Dose-dependent seizure control with MEK inhibitor therapy for progressive glioma in a child with neurofibromatosis type 1.

BACKGROUND: Low-grade gliomas (LGGs) occurring in children can result in many different neurologic complications, including seizures. MEK inhibitors are increasingly being used to treat LGG, but their effect on associated neurologic symptoms has not been established. RESULTS: Here, we report a patient with neurofibromatosis type 1 (NF1), medically refractory epilepsy (MRE), and an extensive optic pathway glioma (OPG) who developed dose-dependent seizure control while being treated with selumetinib. Seizure frequency rebounded after dose reduction for cardiac toxicity, then improved, and finally ceased after restarting full dosing, allowing confidence in the cause of improvement. CONCLUSION: Selumetinib may have promise in epilepsy management in other children with NF1 or LGG.

Predictors of Patient Return to a Tertiary Neurofibromatosis Subspecialty Clinic.

OBJECTIVE: To evaluate sociodemographic and medical predictors of patient return to a neurofibromatosis subspecialty clinic. STUDY DESIGN: Data were collected from the Washington University Neurofibromatosis Clinical Program electronic medical records. A total of 713 subjects with initial visits to the Washington University Neurofibromatosis Clinical Program between July 1, 2005 and December 18, 2020 were included. Variables collected included sex, race, ethnicity, age, date of first visit, place of residence, diagnosis, insurance payer, physician recommendation for return, and subject return. Return rates for each demographic group were calculated. Bivariate analyses were performed to inform variable inclusion in the model, and a binary logistic regression model was calculated to predict subject return. RESULTS: The overall return rate was 76%. The binary logistic regression model was statistically significant (χ29 = 131.094; P < .001) and showed that subjects who self-identified as Black and/or African American, presented with or received a diagnosis of café-au-lait macules at their initial visit, were from a rural area, were older, or who lived farther from the Washington University Neurofibromatosis Clinical Program were less likely to return to clinic. CONCLUSIONS: These findings support the implementation of tailored communication and monitoring interventions to improve the care for children with neurofibromatosis type 1.

SARS-CoV-2 screening testing in schools for children with intellectual and developmental disabilities.

BACKGROUND: Transmission of SARS-CoV-2 in schools primarily for typically developing children is rare. However, less is known about transmission in schools for children with intellectual and developmental disabilities (IDD), who are often unable to mask or maintain social distancing. The objectives of this study were to determine SARS-CoV-2 positivity and in-school transmission rates using weekly screening tests for school staff and students and describe the concurrent deployment of mitigation strategies in six schools for children with IDD. METHODS: From November 23, 2020, to May, 28, 2021, weekly voluntary screening for SARS-CoV-2 with a high sensitivity molecular-based saliva test was offered to school staff and students. Weekly positivity rates were determined and compared to local healthcare system and undergraduate student screening data. School-based transmission was assessed among participants quarantined for in-school exposure. School administrators completed a standardized survey to assess school mitigation strategies. RESULTS: A total of 59 students and 416 staff participated. An average of 304 school staff and students were tested per week. Of 7289 tests performed, 21 (0.29%) new SARS-CoV-2 positive cases were identified. The highest weekly positivity rate was 1.2% (n = 4) across all schools, which was less than community positivity rates. Two cases of in-school transmission were identified, each among staff, representing 2% (2/103) of participants quarantined for in-school exposure. Mitigation strategies included higher than expected student mask compliance, reduced room capacity, and phased reopening. CONCLUSIONS: During 24 weeks that included the peak of the COVID-19 pandemic in winter 2020-21, we found lower rates of SARS-CoV-2 screening test positivity among staff and students of six schools for children with IDD compared to community rates. In-school transmission of SARS-CoV-2 was low among those quarantined for in-school exposure. However, the impact of the emerging SARS-CoV-2 Delta variant on the effectiveness of these proven mitigation strategies remains unknown. TRIAL REGISTRATION: Prior to enrollment, this study was registered at ClinicalTrials.gov on September 25, 2020, identifier NCT04565509 , titled Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic.

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis.

Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.

SARS-CoV-2 Screening Testing in Schools for Children with Intellectual and Developmental Disabilities.

BACKGROUNDTransmission of SARS-CoV-2 in schools primarily for typically developing children is rare. However, less is known about transmission in schools for children with intellectual and developmental disabilities (IDD), who are often unable to mask or maintain social distancing. The objectives of this study were to determine SARS-CoV-2 positivity and in-school transmission rates using weekly screening tests for school staff and students and describe the concurrent deployment of mitigation strategies in six schools for children with IDD.METHODSFrom 11/23/20 to 5/28/21, weekly voluntary screening for SARS-CoV-2 with a high sensitivity molecular-based saliva test was offered to school staff and students. Weekly positivity rates were determined and compared to local healthcare system and undergraduate student screening data. School-based transmission was assessed among participants quarantined for in-school exposure. School administrators completed a standardized survey to assess school mitigation strategies.RESULTSA total of 59 students and 416 staff participated. An average of 304 school staff and students were tested per week. Of 7,289 tests performed, 21 (0.29%) new SARS-CoV-2 positive cases were identified. The highest weekly positivity rate was 1.2% (n = 4) across all schools, which was less than community positivity rates. Two cases of in-school transmission were identified, each among staff, representing 2% (2/103) of participants quarantined for in-school exposure. Mitigation strategies included higher than expected student mask compliance, reduced room capacity, and phased reopening.CONCLUSIONSDuring 24 weeks that included the peak of the COVID-19 pandemic, we found no evidence for elevated SARS-CoV-2 screening test positivity among staff and students of six schools for children with IDD compared to community rates. In-school transmission of SARS-CoV-2 was low among those quarantined for in-school exposure.Clinical Trial RegistryPrior to enrollment, this study was registered at ClinicalTrials.gov on 9/25/2020, identifier NCT04565509, titled Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic (https://clinicaltrials.gov/ct2/show/NCT04565509?term=NCT04565509).

Seizures in Fragile X Syndrome: Associations and Longitudinal Analysis of a Large Clinic-Based Cohort.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, learning disability, and autism spectrum disorder, is associated with an increased prevalence of certain medical conditions including seizures. The goal of this study was to better understand seizures in individuals with FXS using the Fragile X Online Registry with Accessible Research Database, a multisite observational study initiated in 2012 involving FXS clinics in the Fragile X Clinic and Research Consortium. Seizure data were available for 1,607 participants, mostly male (77%) and white (74.5%). The overall prevalence of at least one seizure was 12%, with this rate being significantly higher in males than females (13.7 vs. 6.2%, p < 0.001). As compared to individuals with FXS without seizures, those with seizures were more likely to have autism spectrum disorder, current sleep apnea, later acquisition of expressive language, more severe intellectual disability, hyperactivity, irritability, and stereotyped movements. The mean age of seizure onset was 6.4 (SD 6.1) years of age with the great majority (>80%) having onset of seizures which was before 10. For those with epilepsy, about half (52%) had seizures for more than 3 years. This group was found to have greater cognitive and language impairment, but not behavioral disruptions, compared with those with seizures for <3 years. Antiepileptic drugs were more often used in males (60.6%) than females (34.8%), and females more often required more than one medication. The most commonly used anticonvulsants were oxcarbazepine, valproic acid, lamotrigine, and levetiracetam. The current study is the largest and first longitudinal study ever conducted to describe seizures in FXS. Overall, this study confirms previous reports of seizures in FXS and extends previous findings by further defining the cognitive and behavioral phenotype of those with epilepsy in FXS. Future studies should further investigate the natural history of seizures in FXS and the characteristics of seizures in FXS in adulthood.

Predictive Modeling for Clinical Features Associated With Neurofibromatosis Type 1.

OBJECTIVE: To perform a longitudinal analysis of clinical features associated with neurofibromatosis type 1 (NF1) based on demographic and clinical characteristics and to apply a machine learning strategy to determine feasibility of developing exploratory predictive models of optic pathway glioma (OPG) and attention-deficit/hyperactivity disorder (ADHD) in a pediatric NF1 cohort. METHODS: Using NF1 as a model system, we perform retrospective data analyses using a manually curated NF1 clinical registry and electronic health record (EHR) information and develop machine learning models. Data for 798 individuals were available, with 578 comprising the pediatric cohort used for analysis. RESULTS: Males and females were evenly represented in the cohort. White children were more likely to develop OPG (odds ratio [OR]: 2.11, 95% confidence interval [CI]: 1.11-4.00, p = 0.02) relative to their non-White peers. Median age at diagnosis of OPG was 6.5 years (1.7-17.0), irrespective of sex. Males were more likely than females to have a diagnosis of ADHD (OR: 1.90, 95% CI: 1.33-2.70, p < 0.001), and earlier diagnosis in males relative to females was observed. The gradient boosting classification model predicted diagnosis of ADHD with an area under the receiver operator characteristic (AUROC) of 0.74 and predicted diagnosis of OPG with an AUROC of 0.82. CONCLUSIONS: Using readily available clinical and EHR data, we successfully recapitulated several important and clinically relevant patterns in NF1 semiology specifically based on demographic and clinical characteristics. Naive machine learning techniques can be potentially used to develop and validate predictive phenotype complexes applicable to risk stratification and disease management in NF1.

Nonoptic pathway tumors in children with neurofibromatosis type 1.

OBJECTIVE: To define the radiologic features and natural history of nonoptic pathway tumors (non-OPTs) in children with neurofibromatosis type 1 (NF1). METHODS: We performed a retrospective cross-sectional analysis of 64 children with NF1 harboring 100 probable non-OPTs. Age at diagnosis, sex, tumor location, number of tumors, symptomology, concurrent OPT, radiographic progression (defined as qualitative and quantitative increases in size), and treatment were assessed. Tumor volumes were measured from initial presentation until treatment or end of disease progression. RESULTS: Sixty-three percent of probable non-OPTs progressed over time, where radiographic progression was concomitantly associated with clinical progression. Fifty-two percent of patients had incidentally identified probable non-OPTs. Twenty-five percent of patients were symptomatic at initial diagnosis, all of whom harbored tumors that grew on subsequent scans and required tumor-directed therapy. There were no clinical differences between probable non-OPTs localized to the brainstem vs other locations with respect to age, sex, concurrent optic pathway glioma, symptomology, and treatment. The average time from diagnosis to stabilization or decrease in tumor size was 2.34 years (SD, 2.15 years). Nineteen biopsied lesions were all histopathologically confirmed as tumor. Six children (9%) had deep extensive tumors, who presented earlier (mean age at diagnosis, 3.88 years), required multiple treatments, and had a shorter mean progression-free survival (48 months). CONCLUSIONS: Over half of children with NF1 in this study developed probable non-OPTs, the majority of which were clinically and radiographically progressive. While brainstem and nonbrainstem gliomas share similar clinical features and natural history, deep extensive tumors comprise a distinct aggressive group of tumors that warrant close attention.

Sorting nexin 27 (SNX27) variants associated with seizures, developmental delay, behavioral disturbance, and subcortical brain abnormalities.

Sorting nexin 27 (SNX27) influences the composition of the cellular membrane via regulation of selective endosomal recycling. Molecular analysis indicates that SNX27 regulates numerous cellular processes through promiscuous interactions with its receptor cargos. SNX27 deficient (Snx27 -/- ) mice exhibit reduced embryonic survival, marked postnatal growth restriction and lethality. Haploinsufficient mice (Snx27 +/- ) show a less severe phenotype, with deficits in learning, memory, synaptic transmission and neuronal plasticity. One family previously reported with a homozygous SNX27 frameshift variant (c.515_516del;p.His172Argfs*6), exhibited infantile intractable myoclonic epilepsy, axial hypotonia, startle-like movements, cardiac septal defects, global developmental delay, failure to thrive, recurrent chest infections, persistent hypoxemia and early death secondary to respiratory failure. Here, we report two additional patients with compound heterozygous SNX27 variants, that are predicted to be damaging: (a) c.510C>G;p.Tyr170* and c.1295G>A;p.Cys432Tyr, and (b) c.782dupT;p.Leu262Profs*6 and c.989G>A;p.Arg330His. They exhibit global developmental delay, behavioral disturbance, epilepsy, some dysmorphic features and subcortical white matter abnormalities. In addition, possible connective tissue involvement was noted. Epilepsy, developmental delays and subcortical white matter abnormalities appear to be core features of SNX27-related disorders. We correlate the observed phenotype with available in vitro, in vivo and proteomic data and suggest additional possible molecular mediators of SNX27-related pathology.

Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging.

AIM: To characterize the adaptive behavior profile of children with neurofibromatosis type 1 (NF1) and determine its relationship to neuropsychological functioning and non-neoplastic T2-weighted hyperintense brain lesions on brain magnetic resonance imaging (MRI). METHOD: In this cross-sectional study, we retrospectively reviewed neuropsychological reports from 104 children with NF1 (56 males, 48 females; mean age 10y 4mo; standard deviation [SD] 3y 4mo; range 3y 5mo-17y 6mo), and extracted data from a range of cognitive and behavioral measures, including the Adaptive Behavior Assessment System (ABAS). Brain MRI was retrospectively reviewed in 42 individuals. RESULTS: Adaptive Behavior Assessment System scores were continuously distributed and pathologically shifted by 0.79 to 1.26SD across Conceptual, Social, and Practical domains, and 46.5% of individuals had a composite score in the borderline or impaired range. Impairment in adaptive functioning was correlated with deficits in executive function (r=-9.543, p<0.001), externalizing problems (r=-0.366, p<0.001), and attention (r=-9.467, p=0.001). Cluster analysis revealed three distinct phenotypic subgroups, one of which exhibited normal cognitive ability, but impaired adaptive functioning, with persistent deficits in executive function, behavioral problems, and attention-deficit/hyperactivity disorder symptomatology. There was no relationship between ABAS scores and the number or location of unidentified bright objects. INTERPRETATION: Adaptive functioning deficits are common among children with NF1 and are associated with impairment in other cognitive/behavioral domains, independent of general cognitive ability. WHAT THIS PAPER ADDS: Deficits in adaptive behavior are common in children with neurofibromatosis type 1 (NF1). Poor adaptive functioning is associated with impairments in executive function, externalizing behaviors, and attention, regardless of cognitive ability. The presence or location of unidentified bright objects do not predict adaptive behavior skills in children with NF1.

FUNCIONAMIENTO ADAPTATIVO EN NIÑOS CON NEUROFIBROMATOSIS TIPO 1: RELACIÓN ENTRE COGNICIÓN, COMPORTAMIENTO E IMÁGENES DE RESONANCIA MAGNÉTICA: OBJETIVO: Caracterizar el perfil del comportamiento adaptativo de niños con neurofibromatosis tipo 1 (NF1) y determinar la relación entre el funcionamiento neuropsicológico y las lesiones hiperintensas cerebrales no neoplásicas en T2-pesado de la resonancia magnética cerebral (RM). MÉTODO: En este estudio transversal, revisamos de forma retrospectiva reportes neuropsicológicos de 104 niños con NF1 (56 varones, 48 mujeres, media de edad 10 años 4 meses; desviación estándar (DE) 3 años 4 meses; rango 3 años 5 meses a 17 años 6 meses), y se extrajeron datos de una serie de mediciones cognitivas y conductuales, incluyendo el test sistema de evaluación de la conducta adaptativa (Adaptative Behaivor Assesment System ABAS). Se revisaron 42 RM cerebrales de forma retrospectiva. RESULTADOS: Los resultados ABAS fueron continuamente distribuidos y se cambiaron patológicamente entre 0,79 a 1,26 DE en los dominios de lo conceptual, social y práctico, y 46,5 por ciento de los individuos tuvieron un puntaje limítrofe o sin afectación. La afectación en las funciones adaptativas fue correlacionada con los déficits en funciones ejecutivas (r = -9,543, p < 0,001), externalizar problemas (r = -0,366, p < 0,001), y atención (r = -9,467, p = 0,001). El análisis de grupo revelo tres subgrupos fenotípicos distintos, uno de ellos exhibía una habilidad cognitiva tipica, pero afectación en el funcionamiento adaptativo, con déficits persistentes en función ejecutiva, problemas conductuales, y sintomatología de déficit de atención/hiperactividad. No hubo relación entre el puntaje ABAS y el número o localización de imágenes brillantes no identificadas en la RM cerebral. INTERPRETACIÓN: Los déficits de funcionamiento adaptativo son comunes entre niños con NF1 y son asociados con afectación de otros dominios cognitivo/conductual, independiente de la habilidad cognitiva en general.

FUNCIONAMENTO ADAPTATIVO EM CRIANÇAS COM NEUROFIBROMATOSE TIPO 1: RELAÇÃO COM COGNIÇÃO, COMPORTAMENTO, E IMAGEM DE RESSONÂNCIA MAGNÉTICA: OBJETIVO: Caracterizar o comportamento adaptativo de crianças com neurofibromatose tipo 1 (NF1) e determinar sua relação com funcionamento neuropsicológico e lesões em T2 hiperintensas não neoplásticas ao exame de ressonância magnética (RM). MÉTODO: Neste estudo transversal, revisamos retrospectivamente os relatórios neuropsicológicos de 104 crianças com NF1 (56 do sexo masculino, 48 do sexo feminino; média de idade 10a 4m; desvio padrão [DP] 3a 4m; variação 3a 5m-17a6m), e extraímos dados de uma variedade de medidas cognitivas e comportamentais, incluindo o Sistema de Avaliação do Comportamento Adaptativo (SACA). Imagens de RM cerebral foram retrospectivamente revisadas em 42 indivíduos. RESULTADOS: Os escores SACA foram distribuídos continuamente, e patologicamente deslocados em 0,79 a 1,26 DP nos domínios Conceitual, Social e Prático, e 46,5 por cento dos indivíduos tiveram escore composto na faixa limítrofe ou deficiente. Deficiências no comportamento adaptativo se correlacionaram com déficits na função executiva (r = −9,543, p < 0,001), problemas externalizantes (r = −0,366, p < 0,001), e atenção (r = −9,467, p = 0,001). Análise agrupada revelou três subgrupos genotípicos distintos, um dos quais exibiu capacidade cognitiva normal, mas funcionamento adaptativo deficiente, e sintomatologia de transtorno de deficit de atenção e hiperatividade. Não houve relação entre escores SACA e o número ou localização de objetos luminosos não identificados. INTERPRETAÇÃO: Déficits no funcionamento adaptativo são comuns entre crianças com NF1 e são associados com deficiência em outros domínios cognitivos/comportamentais, independente da capacidade cognitiva geral.

Increased prevalence of brain tumors classified as T2 hyperintensities in neurofibromatosis 1.

BACKGROUND: We sought to define the radiologic features that differentiate neoplastic from non-neoplastic T2 hyperintensities (T2Hs) in neurofibromatosis type 1 (NF1) and identify those lesions most likely to require oncologic surveillance. METHODS: We conducted a single-center retrospective review of all available brain MRIs from 68 children with NF1 (n = 190) and 46 healthy pediatric controls (n = 104). All T2Hs identified on MRI were characterized based on location, border, shape, degree of T1 hypointensity, and presence of mass effect or contrast enhancement, and subsequently classified using newly established radiologic criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 10 NF1 cases. RESULTS: T2Hs were a highly sensitive (94.4%; 95% confidence interval [CI] 86.4%-98.5%) and specific (100.0%; 95% CI 92.3%-100.0%) marker for the diagnosis of NF1. UBOs constituted the majority of T2Hs (82%) and were most frequently located in cerebellar white matter, medial temporal lobe, and thalamus, where they were more likely than probable tumors to be bilateral (p < 0.001) and have nondiscrete borders (p < 0.001). Surprisingly, 57% of children with T2Hs harbored lesions classified as probable tumors, and 28% of children with probable tumors received treatment. In contrast to UBOs, probable tumors were most frequently located within the globus pallidus and medulla, and rarely occurred prior to 3 years of age. CONCLUSIONS: With the implementation of standardized radiologic criteria, a high prevalence of brain tumors was identified in this at-risk population of children, of which nearly one-third required treatment, emphasizing the need for appropriate oncologic surveillance for patients with NF1 harboring nonoptic pathway brain tumors.

Children with 5'-end NF1 gene mutations are more likely to have glioma.

OBJECTIVE: To ascertain the relationship between the germline NF1 gene mutation and glioma development in patients with neurofibromatosis type 1 (NF1). METHODS: The relationship between the type and location of the germline NF1 mutation and the presence of a glioma was analyzed in 37 participants with NF1 from one institution (Washington University School of Medicine [WUSM]) with a clinical diagnosis of NF1. Odds ratios (ORs) were calculated using both unadjusted and weighted analyses of this data set in combination with 4 previously published data sets. RESULTS: While no statistical significance was observed between the location and type of the NF1 mutation and glioma in the WUSM cohort, power calculations revealed that a sample size of 307 participants would be required to determine the predictive value of the position or type of the NF1 gene mutation. Combining our data set with 4 previously published data sets (n = 310), children with glioma were found to be more likely to harbor 5'-end gene mutations (OR = 2; p = 0.006). Moreover, while not clinically predictive due to insufficient sensitivity and specificity, this association with glioma was stronger for participants with 5'-end truncating (OR = 2.32; p = 0.005) or 5'-end nonsense (OR = 3.93; p = 0.005) mutations relative to those without glioma. CONCLUSIONS: Individuals with NF1 and glioma are more likely to harbor nonsense mutations in the 5' end of the NF1 gene, suggesting that the NF1 mutation may be one predictive factor for glioma in this at-risk population.

Neurodevelopmental disorders in children with neurofibromatosis type 1.

Over the past several decades, neurofibromatosis type 1 (NF1) has become increasingly recognized as a neurodevelopmental disorder conferring increased risk for several important neurodevelopmental problems. In this review, we summarize the specific neurodevelopmental problems encountered in the context of NF1. These include impairments in general cognitive function, deficits in specific cognitive domains such as executive function and visuospatial processing and risk for specific learning disorders, impairments in attention and social skills and the overlap with attention-deficit-hyperactivity disorder and autism spectrum disorder, and the risk of developing other psychiatric conditions including anxiety and depression. Early recognition of these developmental impairments is important for the effective treatment of children with NF1, and further characterization is essential to improve our understanding of how mutations in the NF1 gene create the diversity of clinical neuropsychiatric symptomatology observed in this at-risk population.

A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1.

OBJECTIVE: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1). METHODS: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed. RESULTS: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups. CONCLUSIONS: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only.

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT).

IMPORTANCE: Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. OBJECTIVE: To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. DESIGN, SETTING, AND PARTICIPANTS: Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. MAIN OUTCOMES AND MEASURES: Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. RESULTS: Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. CONCLUSIONS AND RELEVANCE: This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

Macrocephaly Is Not a Predictor of Optic Pathway Glioma Development or Treatment in Neurofibromatosis Type 1.

Neurofibromatosis type 1 is a common neurogenetic disorder characterized by significant clinical variability. As such, numerous studies have focused on identifying clinical, radiographic, or molecular biomarkers that predict the occurrence or progression of specific clinical features in individuals with neurofibromatosis type 1. One of these clinical biomarkers, macrocephaly, has been proposed as a prognostic factor for optic pathway glioma development. In the current study, the authors demonstrate that macrocephaly is not associated with the development of these brain tumors or the need to institute treatment for clinical progression. These findings suggest that macrocephaly is not a robust biomarker of optic pathway glioma formation or progression in children with neurofibromatosis type 1.