Ethanol-Induced Face-Brain Dysmorphology Patterns Are Correlative and Exposure-Stage Dependent

Prenatal ethanol exposure is the leading preventable cause of congenital mental disability. Whereas a diagnosis of fetal alcohol syndrome (FAS) requires identification of a specific pattern of craniofacial dysmorphology, most individuals with behavioral and neurological sequelae of heavy prenatal ethanol exposure do not exhibit these defining facial characteristics. Here, a novel integration of MRI and dense surface modeling-based shape analysis was applied to characterize concurrent face-brain phenotypes in C57Bl/6J fetuses exposed to ethanol on gestational day (GD)7 or GD8.5. The facial phenotype resulting from ethanol exposure depended upon stage of insult and was predictive of unique patterns of corresponding brain abnormalities. Ethanol exposure on GD7 produced a constellation of dysmorphic facial features characteristic of human FAS, including severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum. In contrast, ethanol exposure on GD8.5 caused mild midfacial hypoplasia and palpebral fissure shortening, a shortened upper lip, and a preserved philtrum. These distinct, stage-specific facial phenotypes were associated with unique volumetric and shape abnormalities of the septal region, pituitary, and olfactory bulbs. By demonstrating that early prenatal ethanol exposure can cause more than one temporally-specific pattern of defects, these findings illustrate the need for an expansion of current diagnostic criteria to better capture the full range of facial and brain dysmorphology in fetal alcohol spectrum disorders.

产前乙醇暴露是导致先天性智力障碍的首要可预防病因。胎儿酒精综合征（fetal alcohol syndrome, FAS）的诊断需要识别特定的颅面畸形表型，但大多数因重度产前乙醇暴露出现行为与神经后遗症的个体，并不会表现出这些特征性的面部体征。本研究将磁共振成像（Magnetic Resonance Imaging, MRI）与基于密集表面建模的形状分析技术进行创新性整合，用于表征在妊娠第7天（gestational day, GD7）或第8.5天（GD8.5）暴露于乙醇的C57Bl/6J胎鼠的同步面-脑表型。乙醇暴露所致的面部表型取决于暴露的时间节点，且可预测对应脑结构异常的独特模式。在GD7暴露于乙醇的胎鼠，会出现人类FAS特征性的一系列面部畸形表型，包括严重的面中部发育不全、睑裂缩短、上唇过长以及人中发育不良。与之相反，在GD8.5暴露于乙醇的胎鼠则表现为轻度面中部发育不全、睑裂缩短、上唇过短且人中形态保留完好。这些独特的、暴露时间特异性的面部表型，与隔区、垂体以及嗅球的独特体积与形状异常存在关联。本研究证实，早期产前乙醇暴露可引发多种具有时间特异性的缺陷模式，这些结果表明，当前的胎儿酒精谱系障碍诊断标准亟需扩充，以更好地覆盖胎儿酒精谱系障碍中全部的面部与脑畸形表型。