Does Social Shyness Predict Autism in High Risk Preschoolers with FXS? A Longitudinal Examination of Behavioral and Biomarkers of Autism

Background: Approximately 40-60% of children with fragile X syndrome (FXS) also meet DSM IV criteria for an autism spectrum disorder (ASD), and up to 90% display autistic symptoms.  Distinguishing the precursors, emergence, and presentation of autism in children with comorbid FXS and autism (“FXS+ASD”) may inform the neuobiological and behavioral underpinnings of autism in FXS and other clinical and non-clinical samples. Although social symptoms are among the most striking features of both FXS and ASD, no studies have prospectively examined behavioral and biomarkers of social approach to predict autism in FXS.  Observational and physiological data have suggested atypical patterns of social response in children with FXS+ASD, warranting further examination of whether subtle behavioral and biomarkers of autism can be detected in infants and young children using laboratory-based paradigms.

Objectives: The present study prospectively examined the relationship between autism outcomes and both behavioral and physiological indicators of social shyness during a laboratory paradigm in young children with FXS and TD controls.  

Methods: Participants include 51 males with FXS and 33 typically developing (TD) controls, each observed between 2-4 times between ages 10 and 76 months (totaling 189 assessments). We used the stranger approach episode of the Laboratory Temperament Assessment Battery (Lab-TAB) to elicit behavioral and physiological markers of social shyness and anxiety. Outcomes included the Childhood Autism Rating Scale (CARS) and Child Behavior Checklist (CBCL) withdrawn and DSM-Anxiety subscales. We used multilevel modeling to examine the effects of genetic status, autism outcomes, and anxiety outcomes on mean levels and change in facial fear, distress vocalizations and escape behaviors. We also examined partial correlations among CARS scores and physiological data (vagal tone – VT; interbeat interval – IBI; cortisol) from a subset of our sample (n=32, 53 assessments).

Results: Behavioral variables were screened for normality, transformed as needed, and standardized. The first set of MLM analyses included all FXS and TD participants (n=84, 189 observations). The FXS group demonstrated a curvilinear pattern of escape behaviors, with increased intensity at younger ages and decreased intensity at older ages; as well as less decreased distress vocalizations over time. Within the FXS group, lower escape behaviors predicted more severe autistic outcomes, and more intense distress vocalizations predicted increased withdrawal and anxiety outcomes. Lower VT correlated with more severe autistic outcomes in the FXS group. This relationship was not present in the TD group; instead, lower VT correlated with higher escape behaviors during several phases.

Conclusions: Our results are consistent with findings that social interactions differentiate children with FXS+ASD and FXS-only (Kaufmann et al., 2004). Consistent with similar studies using parent report, several approach behaviors predicted anxiety outcomes. However, autism outcomes were also related to several predictors, including lower escape behaviors and vagal tone during the approach paradigm. These results suggest that children with FXS who later demonstrate severe autistic outcomes may be distinguished by early biobehavioral patterns of social approach. These findings may inform early detection of autism in high risk samples and differential diagnosis of autism and anxiety symptoms in children with neurodevelopmental disorders.