暂无摘要。

OBJECTIVE: Neurofibromatosis type 1 (NF1) is a genetic cancer predisposition syndrome that can impact multiple organ systems and is associated with plexiform neurofibroma tumors, requiring care from birth through adulthood. Adolescents and young adults (AYAs) with NF1 face several barriers to transition from pediatric to adult care. This cross-sectional study aimed to assess transition readiness in this population and to evaluate relationships between specific NF1 symptoms and transition readiness.
METHODS: AYAs (aged 16-24) enrolled in existing studies related to NF1 were eligible. AYAs and their parents completed measures of transition readiness (Transition Readiness Assessment Questionnaire version 4 [TRAQ-4]), and AYAs also completed a transition readiness interview (UNC TRxANSITION).
RESULTS: Thirty-eight AYAs (mean age = 19.95 ± 2.68 years) participated in the study. Average TRAQ scores indicated that AYAs were still learning Self-Management skills (M = 3.37, SD = 1.08) and Self-Advocacy skills (M = 3.98, SD = 0.67). Older AYAs had higher TRAQ scores for Self-Management (r = 0.70, p < .001) and Self-Advocacy (r = 0.41, p = .011) than younger AYAs. Parents and AYAs had similar TRAQ scores. About one third of AYAs (37.8%, n = 14) expressed uncertainty about how NF1 might affect them in the future. The remaining AYAs mostly expressed concerns regarding tumor growth, pain, or cancer.
CONCLUSIONS: In this small study, preliminary findings suggest that AYAs with NF1 express confidence in many areas of transition readiness but continue to require support, particularly with Self-Management skills. Given the gaps in understanding of future health risks, AYAs with NF1 would benefit from early assessment, psychoeducation, and support for transition readiness to adult care.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype-phenotype associations in a large Chinese cohort of NF1 patients.
METHODS: We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains.
RESULTS: A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18 years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy.
CONCLUSIONS: Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumours: cutaneous (cNFs), subcutaneous (scNFs) and plexiform (pNFs) neurofibromas.
OBJECTIVE: To identify neurofibroma modifier genes, in order to develop a database of patients with NF1.
METHODS: All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1333 patients with NF1 who were genotyped for > 7 million common variants.
RESULTS: A genome-wide association case-only study identified a significant association with 9q21.33 in the pNF phenotype in the discovery cohort. Twelve, three and four regions suggestive of association at the P ≤ 1 × 10-6 threshold were identified for pNFs, cNFs and scNFs, respectively. Evidence of replication was observed for 4, 2 and 6 loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS-mitogen-activated protein kinase pathway, cell-cycle control and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNF and scNF candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cell growth.
CONCLUSIONS: Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will, hopefully, contribute to the development of personalized care for patients with this deleterious and life-threatening condition.

Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN.
This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles.
Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug-related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing.
FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication.
ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

This article obtains an overview of the health status of children and adolescents with neurofibromatosis type 1 (NF1) with a focus on the clinical course of the disease, neuropsychodiagnostic findings, and their impact on quality of life (QoL). In this observational study, data were collected from 24 children and adolescents with NF1 who were cared for at the University Hospital in Innsbruck, Austria, from 2008 to 2022. Data were collected every 6 to 12 months from routine check-ups, including clinical features and imaging findings. Results of neuropsychodiagnostic tests and the KINDL questionnaire to assess QoL were included. Of 24 patients, 15 underwent a neuropsychological examination. Attention performance was examined in 11 of them. Eight of 11 (72%) showed an attention deficit. Assessment for specific developmental disorders showed visual-spatial difficulties in 12/15 (80%) patients. The KINDL questionnaire values ranged from 58.22 to 97.92 (0 stands for reduced QoL, 100 for very good QoL). Patients with scoliosis had a lower range of QoL (56.33-73.96). No trend in QoL was observed in children and adolescents with plexiform neurofibromas, below-average intelligence or optic gliomas. NF1 patients show very different clinical courses. Regular neuropsychological assessment especially with regard to visual-spatial skills and attention deficits is necessary to offer appropriate support, promote children\'s development, and thus improve their QoL.

Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies.
This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index).
For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment.
With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, progression, and need for medical treatment in patients with inoperable PN. CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded. Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3-6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated. In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN management. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden.

BACKGROUND: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise.
METHODS: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits.
RESULTS: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred.
CONCLUSIONS: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Neurofibromatosis 1 (NF1) is a common autosomal dominant syndrome with complete penetrance and highly variable expressivity. The cutaneous neurofibroma (Cnf) and plexiform neurofibroma (Pnf), café-au-lait spots, and freckle-like lesions are common in NF1, but many other manifestations can occur. We aimed to evaluate head circumference, height, weight, body mass index (BMI), head circumference-to-height ratio (HCHR) and waist-hip ratio (WHR) in adult NF1 Brazilian individuals versus a paired control group and investigate their correlation with the presence of clinically visible Pnfs, and number of \"skin neurofibromas\" (Snf), which include both cutaneous and subcutaneous neurofibromas.
A case-control study was conducted with 168 individuals, 84 with NF1 and 84 without NF1, paired by sex and age. Head circumference and anthropometric measurements, Snf quantification, evaluation of clinically visible Pnf and familial inheritance were accessed.
Prevalence of macrocephaly was significantly higher in NF1 women. Height and weight were significantly lower in both males and females with NF1. HCHR was higher in the NF1 group than in the control group for both sexes. BMI was significantly lower in men with NF1. Waist and hip circumferences were significantly reduced in NF compared with the controls, but the mean WHR was significantly lower only in NF1 women. No correlation was found between the Snf and head circumference and anthropometric measurements, sex or family history. The presence and larger size of clinically visible plexiform neurofibromas were associated with normal stature (p = 0.037 and p = 0.003, respectively).
NF1 individuals have increased prevalence of macrocephaly, short stature, low BMI, and reduced abdominal fat. There is no relation between head circumference and anthropometric data with family history, or neurofibromas.