Paediatrics (RCH) - Research Publications

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    Delineating the autistic phenotype in children with neurofibromatosis type 1
    Chisholm, AK ; Haebich, KM ; Pride, NA ; Walsh, KS ; Lami, F ; Ure, A ; Maloof, T ; Brignell, A ; Rouel, M ; Granader, Y ; Maier, A ; Barton, B ; Darke, H ; Dabscheck, G ; Anderson, VA ; Williams, K ; North, KN ; Payne, JM (BMC, 2022-01-04)
    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.
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    Social cognition in autism spectrum disorder and neurogenetic syndromes
    Maier, A ; Ryan, N ; Chisholm, A ; Payne, J ; McDonald, S (Routledge, 2021)
    Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterised by impairing social communication deficits and restricted and repetitive behaviours. Over the past few decades, a growing body of research has proposed that social cognitive deficits are a key psychological driver of ASD. In the following chapter, we review evidence for this and show that while social cognitive deficits are common in individuals with ASD, they do not hold clear relationships with ASD symptoms and are not necessary nor sufficient for a diagnosis of ASD. We consider several reasons for this, including the heterogeneity inherent within individuals with ASD, at the symptom, cognitive and aetiological levels. We then discuss the utility of examining ASD and social cognition within syndromic ASD populations which reduce the heterogeneity in the idiopathic population and can be thought of as human ‘genetic models’ of ASD. These syndromic cases of ASD offer a valuable opportunity to elucidate the neurobiological and developmental pathways that lead to both ASD symptoms and aberrant social cognitive processing that are due to a single gene mutation. The possibility of this research to translate into targeted treatments is also explored.
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    Social skills and autism spectrum disorder symptoms in children with neurofibromatosis type 1: evidence for clinical trial outcomes
    Payne, JM ; Walsh, KS ; Pride, NA ; Haebich, KM ; Maier, A ; Chisholm, A ; Glad, DM ; Casnar, CL ; Rouel, M ; Lorenzo, J ; Del Castillo, A ; North, KN ; Klein-Tasman, B (WILEY, 2020-07-01)
    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.
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    Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study
    Haebich, KM ; Pride, NA ; Walsh, KS ; Chisholm, A ; Rouel, M ; Maier, A ; Anderson, V ; Barton, B ; Silk, T ; Korgaonkar, M ; Seal, M ; Lami, F ; Lorenzo, J ; Williams, K ; Dabscheck, G ; Rae, CD ; Kean, M ; North, KN ; Payne, JM (BMJ PUBLISHING GROUP, 2019-09)
    INTRODUCTION: Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. METHODS AND ANALYSIS: This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. ETHICS AND DISSEMINATION: This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.