Abstract
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.
Highlights
Prenatal ethanol exposure causes a range of structural and functional abnormalities, collectively termed fetal alcohol spectrum disorder (FASD)
At the severe end of this spectrum is fetal alcohol syndrome (FAS), which is characterized by growth retardation, CNS dysfunction, and a specific pattern of craniofacial dysmorphology
Whereas CNS abnormalities are the most disabling manifestation of FAS, current diagnostic approaches are directed at the recognition of a specific pattern of craniofacial dysmorphology, including reduced head circumference, shortened palpebral fissures, and an upper lip with a thin vermillion border and relatively indistinct philtrum [8,9]
Summary
Prenatal ethanol exposure causes a range of structural and functional abnormalities, collectively termed fetal alcohol spectrum disorder (FASD). Development of the face and brain is intimately interrelated, as the brain provides structural, cellular, and molecular input that the guides development of the adjacently developing face [3,4,5,6]. This relationship is exploited in clinical diagnostics, as syndromes involving primary brain abnormalities can often be recognized by associated facial dysmorphism [7]. Failure to identify ethanol-affected individuals represents a major hindrance to the effective implementation of appropriate and timely interventions for FASD [11]
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