Neurofibromatosis 1-associated optic pathway gliomas (OPGs) may co-occur with central precocious puberty (CPP). Using large language model-based data analysis from 2 NF centers, we compared OPGs in children with NF1, with and without CPP. CPP was associated with hypothalamic involvement, poorer vision, and a higher likelihood of OPG treatment.

BACKGROUND AND OBJECTIVES:Machine learning (ML) and natural language processing (NLP) approaches are increasingly used to support nuanced phenotyping, surveillance, and trial readiness using electronic health records (EHRs) in neurologic disease. However, inconsistent clinical documentation limits data harmonization and model performance, particularly in complex heterogeneous disorders such as neurofibromatosis type 1 (NF1). The primary research question was whether physician-authored EHR documentation of NF1-related features demonstrates systematic lexical variation that may impede computational phenotyping. The primary objective was to characterize lexical variation and documentation completeness for core NF1 features, while a secondary objective aimed to develop a standardized, data-informed clinical lexicon aligned with contemporary clinical practice and terminology standards. METHODS:We conducted a retrospective observational study of outpatient progress notes from pediatric patients with NF1 evaluated at 2 large tertiary care programs serving similar patient populations in the Midwest. A rule-based NLP algorithm was developed to identify 10 core NF1 features and extract the range of terms used to document each feature. Lexical variants and documentation frequency were quantified across institutions, providers, and time. Based on observed usage patterns, a standardized clinical lexicon was developed and mapped to existing terminology standards. RESULTS:A total of 5,393 outpatient notes representing 1,661 individual pediatric patients were analyzed. Substantial lexical variation was observed for most NF1 features, including variation within and across individual providers. Clinically significant features, such as optic pathway glioma, were documented using numerous nonstandard terms, with preferred terminology appearing in a minority of notes. Cutaneous neurofibromas demonstrated higher internal consistency but lagged behind current clinical trial nomenclature, while plexiform neurofibromas and attention-deficit/hyperactivity disorder were documented more consistently. Documentation completeness also varied across providers and over time, with many previously documented features absent from later follow-up notes. DISCUSSION:Physician-authored EHR documentation of NF1-related features demonstrates substantial lexical variation and incomplete longitudinal capture, which limit the accuracy and generalizability of NLP-based and ML-based phenotyping. Establishing a standardized, data-informed clinical lexicon aligned with current care and research practices represents a scalable strategy to improve interoperability, phenotypic consistency, and readiness for clinical trials and real-world evidence generation in NF1 and other complex neurologic disorders.

Abstract BACKGROUND NF1-OPGs are amorphous tumors involving either single or multiple locations (optic nerve, chiasm, tract) along the anterior visual pathway (AVP). In this prospective study, we investigated how volumetric MRI measures of the AVP as well as other clinical variables are associated with treatment decisions in children with newly diagnosed NF1-OPGs. METHODS Children with newly diagnosed NF1-OPG whose MRI included a T1-weighted volumetric sequence without significant artifact at their enrollment visit were eligible for inclusion. All subjects underwent a quantitative ophthalmic exam to determine if visual acuity (VA) was normal. The neuro-oncologist/NF1 expert determined whether the subject would be observed or undergo treatment at that baseline visit. Volumetric MRI analysis was automatically performed using a deep learning network that measured AVP volume (mm3). Non-parametric group comparisons and multivariable logistic regression models evaluated the impact of age at enrollment, sex, NF1 inheritance type, AVP volume, and VA on the decision for immediate treatment with chemotherapy versus observation. RESULTS One-hundred twenty-three subjects met inclusion criteria. Subjects assigned to observation (N=112, 44% female) and subjects immediately treated with chemotherapy (N=11, 80% female) at enrollment were of similar age (2.7 and 2.8 years, respectively) and inheritance (p > 0.05). Abnormal VA was present more often in the treatment group (46%) compared to the observation group (17%, p <0.001). AVP volume was significantly greater in the treatment group (4,181.1mm3) compared to the observation group (1,819.8mm3, p <0.001). AVP volume, sex, and VA reached significance in univariable regression, however, in the multivariable regression model only the AVP volume (p < 0.001) was significantly associated with treatment initiation. DISCUSSION Children with greater NF1-OPG AVP volumes are treated more often compared with those with lower volumes. Volumetric measures of NF1-OPGs are a valuable metric in understanding treatment patterns and are positioned to help inform clinical decision making.

Abstract BACKGROUND Treatment and clinical management decisions for children with NF1-OPGs remain challenging as most existing data are retrospective and have not included standardized visual outcomes. In this study, we prospectively enrolled newly diagnosed NF1-OPGs and performed standardized neuro-oncology and ophthalmology assessments in order to develop evidence-based guidelines for monitoring and treatment. METHODS Children with NF1-OPG on MRI who were evaluated by both a study ophthalmologist and neuro-oncologist/NF1 expert within 1 month of radiologic diagnosis were eligible for enrollment. All subjects attempted quantitative visual acuity using Teller acuity cards (TAC) as well as ATS-HOTV testing. The neuro-oncologist/NF1 expert provided reasons for obtaining the MRI as well as initiating treatment, if applicable. Descriptive statistics calculated the success rate of acquiring TAC and reasons to obtain the MRI. RESULTS Two-hundred fifty subjects from 22 institutions were enrolled and had at least one visit beyond baseline (Median age 3.1 years, range 0.1–16.8; 53% female). TAC was successfully acquired in both eyes (N=195, 78%) and at least one eye in (N=206, 82%). ATS-HOTV was successfully acquired in both eyes (N=97, 39%) and at least one eye in (N=98, 39%). The two most common reasons to obtain an MRI were screening due to a diagnosis of NF1 (N=99, 39%) and ophthalmologic concern (N=81, 32%). At enrollment, continued observation occurred in a majority of subjects (N=221, 88%) while treatment with chemotherapy was initiated in only 11% (N=29). Twenty-nine (11%) subjects initially observed transitioned to treatment after enrollment (range: 2.5–25 months) thus far. DISCUSSION We present a prospective multicenter study of children with newly diagnosed NF1-OPGs. The ability to acquire quantitative visual acuity was higher than anticipated. The frequency of NF1-OPGs requiring treatment is lower than previously reported. Regression models of clinical and MRI features that prompted immediate treatment with chemotherapy versus observation will be discussed.

This multi-institutional, descriptive study of 19 children with neurofibromatosis 1 examines the link between optic pathway gliomas (OPGs) and central precocious puberty (CPP). We report that CPP can arise without OPG chiasmal involvement and that prior OPG chemotherapy does not prevent the development of CPP.

Neurofibromatosis type 1 (NF-1) microdeletion syndrome accounts for 5 to 11% of individuals with NF-1. The aim of our study was to characterize a large cohort of individuals with NF-1 microdeletion syndrome and expand its natural history. We conducted a retrospective chart review from 1994 to 2024 of individuals with NF-1 microdeletion syndrome followed at two large Neurofibromatosis Clinics. This cohort consists of 57 individuals with NF-1 microdeletion syndrome (28 type-1, 4 type-2, 2 type-3, 9 atypical deletions, and 14 indeterminate). We note 38/56 (67.9%) with describable facial features, 25/57 (43.8%) with plexiform neurofibromas, and 3/57 (5.2%) with malignant peripheral nerve sheath tumors within the observed period. The most reported neurodevelopmental manifestations from school-age or older individuals included 39/49 (79.6%) with developmental delays, 35/49 (71.4%) with expressive and/or receptive speech delays, 33/41 (80.5%) with learning difficulties, and 23/42 (54.8%) with attention-deficit/hyperactivity disorder. Full-scale IQ testing data was available for 22 individuals (range: 50-96). Of the 21 adults in this cohort, 14/21 (66.7%) graduated from high school, and 4/21 (19.0%) had some college experience. Many individuals received academic support (i.e., special education, individual education plan). In this cohort, neurocognitive outcomes in adults varied more than typically reported in the literature.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant condition characterized by café-au-lait spots, neurofibromas, and multisystem involvement, including vasculopathy that may lead to ischemic or hemorrhagic events. Cases of vascular occlusions involving the retinal or ophthalmic circulation have also been described. The majority of cases with reported outcomes describe poor visual acuity following resolution. We report a case of retinal and ophthalmic artery occlusion resulting in ocular ischemic syndrome in a patient with NF1 who had remarkable improvement in retinal perfusion and visual acuity following high-dose corticosteroid treatment.

Objective: To describe the neurocognitive manifestations in patients with NF1 microdeletion syndromes. Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome that affects 1 in 2500–3000 people. About 5–11% of NF1 patients have NF1 microdeletion syndrome, historically associated with a higher risk of intellectual disability than the NF1 population. Design/Methods: We performed a retrospective study of pediatric patients with molecularly confirmed NF1 microdeletion syndrome seen in the Neurofibromatosis Clinic of the Ann & Robert H. Lurie Children's Hospital of Chicago from 01/01/2000 to 09/01/2022. Clinical data was collected from medical records. Results: A total of 12 patients were identified with NF1 microdeletions. The mean age at diagnosis was 2.38 years (range 3 months to 5 years), and 58% were female. The most common deletion was type 1 (1.4-MB). Macrocephaly was present in 33% of individuals. One individual presented with a symptomatic chiasmatic optic pathway glioma. Plexiform neurofibromas were reported in 4 (33%) without any known malignant transformation. Neurodevelopmental manifestations included speech difficulties (expressive/receptive) in 8 (66%), attention-deficit/hyperactivity disorder (ADHD) in 5 (42%), gross motor delays in 4 (33%), fine motor delays in 4 (33%), and autism spectrum disorders in 3 (25%). There were 2 adults with NF1 microdeletions attending college. Other comorbidities include anxiety (6, 50%), depression (3, 25%), and sleep disturbances (5, 42%). Conclusions: In this Study, NF1 microdeletion patients were diagnosed at an early age. NF1 microdeletion individuals have variable neurological and neurodevelopmental manifestations which require tailored developmental interventions. Sleep difficulties appear common in this cohort in addition to other neurological manifestations. Two adults with NF1 microdeletions were in College suggesting that, at least in some individuals, the neurocognitive outcome may be better than has previously been described. Disclosure: Dr. Garzon has nothing to disclose. Miss Patete has nothing to disclose. Miss Serbinski has stock in Illumina. Miss Hankins has nothing to disclose. The institution of Dr. Sawin has received research support from National Institute of Neurological Disorders and Stroke (NINDS). Ms. Goetsch Weisman has nothing to disclose. Ms. Kim has nothing to disclose. Dr. Charrow has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Charrow has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Listernick has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AstroZeneca. Dr. Listernick has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for White and Williams. Dr. Prada has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genzyme Sanofi . Dr. Prada has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. Dr. Prada has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Prada has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for America Journal of Medical Genetics. The institution of Dr. Prada has received research support from National Institute of Neurological Diseases and Stroke (NINDS). The institution of Dr. Prada has received research support from Department of Defense (DOD).

BACKGROUND:Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure.METHODS:We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse.RESULTS:Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment.CONCLUSION:Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies.

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.

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

PURPOSE: This study reports on neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (OPGs) and a follow-up period of at least 10 years in a cohort of children. OPGs are a common manifestation of NF1 and can cause significant visual morbidity. Long-term follow-up in children with NF1-associated OPGs has not been reported previously. DESIGN: Retrospective observational case series. METHODS: This study included children with a documented follow-up of at least 10 years. Three final outcomes were evaluated: visual acuity (VA) per eye (i.e., in the more severely affected eye), VA per patient (i.e., VA when both eyes were open), and the presence of optic nerve head pallor. RESULTS: A total of 45 children were included, followed for a mean of 14 years (range, 10-21 years). At the end of follow-up, abnormal VA (considered moderate to severe impairment) in the more severely affected eye was present in 36% of the patients and in both eyes in 11%. Optic nerve head pallor of 1 or both nerves was present in 62%. In multivariate analysis, only initial VA and optic nerve head appearance at presentation were found to predict the final outcomes. All patients, except for 1, were asymptomatic at presentation and had normal VA and nerves that appeared normal, preserved their good vision in both eyes. Only 1 patient, who had normal VA and normal appearing nerves at presentation, had moderate to severe VA loss at long term follow-up. CONCLUSIONS: In this study, children with NF1-associated OPG whose examination signs and symptoms were normal had a normal initial examination and excellent long-term visual and anatomical outcomes. VA and the appearance of the optic nerve head at presentation predict long-term outcome. ((C) 2020 Published by Elsevier Inc.)

Clinical characteristics of patients affected by neurofibromatosis type 1 carrying missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423

BACKGROUND:Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy.METHODS:We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs.RESULTS:A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects.CONCLUSIONS:In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.

Optic pathway gliomas (OPGs) are a common manifestation of Neurofibromatosis type 1 (NF1) and can cause significant visual morbidity. In this study we describe a very long follow-up on children with NF1-associated OPGs.

OBJECTIVE:To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children.METHODS:A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed.RESULTS:The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%).CONCLUSIONS:Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.