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PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity. ispartof: GENETICS IN MEDICINE vol:24 issue:9 pages:1967-1977 ispartof: location:United States status: published

The coronavirus pandemic increased anxiety and stress and prevented access to health care worldwide; it is unclear how COVID‐19 affected adults with a multisystem genetic disorder such as neurofibromatosis (NF). An anonymous online survey was distributed through an international registry and foundations to adults with NF (June–August 2020) to assess the impact of the pandemic on mental health and NF health care. Six hundred and thirteen adults (18–81 years; M = 45.7) with NF1 (77.8%), NF2 (14.2%), and schwannomatosis (7.8%) provided complete responses. Respondents rated moderate‐to‐high amounts of worry about the impact of COVID‐19 on their emotional (46.3%) and physical health (46.7%), and 54.8% endorsed moderate‐to‐high pandemic‐related stress. Adults with diagnosed/suspected mental health disorders or moderate‐to‐severe NF symptom impact as well as females endorsed higher COVID‐19 stress (ps

ObjectiveTo review parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6–18 years) with neurofibromatosis type 1 (NF1).MethodsSearches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials.ResultsTwo measures were ultimately recommended by the committee: the Social Responsiveness Scale–2 (SRS-2) and the Social Skills Improvement System–Rating Scale (SSIS-RS).ConclusionsEach of the 2 measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning; the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

Early‐phase clinical trials using oral inhibitors of MEK, the mitogen‐activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)‐associated tumors, particularly progressive low‐grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side‐effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. Implications for Practice Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low‐grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1‐related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects., As treatment for neurofibromatosis type 1 (NF1)‐associated complex and inoperable tumors, MEK inhibitor therapy is likely to become more widely used. To aid clinicians who may not have experience with the use of this class of agents, the Clinical Care Advisory Board of the Children's Tumor Foundation presents an overview of the use of MEK inhibitors in the NF1 population, covering relevant clinical trial results, common side effects, basic symptom management, recommended screening guidelines, and patient counseling approaches.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

Objective Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism‐based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test‐retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods Data were analyzed from the STARS clinical trial (n = 146), a multi‐center double‐blind placebo‐controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra‐class correlation coefficients were generated between pre‐ and post‐performances (16‐week interval) on neuropsychological endpoints in the placebo group to determine test‐retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results Test‐retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test‐retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test‐retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. ispartof: GENETICS IN MEDICINE vol:23 issue:8 pages:1506-1513 ispartof: location:United States status: published

ObjectiveTo assess the perspectives of adults with neurofibromatosis 1 (NF1) regarding cutaneous neurofibroma (cNF) morbidity, treatment options, and acceptable risk–benefit ratio to facilitate the design of patient-centered clinical trials.MethodsAn online survey developed by multidisciplinary experts and patient representatives of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) cNF Working Group was distributed to adults with NF1 (n = 3,734) in the largest international database of individuals with any form of NF. Eligibility criteria included self-reported NF1 diagnosis, age ≥18 years, ≥1 cNF, and ability to read English.ResultsA total of 548 adults with NF1 responded to the survey. Respondents ranked appearance, number, and then location as the most bothersome features of raised cNF. Seventy-five percent of respondents considered a partial decrease of 33%–66% in the number or size of cNF as a meaningful response to experimental treatments. Most respondents (48%–58%) were willing to try available cNF treatments but were not aware of options outside of surgical removal. Regarding experimental agents, respondents favored topical, then oral medications. Most individuals (>65%) reported being “very much” or “extremely willing” to try experimental treatments, especially those with the highest cNF burden. Many respondents were not willing to tolerate side effects like nausea/vomiting (51%) and rash (46%). The greatest barriers to participation in cNF clinical trials were cost of participation and need to take time off work.ConclusionsMost adults with NF1 are willing to consider experimental therapies for treatment of cNF. These data will guide the design of patient-centered clinical trials for adults with cNF.

There have been no published reports of central respiratory control abnormalities in pediatric patients with UNC80 or KCNJ11 mutations which cause neurologic channelopathies. We describe an 8-year-...

An 11 year old boy presented with a three month history of progressive bilateral lower extremity weakness associated with recent intermittent incontinence. Spine MRI showed a right-sided T11-T12 paraspinal mass extending through the neural foramina into the epidural space and causing severe spinal cord compression. Skin showed a large macular lightly-hyperpigmented café au lait spot with irregular borders along the T10-T12 dermatome extending from the spine to approximately the anterior-axillary line. He was suspected to have segmental neurofibromatosis type 1 (NF1) as no additional clinical findings, radiographic features or family history of NF1 were identified. Patient underwent T10-12 laminectomy for resection of the epidural tumor component. Post-operative MRI showed resolution of the mass effect on the thecal sac and cord, with expected tumor residual lateral to the neural foramen. His residual spinal tumor and mild scoliosis remained stable over the two years of follow up to date. Pathological and molecular analysis of the resected tumor revealed a neurofibroma harboring an activating KRAS c.35G>A, p.Gly12Asp (KRAS-G12D) pathogenic variant at 27% variant allele frequency. Melanocytes cultured from two hyperpigmented skin biopsies showed the same KRAS-G12D pathogenic variant. This KRAS-G12D pathogenic variant was not found in leukocytes, indicating a post-zygotic origin. No NF1 pathogenic variant was identified in tumor tissue, melanocytes or leukocytes. The clinical findings were consistent with a mosaic KRASopathy due to a post zygotic KRAS-G12D pathogenic variant. The presence of the KRAS variant in the spinal neurofibroma and overlaying café au lait spot without an NF1 etiology in associated tissues demonstrates overlapping variability of presentations of RAS-MAPK pathway disorders. This case highlights the need for full clinical and genetic evaluation of patients presenting with segmental neurocutaneous disorders.

Background Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally mediated functions. Mouse models of NF1 show irregularities in gamma-aminobutyric acid release and striatal dopamine metabolism. We hypothesized that youths with NF1 would show abnormal behavior and neural activity on a task of risk taking reliant on prefrontal-striatal circuits. Methods Youths with NF1 ( n = 29) and demographically comparable healthy control subjects ( n = 22), aged 8 to 19 years, were administered a developmentally sensitive gambling task in which they chose between low-risk gambles with a high probability of obtaining a small reward and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging to investigate neural activity associated with risky decision making as well as age-associated changes in these behavioral and neural processes. Results Behaviorally, youths with NF1 tended to make fewer risky decisions than control subjects. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to control subjects during the task. We also observed atypical age-associated changes in neural activity in patients with NF1 such that during risk taking neural activity tended to decrease with age in control subjects, whereas it tended to increase with age in patients with NF1. Conclusions Findings suggest that developmental trajectories of neural activity during risky decision making may be disrupted in youths with NF1.

PURPOSE Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. PATIENTS AND METHODS Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers. RESULTS Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. CONCLUSION High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

INTRODUCTION Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments. METHODS Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects. RESULTS One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively). CONCLUSION Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.

BACKGROUND: Plexiform neurofibromas (PNs) are histologically complex peripheral nerve sheath tumors composed of Schwann cells and fibrocytes. Pre-clinical models have demonstrated that altering the microenvironment with molecular targeting therapy may lead to the shrinkage of PN. Here we test the activity of Cabozantinib, a tyrosine kinase inhibitor of KIT, MET, VEGF, and AXL, in adolescents and adults with NF1-associated PN. METHODS: The NFCTC conducted a study (NCT02101736) evaluating Cabozantinib in subjects ≥16 years with clinically significant PN. Response was determined by MRI assessment of tumor volume. Cabozantinib was administered daily on a continuous dosing schedule for up to 2 years. Starting dose was 40 mg oral daily dose with a dose escalation to 60 mg. Success was determined as ≥ 25% of subjects achieving and maintaining ≥ 20% decrease in tumor volume. RESULTS: 19 evaluable subjects were assessed with a mean age of 23. Subjects were evaluable if they completed at least 1 cycle of therapy and had at least one follow-up tumor imaging. 4 subjects were not evaluable due to enrollment error (n=2), withdrawal during cycle 1 (n=1), ineligible due to eligibility exclusions (n=1). Eight patients (42%) met criteria for PR by 1 year. No subjects had PN progression. Common toxicities were gastrointestinal, hypothyroidism, fatigue, headaches, skin and leukopenia. Three subjects experiencing grade 3 SAEs remained on study after dose reductions. CONCLUSIONS: Cabozantinib demonstrated activity and was well tolerated in patients with clinically significant PN. This trial will be expanded to include a cohort of children

Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. However, the optimal treatment dose and schedule are unknown. This multicenter, phase II, open-label study evaluated subjects (≥6 years old) with NF2 and progressive VS. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as ≥20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. We enrolled 22 subjects (median age=23 years). The overall hearing and radiographic response rates were 41% (9/22) and 23% (5/22), respectively. In an unplanned post-hoc analysis, the hearing and radiographic response rates were 14% (1/7) and 0% in pediatric subjects ≤21 years, as compared with 53% (8/15) and 33% (5/15) in adult subjects. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 women with elevated FSH underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates comparable to previous studies using lower doses. Pediatric subjects appear to benefit less than adults during bevacizumab treatment.

There have been no published reports of central respiratory control abnormalities in pediatric patients with UNC80 or KCNJ11 mutations which cause neurologic channelopathies. We describe an 8-year-old male with a pathogenic UNC80 mutation, intellectual disability, hypotonia and epilepsy with severe central sleep apnea (213.5 events/h) on polysomnography (PSG). We also describe a 20-month-old female with a KCNJ11 mutation, neonatal diabetes and developmental delay who had severe central sleep apnea (131.1 events/h). Both patients had irregular respiratory patterns during sleep and wakefulness and were placed on empiric bilevel positive airway pressure therapy, which was well tolerated with resolution of abnormal respiratory control and hypercapnia. Patients with UNC80 and KCNJ11 gene mutations may have abnormal respiratory rhythm during sleep and wakefulness, mirroring animal models. We recommend routine PSG tests and further investigation into the respiratory control of patients with pediatric channelopathies involved in chemoreceptor function or central integration of respiratory control.

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.

The 2013 Neurofibromatosis (NF) Conference took place at the Portola Hotel and Spa, Monterey, CA, from June 8-11, 2013. This international meeting is sponsored annually by the Children's Tumor Foundation (CTF), with the goal of bringing together NF researchers and clinicians from disparate fields of expertise. The conference agenda included a range of preclinical topics with a focus on signaling pathways and mouse models and a number of clinical topics, including a symposium on the interaction of academics, government, and industry in NF clinical trials. Neurofibromatosis is a group of inherited genetic disorders – NF1, NF2, and schwannomatosis – that together affect about 100,000 persons in the US. NF1 is the most common, with an estimated birth prevalence of 1:3,000 [Friedman., 1999; Lammert et al., 2005]; for NF2 and schwannomatosis, the estimated birth prevalence is 1:25,000 and 1:40,000, respectively [Antinheimo et al., 2000; Evans et al., 2005]. NF1, NF2 and schwannomatosis have in common that they predispose affected individuals to develop Schwann cell tumors such as neurofibromas and schwannomas. At a lower frequency, they also predispose to the development of a number of other benign and malignant tumor types, as well as some developmental abnormalities including learning disabilities (in NF1). The disorders arise from mutations in different genes, each of which plays a key role in regulating cellular function. The NF1 gene on human chromosome 17 encodes an intracellular signaling molecule that functions as a GTPase activating protein for Ras proteins, whereas the NF2 gene on human chromosome 22 encodes a cytoskeletal-membrane linking protein with reported roles in the suppression of several different growth-associated signaling pathways. The biology of schwannomatosis remains understudied despite the identification of germline SMARCB1 mutations in schwannomatosis patients in 2007.

INTRODUCTION: Punctate white matter lesions (pWMLs) and diffuse excessive high signal intensity (DEHSI) are commonly observed signal abnormalities on MRI scans of high-risk preterm infants near term-equivalent age. To establish whether these features are indicative abnormalities in axonal development or astroglia, we compared pWMLs and DEHSI to markers of axons and astrogliosis, derived from magnetic resonance spectroscopy (MRS). METHODS: Data from 108 preterm infants (gestational age at birth 31.0 weeks±4.3; age at scan 41.2 weeks±6.0) who underwent MR examinations under clinical indications were included in this study. Linear regression analyses were used to test the effects of pWMLs and DEHSI on N-acetyl-aspartate (NAA) and myoinositol concentrations, respectively. RESULTS: Across the full sample, pWMLs were associated with a reduction in NAA whereas moderate to severe DEHSI altered the normal age-dependent changes in myoinositol such that myoinositol levels were lower at younger ages with no change during the perinatal period. Subgroup analyses indicated that the above associations were driven by the subgroup of neonates with both pWMLs and moderate to severe DEHSI. CONCLUSION: Overall, these findings suggest that pWMLs in conjunction with moderate/severe DEHSI may signify a population of infants at risk for long-term adverse neurodevelopmental outcome due to white matter injury and associated axonopathy. The loss of normal age-associated changes in myoinositol further suggests disrupted astroglial function and/or osmotic dysregulation.

Background: Cabozantinib, an oral FDA approved multi-receptor tyrosine kinase inhibitor, was tested in our preclinical mouse model of PN. After finding significant reduction of tumor number and size in cabozantinib treated versus control mice, we sought to translate these findings to a phase 2 human study. Here we report the activity of cabozantinib in adolescents and adults with NF1-associated PN. Methods: A multicenter, nonrandomized phase 2 trial (NCT02101736) of cabozantinib in subjects ≥16 years with NF1 and either progressive or clinically significant inoperable PN was performed by the NFCTC (NF-105). The primary study aim was volumetric response of the target PN determined by MRI read centrally. Cabozantinib was administered continuously for up to 24 cycles, each cycle was 28 days. The starting dose was 40 mg once daily with planned escalation to a target dose of 60 mg once daily after 2 cycles. Dose reductions for toxicity were allowed to 20 mg once daily. Partial response (PR) was defined as ≥20% reduction in tumor volume from baseline. Subjects were considered evaluable for response if they completed ≥1 cycle of therapy and had a follow-up MRI. Success was defined as ≥25% of subjects achieving and maintaining a PR after 12 cycles without significant toxicity. Investigation of the impact of cabozantinib on the PN kinome network was performed on murine samples. Results: Twenty-three subjects enrolled; 21 subjects (median age 22 years) were evaluable for toxicity (2 noted to be ineligible before receiving study drug) and 19 subjects (median age 23 years) were evaluable for response (1 subject withdrew during cycle 1 and 1 was found ineligible after starting study drug). Baseline median tumor size was 557 mL (range 57-2954 mL). Among the evaluable patients, 8 (42%) met criteria for PR by cycle 12. Median change in tumor volume was -15.2% (range +2.2% to -36.9%). No subject had PN progression on treatment; maximal tumor response was not achieved until at least 18 cycles in 6/8 responders. A significant portion of patients underwent dose reductions or discontinued cabozantinib due to low grade adverse events (AE) that impaired quality of life; however, 3 responders reduced to 20 mg maintained or improved their response at this dose. The most common AEs (any grade) in ≥10 patients included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia (PPE). Eleven grade 3 AEs occurred in 8 patients, mainly PPE (n=4) and hypertension (n=2); no grade 4 or 5 AEs occurred. Analysis of kinase activity in murine PN treated with cabozantinib showed significantly decreased activity of AXL, MERTK and MET, known cabozantinib targets, but also of DDR1 and DDR2. Conclusions: Cabozantinib demonstrates considerable clinical activity for PN with a radiographic response rate of 42%. Although there were few severe AEs, low grade toxicities impacted the willingness of many subjects to continue treatment. Quantitative kinome analysis revealed that inhibition of DDR1, DDR2, AXL, MERTK and MET might underpin the therapeutic responses seen in these patients. Lower doses of cabozantinib may be optimal for the NF1 population and still lead to therapeutic response. This trial is now enrolling a pediatric cohort of children aged 3 to 15 years. Supported by DOD Award W81XWH-12-1-0155 and Exelixis Citation Format: Chie-Schin Shih, Jaishri Blakeley, D. Wade Clapp, Amy E. Armstrong, Pam Wolters, Eva Dombi, Gary Cutter, Nicole J. Ullrich, Jeffrey Allen, Roger Packer, Stewart Goldman, David H. Gutmann, Scott Plotkin, Tena Rosser, Kent Robertson, Brigitte Widemann, Steven Rhodes, Steven Angus, Gary Johnson, Bruce Korf, Michael J. Fisher. Treatment of neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN) with cabozantinib (XL184): A Neurofibromatosis Clinical Trials Consortium Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT233.

Neurofibromatosis type 1 (NF1) is a common single gene disorder resulting in multi-organ involvement. In addition to physical manifestations such as characteristic pigmentary changes, nerve sheath tumors, and skeletal abnormalities, NF1 is also associated with increased rates of learning disabilities, attention deficit hyperactivity disorder, and autism spectrum disorder. While there are established NF1-related structural brain anomalies, including brain overgrowth and white matter disruptions, little is known regarding patterns of functional connectivity in NF1. Here, we sought to investigate functional network connectivity (FNC) in a well-characterized sample of NF1 participants (n = 30) vs. age- and sex-matched healthy controls (n = 30). We conducted a comprehensive investigation of both static as well as dynamic FNC and meta-state analysis, a novel approach to examine higher-dimensional temporal dynamism of whole-brain connectivity. We found that static FNC of the cognitive control domain is altered in NF1 participants. Specifically, connectivity between anterior cognitive control areas and the cerebellum is decreased, whereas connectivity within the cognitive control domain is increased in NF1 participants relative to healthy controls. These alterations are independent of IQ. Dynamic FNC analysis revealed that NF1 participants spent more time in a state characterized by whole-brain hypoconnectivity relative to healthy controls. However, connectivity strength of dynamic states did not differ between NF1 participants and healthy controls. NF1 participants exhibited also reduced higher-dimensional dynamism of whole-brain connectivity, suggesting that temporal fluctuations of FNC are reduced. Given that similar findings have been observed in individuals with schizophrenia, higher occurrence of hypoconnected dynamic states and reduced temporal dynamism may be more general indicators of global brain dysfunction and not specific to either disorder., Highlights • Exploring static, dynamic, and higher-dimensional properties of functional connectivity in NF1. • Static connectivity within the cognitive control domain is altered in NF1. • Altered higher-dimensional dynamics suggest global brain dysfunction.

Background Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs. Methods We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS). Results Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs. Conclusions Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders. © 2013 The American Society of Human Genetics.

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8–15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = −0.15, 95% confidence interval −0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval −0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Association of occipital intermittent rhythmic delta activity with absence seizures has been well documented in the published literature. Two recent studies have also described an association with focal seizures. After obtaining approval from our Institutional Review Board, all electroencephalograms with occipital intermittent rhythmic delta activity at our institution between July 1, 2006 and December 31, 2009 were identified. Charts of these patients were reviewed to collect clinical data. A matched comparison group was assembled. Thirty-one of the patients who met criteria had evaluable clinical data. Fifteen had generalized seizures (9 absence; 2 tonic-clonic; 3 absence and tonic-clonic; 1 absence, tonic-clonic, myoclonic, and atonic). Eleven had focal seizures. One had both generalized tonic-clonic and focal seizures. Events in 1 were nonepileptic in nature. Documentation was inadequate for seizure classification in 3. There was a statistically significant difference between the study and comparison groups for absence seizures, but not for focal seizures.

Plexiform neurofibromas (PNs) can cause significant disfigurement, compression of vital structures, neurologic dysfunction, and pain. MEK pathway inhibition results in significant PN shrinkage in neurofibromatosis type 1 (NF1) mouse models of PN. We evaluated the efficacy of the MEK inhibitor, PD0325901, in adolescents (≥ 16 years of age) and adults with symptomatic or growing NF1-PN in a phase II open label study. The primary aim was to assess tumor response by cycle 12 using centrally read MRI, defined as at least 20% decrease in tumor volume from baseline. Subjects received PD-0325901 by mouth twice daily at 2 mg/m2/dose (maximum dose 4 mg bid). Each course was 4 weeks, and subjects received drug on a 3 week on / 1 week off schedule. NF106 enrolled 19 subjects (7M;12F) in two stages with a median age of 24 years (range 16-39 years). The mean PN volume was 797.8 mL. Eight subjects (42.1%; 95% CI: 20%, 67%) had a response. PD0325901 was well tolerated, with the most common dose limiting toxicity being acneiform rash in 3/19 patients (16%). Five subjects (26.3%) developed Grade 3 toxicities, mostly pain (4/19; 21%). No subjects developed Grade 4 or higher toxicities. Five subjects (26.3%) had a dose reduction for toxicity: one for Grade 3 abdominal and back pain, the others for intolerable Grade 1-2 nausea, rash, or fatigue. This study demonstrated that PD0325901 is well tolerated and results in PN shrinkage in 42% of adolescent and adult subjects with NF1-PN. Supported by DOD Award W81XWH-12-1-0155.

2056Background: Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with...

Brain malformations such as agenesis and dysgenesis of corpus callosum, pituitary hypoplasia, hypothalamic hamartoma, mesial temporal periventricular heterotopia, and abnormally oriented and misshapen hippocampi have been described with SOX2 gene mutations. A neocortical malformation is presented here in association with SOX2 deletion that over time underwent spontaneous evolution and decrease in size.

We describe the clinicopathologic features of an Epstein-Barr virus (EBV)-associated smooth muscle tumor arising in the basal ganglia of a 10-year-old human immunodeficiency virus (HIV)-positive child. Only a few cases of intracranial smooth muscle tumors are reported in the literature and virtually all of these have been extra-axial, involving the dura or sinuses in HIV+ adults. Our case underscores the need to include an EBV-associated smooth muscle tumor in the differential diagnosis when evaluating intracranial mass lesions in immunodeficient children.

The cognitive dysfunction associated with neurofibromatosis type 1 (NF1) is an intriguing aspect of this phenotypically heterogeneous genetic neurocutaneous disorder. A broad range of both nonverbal and verbal learning disabilities are evident in approximately 30% to 65% of children with NF1. Deficits in IQ, executive function, attention, and motor skills have also been documented. Current challenges lie in discovering the underlying multifactorial etiologies of the cognitive abnormalities found in NF1. Likely answers lie in neuroanatomic correlates as seen on neuroimaging as well as in molecular and genetic advances into the role of neurofibromin, the protein product of the NF1 gene. The development of NF1 animal models with learning and memory difficulties similar to those seen in humans demonstrates promising preliminary evidence that medical treatment of cognitive abnormalities may one day be possible.

Aicardi syndrome is an X-linked-dominant condition characterized by infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. We reviewed the Aicardi Syndrome Foundation's compilation of family-based, self-reported questionnaires for the year 2000. Information was obtained from 77 females with Aicardi syndrome regarding developmental milestones, seizure frequency, seizure classification, antiepileptic drug use, and medical problems. Patient ages ranged from 1 to 25 years (mean = 7.2 years). All patients were significantly developmentally delayed with milestones ranging from 2 to 36 months. Of the patients, 91% attained milestones no higher than 12 months. Seizures were reported in 92% of patients and occurred daily in 67%. Infantile spasms were the most common seizure type observed in 17%, although a variety of other seizure types were also reported. Multiple antiepileptic drugs were used in these patients with 73% of patients taking two or more antiepileptic drugs. Five patients had a vagal nerve stimulator implanted, and one patient underwent a hemispherectomy. The most common medical problems cited included scoliosis, constipation, gastroesophageal reflux, aspiration pneumonia, and otitis media, but overall health was perceived to be good. Our review demonstrates the spectrum of developmental disabilities, epilepsy severity, and prognosis in a large group of Aicardi patients.

Plexiform neurofibromas are one of the most common and disabling features of neurofibromatosis 1. Treatment options for patients with plexiform neurofibromas have been limited, with surgery being the primary option for patients with progressive lesions causing significant morbidity. Trials have evaluated other treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic agents. The design of such trials and entry criteria have been quite variable, and results have been difficult to interpret. As more is understood concerning the molecular genetic underpinnings of plexiform neurofibromas, new avenues of treatment are being explored. Evaluation of clinical trials is challenging because of the unpredictable nature of plexiform neurofibromas and difficulties in measuring objective responses. The use of innovative neuroimaging techniques and other outcome measures may greatly improve the design of trials and evaluation of potential effective agents. (J Child Neurol 2002;17:638-641).

Neurofibromatosis 1 is a common autosomal dominant disease reported in approximately 1 in 3000 individuals. Although some features of neurofibromatosis 1, such as café-au-Iait spots and Lisch nodules, are clinically silent, neurofibromas cause a significant degree of morbidity, mortality, and cosmetic disfigurement. Childhood through early adulthood is a vulnerable period for the growth of these lesions. Neurofibromas are a heterogeneous group of benign tumors that grow from intraneural and extraneural tissues. These tumors take on different morphology, grow at variable rates, and occur in multiple locations. Symptoms arise as neurofibromas enlarge, compressing and distorting local structures. The unpredictable nature of neurofibromas has a serious impact on the quality of life of patients with neurofibromatosis 1, and their management is challenging for physicians. Surgical removal remains the mainstay of treatment. However, advances in the understanding of the genetics and pathogenesis of neurofibromatosis 1 have led to the development of promising new biologically directed therapies. The purpose of this review is to summarize the defining characteristics, incidence, clinical course, management options, and outcome of neurofibromas in children with neurofibromatosis 1. (J Child Neurol 2002;17:585-591).

Neurofibromatosis 1 is associated with an increased risk for the development of benign and malignant tumors involving neural and non-neural tissues. Children as well as adults with neurofibromatosis 1 are affected. Central nervous system neoplasms represent a significant portion of these malignancies and appear primarily in children less than 10 years of age. Optic pathway gliomas and brainstem gliomas are the most common intracranial neoplasms found in neurofibromatosis 1, although there also is an increased incidence of other brain tumors in this population. The majority of these intracranial neoplasms are benign pilocytic astrocytomas, which may behave in a less aggressive manner than histologically identical tumors in non-neurofibromatosis 1 patients. Owing to the indolent nature of these tumors, conservative management with close follow-up is recommended. When intervention is required, conventional treatment with surgery, radiation, or chemotherapy has been used with variable results. The current challenge lies in understanding the pathogenesis of gliomas in neurofibromatosis 1, which may lead to the development of biologically directed therapies with less associated morbidity and mortality for neurofibromatosis 1 as well as non-neurofibromatosis 1 children. (J Child Neurol 2002;17:630-637).

Vestibular schwannomas (VSs) in patients with neurofibromatosis 2 (NF2) are associated with hearing loss. Recently published data from a prospective clinical trial showed that bevacizumab treatment at a fixed dose of 7.5 mg/kg every 3 weeks was associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. The optimal treatment dose and schedule, however, are unknown. The primary aim of this study was to determine the hearing response rate during induction therapy with bevacizumab at 10 mg/kg every 2 weeks; secondary aims included radiographic response rate. This multicenter, phase II, open label study evaluated children and adults (≥6 years of age) with NF2 and progressive VSs treated with bevacizumab. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as ≥20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. We enrolled 22 subjects (9M;13F) with a median age of 23 years (range 12-62 years). Nineteen subjects have completed induction therapy. 8/19 (42%) subjects had hearing response and 4/19 subjects (21%) had a radiographic response in the target VS. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 female subjects had elevated FSH and underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates at 6 months that are similar to previous studies using lower doses. Future analyses will address the durability of hearing and radiographic responses during 18 months of maintenance therapy.

The case of a 10-year-old female with Marfan syndrome and postural headache secondary to spontaneous intracranial hypotension is described. The patient was found to have multiple dural ectasias and a cerebrospinal fluid leak at the left cervicothoracic junction. Her presentation, diagnostic work-up, and management are reviewed, and the relevant literature is discussed. Spontaneous intracranial hypotension secondary to cerebrospinal fluid leaks from dural ectasia should be recognized as a potential complication in children with Marfan syndrome and other connective tissue diseases. ( J Child Neurol 2005;20:153—155).

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well–characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.

Paclitaxel is an antineoplastic agent that is used in the treatment of a variety of solid tumors. Dose-limiting side effects of myelosuppression and peripheral neuropathy are well known. Paclitaxel has minimal penetration of the blood-brain barrier and central nervous system side effects are rare. However, transient encephalopathy following paclitaxel infusion has been described in adults but not in children. We present the case of a 14-year-old female with a recurrent suprasellar germinoma who developed an acute encephalopathy 4-6 hr following paclitaxel infusion.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous disorder. TSC results in hamartomatous lesions primarily involving the skin, central nervous system, kidneys, eyes, heart, and lungs. The clinical findings and severity of TSC are highly variable. Recent advances in our understanding of the complexities of the TSC1 and TSC2 genes are making genotype-phenotype correlations possible. While managing seizures, cognitive dysfunction, and behavioral abnormalities are the primary responsibility of the neurologist, familiarity with all aspects of this disease helps provide better comprehensive care for affected individuals.

Neurofibromatosis type 1 (NF1) is associated with vasculopathy, which may result in a variety of cerebrovascular complications. The purpose of this study was to evaluate the spectrum of cerebrovascular disease in a pediatric population with NF1. Of 316 patients with NF1 who underwent brain MRI, 8 (2.5%) children were reported to have an abnormality of the cerebrovascular system, including narrowed or ectatic vessels, vascular stenoses, aneurysm, and moyamoya.

Neurofibromatosis 1 is associated with an increased risk for the development of benign and malignant tumors involving neural and non-neural tissues. Children as well as adults with neurofibromatosis 1 are affected. Central nervous system neoplasms represent a significant portion of these malignancies and appear primarily in children less than 10 years of age. Optic pathway gliomas and brainstem gliomas are the most common intracranial neoplasms found in neurofibromatosis 1, although there also is an increased incidence of other brain tumors in this population. The majority of these intracranial neoplasms are benign pilocytic astrocytomas, which may behave in a less aggressive manner than histologically identical tumors in non-neurofibromatosis 1 patients. Owing to the indolent nature of these tumors, conservative management with close follow-up is recommended. When intervention is required, conventional treatment with surgery, radiation, or chemotherapy has been used with variable results. The current challenge lies in understanding the pathogenesis of gliomas in neurofibromatosis 1, which may lead to the development of biologically directed therapies with less associated morbidity and mortality for neurofibromatosis 1 as well as non-neurofibromatosis 1 children.

Neurofibromatosis 1 is a common autosomal dominant disease reported in approximately 1 in 3000 individuals. Although some features of neurofibromatosis 1, such as café-au-lait spots and Lisch nodules, are clinically silent, neurofibromas cause a significant degree of morbidity, mortality, and cosmetic disfigurement. Childhood through early adulthood is a vulnerable period for the growth of these lesions. Neurofibromas are a heterogeneous group of benign tumors that grow from intraneural and extraneural tissues. These tumors take on different morphology, grow at variable rates, and occur in multiple locations. Symptoms arise as neurofibromas enlarge, compressing and distorting local structures. The unpredictable nature of neurofibromas has a serious impact on the quality of life of patients with neurofibromatosis 1, and their management is challenging for physicians. Surgical removal remains the mainstay of treatment. However, advances in the understanding of the genetics and pathogenesis of neurofibromatosis 1 have led to the development of promising new biologically directed therapies. The purpose of this review is to summarize the defining characteristics, incidence, clinical course, management options, and outcome of neurofibromas in children with neurofibromatosis 1.

Plexiform neurofibromas are one of the most common and disabling features of neurofibromatosis 1. Treatment options for patients with plexiform neurofibromas have been limited, with surgery being the primary option for patients with progressive lesions causing significant morbidity. Trials have evaluated other treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic agents. The design of such trials and entry criteria have been quite variable, and results have been difficult to interpret. As more is understood concerning the molecular genetic underpinnings of plexiform neurofibromas, new avenues of treatment are being explored. Evaluation of clinical trials is challenging because of the unpredictable nature of plexiform neurofibromas and difficulties in measuring objective responses. The use of innovative neuroimaging techniques and other outcome measures may greatly improve the design of trials and evaluation of potential effective agents.