Objectives: In the context of an endophenotyping initiative within the Autism Genetic Resource Exchange (AGRE), we have performed quantitative assessment of craniofacial dysmorphology on a collection of multiplex families. Our approach is to apply objective and reliable methodology to the diagnosis of craniofacial dysmorphology. We employ embryologic principles to provide potential insight into the developmental neurobiology of individuals with ASDs. Rather than studying single anomalies, we focus on embryologically-derived combinations of anomalies that are based on specific developmental factors.
Methods: We recruited 40 multiplex families with ASD from the AGRE program and acquired images using a noninvasive stereophotogrammetric device (3dMD, Atlanta). Surface images were then analyzed using 3D morphometry, and standardized scores were computed for craniofacial anomalies. These scores were computed on a continuously-distributed scale, conditioning on age, gender, and ethnicity.
Results: There was a marked excess of craniofacial anomalies among the probands with autism relative to the general population (p < .0001). We also analyzed dysmorphology as a function of facial embryonic primordia (Anlagen), discrete regions that are formed early in development and which can be readily identified in the course of differentiation. The probands with ASD displayed an overrepresentation of anomalies within the frontonasal (p < .005), maxillary (p < .002), and auricular (p < .0001) Anlagen derivatives. In contrast, mandibular and orbital anomalies were not excessive.
Conclusions: Craniofacial dysmorphology, quantified using a combination of 3D imaging and statistical morphometry, was pronounced. These anomalies corresponded to specific embryologic regions: derivatives of the frontonasal, maxillary, and auricular primordia. There is an intimate developmental relationship between brain and face. Embryological "fate-mapping" studies have described how embryonic regions correspond to specific derivatives in both craniofacial and brain regions. Because there is a topographic correspondence between face and brain morphogenesis, craniofacial dysmorphology may delineate brain pathology. For instance, the frontonasal neural crest arises primarily from the neural fold area corresponding to the anterior telencephalon and the posterior diencephalon. Thus, brain anatomic regions are embryologically linked to specific craniofacial Anlagen, and the derivatives identified in this study may circumscribe areas of potential importance in ASD.