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Simple Summary: Difficulties in sensory processing are often found in neurodevelopmental disorders and can significantly impact how a child responds to and functions within their environment. Studies examining sensory processing in children with neurofibromatosis type 1 (NF1) are sparse. This cross-sectional study aims to address this gap by examining parent-reported sensory processing in a sample of 152 children with NF1. Approximately 61% of children with NF1 displayed differences in how they respond to sensory stimuli when compared to a typically developing control group. These difficulties were seen equally across ages and sex and were found to be associated with a higher degree of autistic behaviors, ADHD symptoms, lower adaptive skills, poorer social skills, and increased anxiety and affective symptoms. The results highlight the importance of accommodating multisensory processing difficulties at home and school when deciding how to support a child with NF1 across environments. Despite the evidence of elevated autistic behaviors and co-occurring neurodevelopmental difficulties in many children with neurofibromatosis type 1 (NF1), we have a limited understanding of the sensory processing challenges that may occur with the condition. This study examined the sensory profile of children and adolescents with NF1 and investigated the relationships between the sensory profiles and patient characteristics and neuropsychological functioning. The parent/caregivers of 152 children with NF1 and 96 typically developing children completed the Sensory Profile 2 (SP2), along with standardized questionnaires assessing autistic behaviors, ADHD symptoms, internalizing symptoms, adaptive functioning, and social skills. Intellectual functioning was also assessed. The SP2 data indicated elevated sensory processing problems in children with NF1 compared to typically developing children. Over 40% of children with NF1 displayed differences in sensory registration (missing sensory input) and were unusually sensitive to and unusually avoidant of sensory stimuli. Sixty percent of children with NF1 displayed difficulties in one or more sensory modalities. Elevated autistic behaviors and ADHD symptoms were associated with more severe sensory processing difficulties. This first detailed assessment of sensory processing, alongside other clinical features, in a relatively large cohort of children and adolescents with NF1 demonstrates the relationships between sensory processing differences and adaptive skills and behavior, as well as psychological well-being. Our characterization of the sensory profile within a genetic syndrome may help facilitate more targeted interventions to support overall functioning. [ABSTRACT FROM AUTHOR]

This study investigated sex and age differences in autistic behaviours in children with neurofibromatosis type 1 (NF1) who scored within the clinical range on the Social Responsiveness Scale - Second Edition (T score ≥ 60). Thirty-four males and 28 females (3–16 years) were assessed with the Autism Diagnostic Observation Schedule - Second Edition and Autism Diagnostic Interview - Revised. Across both measures, males exhibited greater social communication deficits relative to females. Age-related abatement of social communication difficulties was observed for males but not females. Conversely, no sex differences were found for restricted/repetitive behaviours, which were stable over time for both males and females. The findings are discussed within the context of broader neurodevelopmental considerations that are common in NF1. [ABSTRACT FROM AUTHOR]

Background: A high proportion of patients with neurofibromatosis type 1 (NF1) present with functional hearing deficiency as a result of neural abnormality in the late auditory brainstem. Methods: In this randomized, two-period crossover study, we investigated the hypothesis that remote-microphone listening devices can ameliorate hearing and communication deficits in affected school-aged children (7–17 years). Speech perception ability in background noise was evaluated in device-active and inactive conditions using the CNC-word test. Participants were then randomized to one of two treatment sequences: (1) inactive device for two weeks (placebo), followed by active device use for two weeks, or (2) active device for 2 weeks, followed by inactive device for 2 weeks. Listening and communication ratings (LIFE-R Questionnaire) were obtained at baseline and at the end of each treatment phase. Results: Each participant demonstrated functional hearing benefits with remote-microphone use. All showed a speech perception in noise increase when the device was activated with a mean phoneme-score difference of 16.4% (p < 0.001) and reported improved listening/communication abilities in the school classroom (mean difference: 23.4%; p = 0.017). Discussion: Conventional hearing aids are typically ineffective as a treatment for auditory neural dysfunction, making sounds louder, but not clearer for affected individuals. In this study, we demonstrate that remote-microphone technologies are acceptable/tolerable in pediatric patients with NF1 and can ameliorate their hearing deficits. Conclusion: Remote-microphone listening systems offer a viable treatment option for children with auditory deficits associated with NF1. [ABSTRACT FROM AUTHOR]

Children with neurofibromatosis type 1 (NF1) often experience executive dysfunction, attention deficit/hyperactivity disorder (ADHD) symptoms and poor social skills, however, the nature of the relationships between these domains in children with NF1 is unclear. This study investigated these relationships using primary caregiver ratings of executive functions, ADHD symptoms and social skills in children with NF1. Participants were 136 children with NF1 and 93 typically developing (TD) controls aged 3–15 years recruited from 3 multidisciplinary neurofibromatosis clinics in Melbourne and Sydney, Australia, and Washington DC, USA. Mediation analysis was performed on primary outcome variables: parent ratings of executive functions (Behavior Rating Inventory of Executive Function, Metacognition Index), ADHD symptoms (Conners-3/Conners ADHD Diagnostic and Statistical Manual for Mental Disorders Scales) and social skills (Social Skills Improvement System-Rating Scale), adjusting for potential confounders (full scale IQ, sex, and social risk). Results revealed significantly poorer executive functions, elevated ADHD symptoms and reduced social skills in children with NF1 compared to controls. Poorer executive functions significantly predicted elevated ADHD symptoms and poorer social skills. Elevated ADHD symptoms significantly mediated the relationship between executive functions and social skills problems although did not fully account for social dysfunction. This study provides evidence for the importance of targeting ADHD symptoms as part of future interventions aimed at promoting prosocial behaviors in children with NF1. [ABSTRACT FROM AUTHOR]

Background: Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. Methods: Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. Results: The study cohort comprised 68 children (3–15 years). Sixty-three per cent met the ADOS-2 'autism spectrum' cut-off, and 34% exceeded the more stringent threshold for 'autistic disorder' on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by 'insistence on sameness' (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. Limitations: Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. Conclusions: Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management. [ABSTRACT FROM AUTHOR]

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

Objective: To examine associations between executive function (EF) domains (attentional control, information processing, cognitive flexibility, and goal setting) and math computation performance at 7 and 13 years in children born very preterm (VP; <30 weeks' gestation), and secondly, to investigate the associations of 7-year EF with change in math performance from 7 to 13 years. Participants and Methods: In the prospective, longitudinal Victorian Infant Brain Studies (VIBeS) cohort of children born VP, assessment of EF and math performance was undertaken at 7 (n = 187) and 13 years (n = 174). Univariable and multivariable regression models (including all domains of EF) were used to examine associations between EF domains at both timepoints with math performance, as well as associations between EF at 7 years with change in math from 7 to 13 years. Results: At 7 and 13 years, all EF domains were positively associated with concurrent math performance, with multivariable models finding information processing, cognitive flexibility and goal setting independently contributed to math performance at both ages. All EF domains were positively associated with improvement in math performance from 7 to 13 years, with multivariable models finding that goal setting contributed unique variance to improvement in math over this period. Conclusions: This study provides evidence for a strong, consistent association between EF and math performance in children born VP and emphasizes the importance of goal setting capacity for later improvement in math performance. [ABSTRACT FROM AUTHOR]

Executive dysfunction including impaired goal setting (i.e., planning, organization skills, strategic reasoning) is documented in children born very preterm (VP; <30 weeks/<1250 g), however the neurological basis for this impairment is unknown. This study sought to examine the relationship between brain abnormalities and brain volumes on neonatal magnetic resonance imaging (MRI) and goal setting abilities of VP 13-year-olds. Participants were 159 children born VP in a prospective longitudinal study. Qualitative brain abnormality scores and quantitative brain volumes were derived from neonatal MRI brain scans (40 weeks' gestational age ± 2 weeks). Goal setting at 13 years was assessed using the Delis-Kaplan Executive Function Systems Tower Test, the Rey Complex Figure, and the Behavioural Assessment of the Dysexecutive System for Children Zoo Map and Six Part Test. A composite score was generated denoting overall performance on these goal setting measures. Separate regression models examined the association of neonatal brain abnormality scores and brain volumes with goal setting performance. There was evidence that higher neonatal white matter, deep grey matter and cerebellum abnormality scores were associated with poorer goal setting scores at 13 years. There was also evidence of positive associations between total brain volume, cerebellum, thalamic and cortical grey matter volumes and goal setting performance. Evidence for the associations largely persisted after controlling for potential confounders. Neonatal brain abnormality and brain volumes are associated with goal setting outcome in VP 13-year-olds. Used in conjunction with other clinical indicators, neonatal MRI may help to identify VP children at risk for later executive dysfunction. [ABSTRACT FROM AUTHOR]

Aim: We examined key features of two outcome measures for social dysfunction and autism spectrum disorder traits, the Social Responsiveness Scale, Second Edition (SRS-2) and the Social Skills Improvement System - Rating Scales (SSIS-RS), in children with neurofibromatosis type 1 (NF1). The aim of the study was to provide objective evidence as to which behavioural endpoint should be used in clinical trials.Method: Cross-sectional behavioural and demographic data were pooled from four paediatric NF1 tertiary referral centres in Australia and the United States (N=122; 65 males, 57 females; mean age [SD] 9y 2mo [3y], range 3-15y).Results: Distributions of SRS-2 and SSIS-RS scores were unimodal and both yielded deficits, with a higher proportion of severely impaired scores on the SRS-2 (16.4%) compared to the SSIS-RS (8.2%). Pearson's product-moment correlations revealed that both questionnaires were highly related to each other (r=-0.72, p<0.001) and to measures of adaptive social functioning (both p<0.001). Both questionnaires were significantly related to attention-deficit/hyperactivity disorder symptoms, but only very weakly associated with intelligence.Interpretation: The SRS-2 and SSIS-RS capture social dysfunction associated with NF1, suggesting both may be suitable choices for assessing social outcomes in this population in a clinical trial. However, careful thought needs to be given to the nature of the intervention when selecting either as a primary endpoint.What This Paper Adds: The Social Responsiveness Scale, Second Edition yielded a large deficit relative to population norms. The Social Skills Improvement System - Rating Scales yielded a moderate deficit relative to population norms. Both scales were highly correlated, suggesting that they are measuring a unitary construct. [ABSTRACT FROM AUTHOR]

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

Objectives: Preterm children demonstrate deficits in executive functions including inhibition, working memory, and cognitive flexibility; however, their goal setting abilities (planning, organization, strategic reasoning) remain unclear. This study compared goal setting abilities between very preterm (VP: <30 weeks/<1250 grams) and term born controls during late childhood. Additionally, early risk factors (neonatal brain abnormalities, medical complications, and sex) were examined in relationship to goal setting outcomes within the VP group. Methods: Participants included 177 VP and 61 full-term born control children aged 13 years. Goal setting was assessed using several measures of planning, organization, and strategic reasoning. Parents also completed the Behavior Rating Inventory of Executive Function. Regression models were performed to compare groups, with secondary analyses adjusting for potential confounders (sex and social risk), and excluding children with major neurosensory impairment and/or IQ<70. Within the VP group, regression models were performed to examine the relationship between brain abnormalities, medical complications, and sex, on goal setting scores. Results: The VP group demonstrated a clear pattern of impairment and inefficiency across goal setting measures, consistent with parental report, compared with their full-term born peers. Within the VP group, moderate/severe brain abnormalities on neonatal MRI predicted adverse goal setting outcomes at 13. Conclusions: Goal setting difficulties are a significant area of concern in VP children during late childhood. These difficulties are associated with neonatal brain abnormalities, and are likely to have functional consequences academically, socially and vocationally. (JINS, 2018, 24, 372–381) [ABSTRACT FROM AUTHOR]