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Mouse models are central to studying and understanding the genotypic‐to‐phenotypic outcomes of Down syndrome (DS), a complex condition caused by an extra copy of the long arm of human chromosome 21. The recently developed TcMAC21—a transchromosomic mouse strain with comparable gene dosage to human chromosome 21 (Hsa21)—includes more Hsa21 genes than any other model of DS. Recent studies on TcMAC21 have provided valuable insight into the molecular, physiological, and neuroanatomical aspects of the model. However, relatively little is known about the craniofacial phenotype of TcMAC21 mice, particularly as it compares to the widely studied Ts65Dn model. Here we conducted a quantitative study of the cranial morphology of TcMAC21 and Ts65Dn mice and their respective unaffected littermates. Our comparative data comprise forty three‐dimensional cranial measurements taken on micro‐computed tomography scans of the heads of TcMAC21 and Ts65Dn mice. Our results show that TcMAC21 exhibit similar patterns of craniofacial change to Ts65Dn. However, the DS‐specific morphology is more pronounced in Ts65Dn mice. Specifically, Ts65Dn present with more medio‐lateral broadening and retraction of the snout compared to TcMAC21. Our findings reveal the complexity of potential gene interaction in the production of craniofacial phenotypes. [ABSTRACT FROM AUTHOR]

Background: Orthodontic science centers primarily on the growth, development and advancement of the craniofacial structures. Geometric morphometrics (GMM) is a new approach for shape identification in forensic sciences. Purpose: The aim of this study was to examine the shape variation in the Indian sample in order to assess sexual dimorphism by application of two-dimensional GMM. Materials and Methods: The sample comprised a total of 105 lateral cephalograms (54 males–51 females) of Angle's Class I malocclusion patients that were later subjected to principal component (PC) analysis and discriminant analysis. Results: The PC analysis showed over 96% of shape variation. The initial three PCs were statistically significant that depicted as 58.37% of total shape variability, with PC1 represent for the most significant variance 28.48%, PC2 described 18.83% and PC3 11.06%. Conclusion: Sex of an individual was clearly associated with occlusion of teeth and showed considerable variation. GMM is an alternative research tool and can be utilized for diagnosing individual characterization and classification of malocclusion. [ABSTRACT FROM AUTHOR]

We present a fully-automatic statistical 3D shape modeling approach and apply it to a large dataset of 3D images, the Headspace dataset, thus generating the first public shape-and-texture 3D morphable model (3DMM) of the full human head. Our approach is the first to employ a template that adapts to the dataset subject before dense morphing. This is fully automatic and achieved using 2D facial landmarking, projection to 3D shape, and mesh editing. In dense template morphing, we improve on the well-known Coherent Point Drift algorithm, by incorporating iterative data-sampling and alignment. Our evaluations demonstrate that our method has better performance in correspondence accuracy and modeling ability when compared with other competing algorithms. We propose a texture map refinement scheme to build high quality texture maps and texture model. We present several applications that include the first clinical use of craniofacial 3DMMs in the assessment of different types of surgical intervention applied to a craniosynostosis patient group. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between the number of third molars and craniofacial shape., Subjects and Methods: The study sample comprised 470 individuals (194 males and 276 females), out of whom 310 (124 males, mean age: 14.6 years and 186 females, mean age: 14.1 years) had a full permanent dentition including third molars and 160 (70 males, mean age: 13.7 years and 90 females, mean age: 13.9 years) had at least one missing third molar. Pre-orthodontic treatment cephalometric images were digitized using 127 landmarks to describe the shape of the entire craniofacial configuration, the cranial base, the maxilla, and the mandible. The shapes of the various configurations were described by principal components (PCs) of shape. The effect of third molar agenesis on craniofacial shape was evaluated with multivariate regression models, considering shape PCs as the dependent variables, and age and sex as predictors., Results: There was a strong association between third molar agenesis and the shape of all craniofacial configurations in both sexes. Individuals with missing third molars presented a less convex craniofacial configuration, a shorter anterior facial height and a more retrusive maxilla and mandible. In cases with third molar agenesis only in one jaw, shape differences were also evident in the opposing jaw., Limitations: Interpretation of study outcomes should take into consideration the two-dimensional data and the analysis of only white-European subjects., Conclusions: There is a strong association between third molar formation and craniofacial shape. The effect is rather generalized than local and is potentially linked to an ongoing evolutionary mechanism that leads to smaller and fewer teeth, as well as smaller craniofacial configurations, in modern humans., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It has become apparent that natural hybridization is far more common and may play a much greater role in evolution than has historically been recognized. The skeletal morphology of hybrid primates is notoriously variable and difficult to predict. Indeed, before the advent of genetic sequencing techniques, many wild hybrid populations went undetected. Though many species of primates are now known to hybridize naturally and are likely to have done so for millions of years, anthropogenic alterations to the environment are increasingly restricting or altering primate species ranges and contact zones and driving hybridization between populations that may otherwise never have come into contact. The case of hybridizing Japanese and Taiwanese macaques (Macaca fuscata and Macaca cyclopis) is an excellent example of this, as these two island species could not have come into contact without human interference. Here we apply 3D geometric morphometrics and nonmetric trait analysis to the crania and dentition of hybrid macaques (N = 70) and their parental species, M. fuscata (N = 57) and M. cyclopis (N = 51). The exploration of 3D shape variation identifies mildly transgressive morphology in the hybrids and a general tendency toward the M. fuscata morphotype overall, but less variability in the hybrid morphotype than has been identified in previous studies of primate hybrids. We also identify a small number of nonmetric traits that differentiate the hybrids from the parental species, although the power of these traits to distinguish between groups is weak and their relationship with hybridity is unclear. We conclude that the relatively short divergence time between the parent species is likely to help explain the observed differences in hybrid morphotype, and that further exploration of the relationship between degree of evolutionary divergence and hybrid morphology may help us to better explain and predict hybrid morphology in other taxa. [ABSTRACT FROM AUTHOR]

Here, we explore the effects of prenatal alcohol exposure (PAE) in adolescence. We investigated associations between meconium ethyl glucoronide (EtG) and facial malformation. For 129 children (66/63 male/female; M = 13.3, SD = 0.32, 12–14 years), PAE was implemented by newborn meconium EtG and maternal self-reports during the third trimester. Cognitive development was operationalized by standardized scores (WISC V). The EtG cut-off values were set at ≥10 ng/g (n = 32, 24.8% EtG10+) and ≥112 ng/g (n = 20, 15.5% EtG112+). The craniofacial shape was measured using FAS Facial Photographic Analysis Software. EtG10+− and EtG112+-affected children exhibited a shorter palpebral fissure length (p = 0.031/p = 0.055). Lip circularity was smaller in EtG112+-affected children (p = 0.026). Maternal self-reports were not associated (p > 0.164). Lip circularity correlated with fluid reasoning (EtG10+ p = 0.031; EtG112+ p = 0.298) and working memory (EtG10+ p = 0.084; EtG112+ p = 0.144). The present study demonstrates visible effects of the facial phenotype in exposed adolescents. Facial malformation was associated with a child’s cognitive performance in the alcohol-exposed group. The EtG biomarker was a better predictor than maternal self-reports.

Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS.

Approximately eleven thousand years ago humans beings went from feeding on animals they hunted or fished and fruits and plants they gathered, to crops they could grow through agriculture. This change dramatically altered the shape of the skull, particularly the face, which became more gracile, and also reduced the contribution of key nutrients. Along with industrialization, there was great deterioration of oral health. Leaving behind the hunter-gatherer diet has even been attributed to the origins of dental malocclusions, as masticatory stress was reduce, and reducing the size of the maxilla and mandible with respect to the teeth. Nowadays, there is greater awareness in the general population regarding personal care and their surroundings. Diets that exclude certain types of foods such as animal products are becoming more prevalent. The vegetarian diet has several characteristics that can affect metabolism, particularly the bones, as did the change from hunter-gatherer to agriculture in the past. The present review seeks to analyze the changes of the human diet, from the nutritional and mechanical point of view and how these have affected the shape of the face. This in order to understand the possible effects of the introduction of restrictive type feeds, such as the vegetarian diet in the body, particularly in facial anatomy. [ABSTRACT FROM AUTHOR]

Ecological opportunity is often regarded as a key factor that explains why diversity is unevenly distributed across life. Colonization of novel environments or adaptive zones may promote diversification. North American minnows exhibit an ancestral benthic-to-pelagic habitat shift that coincided with a burst in diversification. Here, we evaluate the phenotypic and ecological implications of this habitat shift by assessing craniofacial and dietary traits among 34 species and testing for morphology-diet covariation, convergence and adaptive optima. There were several instances of morphology-diet covariation such as correlations between mouth angle and the consumption of terrestrial insects and between relative gut length and the consumption of algae. After accounting for size and phylogenetic nonindependence, benthic species had longer heads, longer snouts, eyes positioned higher on their head, smaller mouth angles and longer digestive tracts than pelagic minnows. Benthic minnows also consumed more algae but less terrestrial insects, by volume, than pelagic minnows. Lastly, there were three distinct evolutionary regimes and more convergence in morphology and dietary characteristics than expected under a Brownian motion model of evolution. These findings indicate that colonization of the pelagic zone by minnows involved myriad phenotypic and dietary changes associated with exploitation of terrestrial subsidies. Thus, minnows exhibit phenotype-dietary covariation, an expansion of ecological roles and a burst in diversification rates in response to the ecological opportunity afforded by the colonization of a novel habitat. [ABSTRACT FROM AUTHOR]

Objectives Past studies using traditional morphometric approaches have reported a handful of differences in craniofacial dimensions between individuals with and without otitis media (OM). In this study, a geometric morphometry (GM) approach was used to determine if craniofacial shape is different among children with no history of OM and a history of recurrent acute OM (RAOM) at two different ages. Methods Nineteen standard landmarks were identified on lateral cephalometric radiographs from 79 children (41 Control, 38 RAOM) at 4 years and 52 children (27 Control, 25 RAOM) at 6 years of age. Following Procrustes superimposition of the landmark coordinate data, comparisons of group differences in overall size and shape were performed. Discriminant function analysis and principal component analysis were used to determine which, if any, aspects of shape variation distinguished RAOM from Control groups. Results At 4 years of age, craniofacial size and shape were significantly different between RAOM and Control groups ( p < 0.05). Shape differences were evident in the relative positions of the mandible, cranial base, external acoustic meatus, sphenoid and palate. Those shape differences were not found in the 6-year old group. Conclusions At 4 years of age, the RAOM and Control groups have distinct craniofacial morphologies, but by 6 years of age these differences have largely disappeared. This is consistent with the clinical observation that excess RAOM risk resolves around 6 years of age and the hypothesis that this resolution is partially a result of age-related craniofacial changes. [ABSTRACT FROM AUTHOR]

The identification of the genes involved in morphological variation in nature is still a major challenge. Here, we explore a new approach: we combine 178 samples from a natural hybrid zone between two subspecies of the house mouse ( Mus musculus domesticus and Mus musculus musculus), and high coverage of the genome (~ 145K SNPs) to identify loci underlying craniofacial shape variation. Due to the long history of recombination in the hybrid zone, high mapping resolution is anticipated. The combination of genomes from subspecies allows the mapping of both, variation within subspecies and inter-subspecific differences, thereby increasing the overall amount of causal genetic variation that can be detected. Skull and mandible shape were measured using 3D landmarks and geometric morphometrics. Using principal component axes as phenotypes, and a linear mixed model accounting for genetic relatedness in the mapping populations, we identified nine genomic regions associated with skull shape and 10 with mandible shape. High mapping resolution (median size of significant regions = 148 kb) enabled identification of single or few candidate genes in most cases. Some of the genes act as regulators or modifiers of signalling pathways relevant for morphological development and bone formation, including several with known craniofacial phenotypes in mice and humans. The significant associations combined explain 13% and 7% of the skull and mandible shape variation, respectively. In addition, a positive correlation was found between chromosomal length and proportion of variation explained. Our results suggest a complex genetic architecture for shape traits and support a polygenic model. [ABSTRACT FROM AUTHOR]

Background: Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. Results: We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. Conclusions: We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation. Developmental Dynamics, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Skeletal anomalies are common in patients with muscular dystrophy, despite an absence of mutations to genes that specifically direct skeletogenesis. In order to understand these anomalies further, we examined two strains of muscular dystrophy (laminin- and merosin-deficient) relative to controls, to determine how the weakened muscle forces affected skull shape in a mouse model. Shape was characterized with geometric morphometric techniques, improving upon the limited analytical power of the standard linear measurements. Through these techniques, we document the specific types of cranial skeletal deformation produced by the two strains, each with individual shape abnormalities. The mice with merosin deficiency (with an earlier age of onset) developed skulls with more deformation, probably related to the earlier ontogenetic timing of disease onset. Future examinations of these mouse models may provide insight regarding the impact of muscular forces and the production and maintenance of craniofacial integration and modularity. [ABSTRACT FROM AUTHOR]

An evolutionary, diachronic approach to the phenotypic craniofacial pattern arisen in a human population after high levels of admixture and gene flow was achieved by means of geometric morphometrics. Ad-mixture has long been studied after molecular data. Nevertheless, few efforts have been made to explain the morphological outcome in human craniofacial samples. The Spanish-Amerindian contact can be considered a good scenario for such an analysis. Here we present a comparative analysis of craniofacial shape changes observed between two putative ancestor groups, Spanish and precontact Aztecs, and two diachronic admixed groups, corresponding to early and late colonial periods from the Mexico's Central Valley. Quantitative shape comparisons of Amerindian, Spanish, and admixed groups were used to test the expectations of quantitative genetics for admixture events. In its simplest form, this prediction states that an admixed group will present phenotypic values falling between those of both parental groups. Results show that, in general terms, although the human skull is a complex, integrated structure, the craniofacial morphology observed fits the theoretical expectations of quantitative genetics. Thus, it is predictive of population structure and history. In fact, results obtained after the craniofacial analysis are in accordance with previous molecular and historical interpretations, providing evidence that admixture is a main microevolutionary agent influencing modern Mexican gene pool. However, expectations are not straightforward when moderate shape changes are considered. Deviations detected at localized structures, such as the upper and lower face, highlight the evolution of a craniofacial pattern exclusively inherent to the admixed groups, indicating that quantitative characters might respond to admixture in a complicated, nondirectional way. [ABSTRACT FROM AUTHOR]

Summary: The head of a land-living vertebrate is exposed to the forces of acceleration, in particular the permanent earth acceleration (= gravity) and the muscle-generated bite and chewing forces. In mammals, at least, the latter seem to play the dominant role. Bite forces are applied to the teeth and close the circle of forces by passing through the facial skeleton to the insertions of the mandibular adductors. With the aid of three-dimensional Finite Element Systems Analysis (FESA), the stress flows in homogenous bodies are investigated, whereby the braincase, the orbits and the nasal channel are taken as preconditions. The muscle insertions are varied systematically. The resulting stress flows in all cases turn out to be very similar to the bony structures of a skull. Little or not stressed parts of the available homogenous body indicate the external surface or hollow spaces (= sinuses) inside the skull. The possible applications of forces (i.e., the forms and positions of the dental arcade in relation to the braincase) determine the pathways along which the forces are transmitted. It seems that the factors mentioned above as preconditions represent the selective pressures exerted by the lifestyle of the animal and its environment (= ecological conditions). The results that can be obtained by our deductive approach in comparison to inductive, experimental procedures are discussed briefly. [Copyright &y& Elsevier]

Background: Over early fetal life, when disturbances in schizophrenia have been posited and craniofacial dysmorphogenesis reported, cerebral morphogenesis proceeds in embryological intimacy with craniofacial morphogenesis. Digitization technologies now allow 3D recording of craniofacial surface landmarks and modeling of craniofacial shape differences using geometric morphometrics.Methods: Using normal sexual dimorphism as an exemplar, facial surfaces of 131 Medical School employees [82 females, 49 males] were recorded in 3D using a portable, handheld laser scanner; 3D coordinate data were then analyzed using geometric morphometrics.Results: Males and females differed markedly on an omnibus test of craniofacial shape. Logistic regression analysis of 16 principal components of shape variability, explaining 84.9% of the overall sample variance, generated 8 principal components as significant and independent discriminators. On visualization, the female face is wider and flatter; the eyes are more lateral, anterior and are further apart, and nasal bridge is posterior; the nose is smaller; the lips are fuller and the chin more forward. These findings are complementary to sexual dimorphism in cerebral structures.Conclusions: This technique reliably discriminates geometric features of craniofacial morphology that are associated with aspects of cerebral morphology, and may inform on putative neurodevelopmental disorders characterised by dysmorphogenesis. [ABSTRACT FROM AUTHOR]

Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS., (© 2015. Published by The Company of Biologists Ltd.)