Trisomy 21 and facial developmental instability

Abstract

The most common live-born human aneuploidy is trisomy 21, which causes Down syndrome (DS). Dosage imbalance of genes on chromosome 21 (Hsa21) affects complex gene-regulatory interactions and alters development to produce a wide range of phenotypes, including characteristic facial dysmorphology. Little is known about how trisomy 21 alters craniofacial morphogenesis to create this characteristic appearance. Proponents of the “amplified developmental instability” hypothesis argue that trisomy 21 causes a generalized genetic imbalance that disrupts evolutionarily conserved developmental pathways by decreasing developmental homeostasis and precision throughout development. Based on this model, we test the hypothesis that DS faces exhibit increased developmental instability relative to euploid individuals. Developmental instability was assessed by a statistical analysis of fluctuating asymmetry. We compared the magnitude and patterns of fluctuating asymmetry among siblings using three-dimensional coordinate locations of 20 anatomic landmarks collected from facial surface reconstructions in four age-matched samples ranging from 4 to 12 years: 1) DS individuals (n=55); 2) biological siblings of DS individuals (n=55); 3) and 4) two samples of typically developing individuals (n=55 for each sample), who are euploid siblings and age-matched to the DS individuals and their euploid siblings (samples 1 and 2). Identification in the DS sample of facial prominences exhibiting increased fluctuating asymmetry during facial morphogenesis provides evidence for increased developmental instability in DS faces. We found the highest developmental instability in facial structures derived from the mandibular prominence and lowest in facial regions derived from the frontal prominence.

Axial skeletogenesis in human autosomal aneuploidies: A radiographic study of 145 second trimester fetuses

“…Although in our sample we were not able to measure asymmetry in all body sites, we noted unilateral cervical ribs in 15.8% of the fetuses and this finding is further support for aneuploidy as a source of increased developmental instability in humans. This is in line with recent work identifying a high rate of limb asymmetry in human aneuploid fetuses and facial asymmetry in trisomy 21 [Starbuck et al, 2013;Bots et al, 2014].…”

Analyzing Fluctuating Asymmetry with Geometric Morphometrics: Concepts, Methods, and Applications

“…Methods for studying fluctuating asymmetry using this approach have been developed [199], but have been used in only relatively few studies [38,39,47,52,68,138,178,200,201]. The vast majority of studies, however, have used Procrustes approaches and this review therefore is focusing mainly on these.…”

Fluctuating Asymmetry of Human Populations: A Review

“…They found that the dental asymmetry of the Down syndrome individuals was nearly twice that of a control population. More recently, Starbuck et al [168] reported 140%-160% greater facial asymmetry in Down syndrome individuals than in normally developing siblings and sibling pairs. Nevertheless, there have been well-designed studies that have found no increase in fluctuating asymmetry with Down syndrome.…”