Objective syndromic phenotyping: the potential of three-dimensional facial morphometrics

[Truncated] Facial patterns play a unique and important role in identifying conditions of abnormal growth and development, including in syndromic disease. A syndrome is a combination of features that collectively indicate a particular condition. Biologists and clinicians continue to strive for objective assessment of facial form; as a result, different schools of thought have emerged, each presenting different approaches with their own strengths and limitations. Facial dysmorphology and asymmetry are particularly of interest when studying syndromic facial form. Craniofacial abnormalities, including abnormalities of form or asymmetry, are found in many syndromes, and objective approaches are required to supplement subjective clinical assessment; the methodological approach needs to be tailored to the problem at hand. In the field of syndromic facial phenotyping, this objective approach should ideally be able to distinguish between normal and abnormal facial patterns; it should be robust enough to detect wide spectrum of abnormalities (e.g. subtle to severe presentations) and be able to quantify facial abnormalities based both on individual features (regionally) and as a holistic entity (globally).

Our aim was to illustrate how novel techniques can be used as a 3D morphometric toolkit for investigating syndromic facial phenotypes. This was achieved through the use of objective approaches that can (1) analyze syndromic facial asymmetry and dysmorphology patterns on both a global and regional level, and (2) to provide biological insights that might facilitate the diagnoses and treatment monitoring of these conditions. This thereby effectively arms the non-expert with a developing toolkit that translates expert knowledge for availability to a broader base of end-users. In this thesis, we used two main geometric morphometric concepts for application to syndrome analysis, (1) the framework of dysmorphometrics, and (2) the framework for decomposing fluctuating and directional asymmetry in spatially dense landmark configurations. Both are novel recent techniques that, before the tenure of this thesis, had not been applied to syndromic cohorts.