Developmental trajectories in infants and pre-school children with Neurofibromatosis 1

Objective This prospective cohort study examines the cognitive, behavioural, ADHD trait and autism symptom development in infant and pre-school children with Neurofibromatosis 1 (NF1) compared with typically developing (TD) children without a family history of neurodevelopmental conditions. Methods Data from standardised tests was gathered at 5, 10, 14, 24 and 36 months of age (NF1 n=35, TD n=29). Developmental trajectories of cognitive and adaptive behavioural development from 5 to 36 months were analysed using linear mixed modelling. Measures of ADHD and autism traits were assessed at 24 and 36 months. Results The developmental trajectory of cognitive skills (all domains of the Mullen Scales of Early Learning -MSEL) and behavioural skills (four domains of the Vineland Adaptive Behaviour Scale -VABS) differed significantly between NF1 and TD groups. Post-hoc tests demonstrated that the NF1 participants scored significantly lower than TD participants at 24 months on all MSEL and VABS domains. The NF1 cohort demonstrated higher mean autism and ADHD traits at 24 months and 14% of the NF1 cohort met a research diagnostic classification for autism at 36 months. Conclusion By 24 months of age, the NF1 cohort show lower cognitive skills and adaptive behaviour and higher levels of autism and ADHD traits as compared to TD children. ### Competing Interest Statement Conflict of Interest Disclosures (includes financial disclosures): Tony Charman has served as a paid consultant to F. Hoffmann-La Roche Ltd. and Servier; and has received royalties from Sage Publications and Guilford Publications. The other authors have no conflicts of interest to disclose. ### Funding Statement This study was supported by Action for Medical Research (GN2385) Rosetrees Trust (A2213) Medical Research Council (MR/K021389/1 and MR/T003057/1) and MQ (MQ14PP_83). This study was also supported by the EU-AIMS and AIMS-2-TRIALS programmes funded by the Innovative Medicines Initiative Joint Undertaking Grant No.115300 and No.777394. This Joint Undertaking receives support from the European Union Horizon 2020 research and innovation programme, with contributions from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies and funding from Autism Speaks, Autistica and SFARI. This work was also supported by Action for Medical Research, Great Ormond Street Hospital Childrens Charity and the Bailey Thomas Charitable Fund (GN2385), Rosetrees Trust (A2213). Shruti Garg is a Francis Collins Scholar supported by Neurofibromatosis Therapeutic Acceleration Program (NTAP) at the John Hopkins University. Jonathan Green is supported by NIHR Senior Investigator Award. Hannah Slevin is an NIHR Academic Clinical Fellow and Fiona Kehinde is a Houghton-Dunn research associate. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The studies involving human participants were approved by Greater Manchester Central Research Ethics committee (16/NW/0324) and National Research Ethics Service London Central Ethical Committee (16/EE/0167 and 06/MRE02/73). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Deidentified participant data is available through the STAARS network via data sharing procedures that comply with ethical requirements, due to the sensitive nature of the data collected. Available at: . There is no known end date of data availability. * NF1 : neurofibromatosis type 1 ADHD : attention deficit hyperactivity disorder MSEL : Mullen Scales of Early Learning VABS : Vineland Adaptive Behavior Scales ADOS-2 : Autism Diagnostic Observation Schedule BOSA-MV : Brief Observation of Symptoms of Autism for Minimally Verbal children ADI-R : Autism Diagnostic Interview-Revised CBCL : Child Behavior Checklist.