title: Ethanol-induced face-brain dysmorphology patterns are correlative and exposure-stage dependent.
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.
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America. lipinski@med.unc.edu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lipinski
authors.forename: Peter
authors.initials: P
authors.lastname: Hammond
authors.forename: Shonagh K
authors.initials: SK
authors.lastname: O'Leary-Moore
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Ament
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pecevich
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Francois
authors.initials: F
authors.lastname: Budin
authors.forename: Scott E
authors.initials: SE
authors.lastname: Parnell
authors.forename: Michael
authors.initials: M
authors.lastname: Suttie
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Godin
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Everson
authors.forename: Deborah B
authors.initials: DB
authors.lastname: Dehart
authors.forename: Ipek
authors.initials: I
authors.lastname: Oguz
authors.forename: Hunter T
authors.initials: HT
authors.lastname: Holloway
authors.forename: Martin A
authors.initials: MA
authors.lastname: Styner
authors.forename: G Allan
authors.initials: GA
authors.lastname: Johnson
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Sulik
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000196:embryology*; D000431:Ethanol / Q000009:adverse effects*; D005145:Face / Q000002:abnormalities / Q000196:embryology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000209:etiology / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D011247:Pregnancy
chemical_list: D000431:Ethanol