Facial phenotypes in subgroups of prepubertal boys with autism spectrum disorders are correlated with clinical phenotypes

Abstract

Background: The brain develops in concert and in coordination with the developing facial tissues, with each influencing the development of the other and sharing genetic signaling pathways. Autism spectrum disorders (ASDs) result from alterations in the embryological brain, suggesting that the development of the faces of children with ASD may result in subtle facial differences compared to typically developing children. In this study, we tested two hypotheses. First, we asked whether children with ASD display a subtle but distinct facial phenotype compared to typically developing children. Second, we sought to determine whether there are subgroups of facial phenotypes within the population of children with ASD that denote biologically discrete subgroups.

Methods: The 3dMD cranial System was used to acquire three-dimensional stereophotogrammetric images for our study sample of 8- to 12-year-old boys diagnosed with essential ASD (n = 65) and typically developing boys (n = 41) following approved Institutional Review Board protocols. Three-dimensional coordinates were recorded for 17 facial anthropometric landmarks using the 3dMD Patient software. Statistical comparisons of facial phenotypes were completed using Euclidean Distance Matrix Analysis and Principal Coordinates Analysis. Data representing clinical and behavioral traits were statistically compared among groups by using χ2 tests, Fisher's exact tests, Kolmogorov-Smirnov tests and Student's t-tests where appropriate.

Results: First, we found that there are significant differences in facial morphology in boys with ASD compared to typically developing boys. Second, we also found two subgroups of boys with ASD with facial morphology that differed from the majority of the boys with ASD and the typically developing boys. Furthermore, membership in each of these distinct subgroups was correlated with particular clinical and behavioral traits.

Conclusions: Boys with ASD display a facial phenotype distinct from that of typically developing boys, which may reflect alterations in the prenatal development of the brain. Subgroups of boys with ASD defined by distinct facial morphologies correlated with clinical and behavioral traits, suggesting potentially different etiologies and genetic differences compared to the larger group of boys with ASD. Further investigations into genes involved in neurodevelopment and craniofacial development of these subgroups will help to elucidate the causes and significance of these subtle facial differences.

Figure 1

Illustration of the seven facial prominences that give rise to specific regions of the face. Frontonasal prominences (FNP) and lateral nasal prominences (LNP) are shown in purple, maxillary prominences (MAX) are shown in blue, mandibular prominences (MAND) are shown in green and second branchial arch derivatives are shown in shades of pink.

Figure 2

3dMD image acquisition and analysis. (A) Example of a 3dMD image acquired from an individual chosen at random from the study sample.

Figure 3

Illustration of the anthropometric landmarks collected from the 3dMD images. Landmarks are defined in Table 2.

Figure 4

Results of Euclidean Distance Matrix Analysis analyses of landmark coordinate data collected from 3dMD images. White lines are statistically significantly increased in boys with autism spectrum disorder (ASD), and black lines are statistically significantly reduced in boys with ASD relative to typically developing (TD) boys.

Figure 5

Results of Principal Coordinates Analysis of landmark coordinate data collected from 3dMD images. Red circles represent boys with autism spectrum disorder (ASD), and blue diamonds represent typically developing boys. (A) Plot of eigenscores for the first two principal axes. Axis 1 accounts for 31.09% of the variance within the entire sample, and axis 2 accounts for 11.33% of the variance. (B) Plot of eigenscores for the second and third principal axes. Axis 3 accounts for 9.44% of the sample variance.

Figure 6

Illustration of linear distances highly correlated with eigenscores on the first two principal axes of the principal coordinates analysis results. (A) Subgroup 1 morphology. (B) Subgroup 2 morphology. Black lines are increased in boys in the subgroup, and white lines are reduced in boys in the subgroup.