Title Mri study of minor physical anomaly in childhood autismimplicates aberrant neurodevelopment in infancy

Background: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective ‘window’ to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. Methods: We recruited 91 children aged 7–16; 36 with an autism spectrum disorder and 55 ageand gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. Results: Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. Conclusions: Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to ‘‘social brain’’ dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a ‘‘fossil record’’ of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism. Citation: Cheung C, McAlonan GM, Fung YY, Fung G, Yu KK, et al. (2011) MRI Study of Minor Physical Anomaly in Childhood Autism Implicates Aberrant Neurodevelopment in Infancy. PLoS ONE 6(6): e20246. doi:10.1371/journal.pone. 0020246 Editor: Mark W. Greenlee, University of Regensburg, Germany Received October 5, 2010; Accepted April 28, 2011; Published June 8, 2011 Copyright: 2011 Cheung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Dr G McAlonan received funding donation for autism research from ING Asia-Pacific. The authors acknowledge a generous donation from ING Asia Pacific to support autism research in Department of Psychiatry, University of Hong Kong and University of Hong Kong funding support. No other external funding exists for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Dr G McAlonan received funding donation for autism research from ING Asia-Pacific. The authors declare that no conflict of interest, financial or otherwise, arises from this manuscript. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: mcalonan@hkucc.hku. hk