Although total surgical excision is ideal, the high recurrence rate and distant metastases frequently result in a poor prognosis. A biopsy, in this case, revealed spindle cells organized in short fascicles, with minor anisonucleosis and cross-striations indicating rhabdomyomatous differentiation. Positive immunohistochemistry for epithelial membrane antigen (EMA), Desmin, and S100 markers validated the diagnosis. For further treatment, the patient was referred to a cancer center. Even without clinical signs of neurofibromatosis type 1 (NF-1), the research emphasizes the need to evaluate MTTs as a differential diagnosis for individuals presenting with tumors in the head and neck area. Histopathology and immunohistochemistry are useful diagnostic techniques, and early intervention with surgical excision may enhance the outcome. The paper concludes with a review of the histological criteria needed to establish the diagnosis of MTT and the distinctions between sporadic and NF-1-associated tumors.

Vascular Abnormalities and Neurofibromatosis Type 1: A Paediatric Case Series.

Neurofibromatosis type 1 (NF1) is a multisystemic neurocutaneous disease caused by a heterozygous mutation of the NF1 gene that encodes neurofibromin. Complications include vascular and neurologic abnormalities such as moyamoya syndrome, a cerebrovascular disorder with progressive occlusion of the large intracranial arteries, leading to ischemic events and the formation of abnormal vascular networks. Stenosis of the renal artery is another frequent complication of neurofibromatosis type 1, and it represents the most common cause of secondary hypertension in these patients. The purpose of the article is to describe the clinical manifestations of neurofibromatosis type 1 vasculopathy in 4 patients presenting with a wide range of neurologic and reno-vascular manifestations, as well as to examine current diagnostic management and follow-up, current therapeutic options, and to discuss further perspectives in terms of screening, diagnosis, and treatment.

Social Communication in Ras Pathway Disorders: A Comprehensive Review from Genetics to Behavior in Neurofibromatosis Type 1 and Noonan Syndrome.

Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are neurogenetic syndromes caused by pathogenetic variants encoding components of the Ras-ERK-MAPK signaling pathway (Ras pathway). NF1 and NS are associated with differences in social communication and related neuropsychiatric risks. During the last decade, there has been growing interest in Ras-linked syndromes as models to understand social communication deficits and autism spectrum disorders. We systematically review the literature between 2010-2023 focusing on the social communication construct of the RDoC framework. We provide an integrative summary of the research on facial and non-facial social communication processes in NF1 and NS across molecular, cellular, neural circuitry, and behavioral domains. At the molecular and cellular levels, dysregulation in the Ras pathway is intricately tied to variations in social communication through changes in GABAergic, glutamatergic, and serotonergic transmission, as well as inhibitory/excitatory imbalance. Neural circuitry typically associated with learning, attention, and memory in NF1 and NS (e.g., cortico-striatal connectivity), is also implicated in social communication. We highlight less researched, potential mechanisms for social communication, such as white matter connectivity and the default mode network. Finally, key gaps in NF1 and NS literature are identified and a roadmap for future research is provided. By leveraging genetic syndromes research, we can understand the mechanisms associated with behaviors and psychiatric disorders.

T2Hs in Children with Neurofibromatosis type 1.

OBJECTIVE: Areas of increased signal intensity, known as T2 hyperintensities (T2Hs), observed on T2-weighted magnetic resonance imaging (MRI) scans, are linked to a spectrum of brain abnormalities in children with neurofibromatosis type 1 (NF1). Defining the radiological characteristics that distinguish non-neoplastic from neoplastic T2Hs in children with NF1 is crucial. Then, we could identify lesions that most likely to require oncologic surveillance. METHODS: We conducted a single-center retrospective review of all available brain MRIs from 98 children with NF1 and 50 healthy pediatric controls. All T2Hs identified on MRI were characterized based on location, imaging features, presence of lesion related symptoms. Subsequently, all T2Hs were classified using newly established criteria and categorized into three distinct groups: low-risk tumor lesions, medium-risk tumor lesions, and high-risk tumor lesions. Lesions deemed to be high-risk will be recommended for surgical treatment. RESULTS: T2Hs were present in 61 (62.2%) individuals of the NF1 cohort. T2Hs were a highly sensitive (100%; 95% confidence interval [CI] 92.9%-100.0%) and specific (62.2%; 95% CI 51.9%-71.8%) marker for the diagnosis of NF1. In children aged 4-10, the detection rate of T2Hs is significantly higher than in children under 4 years old and those aged between 10 and 18(P<0.05). T2Hs were most frequently located in basal ganglia, cerebellar hemispheres, and brainstem. During the follow-up process, none of lesions categorized as low-risk or medium-risk tumor lesions progressed to high-risk tumor lesions. Seven patients had high-risk tumor lesions and underwent surgical treatment.The pathological assessment identified 5 cases of glioma among the 7 patients, along with 1 case of gliosis and 1 case of vascular dysplasia. CONCLUSIONS: Low-risk and medium-risk tumor lesions can both be classified as unidentified bright objects(UBOs).UBOs constituted the majority of T2Hs in children with NF1. High-risk tumor lesions should be considered as probable tumors.With the application of standardized radiologic criteria, a high prevalence of probable brain tumors will be identified in this at-risk population of children, which underscores the importance of vigilant and appropriate oncological surveillance to ensure timely detection and intervention for these tumors.

Fungiform Papillae and Gustatory Function in Neurofibromatosis Type 1: A Case-Control Study.

OBJECTIVE: Fungiform papillae enlargement is a common oral manifestation of neurofibromatosis type 1 (NF1). This study aimed to objectively evaluate the size, number, and symmetry of fungiform papillae in NF1 individuals and investigate the relationship between these alterations and taste perception, salivary flow, dietary habits, and BMI. MATERIALS AND METHODS: A cross-sectional case-control study was conducted on 80 participants (40 with NF1 and 40 controls), matched by age and sex. Participants underwent quantitative and morphological evaluation of fungiform papillae, gustatory perception tests, sialometry, saliva analysis, xerostomia assessment, dietary assessments, and Body Mass Index calculations. RESULTS: The NF1 group exhibited significantly larger and more asymmetric fungiform papillae and exhibited a higher detection threshold for sweet and sour tastes, as well as hyposalivation and lower preference for healthy foods compared to the controls. No correlation was found between papillae morphology, gustatory perception tests, saliva properties, xerostomia, food preferences, or BMI in the NF1 group. CONCLUSIONS: Enlarged and asymmetric fungiform papillae, hyposalivation, heightened sensitivity to sweet and sour tastes, and reduced healthy eating habits were common in NF1. Although fungiform papillae alterations seem unrelated to taste sensitivity and food preferences, further investigation is needed to better understand the mechanisms underlying these changes.

Autism Spectrum Disorder Symptom Profiles in Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex and Neurofibromatosis Type 1.

Studying Autism Spectrum Disorder (ASD) heterogeneity in biologically homogeneous samples may increase our knowledge of ASD etiology. Fragile X syndrome (FXS), Angelman syndrome (AS), Tuberous Sclerosis Complex (TSC), and Neurofibromatosis type 1 (NF1) are monogenic disorders with high a prevalence of ASD symptomatology. This study aimed to identify ASD symptom profiles in a large group of children and adolescents (0;9-28 years) with FXS, AS, TSC, and NF1. Data on ASD symptomatology (Autism Diagnostic Observation Scale (ADOS-2) & Social Responsiveness Scale (SRS-2)) were collected from children and adolescents with FXS (n = 54), AS (n = 93), TSC (n = 112), and NF1 (n = 278). To identify groups of individuals with similar ASD profiles, we performed two latent profile analyses. We identified a four-profile model based on the ADOS-2, with a (1) 'Non-spectrum symptom profile', (2) 'Social Affect symptom profile', (3)'Restricted/Repetitive Behaviors symptom profile', and (4)'ASD symptom profile'. We also identified a four-profile model based on the SRS, with a (1)'Non-clinical symptom profile', (2)'Mild symptom profile', (3)'Moderate symptom profile', and (4)'Severe symptom profile'. Although each syndrome group exhibited varying degrees of severity, they also displayed heterogeneity in the profiles in which they were classified. We found distinct ASD symptom profiles in a population consisting of children and adolescents with FXS, AS, TSC, and NF1. Our study highlights the importance of a personalized approach to the identification and management of ASD symptoms in rare genetic syndromes. Future studies should aim to include more domains of functioning and investigate the stability of latent profiles over time.

Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1.

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.

The Multimodality Management of Malignant Peripheral Nerve Sheath 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.

Duodenal ampulla neuroendocrine tumor and gastrointestinal stromal tumors in a case of neurofibromatosis type 1: a case report.

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.

Cold Atmospheric Plasma Induces Growth Arrest and Apoptosis in Neurofibromatosis Type 1-Associated Peripheral Nerve Sheath Tumor Cells.

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.

Effect of Everolimus on Prognosis of Neurofibromatosis Type 1 Lesions: A Systematic Review and Meta Analysis.

PURPOSE: This study addresses the effectiveness of oral everolimus in treating various malignancies associated with Neurofibromatosis Type 1 (NF1). The purpose is to determine whether everolimus reduces lesion size in NF1 patients, considering the controversial findings from previous clinical trials. The scientific hypotheses and questions involve evaluating the impact of everolimus on NF1-associated lesions and understanding the variability in treatment outcomes. METHODS: A systematic review and meta-analysis were conducted following PRISMA and Cochrane Collaboration guidelines. The study included four-phase II, single-arm, nonrandomized trials investigating the effect of oral everolimus on NF1-associated lesion size. The search covered multiple databases, and data extraction involved evaluating studies for inclusion criteria and assessing quality using the Cochrane Collaboration's Risk of Bias in Nonrandomized Studies tool. Statistical analysis utilized Open Meta(Analyst). FINDINGS: The search yielded 388 studies, with 10 selected for full-text review and four included in the final analysis. The quality of the studies ranged from low to moderate. The meta-analysis indicated no observed heterogeneity (I^2 = 0%), and the overall estimate suggested no significant reduction in NF1-associated lesion size with everolimus (P = 0.069). IMPLICATIONS: The findings reveal a varied and inconsistent picture of everolimus efficacy in NF1 treatment. The study highlights the need for personalized approaches, considering individual genetic and clinical differences. The limitations, including small sample sizes and nonrandomized trials, call for larger, more standardized research efforts. The study emphasizes ongoing trials and the importance of future research in understanding predictors of everolimus response and optimizing treatment strategies for NF1 patients. CONCLUSION: While everolimus shows promise in reducing lesion size in a subset of NF1 patients, the study cannot draw conclusive results due to limitations in the included studies. Ongoing, adequately powered trials are crucial for advancing the evidence base and informing the potential role of everolimus in NF1 treatment. OTHERS: There was no funding for this review and no conflicts of interest.

Long-term distress throughout one's life: health-related quality of life, economic and caregiver burden of patients with neurofibromatosis type 1 in China.

Introduction: Neurofibromatosis type 1 (NF1) is a rare genetic disorder, with lack of evidence of disease burden in China. We aimed to describe the economic burden, health-related quality of life (HRQL), and caregiver burden of NF1 patients in China. Methods: We conducted an online cross-sectional survey employing the China Cloud Platform for Rare Diseases, with 223 caregivers of NF1 pediatric patients (patients under 18), and 226 adult patients. Economic burden was estimated using direct and indirect costs related to NF1 in 2021, and the Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI-GH). HRQL measures included EQ-5D-Y proxy version and PedsQL™ 4.0 Generic Core Scales (PedsQL GCS) proxy version for pediatric patients, and EQ-5D-5L and PedsQL™ 3.0 Neurofibromatosis Module (PedsQL NFM) for adult patients. Caregiver burden was estimated by Zarit Burden Interview (ZBI). Results: For pediatric patients, the average direct cost in 2021 was CNY 33,614 (USD 4,879), and employed caregivers' annual productivity loss was 81 days. EQ-5D-Y utility was 0.880 ± 0.13 and VAS score was 75.38 ± 20.67, with 52.6% patients reporting having problems in "pain/discomfort" and 42.9% in "anxiety/depression." PedsQL GCS total score was 68.47 ± 19.42. ZBI score demonstrated that 39.5% of caregivers had moderate-to-severe or severe burden. For adult patients, average direct cost in 2021 was CNY 24,531 (USD 3,560). Patients in employment reported an absenteeism of 8.5% and presenteeism of 21.6% according to the results of WPAI-GH. EQ-5D-5L utility was 0.843 ± 0.17 and VAS score was 72.32 ± 23.49, with more than half of patients reporting having problems in "pain/discomfort" and "anxiety/depression" dimensions. PedsQL NFM total score was 68.40 ± 15.57. Conclusion: Both pediatric and adult NF1 patients in China had a wide-ranging economic burden and low HRQL, especially in the psychological dimension. Caregivers for NF1 pediatric patients experienced considerable caregiver burden. More attention and support from policymakers and stakeholders are required to relieve NF1 patients' and caregivers' distress.

Comparing 3D imaging devices for the measurement of cutaneous neurofibromas in patients with Neurofibromatosis Type 1.

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.

Traumatic arteriovenous fistula of the superficial temporal artery caused by massive subcutaneous hematoma prompting surgical removal and endovascular treatment in a patient with neurofibromatosis type 1.

Background: Neurofibromatosis type 1 (NF-1) is often characterized by vascular disorders related to vessel vulnerability that can lead to unfavorable outcomes. Here, we describe a case of NF-1 complicated with a massive subcutaneous hematoma posing a risk of visual impairment for which rapid decompression and a subsequent less invasive approach result in a favorable outcome. Case Description: A 40-year-old woman with NF-1 presented with a massive left subcutaneous temporal hematoma following a mild head contusion. Four days after hospitalization, the hematoma increased in size and severely compressed the left eye, prompting immediate hematoma removal to preserve visual function. Immediately after the hematoma removal, a superficial temporal arteriovenous fistula was found on the digital subtraction angiography and embolized by the endovascular procedure. Her visual acuity was preserved, and no bleeding recurrence was observed throughout the follow-up. Conclusion: Surgical hematoma removal followed by endovascular treatment was effective in preserving visual function. Since vessel fragility is characteristic of patients with NF-1, it should be kept in mind that vascular complications may lead to serious clinical outcomes. In certain NF-1 cases, less invasive treatments for vascular abnormalities may be preferable.

Consensus recommendations on management of selumetinib-associated adverse events in pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas.

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.

Different de novo mutations in the NF1 gene in a family with neurofibromatosis type 1.

The criteria for clinical diagnosis of neurofibromatosis type 1 (NF1) are not sensitive in young children. Recognition is easier when one of their parents has been diagnosed with this condition, and the causal mutation is known. We present a case of a girl with isolated café-au-lait spots, whose father was diagnosed with NF1. However, both were found to carry different de novo mutations in the NF1 gene. This possibility has significant implications for the diagnostic process and genetic counseling.

Neurofibromatosis type 1 adult surveillance form for Austria.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a rare autosomal dominant tumor predisposition syndrome with a birth prevalence of approximately 1 in 2000-3000 individuals. Management of both benign and malignant tumors arising in individuals with NF1 is demanding and tumors may be difficult to treat. Both standardized and individual surveillance programs are therefore highly important to prevent morbidity and mortality in patients with NF1. METHODS: The guidelines for the clinical management of NF1 recently proposed by the European Reference Network for Genetic Tumor Risk Syndromes provide the cornerstone of the present surveillance form and were discussed through three rounds of voting and a final consensus meeting involving experts from five Austrian and one German clinical NF1 centers for adults and one patient organization representative. Subsequently, 31 items within 4 categories were integrated into the proposed surveillance form for Austria. All recommendations, unless otherwise specified, pertain to primarily asymptomatic patients in routine follow-up. RECOMMENDATIONS: At healthcare transition from pediatric to adult surveillance or the initial visit in adulthood, we suggest a thorough clinical, laboratory and radiological examination to obtain a baseline for future diagnostics. To comply with the general screening recommendations in Austria, we suggest extending the frequency of clinical visits from annual to biennial at 50 years of age. In cases of clinical dynamics, early follow-up is recommended to facilitate early detection of potential complications. Particular emphasis should be placed on preventive patient education.

Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.