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1.  Facial Dysmorphism Across the Fetal Alcohol Spectrum 
Pediatrics  2013;131(3):e779-e788.
OBJECTIVE:
Classic facial characteristics of fetal alcohol syndrome (FAS) are shortened palpebral fissures, smooth philtrum, and thin upper vermillion. We aim to help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially among nonsyndromal heavily exposed (HE) individuals without classic facial characteristics.
METHODS:
Of 192 Cape Coloured children recruited, 69 were born to women who reported abstaining from alcohol during pregnancy. According to multifaceted criteria, the remainder were allocated clinically to the FAS (n = 22), partial FAS (n = 26) or nonsyndromal HE (n = 75) categories. We used dense surface modeling and signature analyses of 3-dimensional facial photographs to determine agreement between clinical categorization and classifications induced from face shape alone, to visualize facial differences, and to consider predictive links between face shape and neurobehavior.
RESULTS:
Face classification achieved significant agreement with clinical categories for discrimination of nonexposed from FAS alone (face: 0.97–1.00; profile: 0.92) or with the addition of partial FAS (face: 0.90; profile: 0.92). Visualizations of face signatures delineated dysmorphism across the fetal alcohol spectrum and in half of the nonsyndromal HE category face signature graphs detected facial characteristics consistent with prenatal alcohol exposure. This subgroup performed less well on IQ and learning tests than did nonsyndromal subjects without classic facial characteristics.
CONCLUSIONS:
Heat maps and morphing visualizations of face signatures may help clinicians detect facial dysmorphism across the fetal alcohol spectrum. Face signature graphs show potential for identifying nonsyndromal heavily exposed children who lack the classic facial phenotype but have cognitive impairment.
doi:10.1542/peds.2012-1371
PMCID: PMC3581841  PMID: 23439907
facial dysmorphism; fetal alcohol spectrum disorders; fetal alcohol syndrome; dense surface modeling; signature graphs; prenatal alcohol exposure; alcohol-related neurodevelopmental disorder
2.  The Face Signature of Fibrodysplasia Ossificans Progressiva 
Fibrodysplasia Ossificans Progressiva (FOP) causes extensive heterotopic bone formation due to heterozygous mutations in the glycine-serine activation domain of ACVR1 (ALK2), a bone morphogenetic protein type I receptor. Anecdotal observations of facial similarity have been made by clinicians and parents, but no objective quantitative analysis of the faces of FOP patients has ever been undertaken. We delineated the common facial characteristics of 55 individuals with molecularly confirmed FOP by analysing their face signature (face shape difference normalized against age and sex matched controls) and associated face signature graphs (with face signatures as vertices and adjacency corresponding to greatest similarity). Our analysis identified 10 affected individuals whose face signature is more homogeneous than others with FOP. This distinct subgroup showed the previously identified reduced mandible as well as newly identified features: underdevelopment of the upper orbit/supra-orbital ridge; infra-orbital prominence; and, low-set ears. These findings strongly suggest that the canonical FOP mutation variably affects the postnatal morphogenesis of the normotopic cranial skeleton in the upper midface and mandible and may have important diagnostic and functional implications.
doi:10.1002/ajmg.a.35346
PMCID: PMC3356438  PMID: 22581580
Fibrodysplasia Ossificans Progressiva (FOP); dense surface modelling; face signature graphs; ACVR1; ALK2
3.  Large-scale objective phenotyping of 3D facial morphology 
Human Mutation  2012;33(5):817-825.
Abnormal phenotypes have played significant roles in the discovery of gene function, but organized collection of phenotype data has been overshadowed by developments in sequencing technology. In order to study phenotypes systematically, large-scale projects with standardized objective assessment across populations are considered necessary. The report of the 2006 Human Variome Project meeting recommended documentation of phenotypes through electronic means by collaborative groups of computational scientists and clinicians using standard, structured descriptions of disease-specific phenotypes. In this report, we describe progress over the past decade in 3D digital imaging and shape analysis of the face, and future prospects for large-scale facial phenotyping. Illustrative examples are given throughout using a collection of 1107 3D face images of healthy controls and individuals with a range of genetic conditions involving facial dysmorphism.
doi:10.1002/humu.22054
PMCID: PMC3327801  PMID: 22434506
3D imaging; facial phenotyping; morphometrics; dysmorphology
4.  Fine-grained facial phenotype–genotype analysis in Wolf–Hirschhorn syndrome 
Wolf–Hirschhorn syndrome is caused by anomalies of the short arm of chromosome 4. About 55% of cases are due to de novo terminal deletions, 40% from unbalanced translocations and 5% from other abnormalities. The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum. We used dense surface modelling and pattern recognition techniques to delineate the milder facial phenotype of individuals with a small terminal deletion (breakpoint within 4p16.3) compared to those with a large deletion (breakpoint more proximal than 4p16.3). Further, fine-grained facial analysis of several individuals with an atypical genotype and/or phenotype suggests that multiple genes contiguously contribute to the characteristic Wolf–Hirschhorn syndrome facial phenotype.
doi:10.1038/ejhg.2011.135
PMCID: PMC3234504  PMID: 21792232
Wolf–Hirschhorn syndrome; facial dysmorphism; 3D shape analysis
5.  Atypical face shape and genomic structural variants in epilepsy 
Brain  2012;135(10):3101-3114.
Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development.
doi:10.1093/brain/aws232
PMCID: PMC3470710  PMID: 22975390
epilepsy; dysmorphism; structural variants; genomics; dense surface models
6.  Ethanol-Induced Face-Brain Dysmorphology Patterns Are Correlative and Exposure-Stage Dependent 
PLoS ONE  2012;7(8):e43067.
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.
doi:10.1371/journal.pone.0043067
PMCID: PMC3425589  PMID: 22937012

Results 1-6 (6)