Background
Mosaic neurofibromatosis type 1 (MNF1) poses a diagnostic challenge due to low-level mosaicism and the confinement of pathogenic variants to neuroectodermal lineages, frequently resulting in false-negative findings when testing is limited to peripheral blood. At present, molecular confirmation of NF1 often relies on the detection of pathogenic variants in tumor tissue. However, many young individuals present exclusively with pigmentary manifestations, including café-au-lait macules and freckling, and therefore lack accessible tumor material. Molecular analysis of pigmentary lesions is technically challenging because skin biopsies contain only a small proportion of melanocytes, which particularly hampers the detection of low-level copy number and structural variants using conventional diagnostic approaches.

Methods
Genomic DNA and RNA were extracted from cultured melanocytes and peripheral blood lymphocytes from a woman referred for evaluation of unilateral pigmentary findings in the context of reproductive counseling. NF1 analysis was performed using targeted NGS, cDNA studies, and MLPA. Structural variants were assessed with optical genome mapping (OGM) in melanocytes. Chromosomal abnormalities were further evaluated by conventional karyotyping and FISH on blood.

Results
The combined approach using melanocyte culture and OGM identified a reciprocal balanced translocation disrupting the NF1 locus, t(15;17)(q26.1;q11.2) as the molecular predisposing event. Blood karyotyping and FISH analysis showed a normal female karyotype.

Conclusion
To our knowledge, this is the first report of a reciprocal translocation in mosaic NF1, highlighting the role of structural genomic rearrangements in this disorder and underscoring the diagnostic utility of OGM in suspected cases. Molecular confirmation of MNF1 is critical for accurate diagnosis, clinical management, and genetic counseling.

Background: Legius syndrome (LS) is a rare autosomal dominant RASopathy caused by pathogenic variants in the SPRED1 gene. It is primarily characterized by café-au-lait macules and other pigmentary findings, such as intertriginous freckling. Additional clinical manifestations commonly reported include lipomas, macrocephaly, peculiar facial features, learning disabilities, attention-deficit/hyperactivity disorder (ADHD), and developmental delay. Despite increasing molecular diagnoses, the clinical spectrum remains incompletely defined, and genotype-phenotype correlations are still poorly understood.
This study aims to describe the clinical features and molecular data of a large cohort of molecularly confirmed LS patients to better delineate the phenotypic variability and explore potential genotype-phenotype correlations.
Methods: We conducted a retrospective multicenter analysis of clinical and molecular data from 70 individuals affected by LS, belonging to 42 unrelated families. Demographic, dermatological, neurodevelopmental, and systemic features were methodically collected and analyzed. Molecular analysis was performed through next-generation sequencing and multiplex ligation-dependent probe amplification (MLPA).
Results: Our cohort demonstrated marked clinical heterogeneity, both between unrelated families and among affected members of the same family. While pigmentary manifestations were the most consistent finding, additional features, particularly neurodevelopmental involvement, varied considerably in severity and presentation. No clear genotype-phenotype correlations emerged from the analysis.
Conclusion: Legius syndrome shows significant inter- and intra-familial clinical variability, complicating the delineation of a well-defined phenotypic spectrum, suggesting the contribution of modifying genetic, epigenetic, or environmental factors. The absence of a consistent genotype-phenotype correlation highlights the need for larger collaborative studies and longitudinal data in order to implement standardized, evidence-based follow-up protocols.

Background: Mosaic neurofibromatosis type 1 (NF1) results from postzygotic NF1 variants and exhibits a highly variable phenotype, often milder or segmental compared with classical NF1. Because of this phenotypic variability and the technical challenges associated with detecting low-level variants, mosaic NF1 remains substantially under-recognized in clinical practice.
Methods: We retrospectively analyzed 105 patients with molecularly confirmed mosaic NF1, diagnosed by targeted next-generation sequencing (NGS) in a single reference center. Clinical data were compared with those from a reference cohort of 601 patients with constitutional NF1 to delineate phenotypic and molecular differences.
Results: Pathogenic NF1 variants included nonsense (56%), missense (3%), splice-site (11%), frameshift (22%) variants, and large deletions (8%). Compared with constitutional NF1, mosaic cases showed a significantly lower proportion of missense variants and small inframe variants (3% vs 19%, p = <0.0001) and a predominance of truncating variants. Clinically, Lisch nodules and cutaneous neurofibromas were markedly less frequent in mosaic NF1 (33% and 57%, respectively) than in classical NF1 (59% and 91%, p < 0.001). Disease severity tended to increase with higher variant allele frequency (VAF > 10%), suggesting a correlation between the proportion of mutant cells and clinical severity.
Conclusion: This study refines the clinical spectrum of mosaic NF1 and highlights distinctive quantitative and topographical differences from constitutional NF1. Quantitative assessment of mosaicism using NGS improves diagnostic accuracy and provides valuable prognostic information for clinical management and genetic counselling.

Background: Postzygotic mutations in NF1 cause Mosaic Neurofibromatosis type 1 (MNF1). Previous publications report variable diagnostic criteria and inconsistent genetic testing, with estimated cancer risk of 11% and recurrence risk of 2–6%.
Aims: To evaluate clinical manifestations, complications, cancer and recurrence in an MNF1 cohort.
Methods: Retrospective (2017–2026) data collection from an MNF1 cohort (n=31) from two NF1 centers. MNF1 was defined by revised diagnostic MNF1 criteria, or NF1 criteria with negative NF1/SPRED1 germline testing. Phenotype was classified per Ruggieri and Hudson categories.
Results: Mean age at first visit was 12.6 years (range 10 months–37 years); 55% were males and 74% were children. Localized disease was present in 68%; pigmentary anomalies alone were the most common category (58%). Additional features included Lisch nodules (26%), neurofibromas (16%), plexiform neurofibromas (13%), sphenoid dysplasia and pseudoarthrosis (3%), and learning difficulties or ADHD (19%). None developed optic glioma or cancer over a mean follow-up of 3.2 years (range 0.25–14 years). Mosaic NF1 was confirmed in 9/25 tested (36%): seven in blood (variant allele fraction 2.5–28%) and two in melanocytes only. Blood-detectable variants were associated with generalized pigmentary disease and higher rates of neurofibromas (5/7 vs. 0/16), plexiform neurofibromas (3/7 vs. 0/16), and Lisch nodules (4/7 vs. 4/16). Both individuals with melanocyte-detected variants had localized pigmentary manifestations only. Four affected adults had offsprings, all healthy.
Conclusions: Optic glioma and cancer are rare in MNF1 and may be associated with a detectable NF1 variant in blood. Further long-term studies are required.

Background: NF2-related Schwannomatosis (NF2-SCH) is an autosomal dominant condition
predisposing to the development of schwannomas and multiple meningiomas. The detection of
bilateral vestibular nerve schwannomas is considered enough to establish a clinical diagnosis of
NF2-related Schwannomatosis. Ring chromosome 22 represents a rare cause of NF2-SCH,
usually presenting with other features including intellectual disability or neurodevelopmental delay.
Methods: We report a case of a 37 years old male referred to our center because of bilateral
vestibular Schwannomas, in the absence of other clinical findings, except for azoospermia. His
brother and mother presented the same clinical picture. We performed a comprehensive genetic
analysis, including NGS, MLPA, chromosome exam with FISH, array-CGH and PacBio long-read
sequencing (LRS).
Results: Cytogenetic analysis detected a ring chromosome 22 and a translocation
t(1;22)(p36.3;q13.1) while no pathogenic variant was identified by NGS and MLPA. Further
characterization by FISH and LRS uncovered the translocation breakpoints on chromosome 22
and 1 and showed that led to constitutional ~104kb deletion on chromosome 22,. As expected,
molecular characterization of DNA from the left VIII cranial nerve Schwannoma showed 22q loss
except for the 22q13.1-13.33 region translocated to chromosome 1.
Conclusions: Azoospermia and peripheral nervous system tumors are described in patients with
complex rearrangements involving chromosome 22. However, chromosomal analysis is rarely
performed in cases of familial NF2. Our case highlights the importance of considering cytogenetic
analysis.

Background: Neurofibromatosis type 1 (NF1) is a common AD disorder caused by pathogenic NF1 variants. Population-representative molecular data from Eastern Europe remain scarce. We report the genetic spectrum and diagnostic yield from a national Russian Federation patient registry.
Methods: Data were collected prospectively via standardized electronic case report forms across a multidisciplinary national registry. Molecular testing employed sequencing and copy-number analysis of NF1 in peripheral blood leukocyte DNA. In patients with uninformative standard results, complementary approaches were applied: analysis in melanocyte cultures derived from café-au-lait macules for suspected somatic mosaicism, and allelic imbalance analysis to detect monoallelic NF1 expression.
Results: The registry comprised 4,230 patients from 84 Russian regions; 29% (n=1,227) had no molecular testing performed. Among 3,003 tested patients, 2,225 (74%) had germline NF1 variants confirmed in peripheral blood DNA, representing 53% of the full cohort. An additional 6 mosaic cases were confirmed exclusively via melanocyte culture analysis, and 38 via allelic imbalance testing, yielding 2,269 molecularly confirmed individuals overall (75% of those tested). Among 2,225 patients with fully characterized germline variants, point mutations accounted for 89% (n=1,980), copy-number changes for 8% (n=179), and other variant types for 3% (n=67). The fifteen most frequent SNV represented 15% of SNV-carriers; p.(Arg1513*) and p.(Arg1947*) were most prevalent.
Conclusion: In this large national cohort, melanocyte culture analysis and allelic imbalance testing enabled molecular confirmation in cases undetectable by conventional blood-based sequencing, improving overall diagnostic yield. These data contribute underrepresented population diversity to the global understanding of NF1 genotype distribution and support future genotype-phenotype correlation studies.

Backgroud: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in the NF1 gene, with a broad phenotypic spectrum that includes endocrine disorders (EDs). While genotype–phenotype associations have been explored for several NF1 features, the relationship between specific NF1 variants and EDs remains poorly characterized. Aim: to characterize the genotype of NF1 patients followed in our Endocrinology department.


Methods: Retrospective analysis of NF1 patients with genotype characterization followed at a tertiary referral center. Patients with negative genetic testing, mosaicism, or more than one NF1 variant were excluded. Of 250 eligible patients, 96 were followed in our Endocrinology department.


Results: Fifty-eight percent were female. Median age at first endocrinology visit was 13 years (1–59), with a median follow-up of 3 years (0–17). Seventy-seven percent were referred during childhood. Overall, 26.0% had at least one ED, including short stature (12.5%), growth hormone deficiency (8.3%), pubertal disorders (9.4%), and adrenal disorders (5.2%). Variant types included insertions, deletions (indels), and duplications (39.6%), missense variants (37.5%), splice-site variants (12.5%), and large deletions (10.4%); 62.5% were truncating. Patients carrying indels/duplications more frequently presented with short stature (p=0.043) and EDs (p=0.007). Large deletions and truncating mutations showed a trend toward a lower (p=0.059) and higher (p=0.051) prevalence of EDs, respectively. Among pediatric patients, pubertal disorders were associated with N-terminal region variants (p=0.042).


Conclusion: EDs in NF1 may be influenced by the underlying genotype. These findings support a genotype–endocrine phenotype association in NF1 and warrant confirmation in larger multicenter cohorts.

Background:
Neurofibromatosis (NF) may affect physical, psychological, and social functioning. To address these multidimensional needs, the NF expertise centre at the Medical University of Vienna provides joint interdisciplinary outpatient consultations with patients and their families, involving medical, nursing, and psychosocial professionals. This study aimed to characterize the most frequently addressed concerns of patients/families and corresponding interventions, and to evaluate the clinical utility of this model of care.

Methods:
Psychosocial documentation was retrospectively analysed using combined qualitative content analysis (Kuckartz & Rädiker, 2024). Data included frequency and type of psychosocial concerns and interventions, as well as the proportion of concerns managed directly during the consultation versus those requiring referral to profession-specific internal/external services.

Results:
Psychosocial documentation from 280 patients with NF and their families who attended the clinic between 2010 and 2026 was included in the analysis. The most frequently addressed concerns comprised (1) fears/worries about disease progression and prognosis, (2) fear of or reluctance toward medical examinations and procedures, (3) communication about the disease/concerns related to stigma, (4) neuropsychological difficulties, (5) educational or career-related issues, and (6) social challenges. Approximately 70% of concerns were managed directly during the consultation through brief psychosocial counselling, including information, guidance, emotional support, and procedural preparation and support. Approximately 30% required referral to internal/external specialized services for comprehensive assessment or intervention.

Conclusion:
From a psychosocial perspective, the model facilitated the early identification of both clinical and subclinical psychosocial distress that might otherwise have remained undetected, thereby enabling timely, integrated psychosocial support and appropriate intervention.

Background: The PAin INtensity Scale for Plexiform Neurofibromas (PAINS-pNF) is a patient-reported outcome measure for assessing plexiform neurofibroma (PN)-associated pain intensity in individuals with neurofibromatosis type 1. This study aimed to quantitatively demonstrate suitability of PAINS-pNF target PN pain scores for KOMET (NCT04924608) endpoint evaluation.
Methods: Test–retest reliability of PAINS-pNF scores was evaluated using intraclass correlation coefficients (ICC). Construct validity was evaluated using the association of PAINS-pNF with Patient Global Impression of Severity (PGIS) and a measure of pain interference with daily life (Pain Interference Index-pNF). Ability to detect change was assessed using PGIS and Patient Global Impression of Change (PGIC). Meaningful score difference (MSD) was evaluated from baseline to Cycle (C) 12 using both anchors.
Results: Adults (n=145) completed the electronic PAINS-pNF daily. Overall, <4% of scores were missing across cycles except C12 (7%). Good-to-excellent ICC: 0.92–>0.95, and adequate-to-excellent: 0.82–>0.95 test–retest reliability was demonstrated with PAINS-pNF chronic and spike target PN pain scores, respectively. Spearman correlations (>0.3) between changes in PAINS-pNF scores and PGIS/PGIC indicated good construct validity. PAINS-pNF chronic target PN pain scores showed good ability to capture improvement between baseline and C12. PAINS-pNF chronic pain scores for half of patients with a one-category improvement in PGIS (baseline C12; n=18) decreased by >2.16; scores for <10% of participants with no change in PGIS (n=25) decreased by >2.00.
Conclusion: PAINS-pNF chronic and spike target PN pain measures demonstrated strong psychometric performance in KOMET participants, with clinically meaningful MSD decreases of 2 and 3 points, respectively.

Background: Adults with NF1 experience difficulties in social communication and interaction, but research is limited. The sub-study examined cognitive domains that may be associated with problems with social responsiveness.
Methods: Adults with NF1 and at-risk tumors enrolled in a surveillance study completed performance tests of inhibitory control and cognitive flexibility (D-KEFS Color-Word Inhibition, Inhibition/Switching), attention (Wechsler Digit Span Forward), and working memory (WRAML). Participants completed self-report measures of attention (CAARS-2), everyday executive functioning (BRIEF-2), and social responsiveness (SRS-2). Spearman correlations examined associations of performance-based and self-reported cognitive outcomes selected a priori with social responsivenss; significance set at p<.05.
Results: Thirty-six adults (18-45 years; male 70%) were evaluated. Among participants with valid SRS-2 data, 35.3% scored > the clinical cutoff on SRS-2 Total and 32.4% were elevated on Social Communication/Interaction and Restricted Interests/Repetitive Behaviors. Performance-based attention was not associated with SRS-2 scores, but self-reported attention/executive function problems were significantly associated with SRS-2 Total (each p< .001). Performance-based working memory was associated with the SRS-2 Total score, Social Cognition, and Restricted Interests/Repetitive Behaviors, (each p<.05); similarly, self-reported working memory was significantly related to all SRS-2 domains (each p<.001). Performance-based inhibition/switching (but not inhibition) was associated with all SRS-2 scores (each p<.01) as was self-reported executive functioning (inhibit, shift, working memory; each p<.001).
Conclusions: Social responsiveness difficulties were common in adults with NF1 and strongly associated with inattention and executive function weaknesses. Findings support the need for interventions targeting cognitive flexibility, working memory, inhibition, and social-communication skills through executive-function coaching and social-skill development.

Background: Selumetinib (ARRY-142886, AZD6244) is approved for adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN), and has been associated with reductions in PN volume and prescription pain medication utilization. Mental health (MH) disorders (e.g., anxiety and depression) associated with NF1-PN may be routinely managed with prescription medications. This observational, retrospective claims analysis evaluated real-world MH medication utilization (sleep medications, benzodiazepines, anti-anxiety medications, and antidepressants) in adults pre- and post-selumetinib initiation.
Methods: Patients were identified via Forian CHRONOS (a US claims database). Inclusion criteria were ≥3 selumetinib prescriptions filled (April 10, 2020–June 30, 2025), aged >21 years at initiation, and ≥12 months of continuous enrollment and pharmacy claims activity pre- and post-initiation. Index was date of first selumetinib prescription fill. Baseline was within 3 months of index. Follow-up was ≤36 months (variable) until end of available data.
Results: Of 160 patients, 55.0% were female (mean [standard deviation] age: 38.3 [12.9] years). At baseline, 45.0% had received MH medication, primarily driven by antidepressants (33.1%). From baseline to follow-up at 36-months, utilization of some MH medications decreased: sleep medications (13.1%->5.7%), benzodiazepines (10.0%->2.9%), and anti-anxiety medications (8.1%->5.7%), while antidepressant utilization remained relatively stable (33.1%->34.3%).
Conclusion: MH medication utilization was high at baseline and was approximately 2–3x greater than the national average for adults in the US. Selumetinib was generally associated with reductions in MH medication utilization within ~3 years post-initiation, while antidepressant utilization (chronic MH medication) remained stable. Additional studies are warranted to better understand the observed trends in MH medication utilization.

Background: This study examined the psychometric properties of new electronic surveys evaluating pNF-related pain intensity and interference for clinical trials developed from extensive qualitative research.
Methods: Adults with NF1-pNF were eligible. Participants completed the two newly-developed PRO measures over two weeks on a mobile app: 1) PAin INtensity Scale for pNF (PAINS-pNF) assessing spike, chronic, and total tumor pain intensity of a target pNF (0-10) averaged per week, and 2) Pain Interference Index for pNF (PII-pNF) assessing tumor pain interference (0-6; average total score) weekly, and validated measures of pain intensity (electronic Colored Analog Scale [eCAS]; 0-100) and pain interference (PROMIS-Pain Interference; T-scores).
Results: Seventy-five adults completed the study (mean age=37 years; 18-69). The PAINS-pNF and PII-pNF demonstrated excellent internal consistency. Test-retest reliability (week 1-2) was excellent for spike, chronic, and total tumor pain intensity and total tumor pain interference. Construct validity was strong for the PAINS-pNF scores through correlations with the eCAS general pain item and PII-pNF total score with the PROMIS-PI (Table 1). Known groups validity was demonstrated by significantly higher pain scores between participants taking versus not taking analgesics, and significantly different pain intensity scores across pain categories (none to severe; p<.001). Analysis of the PII-pNF items indicated one pain interference factor.
Conclusions: These new NF1-specific PRO measures demonstrated excellent psychometric properties. In the KOMET phase III selumetinib trial, they showed sensitivity to change (Chen et al., 2025). Thus, the current study produced reliable and valid electronic tools for assessing pNF-related pain in adult NF1 clinical trials.

Background: Attention deficits are common in neurofibromatosis type 1 (NF1) and cause substantial psychosocial burden; however, their course across the lifespan remains poorly understood. Using Test of Variables of Attention (TOVA) scores, we examined age-related differences across five attention domains in a large NF1 cohort.
Methods: We analysed 1016 individuals with NF1 (5–87 years, M = 20.3 years, SD = 15) attending the NF clinic at University Medical Center Hamburg-Eppendorf (first valid, unmedicated TOVA per person). Age-standardized z-scores for omission, commission, response time, variability and target discrimination served as primary outcomes. Clinical impairment was z ≤ -1.5. Age was modeled continuously and across four age groups (5-9, 10-17, 18-39, ≥ 40).
Results: Mean z-scores were below normative means in all five domains (all p < .001), largest for omission and target-discrimination. Overall, 64% were impaired in ≥ 1 domain. With increasing age, inattention decreased (B = +0.017/year,) and processing speed improved (B = +0.028/year), whereas impulsivity worsened relative to age-based norms (B = -0.026/year; all p < .001). Variability and target discrimination showed no age association. Inattention dominated in early childhood (56% of 5-9-year-olds) and declined with age; impulsivity was rare in young children (8%) but affected 35% of adults aged ≥ 40.
Conclusion: Our study confirmed high frequency of attention deficits in NF1 and demonstrates domain specific age-related differences in attention profiles.
Older age was associated with less severe inattention but increased impulsivity, suggesting a shifting phenotype with differing psychological strain. Our findings support age-specific assessment; global attention scores may obscure domain-specific deficits.

Background
Neurofibromatosis type 1 (NF1) is a heterogeneous tumor predisposition syndrome with substantial variability in phenotype and patient experiences. Although Health-related Quality of Life (HRQoL) is an important outcome measure, current knowledge on HRQoL issues and how to assess them in the broader adult NF1 population is limited. This ongoing scoping review aims to provide an overview of HRQoL issues faced by adults with NF1 and to summarize the HRQoL measures currently used in both clinical research and care.

Methods
Six databases (Medline, Embase, Web of Science, Cochrane, Cinahl and PsychInfo) were searched. Quantitative, qualitative and mixed-method studies were included. Data-extraction and synthesis followed the PRISMA guidelines for scoping reviews.

Results
Out of the 713 identified records, 188 underwent full-text screening, resulting in 80 included studies (59 quantitative, 10 qualitative, and 11 mixed-methods studies). HRQoL was assessed using 53 different instruments (12 generic, 31 domain-specific, and 10 disease-specific) covering physical, cognitive, social, and global health domains. Collectively, these findings indicate that all domains of HRQoL were impacted. Included studies frequently focused on only subpopulations (e.g. patients with plexiform neurofibromas).

Conclusion
This study highlights the diverse HRQoL issues associated with NF1 and underscores the variability among the instruments used. While the identified HRQoL issues spanned the entire biopsychosocial spectrum, none of the evaluated instruments comprehensively addressed all domains. Therefore, a broader measurement strategy is needed, e.g. utilizing item lists, to better address the HRQoL concerns of the broader adult NF1 population and its subpopulations.

Background:
Neurofibromatosis (NF) is associated with complex physical, psychological and social challenges requiring holistic multidisciplinary care (Ferner et al., 2011). In 2022, a specialist social work service was established within a national NF service at Guy’s and St Thomas’ National Health Service Foundation Trust, UK, to address these needs. This study evaluates patient-reported outcomes and experiences of the service.

Methods:
A service evaluation was conducted using an anonymised patient and carer questionnaire. Participants who had accessed the specialist NF social work service were invited to complete a structured evaluation assessing the support received, their experience of the service and perceived impact. A total of 33 respondents participated, comprising 31 patients and 2 carers. Quantitative data were analysed descriptively.

Results:
Respondents reported high levels of satisfaction with the service. Over 90% strongly agreed that the social worker improved their ability to cope with NF-related challenges and supported navigation of healthcare, social services and governmental systems. Patients reported improved access across key domains, most notably emotional support (76%) and financial advice (58%). Additional areas included family support (42%), safeguarding interventions (27%), and advocacy with other services (21%). Qualitative feedback highlighted the value of holistic, person-centred intervention, particularly in addressing psychosocial and practical challenges associated with NF.

Conclusion:
This evaluation demonstrates that a dedicated NF specialist social work service has a significant positive impact on coping, system navigation and overall wellbeing. Embedding social work within NF multidisciplinary teams is essential to address the complex neuropsychosocial needs of this population and supports wider integration of such roles internationally.

Background: Neurofibromatosis Type 1 (NF1) is associated with neurodevelopmental difficulties affecting motor and academic functioning. However, handwriting, a key determinant of school participation and learning, remains poorly characterized. We aimed to characterize handwriting performance in children with NF1 and to highlight the clinical relevance of graphomotor assessment.

Methods: Handwriting quality and speed were assessed using the gold-standard test for the diagnosis of dysgraphia, the Brave Handwriting Kinder (BHK). Moderate and severe handwriting impairment were defined as scores between -1 and -2 SD and ≤-2 below age norms, respectively. A retrospective review of clinical records determined the prevalence of graphomotor difficulties among 42 children with NF1 referred for neurodevelopmental assessment. A prospective case-control study then compared handwriting performance in 21 children with NF1 and 21 typically developing controls from the DYSTACMAP study (ID-RCB 2014-A01239-38), using BHK recordings acquired with a graphic tablet.

Results: Retrospectively, 67% of children with NF1 showed impaired handwriting quality, including 36% with severe deficit whereas 30% exhibited reduced writing speed (4% severe). Similar proportions were observed prospectively, with 71.4% showing impaired handwriting quality (42.9% severe); and 33.3% reduced writing speed (0% severe). Compared with controls, children with NF1 demonstrated significantly poorer handwriting quality (p<.001) and slower writing speed (p=.003). Overall, handwriting quality appeared more frequently and more severely impaired than writing kinematics.

Conclusion: Convergent findings from retrospective paper-based and prospective tablet-based assessments indicate that handwriting impairment is a common but under-recognized feature of NF1. Routine graphomotor assessment should be incorporated into the clinical follow-up of affected children.

Background: NF2 is an autosomal dominant condition, resulting in CNS tumours, which can lead to significant disability and reduced quality of life. Research into mental health difficulties in NF2 remains limited, and its relationship with neurodevelopmental conditions, has not been studied. This service evaluation aimed to determine whether there is an unmet need for diagnosis and support for such conditions within the Manchester NF2 service.
Methods: Electronic patient records (EPRs) were reviewed for patients aged 4-25. A subset completed screening questionnaires for autism (AQ-10), ADHD (SNAP-IV or ASRS-v1.1), psychological distress and learning/memory problems (Royal Marsden Worry & Memory Thermometers). The proportions with diagnosis or symptoms of mental health or neurodevelopmental conditions, and under a specialist service were calculated, and descriptive analysis of EPR notes and distress thermometer responses was completed.
Results: Emotional distress, neurodivergent traits and functional impairment were common. EPR review demonstrated frequent suspicion or diagnosis of depression (34%), anxiety (34%), autism (25%) and ADHD (13%). On questionnaire screening, 77% experienced psychological distress, 60% were high-risk for autism and 72% for ADHD. The rates of mental health and neurodevelopmental concerns were greater on questionnaire screening than EPR.
Conclusion: These findings suggest possible under-recognition of neurodevelopmental and mental health concerns in patients with NF2. Additionally, they support the introduction of routine screening and access to specialist services for mental health and neurodevelopmental assessment and support.

Background: Physical manifestations of neurofibromatosis type 1 (NF1) can cause chronic pain. Research has shown that individuals with NF1 may experience extended time with pain that varies in quality, frequency, and location/site. Individuals with NF1 may have communication challenges or co-occurring diagnoses, making the assessment of pain in this population challenging.

Method: This presentation will describe methods and strategies for pain assessment in populations with complex communication needs.

Results: Patient Reported Outcome Measures, Parent Proxy Outcome Measures, Observational Scales, and Biometric Measures will be discussed as options for the assessment of pain in individuals with NF1 with complex communication needs. Considerations for assessment with individuals who are non-speaking and strategies for clinicians in the assessment of pain for these individuals will be discussed.

Conclusions: The assessment of pain in individuals with NF1 with varied communication needs is complex and requires a team approach.

Background: Neurofibromatosis type 1 (NF1) affects approximately 1 in 2600 individuals and increases the risk of benign and malignant tumors. Tumorigenesis typically requires somatic inactivation of the second NF1 allele, yet the earliest cellular events following this second hit remain poorly understood. We aim to establish a second-hit model of NF1-associated brain tumorigenesis in whole-brain organoids (WBOs), derived from induced pluripotent stem cells (iPSCs) from a three-generation family with heterogeneous clinical presentations.
Methods: Fibroblasts from three affected family members were reprogrammed into iPSCs. To distinguish variant-specific from genetic-background effects, CRISPR-Cas9 was used to introduce the same variant into iPSCs from a healthy donor. All clones were characterized by karyotyping, microscopy, expression of pluripotency markers, tri-lineage differentiation, and embryoid body (EB) formation. Dual-SMAD and MEK inhibition were applied to optimize EB and subsequent WBO formation.
Results: We generated and validated patient-derived and isogenic iPSC lines as a source for WBO formation. All clones displayed intact karyotypes and typical iPSC morphology, with pluripotency confirmed by analysis of SOX2, OCT4, SSEA4 and TRA-1-60. Tri-lineage differentiation capacity was verified, showing endodermal (SOX17/FOXA2) and mesodermal (BRACHYURY) marker expression. Ectodermal differentiation yielded low Nestin expression and reduced SOX2 expression in NF1-mutant clones, possibly representing an early, variant-associated effect on neuroectodermal commitment.
Conclusion: We established patient-derived and isogenic iPSC lines that provide the foundation for a faithful second-hit model in WBOs, enabling characterization of the earliest steps of NF1-associated brain tumorigenesis. Additionally, our three-generation family model offers a unique opportunity to assess potential contributors to the marked clinical variability of NF1.

TauT a Cell to Transport, Fed it for a Lifetime: Role of SLC6A6 on Metabolism and Proliferation in MPNST Cells

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare and aggressive soft tissue sarcomas with a poor prognosis that disproportionately affect patients with Neurofibromatosis type 1 (NF1). Taurine is known to support mitochondrial respiration, translation, cellular homeostasis, and energy production; however, the importance of taurine and its transporter, SLC6A6 (TauT), remains unclear in MPNST biology, possibly representing a metabolically relevant vulnerability. We aim to investigate whether TauT contributes to the proliferation, survival, and morphology of malignant peripheral nerve sheath tumor cells.

Methods: To evaluate this possibility, JHU2-002, JHU2-103, and JHU2-079-c cells were treated with the TauT inhibitor guanidinoethane sulfonate (GES), assessed through proliferation and morphology-based assays, and compared with cells undergoing lentiviral shRNA-mediated TauT knockdown.

Results: Preliminary results suggest that inhibition or knockdown of TauT reduces proliferation and alters cell morphology in a condition- and cell-line-dependent manner.

Conclusion: These findings support further investigation of TauT as a potential metabolic functional dependency in MPNST and lay the foundation for future studies using validated knockout models, localization studies, and transcriptomic analyses to define the mechanisms linking taurine transport to MPNST growth.

Background:
Genetic mosaicism arises from postzygotic mutations and is known to be frequent in schwannomatosis. In NF1, mosaicism is less well known. However, in more than 50% of NF1 cases, the pathogenic NF1 variants are not inherited and therefore they can be potentially mosaic. Mosaicism shifts the clinical spectrum toward the milder end.
Method:
A 65 years old patient having multiple lipomas which resembel subcutaneous neurofibromas were clinically and genetically examined.
Results:
An atypical large NF1 deletion of ~1.3Mb was detected in 87% of the blood cells, and 8 to 20% in the 5 lipomas. However, comprehensive and exhaustive clinical and radiological examinations did not detect any neurofibromatosis type 1-related clinical symptoms.
Conclusion:
Due to mosaicism, some de novo pathogenic NF1 variants may not lead to sufficient phenotypes in the carriers so that they do not appear as patients. In addition, de novo cases can be mosaic even when the pathogenic variant appear at an apparently heterozygous level in the blood.

Background: Cutaneous neurofibromas (cNFs) harbor a rich immune microenvironment including mast cells, T cells and macrophages. Here, we aim to explore the between-tumor variation of immune cells in cNFs.

Methods: Fifty cNFs from ten individuals with neurofibromatosis 1 were analyzed. The tumor and the overlying epidermis were annotated using the QuPath software to measure the shortest distance between the epidermis and the tumor, and intratumoral cells positive for immune cell markers were counted.

Results: The distance between the epidermis and the tumor varied from 8.5 µm to 1,460 µm. The distance between the cNF and epidermis was not associated with patient age, tumor site, the presumed growth status of the tumor, or tumor size. Compared with more superficial tumors, deep-seated cNFs displayed significantly lower densities of cells positive for the T cell marker CD3, the cytotoxic T cell marker CD8, and the regulatory T cell marker FoxP3 (P<0.001). We observed no association of epidermis–cNF distance with the densities of cells positive for the macrophage markers CD68 and CD163, or the mast cell marker CD117.

Conclusion: The cNFs display marked between-tumor variation in immune infiltration. Tumor location within the dermis affects the density of T cells but not the density of macrophages or mast cells. Further studies are required to understand the mechanisms of immune cell infiltration into cNFs.

Background: Plexiform neurofibromas (PNFs) in neurofibromatosis type 1 (NF1) can present significant technical challenges when lower limb arthroplasty is required. Extensive soft tissue involvement may prevent safe surgical exposure, compromise wound closure and increase perioperative morbidity. A collaborative approach between plastic and orthopaedic surgeons may facilitate successful joint replacement in selected patients.
Methods: We reviewed our experience of patients with NF1 undergoing staged or synchronous debulking of PNFs to enable hip arthroplasty. Operative planning, intraoperative findings and postoperative outcomes were assessed, with particular focus on bleeding, wound healing and functional recovery.
Results: Debulking of PNFs improved surgical access and enabled hip arthroplasty in patients who would otherwise have presented considerable technical difficulty. Despite the characteristic appearance of PNFs, intraoperative bleeding remained a concern, necessitating meticulous haemostasis and multidisciplinary planning. Wound healing was frequently prolonged, reflecting the abnormal soft tissue environment and extensive surgical dissection required. In some patients, the residual soft tissue envelope failed to provide optimal support for the prosthetic joint, creating additional challenges and revision surgery. These findings emphasised the importance of careful patient selection, realistic preoperative counselling and coordinated postoperative management.
Conclusions: Debulking PNFs can facilitate successful hip arthroplasty in carefully selected patients with NF1, but the procedure carries unique operative risks. Surgeons should anticipate substantial blood loss, delayed wound healing and compromised soft tissue support around the arthroplasty. Close collaboration between orthopaedic and plastic surgeons is essential to optimise outcomes, minimise complications and support complex perioperative decision-making.

Neurofibromatosis type 1 (NF1) is characterized by the development of benign plexiform neurofibromas (PNFs). In 10–15% of patients, these tumors undergo malignant transformation into aggressive malignant peripheral nerve sheath tumors (MPNSTs). The underlying mechanisms driving this malignant progression remain poorly understood, hindering the development of effective therapies. To address this gap, we performed single-cell RNA sequencing on 9 PNF and 5 MPNST samples. Our analysis revealed tumor microenvironment remodeling during malignant progression, marked by a significant increase in immune cells. Within the macrophage compartment, we identified 3 distinct SPP1+ subpopulations. Among these, the SPP1+KYNU+ subset exhibited pronounced upregulation of genes related to tryptophan metabolism. This metabolically active macrophage population exhibited strong interaction with POSTN+ fibroblasts enriched in MPNSTs. Functional experiments found that this crosstalk promotes fibroblast activation and enhances migratory capacity. Furthermore, the metabolic reprogramming of SPP1+KYNU+ macrophages was associated with the establishment of an immunosuppressive microenvironment characterized by T cell dysfunction. Collectively, our findings define a central role for SPP1+KYNU+ macrophages in coordinating both stromal remodeling and immune suppression during MPNST progression. These results not only advance our understanding of NF1-associated tumorigenesis but also identify tryptophan metabolism as a promising therapeutic target and potential diagnostic biomarker for MPNSTs.

Background:
Vestibular schwannomas (VS) are benign tumours of the vestibulocochlear nerve that occur either sporadically or in NF2-related schwannomatosis (NF2-SWN). Both conditions are associated with inactivation of the tumour suppressor gene NF2, resulting in loss or dysfunction of merlin. Schwann cells represent the neoplastic compartment and one of the most abundant cell populations in VS, yet the consequences of NF2 deletion or mutation in this tumour compartment remain poorly defined.

Methods:
Immortalised murine Schwann cells carrying exon (Ex) 2-3 deletion, selected as a clinically relevant model of altered merlin expression, and Ex 1-6 deletion, designed to abolish merlin expression, were generated. Proliferation, cell surface area, migration, and expression of Schwann cell markers were assessed. Bioinformatic analysis of single-cell transcriptomic data from human VS was performed to examine Schwann cell heterogeneity in vivo and compare it with the in vitro models.

Results:
Schwann cells with merlin mutation or loss exhibited increased proliferation, enlarged cell surface area, and enhanced migratory capacity. Moreover, these cells broadly retained expression of core Schwann cell markers, with only limited acquisition of repair-like features observed in vivo.

Conclusion:
These findings indicate that merlin alteration directly affects Schwann cell behaviour, with exon 2-3 knockout Schwann cells providing a relevant model for studying merlin dysfunction. Moreover, VS-associated Schwann cell heterogeneity is not fully recapitulated in vitro and is likely shaped by the in vivo tumour microenvironment.

Background:
Selumetinib has demonstrated efficacy in treating symptomatic, inoperable plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1), promoting tumor volume reduction and patient-reported improvement. However, dermatological adverse effects may impose a significant burden and negatively influence treatment adherence. This study aimed to characterize dermatological manifestations associated with selumetinib therapy and assess their impact on daily life in NF1 patients.

Methods:
A descriptive quantitative study was conducted in NF1 patients with symptomatic, inoperable PN receiving selumetinib and followed at a specialized clinic until December 31, 2024. Adult participants provided informed consent, while for under 18 years, consent and responses were obtained from parents. Data were collected using a questionnaire evaluating current and past dermatological adverse events and their impact on daily activities, including school or work performance, sleep, physical activity, social interactions, and emotional well-being.

Results:
Of 93 eligible patients, 22 were excluded, yielding a final sample of 71 individuals (48 male, 23 female) with a mean age of 17 years. Current dermatological manifestations were reported by 62 patients, most frequently xerosis (41), facial acne (24), extrafacial folliculitis (19), and paronychia (16). Previous events were reported by 55 participants, particularly paronychia (22), folliculitis (18), and xerosis (10). Overall, 39 participants reported a negative impact on daily life, especially in physical activity (22), mobility (20), and self-esteem (19).

Conclusion:
Dermatological adverse effects are common and significantly affect the life in NF1 patients treated with selumetinib. Their recognition is essential to improve multidisciplinary care, optimize management strategies, and enhance treatment adherence in practice.

Background: Hybrid neurofibroma-schwannoma (HNS) are benign peripheral nerve sheath tumors containing schwannoma-like and neurofibroma-like histological areas. HNS occur sporadically or in association with schwannomatosis and, less frequently, neurofibromatosis type 1 (NF1). Despite their clinical relevance, their molecular features remain poorly understood.

Methods: We assembled a cohort of 58 histologically confirmed HNS. Targeted DNA sequencing was performed on tumor tissue and, where available, matched blood samples. Single-nucleus RNA sequencing (snRNA-seq) was conducted of 14 HNS, 5 schwannomas and 5 neurofibromas.

Results: The cohort comprised 38 patients aged 12 to 73 years. Most tumors arose in the extremities (n=36), with additional cases in head, neck, vertebral and pelvic regions. 13 patients had a genetically confirmed tumor predisposition syndrome comprising LZTR1-associated (n=6), NF2-associated (n=4) and SMARCB1-associated (n=2) schwannomatosis, as well as NF1 (n=1). 8 patients had clinical symptoms of a tumor predisposition syndrome without available germline testing. 5 tumors from 3 patients harbored ERBB2 alterations. Previously unreported pathogenic variants for HNS were identified in SMARCA4, SMARCE1, SOX10, RAF1 and FAT1.
Transcriptionally, schwann cell-derived tumor cells in HNS more closely resembled schwannomas than neurofibromas in both cellular composition and molecular profile. Consistent with their hybrid histology, HNS displayed a mesenchymal-rich microenvironment that was significantly more abundant than in schwannomas.

Conclusion: Our findings expand current knowledge of the genomic landscape of HNS by identifying a diversity of mutational combinations and novel candidate driver alterations. SnRNA-seq indicates greater molecular similarity of HNS to schwannomas than to neurofibromas, a finding that will further be investigated using spatial methylation and transcriptomic analyses.

Background:
Schwannomas cause chronic pain, neurological deficits, and impaired quality of life, while effective nonsurgical therapies remain limited. LZTR1 and NF2 are key genetic drivers of schwannomatosis. LZTR1 loss increases RAS abundance and MAPK pathway activity, whereas NF2 loss deregulates Hippo signaling and promotes YAP/TAZ-TEAD-dependent transcription. We hypothesized that pharmacological inhibition of RAS signaling, TEAD activity, or their combination could constrain schwannoma progression. Here, we evaluated the pan-RAS(ON) inhibitor RMC-6236 and the TEAD inhibitors VT104 and VT3989 in genetically defined schwannoma models.

Methods:
Stable shRNA-mediated LZTR1 knockdown and shGFP control cells were generated in NF2-mutant HEI-193 cells. MTT, 2D clonogenic, and soft-agar assays evaluated responses to RMC-6236, VT104, or their combination. Time-course transcriptional profiling explored the underlying mechanisms. In vivo evaluation is ongoing.

Results:
High doses of single agents exerted moderate effects in short-term MTT assays, whereas their combination achieved comparable growth suppression at lower concentrations. In 2D clonogenic assays, single agents showed limited efficacy, while combined inhibition abolished colony formation. Similarly, in soft-agar assays, single-agent treatment reduced anchorage-independent growth, whereas dual RAS-TEAD inhibition completely blocked colony formation. Responses were comparable between shGFP and shLZTR1 cells. Mechanistically, RMC-6236 rapidly suppressed ETS/ELK-dependent transcriptional output, whereas TEAD inhibition alone had little effect on this program. Combined inhibition cooperatively repressed TEAD-dependent transcription, with canonical TEAD targets significantly suppressed by the combination at 2 h.


Conclusion:
Our findings demonstrate that combined pan-RAS and TEAD inhibition potently suppresses schwannoma growth and cooperatively represses TEAD-dependent transcription, supporting further preclinical evaluation of this strategy in NF2-mutant schwannoma.

Background: The Phase 3 KOMET study (NCT04924608) evaluated selumetinib (ARRY-142886, AZD6244) in adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). At study initiation, no approved therapies existed for adults with NF1-PN. This sub-study characterises the adult experience with selumetinib in KOMET.
Methods: KOMET participants who consented to the sub-study in Germany, the UK, Italy, Spain, Canada and the USA were included. Trained moderators conducted three semi-structured 1:1 teleconference interviews (February 2022–December 2024).
Results: Participants were aged 18–59 years (female: 52%; White: 80%). At interview 1 (baseline: n=13 selumetinib; n=12 placebo), target PNs were mostly in the head/neck (28%) and trunk (24%). Common symptoms were chronic pain (80%), sensitivity/numbness (48%), episodic/spike pain (36%), swelling (32%) and itching (28%). Highest reported impacts were on movement (56%), exercise (52%) and school/work (44%). At interview 2 (cycle [C]12; n=12 selumetinib; n=10 placebo), all except one selumetinib participant reported symptom- and impact-improvements, including reduced pain, tingling and PN size, with improvements in sleep, fatigue and mobility; no observed notable changes with placebo. By interview 3 (~20 months post-randomisation; n=8 selumetinib; n=8 crossover [8C selumetinib and 12C placebo]), changes were sustained or further improved for most selumetinib participants. Crossover participants (~8 months of selumetinib) reported similar benefits, including improved sleep, mobility and engagement in physical and social activities.
Conclusion: This study provides qualitative evidence that selumetinib is associated with meaningful improvements in symptoms and daily functioning in adults with NF1-PN, complementing the primary efficacy and patient-reported outcomes results from KOMET.

Background: Selumetinib is the standard systemic therapy for children with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). However, access to MEK inhibitors remains limited in many low- and middle-income countries, often requiring legal action to obtain drug coverage. We report the real-world experience of a Brazilian pediatric oncology referral center, focusing on delays in treatment initiation.
Methods: We retrospectively reviewed seven children with NF1 and symptomatic, inoperable PN treated with selumetinib. Clinical characteristics, time to treatment, adverse events, and clinical outcomes were analyzed.
Results: Seven patients (4 males, 3 females) initiated selumetinib at a median age of 9.0 years. The median interval from treatment indication to therapy initiation was 13 months (range, 7–22), and all obtained access exclusively through legal action. During this period, all had clinically significant symptomatic disease requiring systemic therapy. Common manifestations included pain, dysphagia, dyspnea, visual impairment, headache, hearing loss, motor impairment, and sleep-related symptoms. After a median treatment duration of 12 months, all remained on therapy, experienced meaningful symptomatic improvement, and showed no clinical disease progression. Adverse events were exclusively grade 1–2, most commonly diarrhea, nausea, acneiform rash/dermatitis, headache, dizziness, and hyperhidrosis. One patient required dose reduction because of diarrhea.
Conclusions: Although limited by the small sample size and short follow-up, this real-world experience supports the favorable safety profile and clinical benefit of selumetinib in children with symptomatic NF1-associated PN. Reliance on legal action substantially delayed treatment initiation, highlighting the need for public policies ensuring timely and equitable access to MEK inhibitors.

Background:
Nerve Tumours UK (NTUK) developed a national model embedding specialist clinicians within NHS services, alongside a national helpline. Regional NF clinicians provide specialist advice, patient and family support, educational outreach, school liaison, transition planning and specialist clinics.
This model enables local care, while maintaining integration with specialist centres and multidisciplinary teams. Improving access to expert local care, supporting families and enhancing professional education.

Methods:
Our Network Model was evaluated employing two methodological components:
(1) a service quality assessment was conducted using structured satisfaction surveys completed by service users capturing, patient experience and quality of care.
(2) clinician activity audit was undertaken to examine practice patterns, service delivery and workload distribution.
Data was systematically analysed to evaluate service effectiveness, quality of provision and user experience.

Results:
The service quality assessment indicates improved NF knowledge and understanding among service users and families. Areas for improvement identified pain management and mental wellbeing support.
Baseline clinician activity audit demonstrates a high volume of activity with strong engagement. In regions where clinics are established, provision appears proportionally balanced, whereas NF2 clinic activity is lower, reflecting prevalence.

Conclusion:
The NTUK Network Model represents an innovative, scalable model, embedding specialist clinical expertise into local services to improve access to support, education and providing NF specialist patient-centred care closer to home.
Results present a model baseline review, demonstrating areas for improved service delivery. Identified priority areas should be addressed and re-audited to evaluate ongoing service improvement.

Background:
While the environmental impact on patient experience is increasingly recognised, people with sensory challenges (including visual, hearing and sensory processing differences) still experience inequitable healthcare access. Our systematic review identified a research gap in outpatient settings and sensory challenges, highlighting the value of participatory, experience-based research. This study addresses this gap by supporting collaborative co-design improvements within our Neurofibromatosis service.

Methods:
This protocol outlines a modified Experience Based Co-Design (EBCD) approach incorporating walking-interviews and arts-based co-design. It is underpinned by a post-constructivist, pragmatic philosophy and aligned with the Medical Research Council Framework for Developing and Evaluating Complex Interventions. This 30-month qualitative participatory study explores outpatient experience for people with sensory challenges, identifies barriers and facilitators, and co-designs interventions to improve patient and staff outcomes.

Up to 30 participants will be purposively sampled across four stages:
•Understanding context (~30 hours of observations).
•Collecting information (patient walking-interviews; staff focus groups).
•Priority setting (patient and staff co‑design workshops).
•Co-design (patient and staff improvement groups).

Data will be analysed using Reflexive Thematic Analysis and Reflexive Content Analysis. Process evaluation will explore feasibility, acceptability and methodological modifications.

Results:
Collaboratively developed, context‑specific improvements to outpatient departments alongside analysis of EBCD adaptations.

Conclusion:
This protocol addresses research gaps through collaborative co‑designed outpatient improvements. Transparent reporting will aid transferability of findings and methodological adaptations.

This project is funded by the NIHR; views expressed are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.

Background: Neurofibromatosis type 1 (NF1) is a complex genetic disorder associated with an increased risk of tumor development and substantial healthcare burden. Multidisciplinary care is essential to optimize management and actively involve patients and families in clinical decision-making. In 2024, Meyer Children’s Hospital (Florence, Italy) established a dedicated multidisciplinary clinic for NF1-associated tumors.
Methods: We retrospectively reviewed the clinic activity from January 2024 to June 2026. Overall, 144 patients with a clinical and/or molecular diagnosis of NF1 were followed at our institution. Twenty-nine patients with tumor-related complications were evaluated during 15 multidisciplinary meetings involving neurologists, neuro-oncologists, neurosurgeons, plastic surgeons, dermatologists, ophthalmologists, radiologists, neuroradiologists, and psychologists. Following joint assessment, patients and caregivers discussed diagnostic findings, surveillance, and treatment options, leading to individualized management plans.
Results: Twenty-four patients were evaluated for isolated plexiform neurofibroma, two for plexiform neurofibroma associated with optic pathway glioma, two for isolated optic pathway glioma, and one for malignant peripheral nerve sheath tumor. Management included clinical surveillance (34%), selumetinib therapy (34%), plastic surgery (38%), neurosurgery (14%), chemotherapy (7%), and orthopedic surgery (3%). Adherence to the proposed management plan was 96.6% (28/29 patients). Families appreciated the opportunity to meet all specialists during a single visit, receive immediate feedback, and actively participate in treatment planning.
Conclusion: A dedicated multidisciplinary clinic improved coordination of care, promoted patient and family involvement, facilitated shared decision-making, and represents a reproducible model for the management of NF1-associated tumors.

Background:
Despite its importance in healthcare, evidence of outpatient department experience remains incomplete. This review synthesises qualitative research exploring patient and staff experiences of the built environment in outpatient departments.

Methods:
A systematic search of MEDLINE, PsycINFO, Scopus, Web of Science and the RIBA Catalogue identified qualitative studies published 2012–2023 (rerun in 2025). Eligible studies included adults and used qualitative data collection and analysis. No language limits were applied. Studies were not excluded through a quality threshold but methodological limitations were noted. Two reviewers independently screened and extracted data. A modified biopsychosocial model provided an analytic framework and reflective thematic analysis supported synthesis of final meta-ethnographic interpretations.

Results:
Of 843 records screened, 48 contributed to a contextual overview. Six studies met criteria for full synthesis examining experience of outpatient environments. The overview contextualised final interpretations derived from the meta-ethnographic synthesis.

Findings highlight the multi-layered complexity of outpatient environments: Outpatient environments provoked anxiety and frustration related to physical and emotional safety, presence of sickness, spatial layout, and access to care. This can be exacerbated by divergent needs of individuals seeking care vs the healthcare process.

Conversely healthcare spaces can support positive experience, providing symbolic meaning, social connection and positive distraction.


Conclusion:
Experiences of outpatient environments are underexplored. Outpatient design can increase anxiety and reduce perceived safety or, when thoughtfully considered, support positive experiences.

This project was funded by the NIHR; views expressed are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.

BACKGROUND: Plexiform neurofibromas (PN) are a common feature of neurofibromatosis type 1 (NF1). This study aimed to improve understanding of direct and associated NF1-PN burden in Swedish adult patients.

METHODS: This retrospective longitudinal cohort study utilized Swedish National Patient Registry and Prescribed Drug Registry (2005–2023). It included patients with NF1 (ICD-10 Q85.01); PN was identified using ICD-10 D36.1and D31.6 as proxy codes. Index date was the first PN diagnosis. Descriptive statistics were generated pre- and post–index, including 1-year pre/post-diagnosis periods.

RESULTS: Of 5356 patients with NF1, 575 (10.7%) had a PN diagnosis; of these, 479 (83.3%) were adults aged ≥18 years, representing 8.9% of the overall NF1 cohort (median age: 42 years). Overall, 62.1% of the NF1 and PN diagnoses occurred between ages 26–64 years. During the post-diagnosis period (median: 12.1 years), the number of patients diagnosed with gastrointestinal stromal tumor increased 11-fold, breast cancer 1.3-fold, constipation 1.5-fold, hypertension 1.5-fold, and epilepsy 0.8-fold. Before index date, 31% had a pain diagnosis. Prescribed medication use increased 1-year post-diagnosis versus pre-diagnosis for opioids (+58%), other analgesics (+31%), gabapentin (+27%) and antidepressants (+24%). Post-index, healthcare resource utilization (HRU) increased, with hospitalizations increasing 1.36-fold and average annual surgeries 1.24-fold higher.

CONCLUSION: Findings reveal post-diagnosis increases in comorbidities, medication use, and HRU for adult patients with NF1-PN in Sweden, highlighting the substantial disease burden and importance of well-integrated multidisciplinary care. Notably, this ICD-10-based retrospective analysis may underestimate PN prevalence and limit assessment of associations with medication use and comorbidities.

Background: Neurofibromatosis type 1 (NF1) is a condition diagnosed in childhood, with plexiform neurofibromas (PN) being a significant complication. This study aimed to improve the understanding of direct and associated NF1-PN burden in Swedish pediatric (aged 0–17 years) patients.
Methods: This retrospective longitudinal cohort study utilized data from the Swedish National Patient Registry and Prescribed Drug Registry (2005–2023). It included patients with NF1 (ICD-10 Q85.01); PN was identified using ICD-10 D36.1 and D31.6 as proxy codes. Index date was the first PN diagnosis. Descriptive statistics were generated pre- and post–index, including 1-year pre/post-diagnosis periods.
Results: Of 5356 patients with NF1, 575 (10.7%) had a PN diagnosis; of these, 96 (16.7%) were aged <18 years, representing 1.8% of the overall NF1 cohort (median age: 13 years). During the post-diagnosis period (median: 12.2 years), the number of pediatric patients with NF1-PN diagnosed with anxiety disorder increased 12-fold, hypertension 5-fold, abdominal pain 1.9-fold, benign brain/CNS tumors 1.7-fold, and ADHD 1.2-fold. Before index date, 32% had a pain diagnosis. Prescribed medication use increased 1-year post-diagnosis versus pre-diagnosis for antidepressants (+100%), gabapentin (+67%), and MEK inhibitors (+67%). Over the full observational period, opioid use increased 5-fold following diagnosis. Post-index, healthcare resource utilization (HRU) increased, with hospitalizations up 125%.
Conclusion: Findings reveal a post-diagnosis rise in comorbidities, medication use, and HRU for pediatric patients with NF1-PN in Sweden, highlighting the complex disease burden. Notably, this ICD-10-based retrospective analysis may underestimate PN prevalence and limit assessment of associations with medication use and comorbidities.

Background: This study describes natural history, clinical characteristics, disease burden and treatment patterns among adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) treated in French NF1 specialist centres.
Methods: This retrospective, multicentre observational study included adults (≥18 years) with NF1-PN identified from 2010–2018 across 10 centres. Medical record data were analysed at baseline (mean follow-up: 4.8 years), with data collection ending December 2023. The most clinically relevant PN was designated as the ‘target PN’ for longitudinal assessment.
Results: Of 83 enrolled patients, 57.8% were female (mean age 36.3 years). NF1 origin was sporadic (51.8%), hereditary (39.8%) and not reported (8%). Target PN were internal (36.1%), external (28.9%) or both (33.7%), and most commonly in the lower extremities (27.7%) and trunk (18.1%). Inoperability was primarily due to anatomical constraints (86.7%). At baseline, 80.7% had PN-related morbidity, mainly pain (56.6%). Over follow-up, pain persisted in 61.4%; motor dysfunction doubled (7.2% to 14.5%). Overall, 23.3% underwent PN surgery (17/73 patients), with complications in 5.9% (1/17). Healthcare resource use increased substantially, from 7.2% of patients with ≥1 NF1-PN-related hospitalisation at baseline to 31.3% over follow-up, and from 6.0% with ≥1 surgical procedure at baseline to 39.8% over follow-up. Analgesics were recorded in 13–21% of visits; systemic therapies were rarely used. Disfigurement was documented in ~12% of patients.
Conclusions: Adults with NF1-PN experience persistent morbidity and limited treatment options. Current management relies on partial surgery and symptomatic care, highlighting the need for effective systemic therapies and standardised pain assessment.

Background: There are limited real-world data on the burden of neurofibromatosis type 1-associated plexiform neurofibroma (NF1-PN) for adult patients in Japan. This study describes patient demographics and clinical characteristics, highlighting the impact of NF1-PN in Japan.
Methods: Data were gathered via the Adelphi Real World Disease Specific Programmes™, using a cross-sectional survey, with elements of retrospective data, for adults with NF1-PN and treating physicians in Japan (August 2025–April 2026). Patient demographics, clinical characteristics, resource use and humanistic data were collected; analyses were descriptive.
Results: Twenty-six physicians (50% dermatologists) provided data on 81 patients: mean (standard deviation [SD]) age was 35.3 (17.0) years, 57% were male and 42% were employed (work absence: mean [SD] 1.3 [4.3] days/month).
Physicians reported 53% of patients had an Eastern Cooperative Oncology Group performance status of ≥1 (some restriction). Patients experienced pain (46%) and skin/subcutaneous tissue disorders (37%). Physicians reported patients had ≥1 PN located on the arms (35%), neck (33%) and legs (28%); 43% had impairments in ambulation and 41% in transportation.
Surgery was reported for 39% of patients, most recent procedures included neurofibroma resection (52%) and excision (42%). Over a quarter (26%) had clinically significant PN for which surgery had not been performed.
For patients who self-reported health-related-quality-of-life (n=18), mean (SD) EQ-5D-5L was 0.76 (0.11); 89% reported some level of pain via NRS-11 (>0 scored).
Conclusion: These findings describe the adult population with NF1-PN in Japan, highlighting clinical burden and impact on daily life, showing impact to ambulation/transportation is a potential barrier to regular follow-up for some.

Background: This study characterises disease burden among adults with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) in Europe.
Methods: Descriptive analyses were performed on demographics, clinical characteristics, perceived severity, PN features (including location and surgeries) and work-productivity. Data were retrospectively collected (June–November 2025) from the Adelphi Real World Disease Specific Programme™, a cross-sectional survey, for adults diagnosed with NF1-PN in Germany, Italy, Spain and the UK (reported by their physicians).
Results: Data from 330 patients (Germany, 29%; Italy, 31%; Spain, 24%; UK, 16%) provided by 74 physicians (neurologists, 34%; dermatologists, 31%; oncologists, 14%; other, 23%) were analysed. Mean (standard deviation [SD]) patient age was 35.0 (13.7) years, 56% were male, 95% White, 45% employed. Physicians rated 37% of NF1-PN cases as moderate–very severe, and 65% of patients scored 1–4 on the Eastern Cooperative Oncology Group scale. Patients had ≥1 PN in the legs (46%), arms (38%), chest (30%), neck (30%) and spine (24%). Among those with spinal PN, the largest PN were internal (84%) and in the legs (30%). Pain (50%) and skin-related disorders (40%) were the most common NF1/NF1-PN-related symptoms. Overall, 54% of patients had undergone NF1-PN-related surgery. For those employed, work was affected in 50%; 30% reduced their working hours. Mean (SD) missed days of work per month due to NF1-PN were 1.7 (3.0) days.
Conclusions: Adults with NF1-PN in Europe experienced substantial clinical burden, including symptomatic disease, high surgical intervention rates and meaningful work-productivity loss, highlighting the significant functional and humanistic impact of the condition.

Background: Real-world data for adults with neurofibromatosis type 1-associated plexiform neurofibroma (NF1-PN) in China are limited. This study describes demographics/clinical characteristics and burden of NF1-PN.

Methods: Data were gathered via Adelphi Real World Disease Specific Programmes™, a cross-sectional survey, with elements of retrospective data, for adults with NF1-PN and treating physicians in China (September 2025–April 2026). Patient demographics/clinical characteristics, resource use and humanistic data were collected; analyses were descriptive.

Results: Forty-nine physicians (most common speciality: oncology [43%]) provided data on 104 patients: mean (standard deviation [SD]) age was 34.0 (14.1) years, 59% were male, 37% were employed (work absence: mean [SD] 3.9 [4.5] days/month).

Physicians reported 87% of patients scored ≥1 (some restriction) on the Eastern Cooperative Oncology Group scale. Patients experienced pain (67%), skin/subcutaneous tissue disorders (63%) and nervous system disorders (40%).

Patients had ≥1 PN located on the arms (47%), legs (44%), neck (36%) and spine (34%); for 24%, the most clinically relevant PN was in the spine.

Physicians monitored patients via physical (83%), skin (77%) and neurological (77%) examinations. Patients attended a mean (SD) of 3.8 (3.1) consultations in the year preceding survey, experiencing a mean (SD) 2.0 (3.6) hospitalisations.

For those who underwent surgery (45%), the most recent procedure was neurofibroma excision (52%).

Of the 104 patients, 50 provided self-reported data; mean (SD) EQ-VAS was 67.5 (15.9); 47.8% (23.8) reported activity impairment via the Work Productivity and Activity Impairment tool.

Conclusion: These findings describe the Chinese adult population with NF1-PN, highlighting clinical burden, with physicians noting pain as prevalent.

Background: Plexiform neurofibroma (PN) is a benign tumour and a key diagnostic feature of neurofibromatosis type 1 (NF1). PNs involve multiple nerve fascicles and can cause disfigurement, pain, and compression of adjacent structures. Recent National guidelines has introduced Selumetinib, a Mitogen-activated protein kinase kinase inhibitors(MEKi), as a disease-modifying treatment for children with symptomatic,/inoperable PN. Cases are referred to a National Multidisciplinary Team (MDT) for treatment consideration.
Method: A retrospective audit of 44 children with NF1 and PN attending the Alder Hey NF1 service was undertaken using a structured review of electronic patient records over a 10-year period.
Results: Median age of PN diagnosis was 3.6 years, M:F 1:1. PN was most commonly located in the craniomaxillofacial region (43.2%, n=19), with 18.2% (n=8) involving central sites like brachial plexus or mediastinum. Pain was the most frequent symptom (30%, n=13), while 18% of patients with central PN experienced feeding difficulties or aspiration. Non-specific symptoms were present in 59.1% (n=26), with a proportion identified on clinical assessment or incidental findings. Most patients were managed conservatively. Surgical debulking was performed in 41% (n=18), with 38.8%% (n=7) requiring multiple procedures. Selumetinib was considered as adjunct to treatment in 9.1% (n=4).
Conclusion: PN management in NF1 requires a multidisciplinary approach. Selumetinib offers an alternative option for inoperable cases High index of suspicion is required to identify cases early, given the frequency of non-specific presentations. A local MDT has been developed to facilitate earlier discussion and streamline referrals to the National MDT to improve patient outcomes.

Background:
NF1 is associated with symptomatic inoperable plexiform neurofibromas. MEKi have been available on compassionate use since 2017. A quarterly national MEK multidisciplinary team meeting (MDT) was established in 2017 between the two Highly Specialised Services (HSS) for Complex NF1 based in Manchester and London, to consider suitability for treatment. In May 2022, Selumetinib (MEKi), was approved as targeted treatment by the National Institute for Clinical Excellence (NICE).

Methods:
A retrospective review of children submitted for MDT discussion was conducted. A comparison was made between two cohorts:

Cohort 1 - Pre NICE approval (2017 - 05/2022) 31 patients

Cohort 2 - Post NICE approval (05/2022 - 06/2026) 34 patients

Results:
· The number of patients approved at first discussion increased significantly in cohort 2 – up to 70% versus 41% in cohort 1.

· The median age of patients is lower in cohort 2 – 8.5 years versus 11 years

· The number of patients aged ≤4 approved has increased from 11% of patient discussions in cohort 1, to 29% in cohort 2.

Conclusion:
Over 9 years there has been an observational shift in the HSS Manchester Cohort of children being treated with MEKi.

· Increased treatment approval rates at first MDT review.

· Earlier identification and treatment of younger children.

· Greater utilisation of MEK inhibitors within the national NF1 service.

These findings indicate a significant shift in clinical practice and MDT decision-making following the availability of licensed MEK inhibitor therapy in the UK. Successful patient selection has improved with experience.

Background: Early detection of malignant transformation in Neurofibromatosis type 1 (NF1) remains a critical clinical challenge. Conventional surveillance, relying on histopathology, MRI, and PET, often fails to distinguish stable benign lesions from early-stage malignancies. To bridge this gap, the multicenter IN-BIO-NF pilot study, coordinated by the Veneto Institute of Oncology (IOV), leverages liquid biopsy to characterize genomic signatures from cell-free DNA (cfDNA), aiming to refine a marker panel for personalized diagnosis and therapy prediction.
Methods: This ongoing study enrolls patients across three cohorts: plexiform neurofibromas (PNs), PNs with distinct nodular lesions (DNLs), and MPNSTs. cfDNA and gDNA from 7 patients were analyzed using the ultra-deep MSK-ACCESS targeted NGS panel (146 cancer-associated genes, including CDKN2A/B and NF1) enabling the differentiation of somatic tumor variants from germline and hematopoietic variants.
Results: Constitutional heterozygous NF1 alterations (VAF ~50%) were identified across all cohorts. Crucially, somatic profiling revealed distinct molecular patterns in all tumour samples. Even benign PNs harbored low-frequency somatic variants, including a likely pathogenic CDKN2A alteration (VAF 0.7%) and pathogenic variants in BAP1, POLE, MSH6, RHOA, and FOXL2 genes. These findings reveal early, lesion-specific molecular activity. Ongoing correlation with clinical histories and tissue biopsies will provide a vital layer for marker validation.
Conclusion: High-depth cfDNA profiling successfully detects low-frequency somatic alterations driving NF1 progression, positioning liquid biopsy as a powerful, non-invasive complement to traditional imaging and tissue diagnostics.

Background: Plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) are major complications in adults with neurofibromatosis type 1; we analyzed their clinical features and management in a large cohort of 1,067 adults.

Methods: Clinical data from all adults seen at the Dutch NF1 expertise center (2004-2025) were retrospectively collected, including NF1 diagnostic features, genetic data and details on PNs and MPNSTs. Detailed information was recorded on up to three largest or most symptomatic PNs per patient. Five-year survival after MPNST and risk factors for MPNST were analyzed. Known genotype-phenotype associations were evaluated.

Results: Among 1,067 adult patients with NF1 (1,019 generalized, 48 mosaic), PNs were present in 47%. Surgical management was frequently limited by regrowth and complications. Overall, 5% of patients were deceased; the median age of death was 48 years, most commonly due to MPNST. MPNST occurred in 4% of the patients, predominantly in proximal body regions. The presence of nodular PNs was an independent risk factor for MPNST. Five-year survival after MPNST was 54.5%. 17q11.2 microdeletion was associated with a higher risk for MPNST.

Conclusions: This large cohort study highlights that PNs and the associated risk of malignant transformation represent a significant burden for individuals with NF1. The limitations of surgical management of PNs underscore the need for effective systemic therapies. The prognosis for MPNST remains poor. As early detection can improve outcomes, regular follow-up is essential for all patients with NF1, particularly those in high-risk subgroups.

Background
Malignant peripheral nerve sheet tumors (MPNST) are rare and devastating complications of Neurofibromatosis Type 1 (NF1) disease in children.
Current screening recommendations include a whole-body MRI at the age of 16 years. Surveillance programs for adult NF1 patients allow early detection of MPNST-precursor lesions and reduce the incidence of MPNST.
The tumorigenesis and biology of pediatric MPNST is not fully understood.

Methods
We identified four cases with pediatric MPNST or precursor lesions, treated at our center during the last 5 years detected through clinical symptoms and classified the lesions using epigenetic methylation as well as the Miettinen and Lucas classification.

Results
Case 1: female, 14 years, no pathology report available, Diagnosis “MPNST”, gross-total-resection, event-free survival with chronic pain after 8 years

Case 2: Male, 9 years, epigenetic methylation analysis MPNST, Miettinen ANNUBP, Lucas MPNST, subtotal resection, after progression Ifosfamide, Vincristine, Adriamycin and Selumetinib, death 22 months after initial Diagnosis

Case 3: Male, 12 years, epigenetic methylation analysis schwannoma, Miettinen Low-Grade-MPNST, Lucas ANNUBP with increased proliferation, gross total resection, event-free after 33 Months

Case 4: Female, 14 years, epigenetic methylation analysis not available, but H3K27MR3-loss, Miettinen Low-Grade-MPNST, Lucas MPNST, resected with unknown tumor-margins, residual tumor with stable disease after 26 months

Conclusions
MPNST and precursor lesion arise even at an early age in NF1 patients that benefit from gross total resection. We propose an earlier age for the first whole-body-MRI screening for early detection and MPNST prevention. Future tumor classification should incorporate epigenetic methylation-status based diagnosis.

Background: Plexiform neurofibromas (PN) are the most common tumor type in children with neurofibromatosis type 1 (NF1). In 10-15% of cases there is the risk of malignant transformation (MT), which determines a decrease of patient’s life expectancy.
Methods: The summarized experience of managing of high-risk patients of MT of PNs, focusing on the clinical presentation, imaging data, treatment approaches, and outcomes.
Results: The risk group for MT of PN in patients with NF1 includes some of the pathogenic variants of the NF1 gene, a large volume of PN, the presence of foci of nodular lesions ≥ 3 cm. The key diagnostic methods are functional MRI with diffusion-weighted images and hybrid imaging with PET/CT or PET/MRI. Clinical signs of MT include increased pain, the appearance of new motor/sensory disturbances, organ dysfunction, accelerated tumor growth, changes in its clinical characteristics (density, immobility). Eight cases of multifocal PN with nodular lesions were analyzed. In 62.5% of cases patients received selumetinib for symptomatic PN. Total (50%) or partial resection/biopsy (50%) of nodular lesions was performed due to clinical deterioration (75%) or as a prophylactic measure (15%). Dominant signs were tumor growth (75%) and pain (62,5%). Histology confirmed MPNST in 50%, ANNUBP- in 50% and neurofibroma - in 25%. The mortality rate due to MPNST was 25%.
Coclusions: Careful monitoring and adequate imaging studies are key to the timely diagnosis of PNs MT. Surgical treatment of large nodular lesions within the PN structure is justified, including for the prevention of subsequent MT.

Background
Registries for rare diseases pool medical data across geographically dispersed populations to improve patient care and provide the critical mass needed for robust research.
Large amounts of patient data and protection of sensitive information is paramount for efficient use of this instrument.

Methods
The web application REDCap was employed to build a multicenter “Registry for Neurofibromatosis and Schwannomatosis (RNFS)”.
The nucleus of a Steering Committee (SC), accepting at least one representative of each participating center, has been created. To accelerate acceptance and creation of data volume, a nonprofit organization supporting NF2 research, Merlin Foundation®, offers tiered flat-rate payments for the entry of basic and modular data.

Results
The RFNS in REDCap is conformant with European data security requirements (GDPR).
Data is primarily stored on secure, institutional servers managed by participating universities, hospitals, or research organizations. Data can be collected off-line and later be synced with the main server. Data usage rights remain fully with the input center. In case of multicentric usage, centers participating in the study agree on data exchange. If it is intended to use all data of the registry, approval of the SC is required. The SC also acts as a Scientific Advisory Board (SAB).

Conclusion
The current setup ensures consistency, validity, and data interoperability to answer specific research or clinical question. The registry will support natural history studies, clinical trial design, epidemiological research, pharmacovigilance and outcomes research as well as advanced AI-supported bioinformatic studies including genotype-phenotype correlations and case-similarity analysis. The Executive Board expressly supports its use throughout Europe.

Background
Schwannomas are benign nerve tumours that can occur sporadically or in the context of inherited syndromes mainly due to genetic defects on chromosome 22 (NF2, SMARCB1, or LZTR1). Because different syndromes share overlapping clinical features, accurate molecular diagnosis is essential. Standard blood tests (via NGS) often fail to identify the causative mutation, especially in mosaic forms. Consequently, molecular analysis of tumour tissue is crucial to achieve a definitive diagnosis.
Methods
The aim of this retrospective single centre study on 221 patients was to assess the effectiveness of our molecular diagnostic workflow for schwannomatosis, which consists of molecular analysis on unaffected tissue and, when possible, on tumours. NGS and MLPA were used to identify pathogenic variants in the causative genes, and high-depth sequencing to detect low-grade mosaicism.
Results
In 30% of patients in whom only unaffected tissues were analysed, a genetic diagnosis of schwannomatosis was confirmed. Among the pathogenic germline variants, the majority were identified in LZTR1, followed by NF2. In 40% of cases in which at least two tumour samples were analysed, a genetic diagnosis was confirmed.
Conclusion
In our cohort, LZTR1 was the most frequently gene involved in schwannomatosis. The main factors that allow confirming the molecular diagnosis of schwannomatosis were the availability of multiple anatomically distinct tumours. Remarkably, pathogenic variants in genes associated with rare forms of schwannomatosis were detected and in some cases they allowed to revise the histological diagnosis.

Background: Individuals with neurofibromatosis type 2-related schwannomatosis (NF2-SWN) face physical, psychological and social consequences, including hearing loss, balance problems, facial dysfunction, pain and reduced quality of life. Although end-of-life communication may support person-centred care, patients’ readiness to discuss prognosis, care and end-of-life issues remains poorly understood. This study explored quality of life and adjustment/acceptance factors involved in this readiness.
Methods: We conducted a qualitative descriptive phenomenological study at the Spanish national reference centre for NF2-SWN. Adults with NF2-SWN completed sociodemographic and clinical questionnaires. Semi-structured interviews explored quality of life, disease knowledge, treatment perceptions, coping, social support, emotions, concerns and future expectations. Interviews were analysed using Colaizzi’s seven-step method and thematic analysis. Five interviews were conducted, onsite or online, lasting 50-120 minutes.
Results: Preliminary analysis identified two thematic areas: quality of life and readiness for end-of-life communication. Quality of life was shaped by family support, feelings of difference, anxiety, overthinking, facial appearance-related shame, communication difficulties linked to hearing loss, tinnitus and facial dysfunction, and isolation in non-adapted environments. Readiness was shaped by coping strategies, limited disease knowledge, negative emotions, treatment burden, uncertainty about future health and concerns about progression. Patients with milder symptoms discussed future plans from their current condition, without anticipating worse scenarios until experienced; those with clinically complex disease or poorer prognosis avoided planning ahead and focused on living day by day.
Conclusion: Readiness for end-of-life communication in NF2-SWN appears linked to lived experience and symptom burden. Clinicians should adapt conversations to patients’ adjustment, balancing sensitivity with timely discussion of prognosis.

BACKGROUND:
People with NF2-related Schwannomatosis (NF2-SWN) experience swallowing (dysphagia) and voice (dysphonia) changes due to tumours causing cranial nerve damage and/or secondary to surgical intervention (Best et al, 2017). A dedicated Speech and Language Therapist (SLT) specialising in complex adult cases joined the Manchester multidisciplinary team (MDT); one of four nationally commissioned specialist centres. SLT provides input for 1 day a week, supporting the MDT and SLTs across the north of England. This study reviews the impact of having SLT within the MDT

METHODS:
Since September 2025 SLT attends weekly MDTs to identify patients, proactively screens patients with potentially significant tumour location, performs endoscopic or fluoroscopy assessments for symptomatic patients, provides intervention, and education / awareness amongst the MDT, and liaises with general community services.
Outcomes measuring dysphagia and dysphonia severity were routinely collected.

RESULTS:
Between September 2025 and June 2026, SLT screening identified 48 patients at risk of SLT needs. Assessment identified dysphagia in 20 patients using the Dysphagia Severity Rating Scale and/or DIGEST and dysphonia in 21 using GRBAS. High prevalence of impaired mastication, silent aspiration and vocal fold palsy is identified. Education was provided for asymptomatic patients.
This study highlights specialist interventions previously unavailable. Quantitative and qualitative data from three case examples will demonstrate the impact of SLT.

CONCLUSION:
Individuals living with NF2-SWN experience physical and psychosocial impacts related to swallow and/or communication changes. Timely specialist SLT input benefits this caseload and can improve wellbeing and clinical safety. Future service development will evaluate patient and staff satisfaction and provide annual reviews.

Background: In continental Europe, a multicenter registry for neurofibromatosis and schwannomatosis is missing. However, such a register is critically important for patient care, studies and therapy development.
Methods: We initialized the multicenter “Registry for Neurofibromatosis and Schwannomatosis (RNFS)” on the server-based web application REDCap (Research Electronic Data Capture). Two key models for basic and hallmark data with the most eminent clinical and genetic markers were defined. Modules for additional data (demographics, additional disorders, symptoms, interventions, outcomes etc.) have been added
Results: Locally siloed patient data has been imported from two medical sites into the registry. RedCap’s built-in functions like stats, charts, customizable queries, filters, and automated data export to statistical analysis software (Excel, SPSS, SAS, Stata, R) are available.
A test version of RNFS was constructed and is being tested. Majority of the data entries is via a button-clicking from drop-down/ multiple-choice entrys. At the present stage, the multi-center RNFS has an ethical approval for Germany. The register is hosted and maintained by the University Medical Center Hamburg, Germany. Centers will have access from their own sites. More details regarding structure and parameters focusing on NF1 will be presented
Conclusions: A multicenter register for neurofibromatosis and schwannomatosis is being set-up and will likely be available soon

Background: Neurofibromatosis type 2-related schwannomatosis is a rare genetic disorder associated with hearing loss, balance problems, pain, facial dysfunction and reduced health-related quality of life. The Neurofibromatosis Type 2 Impact on Quality of Life questionnaire is a disease-specific patient-reported outcome measure, but no validated Spanish version is currently available.

Methods: A cross-sectional validation study was conducted in adults with neurofibromatosis type 2-related schwannomatosis recruited from a national reference centre in Spain. Cross-cultural adaptation followed a standardized forward-backward translation process with expert review and cognitive debriefing. Participants completed the Spanish questionnaire, EuroQol 5D, Hospital Anxiety and Depression Scale, Facial Disability Index and pain measures. Internal consistency, exploratory factor analysis and convergent validity were assessed.

Results: Analyses included 100 patients with available Es-NFTI-QoL and EuroQol data. The Es-NFTI-QoL showed good internal consistency (Cronbach’s alpha = 0.87). Exploratory factor analysis supported a one-factor structure, explaining 46% of the variance. Higher Es-NFTI-QoL scores were associated with poorer health-related quality of life, as measured by EQ-5D (ρ = −0.823, p < 0.001) and EQ-VAS (ρ = −0.667, p < 0.001), higher anxiety (ρ = 0.74, p < 0.001), depression symptoms (ρ = 0.68, p < 0.001), poorer facial physical function (ρ = −0.61, p < 0.001) and higher pain intensity (ρ = 0.39, p = 0.002).

Conclusion: Findings support the reliability and validity of the Spanish Neurofibromatosis Type 2 Impact on Quality of Life questionnaire (Es-NFTI-QoL) for assessing disease-specific health-related quality of life in Spanish-speaking adults with neurofibromatosis type 2-related schwannomatosis.

Background:
One of the major concerns of Neurofibromatosis type 1 (NF1) patients is the development of multiple cutaneous neurofibromas (cNFs). Complete loss of the NF1 gene in a Schwann cell (SC) precursor is required for cNF formation. Several topical MEK inhibitors (MEKi) are currently being evaluated for cNFs. Previously, we demonstrated the therapeutic potential of combining cAMP pathway activation with the MEK inhibitor Selumetinib in cNF models. In this work, we aimed to identify an effective combination of cAMP pathway activation and Ras/MAPK inhibition for cNF therapy in vivo.
Methods:
Cell viability, myelination, apoptosis, and recovery assays were performed in patient-derived cNF SCs, iPSC-derived neurofibromaspheres, and Prss56Cre;R26Tom;Nf1flox/flox mouse-derived spheres. Transcriptomic analysis included bulk RNA-seq of co-treatments in patient cNF-SCs and single-cell RNA-seq of cNFs. Maximum tolerated dose (MTD) and pharmacokinetic studies were conducted prior to in vivo evaluation in two distinct cNF mouse models.
Results:
RNA-seq analyses of patient-derived cNF SCs, fibroblasts, and cNFs identified cAMP signaling components enriched in cNF-SCs, which were validated using single-cell RNA-seq data. Screening of 11 cAMP-elevating compounds across human and mouse cNF cellular models confirmed GPR68 allosteric modulator MS48107 and Forskolin as the most promising compounds for co-treatment with Selumetinib. Transcriptomic analysis of these combinations is ongoing. MTD and pharmacokinetic studies were completed, and in vivo evaluation is currently underway in both Prss56Cre;R26Tom;Nf1flox/flox mice and sciatic nerve xenograft models using human luciferase-expressing neurofibromaspheres.
Conclusion:
Extensive in vitro analysis identified MS48107-Selumetinib and Forskolin-Selumetinib as promising therapeutic combinations for cNF therapy, which are currently being evaluated in vivo.

Background: Although neurofibromatosis type 1 (NF1) is considered a monogenic disease, its clinical presentation is highly heterogeneous, suggesting the involvement of additional genetic modifiers. A previous genome-wide association study (GWAS) performed in the NF-France cohort identified 168 candidate modifier genes associated with neurofibroma development. Here, we functionally evaluated these candidate genes using complementary CRISPR-based screening approaches in isogenic Schwann cell models.
Methods: Two immortalized Schwann cell lines were used: NF1-WT cells carrying two functional NF1 alleles and NF1-/- cells in which NF1 was inactivated. Three complementary CRISPR-Cas9 systems were introduced into both cellular backgrounds: CRISPR knockout (CRISPR-KO), CRISPR activation (CRISPRa), and CRISPR inhibition (CRISPRi). Lentiviral single guide RNA (sgRNA) libraries targeting the 168 candidate genes were generated. Following lentiviral transduction, cells were cultured and harvested at multiple time points. sgRNA abundance was quantified by next-generation sequencing (NGS), and data were analyzed using the Robust Rank Aggregation (RRA) algorithm.
Results: Candidate genes were selected according to statistical significance, reproducibility across sgRNAs, and consistency between analytical methods. This integrative analysis identified several high-confidence candidate genes, including E2F7, TUBE1, POC5, RTN4IP1, STAU2, and NMT2.
Conclusion: Overall, this study representes one of the first combined CRISPR-KO, CRISPRi, and CRISPRa functional screening strategies applied to NF1 modifier genes in Schwann cells. It establishes a prioritized list of candidate modifiers and provides a framework for future mechanistic studies and therapeutic target discovery in neurofibroma development.

Background:
Neurofibromatosis type 1 (NF1) is a genetic disorder with an increased risk of central nervous system tumours. Tectal plate gliomas are typically indolent, with management directed at complications, predominantly hydrocephalus. Most evidence derives from sporadic cohorts or NF1 cohorts pooling all brainstem gliomas. We characterised tectal plate gliomas in children with NF1 and asked whether baseline imaging features predicted progression and treatment, with cerebrospinal fluid (CSF) diversion as the primary outcome.

Methods:
Over 3,600 magnetic resonance imaging reports from 965 children managed since 2009 by the nationally commissioned Highly Specialised Service for Complex NF1 (Manchester, UK) were text-mined and graded against predefined criteria. Children with a tectal plate glioma were reviewed for baseline imaging features, radiological progression, clinical course and interventions. Associations were tested using Fisher's exact test.

Results:
Twenty-nine children were identified (15 male, 14 female; median age at diagnosis 10.0 years; median radiological follow-up 7.42 years); all were alive at review. Atypical imaging features were documented in 7 (24.1%) and radiological progression in 6 (20.7%). Twelve (41.4%) required CSF diversion. Symptomatic hydrocephalus at presentation was strongly associated with CSF diversion (11/15 [73%], mostly acute, versus 1/14 [7%] at follow-up; p=0.0005). No specific imaging feature predicted progression, and atypical features did not reliably prompt tumour-directed therapy.

Conclusion:
In children with NF1 tectal plate glioma, management was driven by hydrocephalus and clinical course. Tumour imaging features alone did not direct treatment; symptomatic hydrocephalus at presentation identified children needing intervention, while its absence reliably identified those suitable for surveillance.

Background: Optic Pathway Glioma (OPG) is a benign central nervous system tumour and a key diagnostic feature of neurofibromatosis type 1 (NF1). OPG can arise from any part of optic pathway. Diagnosis relies on clinical suspicion, ophthalmologic assessment and MRI imaging. A progressive/ symptomatic OPGs will be manged by chemotherapy.
Method: A retrospective audit of 34 children with NF1 and OPGs attending the Alder Hey NF1 service was undertaken using a structured review of electronic patient records over a 10-year period.
Results: Median age of OPG diagnosis was 5 years, M:F 1:1. OPGs presented unilaterally in 41.18%, (N=14), bilaterally in 23.53% (N=8) and involved chiasm in 38.24% (N=13). Precocious puberty and visual impairment were the most presenting symptoms (32.35%, n=11). However, 70.6% (N=24) had non-specific presentation and were identified through routine ophthalmological surveillance or incidental MRI findings. Most patients were managed by regular surveillance. 26.47% (N=9) required chemotherapy, in multiple cycles. Of these 77.78%, (N=7) had OPG involving chiasm. Chemo was started after worsening vision in 44.44% (N=4), following disease progression in 55.56%(n=5). Out of that, 22.22% (N=2) required further proton therapy; 55.56% (N= 5) remained stable and monitored under surveillance; while 44.44 % (N=4) with progressive disease started on Mitogen-activated protein kinase kinase inhibitors (MEKi) to improve outcome.
Conclusion: Management of NF1-associated OPG requires a multidisciplinary approach. In our experience, most OPGs remain stable and can be safely managed with clinical and radiological surveillance, A minority of children require targeted therapies such as MEKi for complex or progressive disease.

Background:
Patients with neurofibromatosis type 1 (NF1) have an increased risk of glioma. Focal areas of signal intensity (FASI) are common neuroimaging findings representing myelin vacuolization. Because FASI and gliomas share overlapping magnetic resonance imaging (MRI) features, gliomas are typically distinguished by enhancement, mass effect, or enlargement. We investigated the natural history and relationship between FASI and non-optic gliomas in a large NF1 cohort.

Methods:
Medical records of 1373 NF1 patients (aged 2-81 years) were initially evaluated; from this cohort, further analysis tracking FASI and glioma development was conducted on those with ≥1 MRI available. Ongoing analyses evaluate the risk of FASI conversion to glioma based on characteristics including location and imaging features. Additionally, a blinded assessment characterizing lesions as FASI or glioma is currently in process.

Results:
Of 679 patients with available MRIs, 512 (75.4%) had ≥1 FASI and 160 (23.6%) had ≥1 glioma. Gliomas were significantly more common in patients with FASI (29.5% vs. 5.9% without; p<0.001). Among 370 FASI patients with follow-up imaging, 46 gliomas (12.4%) developed from previously identified FASI (median intervening time: 32 months). Most occurred in the brainstem, corpus callosum, and cerebellum. Notably, 15% were confirmed via biopsy, and 15% required intervention.

Conclusion:
NF1 patients with FASI have a higher risk of gliomas, which often develop in regions previously identified as FASI. This potential relationship may require closer monitoring than currently recommended. Ongoing blinded assessments and analyses will determine whether FASI predisposes patients to gliomas or if early gliomas are misidentified as FASI.

Background: NF2-related schwannomatosis (NF2-SWN) vestibular schwannoma (VS) surgery is still a challenge, particularly in the context of multiple therapeutic options. In the case of surgery after failure of medical treatment, particularly Bevacizumab (BEV), which is frequently currently used.

Methods: We retrospectively reviewed 35 NF2-SWN patients undergoing VS surgical resection from January 2019 to October 2024 and analyzed a retrospective multicentric series of patients having had salvage VS surgery after failure of BEV.

Results: 90% of NF2-SWN cases (n=35, mostly Koos stage 4) had a good facial nerve outcome but only 14% GTR/NTR with more complications and longer stay than other VS cases. Homolateral hearing and visual function, and bad contro-lateral facial function have made surgeries more cautious and less aggressive. For the 21 salvage surgery cases, late BEV discontinuation and high cumulative dose independently predicted perioperative bleeding and longer surgery duration. No other complication such as wound dehiscence was reported.
Conclusions: NF2-SWN VS surgery remains a surgically challenge associated to the difficulty to choose the perfect timing for surgery, of multiple therapeutic options. For salvage surgery, a BEV-free window between 6 weeks and 6 months (depending on the clinical scenario) before tumor resection seems optimal, particularly for patients with high cumulative exposure.

Background: Bevacizumab is currently the only approved therapy for controlling tumor growth in schwannomatosis. This study presents clinical outcomes of bevacizumab treatment for tumor control in NF2-schwannomatosis
Methods: The study cohort included 58 patients with NF2-schwannomatosis. The indications for the therapy were: (i) large vestibular schwannomas (III-IV KOOS), (ii) multiple extramedullary intra- and extradural tumors, and (iii) symptomatic cystic spinal ependymomas where surgical treatment was not feasible.
Results: In 35 patients (60.34%) the target tumor reduction was achieved after only six bevacizumab administrations (four months). In another 19 cases, we observed a reduction in the target tumor after 12 or 18 administrations of bevacizumab. In all these cases, the effect remained stable for 24 months after initiation of the therapy. In four cases (6.8%), we observed continued growth of the target tumor after six administrations (three vestibular schwannomas, one sacral nerve root schwannoma). We selected 25 patients with large vestibular schwannomas and intact hearing. For better tumor control, radiation therapy was administered after 12-24 bevacizumab administrations. All radiation treatments were delivered using the CyberKnife system, with a median marginal dose of 14 Gy. The median follow-up period was 24 months. Tumor shrinkage was observed in nine patients (36%) following the combination therapy. Only three patients experienced progressive hearing loss during bevacizumab treatment. Hearing improvement was documented in 17 patients (68%).
Conclusion:In conclusion, a combined therapy with bevacizumab and stereotactic radiation provides effective local tumor control, significantly enhances the chance of hearing preservation, and may reduce the risk of post-radiation vestibulocochlear neuropathy.

Background: Neurofibromatosis type 2 (NF2) is a rare tumor predisposition syndrome mainly associated with bilateral vestibular schwannomas and progressive hearing impairment. Bevacizumab has emerged as a potential treatment to slow tumor progression and preserve auditory function. We report a single-center experience evaluating hearing outcomes and treatment tolerability in patients with NF2-related tumors.
Methods: We retrospectively reviewed 9 patients with clinically and/or genetically confirmed NF2 treated with intravenous bevacizumab every 21 to 28 days.
Median age at the start of treatment was 26 years (range 13 to 35 years); 6 patients were female and 3 were male. Clinical monitoring included blood tests and urine analysis before each administration. Serial audiological assessments were performed to evaluate changes in cochlear function.
Results: At baseline, 8 patients had vestibular schwannomas and 1 patient had intracranial and spinal meningiomatosis. One patient received bevacizumab combined with irinotecan.
Baseline audiometry was normal in 4 patients, whereas 5 had unilateral hearing loss.
During treatment, hearing remained stable in 3 patients, unilateral deterioration occurred in 1 patient, and bilateral worsening was observed in 5 patients.
Proteinuria developed in 4 patients; 1 patient experienced both proteinuria and arterial hypertension. Treatment was discontinued in 1 patient because of disease progression and in the patient receiving combination therapy due to nephrotic-range proteinuria. Dose reduction or interval prolongation was required in 2 patients.
Conclusion: Bevacizumab was safe and feasible in this NF2 cohort and was associated with hearing stabilization in one third of patients. Renal toxicity requires careful monitoring and may lead to treatment modification or discontinuation.

Background: Children with Neurofibromatosis type 1 (NF1) have an increased risk of developing pediatric low grade glioma (pLGG). Selumetinib and trametinib, orally selective MEK1/MEK2 inhibitors (MEKi), act on the MAPK pathway activated in NF1. Selumetinib is approved for inoperable plexiform neurofibromas in Neurofibromatosis type 1 (NF1). We evaluated MEKi effcacy and safety in NF1 related pLGGs.
Methods: From January 2022 to January 2026 nine patients (5 females, 4 males, median age 12 years) were admitted to our hospital for recurrent pLGGs and NF1. MEKi were administered (7 selumetinib, 2 trametinib) after disease progression. MRI assessment was performed every 3-6 months and radiological response was defined in accordance with RAPNO criteria.
Results: 8 patients were evaluables. At first assestment, 7/8 patients (87.5%) showed a partial radiological response (-45.5% median volume reduction) and 1/8 stable disease. Best response was observed after a mean of 5.12 months. The median best response was -58.5% volume reduction (range 0-98%). Median time to progression has not yet been reached. All 8 patients experienced a clinical benefit: 1 patient with OPG achieved improvement in visual field, 2 patients in alertness and two patients in ataxia. No patient experienced clinical worsening. The most frequent toxicities reported were mucocutaneus.
Conclusion: MEKi represent promising strategies in children with recurrent/progressive LGGs and NF1. In our small series, the treatment was effective and well tolerable. Further studies are needed to establish the possible superiority of MEK inhibitor treatment in patients with pLGGs and NF1 to avoid or delay chemotherapy in this population.

Background: Plexiform neurofibromas (PNs) cause significant morbidity in neurofibromatosis type 1 (NF1). Although comprehensive magnetic resonance imaging (MRI) is the cornerstone of tumor screening and longitudinal monitoring, high resource intensity limits global accessibility. We evaluated the diagnostic efficacy and cost-effectiveness of localized, spine, whole-body (WB-MRI), and total-body MRI (TB-MRI) strategies across diverse economic settings in China and globally.
Methods: Diagnostic metrics were assessed in 401 NF1 patients using TB-MRI as the reference. A decision tree-Markov model simulated lifetime clinical and economic outcomes from a societal perspective across three economic tiers in China and nine representative nations. Costs and utilities were discounted at 3% annually.
Results: TB-MRI achieved a 100% diagnostic yield. WB-MRI also demonstrated high reliability (sensitivity 93.3%, AUC 0.966), significantly outperforming localized and spine-focused modalities. In China, TB-MRI was the dominant strategy in high-income regions, WB-MRI in middle-income regions, and localized MRI in low-income regions. Notably, while localized MRI is optimal at lower WTP thresholds in resource-limited settings, TB-MRI progressively becomes the preferred modality as WTP increases—a trend consistent across all tiers and substantiated by 30-year projections. Internationally, TB-MRI was the optimal strategy for Singapore and China, whereas WB-MRI was superior for Australia and the United States. In other representative nations, localized or MRI of the spine currently serve as more pragmatic baseline selections.
Conclusion: TB-MRI is the superior diagnostic modality for NF1-related PN, but its global implementation requires a tiered approach. Tailoring modality selection to local economic realities ensures both optimal clinical outcomes and efficient global healthcare resource allocation.

Background:
Nodular PNFs ≥3 cm with a well-demarcated appearance on MRI are classified as distinct nodular lesions (DNLs), which are considered precursor lesions of most malignant peripheral nerve sheath tumors and atypical neurofibromatous neoplasms of uncertain biologic potential. However, their long-term prevalence and growth remain poorly understood. We therefore aimed to retrospectively assess DNL prevalence and growth in patients with neurofibromatosis type 1 (NF1) over time.

Methods:
Whole-body MRI (WB-MRI) scans of 346 NF1 patients were considered. Patients with at least one DNL and a prior WB-MRI were included. Maximum DNL diameters were measured on coronal or axial STIR images. Significant growth was defined as a ≥20% increase in maximum diameter. Patients were grouped according to the presence or absence of growing DNLs. Genetic profiles and anatomical DNL distribution were compared.

Results:
Among 346 patients, 130 had ≥1 DNL and a prior WB-MRI and were included in further analysis. The mean number of DNLs increased from 2.6 to 3.3 per patient, and maximum diameters of DNLs differed significantly at follow-up (p<0.05). Overall, 96 patients (mean age at follow-up: 33.0 ± 14.9 years; mean follow-up interval: 8.5±3.1 years) had at least one DNL that demonstrated significant growth. In contrast, 34 patients (mean age at follow-up: 41.6 ± 13.7 years; mean follow-up interval: 7.0±3.7 years) showed no significant growth in any DNL. Genetic mutation types and anatomical DNL distribution were comparable between groups.

Conclusion:
Our findings improve understanding of DNLs prevalence and growth in NF1. AI-based analyses may help predict DNL growth and improve risk stratification.

Background:
Neurofibromatosis type 1 (NF1) is characterized by the development of benign peripheral nerve sheath tumors, including cutaneous (cNF) and plexiform neurofibromas (pNF). Although both arise from NF1 inactivation in Schwann cells (SCs), they exhibit distinct clinical behavior, with only pNFs carrying a risk of malignant transformation into malignant peripheral nerve sheath tumors (MPNST). The main goal of this project is to better understand the distinct biological and clinical behavior between cNF and pNF through bulk and single-cell (sc) transcriptomic analyses.

Methods:
We integrated bulk RNA-seq of whole tumors, primary SCs, and fibroblasts (FB) cultures, and scRNA-seq, comparing tumor profiles against healthy control nerves.

Results:
We analyzed global and single-cell transcriptomes of cNFs and pNFs, specifically focusing on differences in cell composition within the glial and mesenchymal cell compartments. Enrichment analysis comparing cNF-SC versus pNF-SC revealed differences in certain biological processes, like those related to cell chemotaxis pathways in cNFs, and neuronal ensheathment in pNFs. We also explored the lineage differentiation stage on the SC compartment, specific biomarkers and the pro-inflammatory microenvironments of both tumor types. Through this, we identified a potential tumoral SC marker absent in healthy nerves, and highlighted the mesenchymal compartment as a key player in the tumors’ pro-inflammatory microenvironment.

Conclusion:
These preliminary transcriptomic analyses revealed differences in cellular composition, cell identities, activation of biological processes and pro-inflammatory microenvironments comparing benign neurofibromas. Ongoing validation of these preliminary findings will be required to further characterize these tumors and explore their potential clinical applications.

Background: Antigen presentation in neurofibromatosis type 1 (NF1)-associated tumors remains poorly characterized, limiting rational design of cancer vaccines and immune-based therapies. We developed a computational discovery pipeline for NF1-associated peripheral nerve sheath tumors, including plexiform neurofibromas (PNs), atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNSTs), to identify candidate MHC Class I-associated peptide targets.
Methods: NF1 RNA-seq data from the Johns Hopkins NF1 biospecimen repository were analyzed to identify somatic variants and aberrant splicing events. Candidate coding and non-coding sequences were translated in silico, and 8–11 amino acid peptides were generated using a sliding-window approach. Peptides were assessed for HLA-A, HLA-B, and HLA-C binding using NetMHCpan 4.1, then filtered against the human proteome and a reference dataset of normal immune-presented peptides to prioritize tumor-specific peptide candidates.
Results: In silico analysis identified a substantial predicted target space in NF1-associated tumors, including candidate peptides derived from somatic variation and aberrant splicing events. These findings suggest that NF1 tumors may present a diverse landscape of canonical, cryptic, and aberrant MHC-associated peptides.
Conclusions: This work identifies a rich set of potential neoantigen targets that can be further refined through mass spectrometry-based immunopeptidomics validation. Next steps include developing a ranked catalogue of NF1 tumor antigens linked to multi-omics evidence, presentation or surface validation, and prototype therapeutic formats for downstream preclinical development. These
approaches may enable the systemic discovery of neoantigen and cancer-associated targets
presented on HLA class I and II, enabling T-cell therapies and therapeutic cancer vaccines.

Background.
Neurofibromatosis type 1 (NF1) is a multisystem hereditary disorder associated with plexiform neurofibromas, optic pathway gliomas, skeletal abnormalities, and ophthalmological, neurological, and cognitive complications. The heterogeneity of manifestations and risk of severe events require early diagnosis, long-term surveillance, and coordinated multidisciplinary care.

Materials and Methods.
We analyzed NF1 patient management at the Dmitry Rogachev National Medical Research Center from January 2022 to June 2026. Overall, 290 patients were included. The multidisciplinary team involved pediatric oncologists, neurologists, geneticists, ophthalmologists, neurosurgeons, orthopedists, dermatologists, radiologists, drug therapy and rehabilitation specialists, and psychologists. Assessment included clinical examination, molecular genetic testing when indicated, MRI, ophthalmological monitoring, and evaluation of neurological, orthopedic, and cognitive complications. Treatment strategies were discussed at multidisciplinary boards, followed by individualized management plans.

Results.
The multidisciplinary model enabled standardized patient routing, risk stratification, and timely detection of clinically significant NF1-related complications. Selumetinib therapy was administered to 72 patients (25%) with symptomatic, progressive, or functionally significant plexiform neurofibromas, including tumors associated with compression risk, visual, respiratory or motor impairment, or severe pain. Surgical treatment was performed in 32 patients for local complications, pain, functional impairment, disfiguring deformity, or histological verification when malignant transformation was suspected.

Conclusion.
Our experience demonstrates that NF1 care requires an organized multidisciplinary model integrating early diagnosis, risk-adapted surveillance, timely medical and surgical treatment, rehabilitation, and family support. This approach improves care quality, optimizes treatment selection, and may contribute to better long-term outcomes in children with NF1.

Background: NF2‑schwannomatosis is a rare autosomal dominant disorder characterised by multiple nervous system tumours. Generalised polyneuropathy is recognised in NF2 and, although previously attributed to tumour‑related nerve compression, emerging evidence suggests alternative pathogenic mechanisms such schwann cell dysfunction due to Merlin suppression or microscopic schwann cell proliferations. We sought to define the clinical and neurophysiological phenotype in a large NF2 Cohort in Northern England.

Methods: From 532 patients managed within the highly specialised NF2 service in Manchester, UK we identified individuals with polyneuropathy and reviewed their clinical and neurophysiological features through retrospective casenote analysis. Inclusion criteria were confirmed polyneuropathy on clinical and neurophysiological assessment without an alternative cause. Patients under 18, managed at other NF2 centres, or deceased were excluded.

Results: Seven cases of generalised polyneuropathy were identified. Severe truncating NF2 mutations were present in 4/7 patients, while 3/7 were mosaic but exhibited severe clinical phenotypes with high tumour burden. Clinically, 6/7 demonstrated asymmetrical distal motor weakness, and 5/7 had asymmetrical distal upper‑limb involvement.

Neurophysiology showed asymmetrical sensorimotor polyneuropathy of predominantly axonal type in all cases, with EMG evidence of superimposed mononeuropathies not attributable to tumour compression in 6/7.

Conclusion: Asymmetrical axonal sensorimotor neuropathy with additional mononeuropathies appears to be the predominant neuropathic phenotype in NF2‑schwannomatosis. Severe truncating variants were the most frequently identified genetic subtype in affected individuals.

Background:
Plexiform neurofibromas (PNs) are tumours of nerve fascicles arising from Schwann cell progenitors during embryonic development. Approximately 30% of individuals with NF1 are affected, and although present from birth, most are detected later with their size and prevalence increasing throughout childhood. We present an exceedingly rare case of an antenatally-detected PN.

Methods:
A retrospective analysis of case notes.

Results:
At a 12-week antenatal scan, female R was noted to have a posterior cervico-occipital cystic lesion, initially considered to be a cystic hygroma. She was born in good condition at term with no palpable lesion. At 2 months old, her parents reported a slow-growing occipital mass. On examination, she had multiple café-au-lait macules and a soft boggy mass over the left occiput extending into the left cervical region. MR imaging at age 10 months revealed a left sided occipital PN involving the deep neck spaces with extension through the skull base. A repeat scan age 15 months demonstrated slow growth but no significant mass effect. Genetic analysis revealed a de novo heterozygous nonsense variant in the NF1 gene. Following multidisciplinary assessment, she awaits review by the quarterly UK national MEK inhibitor (MEKi) panel as per the national pathway.

Conclusion:
We present a child with an extensive PN detected via antenatal imaging, which has been only very rarely described in the literature. Such cases with the potential for significant growth are increasingly being considered for MEKi at a very young age. This prophylactic role of MEKi is still in evolution.

Background: Gastrointestinal stromal tumours (GIST) are rare mesenchymal neoplasms most commonly diagnosed in older adults and predominantly associated with somatic KIT and PDGFRA alterations. Neurofibromatosis type 1 (NF1) is a multisystemic disorder caused by heterozygous pathogenic variants (PV) in the gene NF1. Patients with NF1 are more likely to develop GIST, often with specific clinicopathologic features. Our aim was to assess clinical, pathological and molecular characteristics of GIST in Slovenian NF1 patients.
Methods: Genetically confirmed NF1 cases referred to the Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, were included in this study. For patients with the diagnosis of GIST, medical records were reviewed, and diagnoses of cancer were verified using the Slovenian Cancer Registry.
Results: In a cohort of 100 NF1 patients (age range 18-76, 68% female), 8 developed GIST. Most were female (87.5%). Median age at diagnosis was 49 (range 28-61). Most patients (75%) had at least one additional cancer diagnosis, most commonly breast cancer. All tumours were located in the small intestine, predominantly the jejunum, and had spindle-cell morphology. One patient (12.5%) had metastatic disease, and 5 (62.5%) had multifocal lesions. Tumour size ranged from 5 to 150 mm, and the mitotic count from 0 to 20 mit/5 mm². Six of 8 tumours were sequenced. NF1 PV were identified in all cases, with loss of heterozygosity in 66.7% and a second somatic hit in 33.3%.
Conclusion: Our findings are in line with those previously published in the literature. The co-occurrence of other NF1-related cancers in GIST patients warrants further investigation.

Background
Neurofibromatosis type 1 (NF1) is a multisystemic genetic disease presenting an autosomal dominant inheritance pattern with estimated prevalence at 1 case per 2500 to 3000 population. Cutaneous and ocular manifestaions (such as cafe-au-lait spots, freckling, cutaneous neurofibromas and Lisch nodules) togheter with neurological manifestations represent one of the most frequent findings.
Brain MRI can diagnose various lesions of the central nervous system: optic pathway gliomas, FASI (Focal Areas of Signal Intensity), brain gliomas, intracranial malformations, aneurysms, and moyamoya syndrome, among others.
Cerebellar anomalies, although previously reported in the literature, are relatively rare.

Methods
The aim of this retrospective study is to describe 3 patients, who were referred to the Clinical Genetics Unit of Padua University Hospital, presenting with congenital cerebellar, describing their clinical, neuroradiological, and molecular characteristics.

Results
A 11 years-old boy with hypoplasia of the left cerebellar hemisphere harbouring a truncating variant of the NF1 gene; a 10 years-old girl with right cerebellar dysplasia carrying an atypical deletion of 1,2 Mb involving the NF1 gene; and a 11 years-old girl with an occipital craniolacunia associated to plexiform neurofibroma, with left cerebellar malacia and encephalocele, carrying a truncating variant of the NF1 gene.

Conclusion
Cerebellar anomalies, although infrequent, even in our own series of cases, are likely underdiagnosed. We therefore believe that a systematic examination of the cerebellum is warranted, even when MRI scans are performed to evaluate more common findings, like OPG.

JMML belongs to the group of the rarest aggressive myeloproliferiations, regarded as the prototypical malignant manifestation of RASopathy, yet fundamentally rooted in constitutive activation of the RAS-MAPK pathway. Both somatic, mostly monoallelic gain of function mutations in PTPN11, NRAS, KRAS genes, and germline, biallelic lost of function in Nf1 and CBL genes resulted in more than 90% of JMML cases. Somatic PTPN11- and germline related NF1-mutated JMML are more aggressive than others and requires prompt allogeneic hematopoietic stem cell transplantation.
Within last 25 years, one out of 5 children diagnosed with JMML, suffered from NF-1. It was the only patient among 1034 NF-1 patients aged 0-30 years, underwent permanent coordinated medical care in our NF-Center, which constitute for <0.1% of all NF-1 children.
The common belief that NF-1 is highly associated with JMML risk, described for decades as 200- to 500-fold higher than in the general population, is responsible for parental misinterpretation responsible for their unjustifiable fears. Meanwhile, being far from the ignorance, yet regarding estimated general yearly incidence of JMML as 1.2/mln children, a naive simplified evaluation might indicate that incidence of NF1-mutated JMML should be as low as one NF-1 child out of 10 mln childhood population per year. In the real-world it places JMML as still an unique threat, even in NF-1 population, which corresponds well with the latest publications’ results and the observation confirmed by our Center. The precise description of our results will be discussed in respect of the reveals of the recent publications.

Background: Hydrocephalus is an uncommon but clinically relevant manifestation of neurofibromatosis type 1 (NF1), most frequently resulting from obstruction of the cerebrospinal fluid pathways. The underlying mechanisms and optimal surgical management may differ considerably between patients. We present two pediatric NF1 cases illustrating distinct causes and treatment strategies.
Methods: We retrospectively reviewed the clinical presentation, neuroimaging findings, surgical treatment and follow-up of two genetically confirmed female NF1 patients who developed progressive obstructive hydrocephalus during routine multidisciplinary follow-up.
Results: The first patient developed hydrocephalus at 7 years of age after intermittent headache, morning nausea and papilledema detected during routine ophthalmological examination. MRI demonstrated aqueductal obstruction with triventricular hydrocephalus, transependymal CSF flow and tonsillar herniation. Two endoscopic third ventriculostomies with biopsy failed to provide durable CSF diversion, ultimately requiring ventriculoperitoneal (VP) shunt placement with sustained ventricular decompression. The second patient developed progressive ventricular enlargement at 3.5 years of age without clinical symptoms. MRI showed progressive aqueductal obstruction without a definite space-occupying lesion. Endoscopic third ventriculostomy was not feasible because of unfavourable anatomy at the foramen of Monro. Primary VP shunting, followed by septostomy procedures for compartmentalized CSF circulation, resulted in stable long-term shunt function. Both patients remain clinically stable during follow-up.
Conclusion: These cases demonstrate that NF1-associated hydrocephalus may present with minimal or absent symptoms despite progressive ventricular enlargement. Careful longitudinal MRI surveillance is essential. The underlying mechanisms are heterogeneous, requiring individualized surgical decision-making, and VP shunting remains an important treatment option when endoscopic CSF diversion is unsuccessful or anatomically not feasible.

Background: Epilepsy is a recognized comorbidity of neurofibromatosis type 1 (NF1), affecting 4–13% of patients. Although seizures are often associated with structural CNS abnormalities, they may also occur in the absence of significant neuroradiological findings, suggesting a role for neurofibromin deficiency in neuronal hyperexcitability. However, EEG findings in NF1, particularly in seizure-free individuals, remain poorly characterized.
Methods: We retrospectively reviewed electroclinical and neuroradiological data from 140 children with NF1 (age range, 1.1–17.3 years) who underwent an EEG at our center.
Results: EEG abnormalities were identified in 60/140 patients (43%). Among these, 12 (20%) had epilepsy. Structural etiologies were found in 4/12 patients (33.3%), three of whom were drug-resistant. Remaining patients had age-related focal (n=3) or generalized (n=3) epilepsy, or focal epilepsy of unknown etiology (n=2), and achieved seizure freedom with first-line antiseizure medication. Among patients without epilepsy, epileptiform discharges were detected in 48/128 (37.5%) and were focal (n=18), multifocal (n=7), generalized (n=21), or combined focal-generalized (n=2). Longitudinal EEG data were available for 44 patients, showing spontaneous resolution of epileptiform discharges in 31 (70%) before 10±3 years of age. No patient exhibited EEG features consistent with encephalopathy with status epilepticus during sleep. Abnormal background activity and/or sleep architecture were observed in 43.7% of patients.
Conclusions: EEG abnormalities are common in pediatric NF1, but epilepsy is uncommon and largely attributable to structural causes. Excluding structural etiologies, epilepsy has a favorable prognosis. In seizure-free patients, epileptiform discharges appear age-dependent and self-limited, supporting the limited value of routine serial EEG monitoring in the absence of clinical seizures.

Background: Population-based studies on neurofibromatosis type 1 (NF1) prevalence in the United States (US) are limited. Estimates of annual diagnosed NF1 prevalence and the proportion of patients with NF1 with plexiform neurofibromas (PN) in the US from 2020–2024 are provided.
Methods: The IQVIA PharMetrics® Plus database (de-identified, individual-level, closed-claims data for ~318 million commercially insured US patients established in 2006) was used. Patients with ≥2 International Classification of Diseases, 10th Revision (ICD-10) NF1 codes (Q85.01) recorded ≥30 days apart in 2016–2024 were included; the first code defined the index. PN were identified via ≥1 ICD-10 code: D36.1–D36.17. Patients were counted as prevalent for each enrolled year from index through 2024. The denominator comprised patients with ≥1 month of enrolment per year. Diagnosed US prevalence was estimated by applying stratum-specific prevalence to US Census age- and sex-specific strata.
Results: 44,326 patients with NF1 were identified (52.8% female). Annual US diagnosed prevalence was 18.7/100,000 in 2020 and 20.5/100,000 in 2024. Diagnosed 2024 prevalence was highest among children (<18 years; 38.0/100,000), followed by adults aged 18–39 (22.1/100,000), 40–64 (12.5/100,000) and ≥65 years (10.9/100,000). Approximately 68,783 patients had NF1 in 2024. Overall, 30.9% of patients with NF1 had PN; PN was diagnosed more frequently in adults (43.4%) than children (21.4%).
Conclusion: US-diagnosed NF1 prevalence was ~21/100,000 in 2024, with higher estimates in children versus adults. Overall, ~31% of patients had NF1-PN, indicating substantial PN burden in the US NF1 population, aligned with previous US and Northern Europe estimates.

Background: Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with altered growth, including reduced height in childhood and adolescence. Existing NF1-specific auxological references are limited, methodologically heterogeneous and mainly derived from non-Central European populations. This study aims to characterize growth in Austrian individuals with NF1 and to establish population-specific reference values and growth curves.

Methods: This non-interventional retrospective cohort study applies descriptive and model-based statistical analyses to longitudinal and cross-sectional auxological data. NF1-specific reference values will be estimated using generalized additive models for location, scale and shape (GAMLSS), allowing age-dependent modelling of growth distributions while accounting for repeated measurements using a random patient factor. If sufficient longitudinal data are available, growth trajectories will additionally be modelled using superimposition by translation and rotation (SITAR). Descriptive comparisons with Austrian population references and exploratory associations with clinical factors will be investigated.

Results: 486 individuals aged 0-21 years with clinically or genetically confirmed NF1 are planned for inclusion. Recorded variables include anthropometric measures, pubertal status, and, where available, bone age, endocrine parameters, parental height, plexiform neurofibromas and NF1 genotype. Individuals with other conditions affecting growth will be excluded. Data collection and analysis are ongoing. The study is expected to present the first Austrian NF1-specific auxological reference dataset and disease-specific growth curves.

Conclusion: This study provides a population-specific framework for growth assessment in Austrian individuals with NF1 and may improve differentiation between NF1-related growth patterns and other pathological causes of impaired growth.

Background: Specialist multidisciplinary services play a pivotal role in the management of patients with neurofibromatosis (NF), providing coordinated surveillance, diagnosis, surgical intervention and lifelong care. Understanding referral patterns and service use is essential for optimising resource allocation and identifying inequities in access to specialist care.
Methods: A retrospective review was undertaken of all patients referred to one of the UK's two nationally commissioned specialist neurofibromatosis services over a 15-year period. Demographic data, diagnosis, geographical location and surgical workload were collected. Referral postcodes were anonymised and analysed to generate heat maps demonstrating referral density and regional variation. Temporal trends in referral volume were also evaluated.
Results: Over the study period, 666 operations were performed in patients with a genetic diagnosis of NF1, NF2 related schwannomatosis and schwannomatosis. Five hundred and ninety five (89.3%) of these were in patients with NF1 with 362 individual patients. Multiple procedures were common ranging from simple excision of cutaneous neurofibroma debulking of plexiform neurofibroma. Referrals originated from across the UK, with highest referral densities observed within established referral networks. The surgical workload evolved with increasing demand for management of cutaneous neurofibromas and complex reconstructive procedures, alongside expanding multidisciplinary clinics and surveillance programmes.
Conclusions: Over 15 years, this specialist neurofibromatosis service has evolved into a national referral centre supporting an increasingly complex patient population. Heat mapping highlights disparities in referral patterns that may represent unmet clinical need. Heat mapping provides a valuable tool for service evaluation, informing outreach, commissioning, and future development of equitable specialist NF care across the UK.

Background: Neurofibromatoses are rare tumour-predisposition syndromes. In ICD-10-GM all forms share one code, Q85.0, which cannot separate NF1, NF2 or schwannomatosis. Nationwide inpatient care in Germany is undescribed. Using §21 administrative data, we characterised this care and distinguished admissions for which neurofibromatosis was the primary reason from those in which it was comorbid.

Methods: Retrospective analysis of the InEK DatenBrowser (annual DRG deliveries, 2019–2024). We extracted case counts, demographics, length of stay, complexity (PCCL), procedures, diagnoses and in-hospital deaths for two cohorts: Q85.0 as primary, and (2024) Q85.0 as secondary diagnosis.

Results: Primary-diagnosis admissions rose from 899 (2019) to 1,088 (2024; total 5,469), dipping in 2020. This cohort was paediatric (56–63% <18), with short stays (mean 2.5–3.5 days) and low complexity. Activity was dominated by cranial and spinal MRI under sedation (skull MRI 39–45% annually); the procedure mix was stable, so rising volume reflected surveillance imaging, not surgery. In 2024, 2,682 admissions carried neurofibromatosis as a secondary diagnosis; these patients were older (57% adult), stayed longer (mean 6.0 days) and were more complex (PCCL ≥3, ~51%). Among them, ≥175 admissions were primarily for malignancy, led by malignant peripheral nerve tumours (MPNST, C47; ≥72) and CNS tumours (≥68), with soft-tissue sarcoma and NF1-associated GIST. In-hospital mortality was not reportable (small-cell suppression).

Conclusions: German inpatient neurofibromatosis care comprises two populations: growing paediatric imaging-surveillance, and older, complex, tumour-directed admissions. Coding cannot resolve subtype, so figures describe neurofibromatosis overall, predominantly NF1. These findings quantify imaging, anaesthetic and oncological demand for specialist-centre planning.

Background:
Large Language Models (LLMs) are systems trained using deep learning algorithms to analyse and process data. By LLM we assessed areas of need for guideline development for neurofibromatosis type 1 (NF1) and schwannomatosis (SWN).
Methods:
A PubMed-search for publications from 2016-2026 using “neurofibromatosis” or “schwannomatosis” and “guideline(s)” or “recommendation(s)” yielded 680 articles, with 540 unique publications. Of these, 351 were assessed with both abstract and full text, 189 on the abstract alone. Triage, data extraction, and categorisation were performed using an LLM with access to abstracts and/or full-text articles. After review, 67 articles containing recommendations related to NF1, SWN, or associated manifestations were identified. Extracted data included NF1/SWN type, manifestation, focus area, and methodological approach.
Results:
Of 67 articles, 43 (64%) focused on NF1, 16 (24%) on NF2-SWN, and 8 (12%) on non-NF2-SWN. Manifestations most frequently addressed included plexiform neurofibromas, malignant nerve sheath tumours, and optic gliomas in NF1, and vestibular schwannoma and hearing loss or deafness in NF2-SWN. A meta-analysis was conducted in 20 publications (30%). Sixty articles (90%) reported expert consensus, and 11 (16%) used a modified Delphi consensus approach. Focus areas included surveillance and management (51; 76%), diagnosis (43; 64%), treatment (41; 61%), genetic testing (19; 28%), and clinical trials (11; 16%).
Conclusion:
LLMs can identify and extract data describing focus areas and methodological approaches of NF1/SWN guidelines. With manual supervision by content experts, this approach proved effective for landscape analysis of guidelines, informing on areas lacking recommendations and guiding future guideline development targeting unmet needs.

Background:

In the UK, people with 'complex'neurofibromatosis type 1 (NF1) are managed by two specialist MDTs, while 'non-complex’ NF1 is monitored annually by GPs. Regional disparities have been reported in a recent patient survey. Along with Northern Ireland, Scotland was reported to have significantly lower levels of patient satisfaction compared to other regions due to disconnected care, lack of familiarity with NF1 or standardised care pathways.

Method:

An attitudes scale was disseminated to all licensed GPs and trainees in Scotland over 3 months.

Outcomes:

321 responded, of which 98% had had no recent training in NF1. Higher NF1 knowledge was strongly associated with greater confidence in management (Spearman’s ρ = 0.773, p = <0.001). Only 32% felt confident in recognising NF1, 14% could identify red-flag features and 2% felt confident in conducting an annual review. 8% understood local referral pathways. Despite this, 49% felt that GPs should take a proactive role in long-term care. 76% felt that GPs would require specific training to do this, and only 2% felt that their health board provides adequate training on NF1. 7% were aware of charities and resources available. 82% would welcome a concise GP-focused NF1 checklist.

There is a clear and monumental need for improved understanding of monitoring of non-complex adults with NF1 in Scotland by GPs. Educational resources and a focus on annual review are important areas for future research, to improve this area of health inequality in Scotland. A longer-term goal is improved access to specialist care in Highly Specialised Centres, based in England.

Background: Neurofibromatosis type 1 (NF1) is a lifelong multisystem tumour predisposition disorder with age dependent manifestations. Although diagnostic, paediatric, adult and tumour surveillance guidance has clarified care standards, implementation remains inconsistent where dedicated neurofibromatosis clinics are unavailable.

Methods: We performed a targeted narrative review of current NF1 guidance, key clinical evidence and rare disease implementation literature. Evidence was mapped across age groups, clinical domains and care levels to distinguish established recommendations from author proposed implementation steps.

Results: We developed a lifespan shared care framework for decentralised settings. It defines a minimum routine surveillance package: interval history, pain and functional assessment, skin and tumour review, neurological screening, blood pressure measurement, paediatric growth and pubertal review, school or work functioning, psychosocial screening and repeated patient education. Age specific review is linked to escalation triggers for tumour, visual, neurological, skeletal, vascular, endocrine and functional change. Red flags include new persistent or nocturnal focal pain, rapid tumour enlargement, hardening, neurological deficit, visual decline, severe hypertension, bowel or bladder dysfunction and major functional deterioration. The framework proposes symptom driven targeted magnetic resonance imaging, baseline whole body magnetic resonance imaging at transition where available, structured paediatric to adult handover, patient held summaries and explicit responsibilities across primary care, local specialists, tertiary neurofibromatosis services, sarcoma teams, genetics, mental health and rehabilitation.

Conclusion: An implementation oriented shared care pathway may support consistent surveillance, earlier recognition of clinically important change and appropriate use of specialist resources where dedicated clinics are limited. Prospective evaluation is required.

Background:
Neurofibromatosis type 1 (NF1) is a lifelong multisystem disorder requiring multidisciplinary follow-up. Describing pediatric cohorts is essential to improve clinical care and the future transition to adult services.

Methods:
A retrospective study included pediatric patients with NF1 followed at a Pediatric Neurology Unit in Portugal. Demographic, clinical, genetic, neuroimaging, and multidisciplinary follow-up data were reviewed.

Results:
Seventeen patients (60% male), aged 1-19 years, were included; five (29%) were ≥ 18 years. A positive family history was present in 10 patients (60%). The mean age at first Pediatric Neurology consultation was 2.5 years in patients without a family history and 5 years in those with affected relatives. All patients presented with café-au-lait macules and 77% had axillary or inguinal freckling. Cutaneous neurofibromas were observed in three patients, subcutaneous neurofibromas in two, and one patient had a bulky plexiform neurofibroma treated with selumetinib. No patients presented with optic pathway glioma or osseous dysplasia. Pathogenic NF1 variants were detected in seven of nine genetically tested patients. Brain MRI showed focal areas of T2 hyperintensity in 60% of examined patients. The most common comorbidities were learning disabilities (n=9), attention-deficit/hyperactivity disorder (n=8), epilepsy (n=2), scoliosis (n=2), and pilocytic astrocytoma (n=1). Patients were followed by a median of five additional specialties besides Pediatric Neurology.

Conclusion:
This study illustrates the broad clinical spectrum of pediatric NF1 and highlights the importance of standardized multidisciplinary follow-up. The considerable proportion of young adults remaining in pediatric care also underscores the need for structured transition pathways to adult healthcare services.

Background: Neurofibromatosis (NF) and schwannomatosis are complex genetic conditions requiring coordinated, lifelong, multidisciplinary care. Adult-focused services remain limited, particularly in Canada, where comprehensive care models are scarce.
Methods: We describe the structure and function of the Elisabeth Raab Neurofibromatosis Clinic; a unique, multidisciplinary adult NF clinic. The clinic supports adults with NF1 through a weekly clinic staffed by neurologists and a family physician with NF expertise. A semiregular clinic for patients with schwannomatosis is led by neurosurgery. A genetics team, including a medical geneticist and genetic counsellor, is embedded within the clinic, ensuring integration of genetic services into diagnosis, management, and family planning. Our clinic provides outpatient care to patients across Ontario.
Results: This model enables comprehensive, longitudinal care tailored to the complex needs of adult NF and schwannomatosis patients. Integrated genetics at every visit facilitates timely diagnosis, variant interpretation, reproductive counselling, and cascade testing. Multidisciplinary staffing supports coordinated management of neurologic, surgical, and general health concerns. The clinic’s broad referral base reflects its role as a specialized adult multidisciplinary clinic in Ontario and highlights the limited availability of comparable adult NF care programs across Canada.
Conclusion: Our clinic represents a novel model for adult NF care in Canada, combining multidisciplinary expertise and embedded genetic services. This integrated approach improves care coordination, supports informed decision-making, and addresses a critical gap in adult NF healthcare delivery. Expanding similar centres in other provinces would help reduce disparities in access and strengthen the national capacity to provide specialized care for adults with NF.

Background: Neurofibromatosis type 1 (NF1) is characterized by phenotypic variability among patients. A major contributor to this unpredictability is the highly heterogeneous nature of NF1 mutations, which are largely "private": the vast majority of patients harbor unique variants rather than recurrent hotspot mutations. This genetic diversity has made it difficult to establish reliable genotype-phenotype correlations using traditional approaches. The recent release of DeepMind's AlphaGenome, a deep learning model capable of predicting thousands of functional genomic tracks across multiple modalities, presents a novel opportunity to computationally model the functional consequences of these private NF1 mutations
Methods: This project will utilize AlphaGenome to generate gene expression predictions for a curated set of NF1 patient-specific mutations, with variant data sourced from the NF Data Portal. Predicted expression changes will be evaluated for potential associations with clinical presentations and molecular markers associated with tumorigenesis risk. The approach will focus on identifying whether AlphaGenome-derived expression signatures can meaningfully stratify patients by phenotypic severity or tumor predisposition, despite the absence of shared causal variants across patients.
Results: This project is in its early planning stages. Preliminary work will focus on establishing a pipeline for variant curation, AlphaGenome prediction generation, and correlation analysis with available clinical/molecular data from the NF Data Portal.
Conclusion: If successful, this approach could offer a scalable, mutation-agnostic computational framework for predicting NF1 disease severity and tumorigenesis risk, addressing a long-standing challenge in NF1 clinical management. This work lays the groundwork for future validation studies incorporating larger patient cohorts and additional genomic modalities.

Background:
Pediatric Neurofibromatosis type 1-associated low-grade gliomas (NF1-pLGG), particularly optic pathway gliomas, represent a unique subset of pLGG due to their impact on visual outcome besides other tumor associated burden. Vinblastine first-line monotherapy has shown long-term antitumoral benefit in NF1-pLGG and has become a standard of care option. Recently, the oral MEK-inhibitor selumetinib demonstrated radiological tumor reduction as well as visual improvement in relapsed/progressive NF1-pLGG. However, the 5yr-progression-free survival was significantly lower when compared to vinblastine monotherapy. Combining MEK inhibition with vinblastine in first-line therapy may offer an advantage to preserve visual acuity, increase duration response and reduce treatment burden in this chronic disease.
Methods:
We propose a multicenter Phase 2 trial for NF1-pLGG patients. Inclusion criteria contain the NCI criteria of NF1 diagnosis and indication for antitumoral pLGG-treatment, including visual deterioration. Exclusion criteria are age below 2 years and prior antitumoral or any treatment with a MEK inhibitor. Antitumoral treatment will consist of 6 months of weekly vinblastine intravenously and oral selumetinib for 26 cycles of 28 days. The protocol will be based on the Master Protocol EU-PEARL NF1 Version 1.0.

Study Design:
We define following primary endpoints: radiologic response rate (RAPNO-LGG) and visual improvement rate after 6 months (Snellen/TAC2 or other equivalent measures). Secondary endpoints are mainly radiologic response rate and visual improvement rate after 12 months. Other secondary endpoints include progression-free- and overall-survival and duration of response and treatment-free interval and patient-reported outcome measures. Exploratory endpoints such as safety and tolerability and biomarker correlates complete the study design .

Background.
Orbital plexiform neurofibroma in neurofibromatosis type 1 (NF1) may cause progressive ptosis, exophthalmos, orbital deformity, amblyopia, compression of visual structures, and irreversible visual loss. Surgery may require enucleation; therefore, organ-preserving systemic options are needed. MEK inhibitors are an emerging systemic treatment option for symptomatic unresectable plexiform neurofibromas; however, data on their use in infants remain extremely limited.

Materials and Methods.
A 12-month-old patient with NF1, diagnosed by multiple café-au-lait macules and a germline NF1 mutation, presented with congenital left upper eyelid ptosis, ocular asymmetry, and exophthalmos. MRI revealed a left orbital plexiform neurofibroma measuring 37 × 32 × 22 mm, volume 14 cm³, extending to the upper eyelid. The tumor was considered unresectable because radical removal was impossible without enucleation. In April 2026, after multidisciplinary review and informed consent, mirdametinib tablets for oral suspension were initiated at 2 mg/m² twice daily. Monitoring included clinical, ophthalmological, MRI, cardiac, and laboratory assessments.

Results.
After 3.5 months, marked clinical improvement was observed, including reduced ptosis, ocular asymmetry, and exophthalmos. Follow-up MRI is scheduled for October 2026. Treatment was well tolerated. Grade 1 skin toxicity and increased creatine phosphokinase and AST levels occurred without dose reduction. No serious adverse events were reported.

Conclusion.
This case demonstrates the potential feasibility of mirdametinib in an infant with severe unresectable NF1-associated orbital plexiform neurofibroma when organ-preserving surgical options are unavailable. Further data are needed to define safety and efficacy in children younger than 2 years.

Background: Adults with neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PNs) have limited prospective treatment data. TQ-B3234 is a selective MEK1/2 inhibitor with pharmacokinetic properties supporting once-daily dosing. This study evaluated its safety, pharmacokinetics, and antitumor activity in adults with NF1-PNs.

Methods: This open-label phase 1 study included dose escalation and expansion. Adults with inoperable NF1-PNs, cutaneous neurofibromas, or malignant peripheral nerve sheath tumors received oral TQ-B3234 once daily. Key objectives included dose-limiting toxicities, maximum tolerated dose, recommended phase 2 dose, safety, pharmacokinetics, and tumor response. PN response was assessed by volumetric MRI. Patient-reported outcomes and baseline single-cell RNA sequencing of pretreatment PN samples were exploratory.

Results: Forty adults were enrolled, including 31 with PNs, 7 with cutaneous neurofibromas, and 2 with malignant peripheral nerve sheath tumors. Grade ≥3 treatment-related adverse events occurred in 7 patients (17.5%). One dose-limiting toxicity, grade 3 fatigue, occurred at 100 mg once daily. The recommended phase 2 dose was 50 mg once daily. Among 30 evaluable PN patients, 28 (93.3%) had target tumor volume reduction, 19 (63.3%) achieved partial response, and 16 (53.3%) achieved confirmed partial response. Median time to response was 11.2 months. Median progression-free survival was not reached. Pharmacokinetic findings supported once-daily administration. Patient-reported outcomes, cutaneous neurofibroma activity, and baseline single-cell transcriptomic findings were exploratory.

Conclusion: TQ-B3234 showed a manageable safety profile and clinically meaningful volumetric activity in adults with NF1-PNs. The 50 mg once-daily dose was selected for further development.

Background: Based on data from the 2021 SPRINT study (NCT01362803) with selumetinib (ARRY-142886, AZD6244) capsules in children with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (NF1-PN), the exposure-response relationship for probability of overall response rate (ORR) was flat (p=0.203), suggesting lower and higher exposure at clinical doses had similar probabilities of response. However, this relationship was significant when ORR was calculated based on post-hoc independent central review (p=0.0428). In 2025, exposure-response analyses/simulations using data from the SPRINKLE study (NCT05309668) were conducted to validate recommended selumetinib dosage for the granular formulation in children with NF1-PN aged ≥1–<7 years.
Methods: All 36 participants received selumetinib granules at a dose equivalent to 25 mg/m² twice daily. Relationship between selumetinib steady state area under the curve (AUCₛₛ) and probability of response was assessed by binomial logistic regression. Virtual population simulations were conducted to evaluate selumetinib AUCₛₛ across different dose-body surface area (BSA) combinations.
Results: A positive exposure-response relationship was observed (p=0.0182), suggesting lower AUCₛₛ was associated with lower ORR. In simulations, 92.2% of AUCₛₛ values for selumetinib 12.5 mg (granule) in patients with BSA 0.4–0.49 m² were within 90% confidence intervals of AUCₛₛ values for 12.5–25 mg doses in patients with BSA 0.5–1.09 m². Predicted ORRs for 10 and 12.5 mg doses in patients with BSA 0.4–0.49 m² increased from 33.8% to 46.2%.
Conclusion: These analyses demonstrate a positive exposure-response relationship for selumetinib in young children with NF1-PN and support dose adjustment in patients with BSA 0.4–0.49 m².

Background: Population pharmacokinetics (PopPK) and exposure–response analyses were performed to support adult selumetinib (ARRY-142886, AZD6244) dosing, characterise pharmacokinetics, and explore the relationship between exposure metrics, selected efficacy endpoints and adverse events of special interest in adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) in KOMET (NCT04924608).
Methods: Four additional studies were added to a previously validated, two-compartment PopPK model for selumetinib/N-desmethyl selumetinib generated using 15 studies in healthy volunteers/patients with NF1-PN, incorporating multiple parameters affecting selumetinib clearance. Steady-state area under the curve (AUCₛₛ) values were derived for exploratory efficacy and safety exposure–response analyses.
Results: Of 657 included individuals; 49.2% had NF1-PN (median [range] age: 27.0 years [1.0–79.0]; body surface area [BSA]: 1.82 m² [0.42–2.40]). Oral selumetinib bioavailability: 63.4%; absorption lag time: 0.365 hours; duration of absorption: 0.576 hours. AUCₛₛ was 14% higher without regard to food versus fasted. Selumetinib clearance was associated with BSA and age. In typical participants with BSAs of 0.710/2.15 m² (5th/95th percentiles), clearance values were anticipated to be 58% lower/18% higher, respectively, than participants with BSA of 1.8 m². In typical participants in the 5th/95th age percentiles, clearance values were anticipated to be 16% higher/6% lower, respectively, than a 29-year-old participant. Of the 66 adults from KOMET, 21.2% had confirmed partial responses. Overlapping selumetinib AUCₛₛ was shown for responders/non-responders (median [range] 7370 [5870–14,400]/7440 [4340–14,400] nM×hour), and those with/without diarrhoea and rash acneiform/non-acneiform.
Conclusion: A 25 mg/m² twice-daily regimen yielded selumetinib exposures within safe/efficacious ranges in adults.

Background: Neurofibromatosis type 1 (NF1) requires lifelong, multidisciplinary follow-up, yet recognition is frequently delayed in primary care, and longitudinal monitoring of treatment parameters, adverse effects, and quality of life across care levels remains fragmented. We describe the design of a prospective, non-interventional study evaluating a digital patient-navigation and monitoring platform intended to support early recognition in primary care and structured longitudinal follow-up in specialist centers.
Methods: This 12-month, prospective, observational, non-interventional study will enroll approximately 80–100 patients with confirmed or suspected NF1 from participating pediatric primary-care practices and NF1 specialist centers. In primary care, the platform applies a structured questionnaire and automated Riccardi-score/NIH-criteria-based decision support to flag patients warranting specialist referrals. In specialist centers, the platform documents baseline status and supports 3-monthly patient/caregiver-reported follow-up covering anthropometric parameters, medication and adverse-effect tracking, and a 12-item quality-of-life instrument across five domains, with automated red-flag alerting to treating physicians for clinically significant symptoms or quality-of-life deterioration. Primary endpoints include referral rates following decision-support use and adherence to recommended screening intervals; secondary endpoints address documentation completeness, quality-of-life trends, and decision-support utilization patterns.
Results: The study protocol, case report forms, and ethics approval have been finalized, and enrolment is planned to begin in mid-2026 across primary-care and specialist sites nationally.
Conclusion: This platform represents a structured approach to bridging primary and specialist NF1 care through decision support and longitudinal monitoring; the study will generate descriptive data on feasibility, usability, and clinical impact to inform broader implementation.

Background: Selumetinib (ARRY-142886, AZD6244) received approval in the EU and US in 2025 for adults with neurofibromatosis type-1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We report Phase 3 KOMET trial (NCT04924608) final data cut-off (DCO) results.
Methods: Adults with NF1-PN were randomised to 28-day cycles of selumetinib 25 mg/m² twice daily or placebo, with crossover to selumetinib at the end of Cycle (C) 12 or earlier if radiological progression. Single-arm objective response rate (ORR; per independent central review-Response Evaluation in Neurofibromatosis and Schwannomatosis) and safety were evaluated at final DCO (last participant completed C24; 17/03/2025). Steady-state pharmacokinetics were collected at C1, Day (D) 8.
Results: Of 145 participants (selumetinib: 71; placebo: 74), 66 from placebo crossed over to selumetinib; 137 participants received selumetinib; 96/137 (selumetinib: 45, placebo/selumetinib: 51) completed the study with investigator-judged clinical benefit, allowing continued post-trial access. Median selumetinib exposure was 554 days, with 99.5% median relative dose intensity. ORR for selumetinib (N=71) was 23.9% (95% confidence interval 14.6–35.5); 10/17 responders remained in response for ≥12 months. During the selumetinib period, 127/137 participants experienced possibly-related adverse events (AEs); 31/137 participants had ≥Grade 3 AEs; 24/137 participants had serious AEs. Increased blood creatine phosphokinase was the most common AE of special interest (43.1%). Overall AE-related discontinuation was 9.5%. Median tmax was 1.5 hours; geometric mean AUC(0-12) was 2986 h × ng/ml at C1D8 (N=64).
Conclusion: In the first placebo-controlled trial for adult NF1-PN, selumetinib sustained clinically meaningful PN-volume reductions with no new safety concerns following longer exposure.

Background: Plexiform neurofibromas (PN) present a significant clinical challenge, with a notable unmet need for effective and well-tolerated therapies, particularly for the adult population.
Methods: A single-arm, open-label, Phase IIa trial of tunlametinib was conducted to assess its efficacy and safety in adults with inoperable, radiologically measurable PN. Patients received tunlametinib at a dose of 9 mg twice daily, following a continuous 21-day cycle regimen. The primary endpoint was the confirmed objective response rate (ORR), and secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and improvements in patient-reported outcomes (PROs) compared to baseline. Exploratory analyses integrating clinical variables and single-cell transcriptomic profiles were performed to explore response heterogeneity.
Results: Of 15 adults (10 males, 5 females; median age, 27 years, range 18 to 45), 8 patients achieved a confirmed partial response (PR), with an ORR of 53.3% (95% CI, 26.69 to 78.73) and a median neurofibroma volume reduction of -23.5% (range 1.6% to -49.1%). Significant improvements in multiple PRO domains were observed, including Patients’ Global Impression of Change and the Plexiform Neurofibromas Quality of Life scale. Regarding safety, all patients experienced at least one treatment-related adverse event (AE), the majority of which were grade 1 or 2. ScRNA-seq profiling of pre-treatment biopsies from one rapid responder and two gradual responders revealed substantial microenvironmental heterogeneity.
Conclusion: Tunlametinib demonstrated promising efficacy and an acceptable safety profile in adults with PN, broadly aligning with prior PN trial including selumetinib and mirdametinib.

Background: Interim data (cut-off: 22 May 2025) from an ongoing post-authorisation study (NCT05388370) characterising the real-world safety profile of selumetinib (ARRY-142886, AZD6244) in children with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) from Europe and Israel are presented.
Methods: Patients (aged ≥3 to 18 years) treated with selumetinib comprised the base cohort (BC); patients aged ≥8 years at Tanner Stage I–IV comprised the nested prospective cohort (NPC). Baseline demographics and clinical characteristics were collected via retrospective chart abstraction (Day −365 to −1). Primary objective: NPC safety outcomes collected for ≤6 years.
Results: 117 patients were enrolled across 33 sites in nine countries. Post-screening, BC included 116 patients (median age: 12.0 years; 61.2% male); NPC included 90 patients (median age: 11.5 years; 62.2% male).
In NPC, median time from NF1-PN diagnosis to treatment initiation was 9.7 months; median exposure duration was 12.0 months (n=88; range 1.2–36.6). Safety outcomes of interest occurred in <5% of patients; 76.7% of patients reported adverse events (AEs), most AEs were Grade 1/2 (28.9%/31.1%); 62.2% were skin and subcutaneous tissue disorders. Selumetinib-related AEs were reported in 73.3% of patients (most common: paronychia [31.1%]). Grade 3/serious AEs were reported in 16.7%/5.6% of patients. No Grade ≥4 AEs were reported. AEs leading to selumetinib dose reduction/interruption occurred in 15.6%/20.0% of patients; none resulted in permanent discontinuation.
Conclusion: Real-world selumetinib safety profile in children was consistent with clinical trial data and known safety profile. No new safety signals were identified; long-term safety characterisation is ongoing.

Purpose: PEDIA study (NCT06175637) is a prospective, multicenter, observational study exploring the effectiveness and safety of selumetinib in Chinese pediatric patients with NF1-PN.
Methods: This multicenter observational study was conducted across more than 40 centers in China, enrolling NF1 patients aged 3–16 years with symptomatic, inoperable PN. Participants received selumetinib 25 mg/m2 twice daily until progressive disease, unacceptable toxicity or patient decision and the data collection period was 24 months since enrolment. Key outcomes included disease characteristics of PN, treatment profiles, and the effectiveness and safety of selumetinib. Effectiveness was measured through an endpoint called "disease status of PN", which was qualitatively evaluated by investigators based on the change of radiological tumor size, tumor progression status, and symptoms.
Results: At data cut off (October 25, 2025), 207 patients were enrolled and median (Q1, Q3) treatment duration was 422 days (376, 451). The demographic and disease characteristics of patients are shown in Table 1. Among the 201 patients who had at least one visit, 56.2% of patients had improved disease status of PN. 91.8% of patients had treatment-emergent adverse events. 86.5% of patients had treatment-related adverse events (TRAE) and 5.8% of patients had ≥Grade 3 TRAEs. The most common TRAEs were paronychia (28.1%), elevated blood creatine phosphokinase (26.6%), and diarrhea (24.6%). 3.4% (7/207) of patients had treatment-related serious adverse events. No patient had drug discontinuation due to TRAE.
Conclusion: This is the first report of effectiveness and safety of selumetinib treating Chinese pediatric patients with NF1-PN in a real-world setting.

Background: Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome marked by substantial phenotypic heterogeneity. Here, we sought to characterize the disease burden of NF1, with a dedicated focus on the hallmark lesion, plexiform neurofibromas.
Methods: This retrospective multicenter cohort study included patients with NF1 treated at 5 specialized NF1 centers in China from 2019 to 2024 for descriptive, comparative and correlation analyses.
Results: Among 2,290 patients with NF1 (mean age 18.5 years; 52% female), the most frequent features were café-au-lait macules (87.1%), axillary/inguinal freckling (62.5%), and cutaneous neurofibromas (39.3%), whereas skeletal abnormalities (<2%) and optic pathway gliomas (0.7%) were uncommon. PN were identified in 51.4%. Symptomatically, more than half of PNs were symptomatic, while 27% of patients underwent treatment. Surgery was most frequent (23%), usually partial resection (43%), whereas pharmacologic therapy (6%), predominantly selumetinib, increased in uptake after 2023. Follow-up was documented only in 57% of patients with PN, of whom 47.6% showed progression, with a median PFS of 23 months.
Conclusions: The study provides the comprehensive landscape of NF1 in China, delineating the substantial burden and heterogeneity of PN, persistent challenges in management, and gaps in current surveillance.

Background:
Neurofibromatosis (NF1)-related plexiform neurofibromas (PN) can be associated with significant morbidity and negative impact on quality of life. Since 2017, following the pivotal SPRINT trial and subsequent FDA (2020) and EMA (2021) approval, 9 patients with symptomatic, inoperable PNs at our tertiary referral centre have been treated with the MEK1/2 inhibitor selumetinib on a compassionate managed-access programme pending national reimbursement.
Methods:
A retrospective chart review of patients treated with selumetinib from September 2017 to May 2026 was performed. Relevant clinical data regarding age, growth, clinical and radiological response to treatment and adverse effects were collected and analysed.
Results:
Nine patients with NF1-related symptomatic inoperable PN received selumetinib treatment, six with progression demonstrated on serial imaging at baseline. Median age at commencement was 7.9 years (range 3-17) and median treatment duration was 58 months (range 20-104). 89% remained on treatment at the time of data collection. Eight patients demonstrated durable stability and one had progression. Improvement in quality of life was reported in 89% and pain reduction in 67%. All experienced adverse effects, of CTCAE grade 1-2 in the majority, requiring dose reduction in two. One patient discontinued treatment due to onset of inflammatory bowel disease.
Conclusion:
Our real-world experience of selumetinib treatment with follow-up extending to 8 years (median 4.8) in patients with inoperable PNs showed high treatment tolerability and efficacy. Adverse effects were common but mild in the majority, requiring drug withdrawal in only one patient. Our experience highlights the important therapeutic impact of selumetinib treatment in children with significant PN-related morbidity.

Background: PAS-004 is a small molecule, allosteric inhibitor of MEK 1/2 and the first macrocyclic structure MEK inhibitor in clinical development.

Methods: Phase 1/1b clinical trial evaluate the safety, pharmacokinetic (PK), and preliminary efficacy of PAS-004 in adult patients with NF1 who have symptomatic and inoperable, incompletely resected, or recurrent NF1-associated plexiform neurofibroma (pNF). Three eligible patients were enrolled in one of 6 dose escalation cohorts receiving PAS-004 tablets once daily: 4mg, 8mg, 12mg, 15mg, 18mg, 24mg. Safety and tolerability are measured through a series of laboratory assessments and physical exams. A detailed PK profile was obtained after administration of PAS-004. PN volume is assessed by volumetric MRI at baseline, Cycle4, and every three months from then on.

Results: As of 22 May 2026, 16 patients have been enrolled across the 6 dose cohorts. Treatment Related Adverse Events (TRAEs) were reported in 68.8% of patients and all but one were Gr1/Gr2. PAS-004 PK analysis suggests linear PK with t1/2 of 60h, and Cmax/Cmin ratio below 2 at steady state. 11 of the 16 patients enrolled had undergone MRI measurement around cycle 6. While the data are not mature the majority of patients (10 of 11) demonstrated some decrease in size of the pNF.

Conclusions: To date, PAS-004 is shown to be a safe and well-tolerated novel MEK inhibitor. These findings provide a compelling rationale to continue to follow these patients for longer, and establish a dose to take into Part B of the study.

Background: The nursing team in the London national NF1 have service received multiple requests for guidance on the safety of GLP-1 receptor agonists for weight loss. Currently, no contraindication exists for this population. We present five NF1 individuals who received this treatment.
Methods: Seven patients contacted the nursing team regarding GLP-1, five individuals commenced GLP-1 and gave informed consent for this report.
Results: Patients lost between 15.1% and 31.2% of body weight, over four to 24 months. After treatment Patient 1 (female, 44 years) presented with a newly “palpable chest lump,” identified on ultrasound as a prominent costochondral junction. Patient 2 (female, 46) reported increased neurofibroma prominence with less pain. Patient 3 (female, 39) developed escalating back pain and was diagnosed with high-grade malignancy. Patient 4 (male, 31) reported resolution of sleep apnoea, improved joint health, increased energy, reduced migraines, but more visible cutaneous neurofibromas. Patient 5 (male, 57) qualified for spinal surgery, reported increased activity and reduced alcohol consumption. The predominant reported side effect was constipation.

Conclusions: Weight loss conferred positive outcomes in four of five patients. Comorbidities were spinal cord compression, sleep apnoea, pain and neurofibromas. All achieved significant weight loss. Patient 3 developed high-grade sarcoma during treatment; unintentional weight loss is an indicator of underlying malignancy and GLP-1-induced weight loss may obscure malignancy. Patient perception of “new” neurofibroma prominence may prompt unnecessary investigations and heightened symptomatic burden. Patients on GLP-1 receptor agonists require monitoring during treatment.

Background: Plexiform neurofibromas (PNs) are a hallmark of neurofibromatosis type 1 (NF1). In early childhood, complete surgical resection is often associated with considerable risks, making treatment challenging. MEK inhibitors (MEKi) offer a non-surgical therapeutic alternative for reducing PN volume; however, age restrictions and limited pediatric formulations complicate their use in infants. Here, we report our experience with off-label MEKi treatment in an infant with a symptomatic, inoperable PN.
Methods: A 4-week-old boy with genetically confirmed NF1 presented with a PN of the right trigeminal nerve, sphenoid wing dysplasia, right-sided exophthalmos, a temporal arachnoid cyst, and structural epilepsy. Within 4 months, MRI demonstrated rapid tumor progression from 3.72 ml to 14.37 ml, accompanied by increasing facial swelling. Since the PN was considered inoperable, MEKi therapy was therefore initiated.
Results: Because the patient was unable to swallow tablets or capsules, off-label treatment with a commercially available oral trametinib solution was started. Tumor reduction was observed and the patient did not experience any adverse events. However, after 1 year, severe adverse effects occurred, including toxic dermatitis, mucosal and skin irritation, and paronychia, requiring treatment discontinuation. After recovery, therapy was switched to a newly available MEKi in a weight-adjusted granule formulation, which was well tolerated.
Conclusion: Even within the same therapeutic class, different formulations of MEKi may improve tolerability. Newly available pediatric formulations appear to be appropriate for infants and may help reduce PN growth and prevent PN-related morbidity. MEKi therapy should therefore be considered even in children under 1 year of age.