Facial Curvature Detects and Explicates Ethnic Differences in Effects of Prenatal Alcohol Exposure

Abstract

Background Our objective is to help clinicians detect the facial effects of prenatal alcohol exposure (PAE) by developing computer based tools for screening facial form. Methods All 415 individuals considered were evaluated by expert dysmorphologists and categorized as 1) healthy control (HC), 2) fetal alcohol syndrome (FAS) or 3) heavily prenatally alcohol exposed (HE) but not clinically diagnosable as FAS. 3D facial photographs were used to build models of facial form to support discrimination studies. Surface curvature based delineations of facial form were introduced. Results Facial growth in FAS, HE and control subgroups is similar in both cohorts. Cohort consistency of agreement between clinical diagnosis and HC-FAS facial form classification is lower for mid-line facial regions and higher for non-mid-line regions. Specific HC-FAS differences within and between the cohorts include: for HC, a smoother philtrum in Cape Coloured individuals;for FAS, a smoother philtrum in Caucasians;for control-FAS philtrum difference, greater homogeneity in Caucasians;for control-FAS face difference, greater homogeneity in Cape Coloured individuals; Curvature changes in facial profile induced by prenatal alcohol exposure are more homogeneous and greater in Cape Coloureds than in Caucasians. The Caucasian HE subset divides into clusters with control-like and FAS-like facial dysmorphism. The Cape Coloured HE subset is similarly divided for non-mid-line facial regions but not clearly for mid-line structures. The Cape Coloured HE subset with control-like facial dysmorphism shows orbital hypertelorism. Conclusions Facial curvature assists the recognition of the effects of prenatal alcohol exposure and helps explain why different facial regions result in inconsistent control-FAS discrimination rates in disparate ethnic groups. Heavy prenatal alcohol exposure can give rise to orbital hypertelorism, supporting a long-standing suggestion that prenatal alcohol exposure at a particular time causes increased separation of the brain hemispheres with a concomitant increase in orbital separation.

Fetal Alcohol Spectrum Disorders: A Review of the Neurobehavioral Deficits Associated With Prenatal Alcohol Exposure

“…Smaller palpebral fissures relate to a decrease in diencephalon volume bilaterally, philtrum size correlates with volume of basal ganglia and diencephalon structures, and decreased IQ scores are associated with smaller basal ganglia structure volumes and increased physical dysmorphology features (Roussotte et al., ). Additionally, certain dysmorphological findings (i.e., orbital hypertelorism) indicate that heavy prenatal alcohol exposure during particular points in pregnancy affects brain development and ultimately results in unique facial dysmorphology (Suttie et al., ). Functional neuroimaging studies have indicated that children with FASD demonstrate altered brain activation patterns during verbal learning (Sowell et al., ), response inhibition (Fryer et al., ), visual attention (Li et al., ), and working memory (Astley et al., ; Malisza et al., ; O'Hare et al., ; Spadoni et al., ) tasks.…”

Prenatal alcohol exposure disrupts Shh pathway and primary cilia genes in the mouse neural tube

“…The Kif3a mutant mouse is a well-characterized model of genetic ciliopathy (24, 46, 73) as Kif3a mutant mice phenocopy many human ciliopathies, including hypertelorism, facial clefting, and brain abnormalities (46, 74). Similar to the defects seen in conditional Kif3a mutant mice, NAE mice can exhibit abnormal cortical hemispheres and ventral midline brain structures (13, 14) and hypertelorism has been reported in some patients with heavy prenatal alcohol exposure who lack the classic FAS facial features (4, 75). Kif3a heterozygous mice have been shown to display similar physical abnormalities, such as situs inversus, to the full knockout but at a much lower rate (76), as Kif3a -/- die by E10.…”

“…Shh transduction occurs within the axoneme of primary cilia, nearly ubiquitous structures of mammalian cells that play a particularly important role during embryonic development. Dysregulation of RVNT primary cilia poses a risk to the normal development of brain regions that arise from this area of the neural tube, namely midline structures such as the hypothalamus, septum, pituitary, and preoptic area (45), many of which have been shown to be altered by NAE Additionally, midline anomalies such as hypertelorism are a hallmark of genetic ciliopathies and have also been reported in a subset of patients with heavy prenatal alcohol exposure (4), suggesting an overlapping etiology between ciliopathies and prenatal alcohol.…”

“…The observed downregulation of Dpcd, a gene normally upregulated during cilia formation and cell division (66), further supports the conclusion that the cell cycle has been affected by NAE as early as 6 hr post-exposure. Transient changes in cell proliferation in this region of the neural tube would impact the development of midline brain and craniofacial tissue (4, 11, 13, 14). A schematic of cilia genes altered following NAE at 6 and 12 hr is shown in Fig 5.…”

“…Alcohol exposure often occurs before pregnancy is identified, during the early, important stages of embryonic development, such as gastrulation and neurulation. Early gestational alcohol exposure has been linked to growth retardation, central nervous system dysfunction, and distinct craniofacial malformations, including the “classic” facial phenotype of Fetal Alcohol Syndrome (FAS) characterized by midline defects such as hypotelorism and an absent philtrum (2, 3), as well as more subtle facial variances (4). Alcohol exposure during gastrulation, the stage when the embryo first forms distinct cell layers (3 rd week in humans, embryonic day [E] 7 in mice), induces widespread cell death in the neuroectoderm (5), and subsequent diminished Sonic hedgehog (Shh) signaling as a pathogenic mechanism for gastrulation-stage alcohol exposure (6–10).…”