Paediatrics (RCH) - Theses

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    Autism spectrum disorder in children with neurofibromatosis type 1: A cross-sectional study of the autistic phenotype and sex- and age-differences in autistic symptoms
    Chisholm, Anita Katherine ( 2021)
    Background: Neurofibromatosis type 1 (NF1) is a monogenic syndrome associated with complex and impairing clinical and neurodevelopmental sequelae. Social difficulties are commonly reported and there is accumulating evidence for an elevated prevalence of autism spectrum disorder (ASD) in children with NF1. While the genetic specificity of NF1 offers a promising model for clarifying the causal pathways to ASD, the autistic symptom profile in children with NF1 remains poorly understood. Aims: This thesis aimed to critically evaluate ASD phenomenology in NF1, and to elucidate the autistic phenotype and the factors that might influence the expression of core autistic symptoms in children with NF1. Methods: We conducted a systematic review and meta-analysis to examine the existing evidence for social dysfunction and ASD in NF1. A cohort of children with NF1 that scored within the clinical range on the Social Responsiveness Scale, Second Edition (SRS-2) was assessed with the Autism Diagnostic Interview - Revised (ADI-R) and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). Participants also underwent evaluation of their intellectual function and data pertaining to emotional and behavioural functioning were gathered via parent rating scales. Results: Meta-analytic data indicated a significantly increased incidence of social dysfunction (g = 0.79) and autistic symptomatology (g = 0.91) in NF1. In the NF1 cohort (N = 68; 3-16 years), a substantial proportion of children met algorithmic cut-offs on the ADI-R (63%) and ADOS-2 (34%). Social communication deficits were analogous to those observed in idiopathic ASD, but we detected a distinct profile of restricted and repetitive behaviours (RRBs) characterised by ‘insistence on sameness’ behaviours such as circumscribed interests and difficulties with minor changes. Males displayed greater social communication deficits relative to females, and age-related gains in social communication skills were evident in males but not females. Generally weak associations were found between autistic symptoms and child characteristics not specific to ASD (e.g., language delay, anxiety). However, sex differences in early language development and verbal intellect contributed to the observed sex disparities in social communication skills. Conclusions: Our novel findings identify a unique autistic phenotype in children with NF1 and establish the relative independence of autistic symptoms from common NF1-related neurodevelopmental comorbidities. This work also provides new insights into the modulating effects of sex and age on the severity of autistic symptoms and underscores the importance of taking non-specific child characteristics into account when interpreting scores from autism measures in this population. Current findings may be used to facilitate earlier and more accurate recognition of ASD in children with NF1 and represent a significant step towards the identification of precise genotype-phenotype relationships in NF1.