Three-dimensional Soft Tissue Asymmetry in Unaffected Relatives of NSCL/P Individuals

Objectives: To compare patterns of three-dimensional facial asymmetry in unaffected siblings of individuals with nonsyndromic cleft lip with or without palate (NSCL/P) to those of controls, including assessment of feasibility, standardization procedures, reliability, and the effects of age and gender as a first step toward the long-term goal of developing a diagnostic system for craniofacial phenotyping.

Methods: Existing 3D facial scans of 51 unaffected siblings (30M/21F) and 29 controls (15M/14F) with no family history of clefting were landmarked by a calibrated rater using 3dMD software (Atlanta, GA) for 8 midline and 8 pairs of bilateral sites, for a total of 24 standard anthropometric soft tissue landmarks .  Subject ages ranged from 5 to 16 years (median 10 years).   3D landmark coordinates were extracted and standardized through translation and rotation.  Reflection of the left landmark configuration over the right yielded bilateral Euclidean distances which were used as measures of facial asymmetry.  Differences in asymmetry between NSCL/P siblings vs. controls were assessed using the Wilcoxon Rank Sum test, and via multivariate logistic regression to adjust for age and gender.  Analyses were carried out with and without centroid scaling to adjust for facial size.

Results: Feasibility of the method was established, with excellent intra-rater reliability (ICCs of 0.83 – 0.99 in all three coordinates of 24 landmarks).  Evidence was found for an effect of age (p=0.037) on crista philtri asymmetry which strengthened (p=0.0085) after facial size adjustment via centroid scaling; a gender effect was also suggested (p=0.06); other suggestive results were noted.  No significant results were found for comparisons of asymmetry measures in relatives of NSCL/P cases vs. controls.

Conclusion: Soft tissue asymmetry studies are feasible and results from this pilot study will provide useful information for future well-powered studies, which should consider adjustment for the effects of age, facial size, and gender.