Geometric morphometric analysis of craniofacial variation,ontogeny and modularity in a cross‐sectional sample of modern humans

This investigation aimed to quantify craniofacial variation in a sample of modern humans. In all, 187 consecutive orthodontic patients were collected, of which 79 were male (mean age 13.3, SD 3.7, range 7.5–40.8) and 99 were female (mean age 12.3, SD 1.9, range 8.7–19.1). The male and female subgroups were tested for differences in mean shapes and ontogenetic trajectories, and shape variability was characterized using principal component analysis. The hypothesis of modularity was tested for six different modularity scenarios. The results showed that there were subtle but significant differences in the male and female Procrustes mean shapes. Males were significantly larger. Mild sexual ontogenetic allometric divergence was noted. Principal component analysis indicated that, of the four retained biologically interpretable components, the two most important sources of variability were (i) vertical shape variation (i.e. dolichofacial vs. brachyfacial growth patterns) and (ii) sagittal relationships (maxillary prognatism vs. mandibular retrognathism, and vice versa). The mandible and maxilla were found to constitute one module, independent of the skull base. Additionally, we were able to confirm the presence of an anterior and posterior craniofacial columnar module, separated by the pterygomaxillary plane, as proposed by Enlow. These modules can be further subdivided into four sub-modules, involving the posterior skull base, the ethmomaxillary complex, a pharyngeal module, and the anterior part of the jaws.     

Beyond the closed suture in apert syndrome mouse models: Evidence of primary effects of FGFR2 signaling on facial shape at birth

Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2^+/S252W and Fgfr2^+/P253R, to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial skeleton is the most affected region of the cranium. Coronal suture patency shows marked variation that is not strongly correlated with skull dysmorphology. The craniofacial effects of the FGFR2 mutations are similar, but Fgfr2^+/S252W mutant mice display significantly more severe dysmorphology localized to the posterior palate. Our results demonstrate that coronal suture closure is neither the primary nor the sole locus of skull dysmorphology in these mouse models for Apert syndrome, but that the face is also primarily affected. Developmental Dynamics 239:3058–3071, 2010. © 2010 Wiley‐Liss, Inc.     

Brain morphology in nonsyndromic unicoronal craniosynostosis

Studies of isolated craniosynostosis have shown biomechanical and biochemical influences on the craniofacial phenotype, resulting from both genetic and epigenetic factors. Much less attention has been directed toward the morphology of the brain, despite the interactive nature of the developing skull and developing brain. The aim of this study is to define the morphology of the brain in nonsyndromic unilateral coronal synostosis (UCS) in order to form more complete hypotheses about the cause of craniosynostosis. Landmark coordinate data were collected from 3D magnetic resonance image reconstructions of the brain in a sample of UCS patients and an age-matched morphologically normal cohort. These data were analyzed using Euclidean distance matrix analysis. The results of our study demonstrate that despite the basic similarity of overall shape of the brain and skull in UCS, the effects of craniosynostosis on the brain are not localized to structures immediately adjacent to the fused suture or to the endocranial surface of the skull. Rather, alterations are observed throughout the volume of the brain, with subcortical structures altered in conjunction with cortical changes. These results indicate that the morphological correlates are different for brain and skull and suggest that there is a large degree of independence in the developmental trajectories of the brain and skull.     

Cranial Suture Biology of the Aleutian Island Inhabitants

Research on cranial suture biology suggests there is biological and taxonomic information to be garnered from the heritable pattern of suture synostosis. Suture synostosis along with brain growth patterns, diet, and biomechanical forces influence phenotypic variability in cranial vault morphology. This study was designed to determine the pattern of ectocranial suture synostosis in skeletal populations from the Aleutian Islands. We address the hypothesis that ectocranial suture synostosis pattern will differ according to cranial vault shape. Ales Hrdlicka identified two phenotypes in remains excavated from the Aleutian Island. The Paleo‐Aleutians, exhibiting a dolichocranic phenotype with little prognathism linked to artifacts distinguished from later inhabitants, Aleutians, who exhibited a brachycranic phenotype with a greater amount of prognathism. A total of 212 crania representing Paleo‐Aleuts and Aleutian as defined by Hrdlicka were investigated for suture synostosis pattern following standard methodologies. Comparisons were performed using Guttmann analyses. Results revealed similar suture fusion patterns for the Paleo‐Aleut and Aleutian, a strong anterior to posterior pattern of suture fusion for the lateral‐anterior suture sites, and a pattern of early termination at the sagittal suture sites for the vault. These patterns were found to differ from that reported in the literature. Because these two populations with distinct cranial shapes exhibit similar patterns of suture synostosis it appears pattern is independent of cranial shape in these populations of Homo sapiens. These findings suggest that suture fusion patterns may be population dependent and that a standardized methodology, using suture fusion to determine age‐at‐death, may not be applicable to all populations. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Changes in Biomechanical Strain and Morphology of Rat Calvarial Sutures and Bone After Tgf‐β3 Inhibition of Posterior Interfrontal Suture Fusion

Craniofacial sutures are bone growth fronts that respond and adapt to biomechanical environments. Little is known of the role sutures play in regulating the skull biomechanical environment during patency and fusion conditions, especially how delayed or premature suture fusion will impact skull biomechanics. Tgf‐β3 has been shown to prevent or delay suture fusion over the short term in rat skulls, yet the long‐term patency or its consequences in treated sutures is not known. It was therefore hypothesized that Tgf‐β3 had a long‐term impact to prevent suture fusion and thus alter the skull biomechanics. In this study, collagen gels containing 3 ng Tgf‐β3 were surgically placed superficial to the posterior interfrontal suture (IFS) and deep to the periosteum in postnatal day 9 (P9) rats. At P9, P24, and P70, biting forces and strains over left parietal bone, posterior IFS, and sagittal suture were measured with masticatory muscles bilaterally stimulated, after which the rats were sacrificed and suture patency analyzed histologically. Results demonstrated that Tgf‐β3 treated sutures showed less fusion over time than control groups, and strain patterns in the skulls of the Tgf‐β3‐treated group were different from that of the control group. Although bite force increased with age, no alterations in bite force were attributable to Tgf‐β3 treatment. These findings suggest that the continued presence of patent sutures can affect strain patterns, perhaps when higher bite forces are present as in adult animals. Anat Rec,, 2012. © 2012 Wiley Periodicals, Inc.     

Heterochrony and patterns of cranial suture closure in hystricognath rodents

Sutures, joints that allow one bone to articulate with another through intervening fibrous connective tissue, serve as major sites of bone expansion during postnatal craniofacial growth in the vertebrate skull and represent an aspect of cranial ontogeny which may exhibit functional and phylogenetic correlates. Suture evolution among hystricognath rodents, an ecologically diverse group represented here by 26 species, is examined using sequence heterochrony methods, i.e. event pairing and parsimov . Although minor nuances in suture closure sequence exist between species, the overall sequence was found to be conserved both across the hystricognath group and, to an increasing degree, within selected clades. At species level, suture closure pattern exhibited a significant positive correlation with patterns previously reported for hominoids. Patterns for most clades revealed the first sutures to close are those contacting the exoccipital, interparietal, and palatine bones. Heterochronic shifts were found along 19 of 35 branches within the hystricognath phylogeny. The number of shifts per node ranged from one to seven events and, overall, involved 21 of 34 suture sites. The topology generated by parsimony analyses of the event pair matrix yielded only one grouping that was congruent with the evolutionary relationships, compiled from morphological and molecular studies, taken as framework. Sutures contacting the exoccipital displayed the highest levels of most complete closure across all species. Level of suture closure is negatively correlated with cranial length ( P  < 0.05). Differing life history and locomotory strategies are coupled in part with differing suture closure patterns among several species.     

Relationship of brain and skull in pre- and postoperative sagittal synostosis

Models of vertebrate skull evolution stress the coordinated developmental relationship between the skull and the brain that it houses. This study investigates the relationship between altered skull morphology and brain morphology in premature fusion of the cranial sagittal suture (isolated sagittal synostosis; ISS), a condition associated with dysmorphology of both neurocranium and brain. Although the skull displays a more normal shape following reconstructive cranial vault surgery, effects of this surgery on the brain have not been investigated. Landmark coordinate data were collected from three-dimensional magnetic resonance imaging reconstructions of the brain in a sample of ISS patients and an age-matched unaffected cohort. These data were analysed using Euclidean distance matrix analysis (EDMA). Results show that the brain in ISS is dysmorphic preoperatively, displaying a posteriorly directed neural expansion that does not 'worsen' with growth. Postoperatively, the brain in ISS displays a more globular shape overall as compared with the preoperative morphology, but differs from normal in its subcortical morphology. These results show that the ISS brain is altered following neurocranial surgery, but does not more closely approximate that of unaffected individuals. This suggests that although the brain is affected by manipulation of the skull, it retains a growth pattern that is, at least in part, independent of the skull.     

Central nervous system phenotypes in craniosynostosis

Though reduction in the number of cranial elements through loss of a suture is a recognized trend in vertebrate evolution, the premature closure of cranial sutures in humans, craniosynostosis, is considered a pathological condition. Previous research on craniosynostosis has focused primarily on the skeletal phenotype, but the intimate relationship between the developing central nervous system (CNS) and skull is well documented. We investigate the morphology of the CNS in patients with isolated craniosynostosis through an analysis of cortical and subcortical features using 3-D magnetic resonance images (MRI). Results show that a distinct CNS phenotype can be defined for specific diagnostic categories. Many differences in CNS morphology observed in the patient samples may be anticipated based on skeletal morphology, but others are not reflected in the skull. We propose a developmental approach to determining the cause of premature suture fusion, which includes investigation of the craniofacial complex as a system, rather than study of isolated tissues.     

The Global Impact of Sutures Assessed in a Finite Element Model of a Macaque Cranium

The biomechanical significance of cranial sutures in primates is an open question because their global impact is unclear, and their material properties are difficult to measure. In this study, eight suture‐bone functional units representing eight facial sutures were created in a finite element model of a monkey cranium. All the sutures were assumed to have identical isotropic linear elastic material behavior that varied in different modeling experiments, representing either fused or unfused sutures. The values of elastic moduli employed in these trials ranged over several orders of magnitude. Each model was evaluated under incisor, premolar, and molar biting conditions. Results demonstrate that skulls with unfused sutures permitted more deformations and experienced higher total strain energy. However, strain patterns remained relatively unaffected away from the suture sites, and bite reaction force was likewise barely affected. These findings suggest that suture elasticity does not substantially alter load paths through the macaque skull or its underlying rigid body kinematics. An implication is that, for the purposes of finite element analysis, omitting or fusing sutures is a reasonable modeling approximation for skulls with small suture volume fraction if the research objective is to observe general patterns of craniofacial biomechanics under static loading conditions. The manner in which suture morphology and ossification affect the mechanical integrity of skulls and their ontogeny and evolution awaits further investigation, and their viscoelastic properties call for dynamic simulations. Anat Rec 293:1477–1491, 2010. © 2010 Wiley‐Liss, Inc.     

A computerized tomography study of the morphological interrelationship between the temporal bones and the craniofacial complex

The hypothesis that the temporal bones are at the center of the dynamics of the craniofacial complex, directly influencing facial morphology, has been put forward long ago. This study examines the role of the spatial positioning of temporal bones (frontal and sagittal inclination) in terms of influencing overall facial morphology. Several 3D linear, angular and orthogonal measurements obtained through computerized analysis of virtual models of 163 modern human skulls reconstructed from cone-beam computed tomography images were analyzed and correlated. Additionally, the sample was divided into two subgroups based on the median value of temporal bone sagittal inclination [anterior rotation group (n = 82); posterior rotation group (n = 81)], and differences between groups evaluated. Correlation coefficients showed that sagittal inclination of the temporal bone was significantly (P < 0.01) related to midline flexion, transversal width and anterior-posterior length of the basicranium, to the anterior-posterior positioning of the mandible and maxilla, and posterior midfacial height. Frontal inclination of the temporal bone was significantly related (P < 0.01) to basicranium anterior-posterior and transversal dimensions, and to posterior midfacial height. In comparison with the posterior rotation group, the anterior rotation group presented a less flexed and anterior-posteriorly longer cranial base, a narrower skull, porion and the articular eminence located more superiorly and posteriorly, a shorter posterior midfacial height, the palatal plane rotated clockwise, a more retrognathic maxilla and mandible, and the upper posterior occlusal plane more inclined and posteriorly located. The results suggest that differences in craniofacial morphology are highly integrated with differences in the positional relationship of the temporal bones. The sagittal inclination of the temporal bone seems to have a greater impact on the 3D morphology of the craniofacial complex than frontal inclination.     

Cranial Suture Closure in Domestic Dog Breeds and Its Relationships to Skull Morphology

Bulldog‐type brachycephalic domestic dog breeds are characterized by a relatively short and broad skull with a dorsally rotated rostrum (airorhynchy). Not much is known about the association between a bulldog‐type skull conformation and peculiar patterns of suture and synchondrosis closure in domestic dogs. In this study, we aim to explore breed‐specific patterns of cranial suture and synchondrosis closure in relation to the prebasial angle (proxy for airorhynchy and thus bulldog‐type skull conformation) in domestic dogs. For this purpose, we coded closure of 18 sutures and synchondroses in 26 wolves, that is, the wild ancestor of all domestic dogs, and 134 domestic dogs comprising 11 breeds. Comparisons of the relative amount of closing and closed sutures and synchondroses (closure scores) in adult individuals showed that bulldog‐type breeds have significantly higher closure scores than non‐bulldog‐type breeds and that domestic dogs have significantly higher closure scores than the wolf. We further found that the prebasial angle is significantly positively correlated with the amount of closure of the basispheno‐presphenoid synchondrosis and sutures of the nose (premaxillo‐nasal and maxillo‐nasal) and the palate (premaxillo‐maxillary and interpalatine). Our results show that there is a correlation between patterns of suture and synchondrosis closure and skull shape in domestic dogs, although the causal relationships remain elusive. Anat Rec, 299:412–420, 2016. © 2016 Wiley Periodicals, Inc.     

人类颅顶骨缝的测量观察

本文采用一种新的颅骨骨缝鉴定方法,即以骨缝大小和形态相结合的评价方法对109例成人颅骨的冠状缝、矢状缝和人字缝进行了测量观察.三个缝之间及各缝不同部位缝的形态各异,呈现不均一性.冠状缝和人字缝左右侧的对应节段具有明显的对称性.男、女性颅顶骨缝的大小和形态无明显性别差异.     

Congenital muscle dystrophy and diet consistency affect mouse skull shape differently

The bones of the mammalian skull respond plastically to changes in masticatory function. However, the extent to which muscle function affects the growth and development of the skull, whose regions have different maturity patterns, remains unclear. Using muscle dissection and 3D landmark‐based geometric morphometrics we investigated the effect of changes in muscle function established either before or after weaning, on skull shape and muscle mass in adult mice. We compared temporalis and masseter mass and skull shape in mice with a congenital muscle dystrophy (mdx) and wild type (wt) mice fed on either a hard or a soft diet. We found that dystrophy and diet have distinct effects on the morphology of the skull and the masticatory muscles. Mdx mice show a flattened neurocranium with a more dorsally displaced foramen magnum and an anteriorly placed mandibular condyle compared with wt mice. Compared with hard diet mice, soft diet mice had lower masseter mass and a face with more gracile features as well as labially inclined incisors, suggesting reduced bite strength. Thus, while the early‐maturing neurocranium and the posterior portion of the mandible are affected by the congenital dystrophy, the late‐maturing face including the anterior part of the mandible responds to dietary differences irrespective of the mdx mutation. Our study confirms a hierarchical, tripartite organisation of the skull (comprising neurocranium, face and mandible) with a modular division based on development and function. Moreover, we provide further experimental evidence that masticatory loading is one of the main environmental stimuli that generate craniofacial variation.     

Craniofacial Shape Variation in Twist1+/− Mutant Mice

Craniosynostosis (CS) is a relatively common birth defect resulting from the premature fusion of one or more cranial sutures. Human genetic studies have identified several genes in association with CS. One such gene that has been implicated in both syndromic (Saethre–Chotzen syndrome) and nonsyndromic forms of CS in humans is TWIST1. In this study, a heterozygous Twist1 knock out (Twist1^+/?) mouse model was used to study the craniofacial shape changes associated with the partial loss of function. A geometric morphometric approach was used to analyze landmark data derived from microcomputed tomography scans to compare craniofacial shape between 17 Twist1^+/? mice and 26 of their Twist1^+/+ (wild type) littermate controls at 15 days of age. The results show that despite the purported wide variation in synostotic severity, Twist1^+/? mice have a consistent pattern of craniofacial dysmorphology affecting all major regions of the skull. Similar to Saethre–Chotzen, the calvarium is acrocephalic and wide with an overall brachycephalic shape. Mutant mice also exhibited a shortened cranial base and a wider and shorted face, consistent with coronal CS associated phenotypes. The results suggest that these differences are at least partially the direct result of the Twist1 haploinsufficiency on the developing craniofacial skeleton. This study provides a quantitative phenotype complement to the developmental and molecular genetic research previously done on Twist1. These results can be used to generate further hypotheses about the effect of Twist1 and premature suture fusion on the entire craniofacial skeleton. Anat Rec, 297:826–833, 2014. © 2014 Wiley Periodicals, Inc.     

Suture formation,premature sutural fusion,and suture default zones in Apert syndrome

On the basis of our studies, we postulate that suture formation in Apert syndrome is related to the relative maturity of abutting calvarial bones. The fused coronal suture, a consistent manifestation at birth, develops first because the ossification centers of the frontal and parietal bones are in intimate contact early during intrauterine life. Calvarial immaturity and the megalencephalic brain characteristic of the Apert syndrome appear to work in concert to produce a widely patent midline calvarial defect extending from the glabella to the posterior fontanelle. Because sagittal growth in the coronal sutures cannot take place, the megalencephalic brain grows upward and laterally, and bulges forward through the midline defect. The defect fills in by coalescence of bony islands without proper suture formation because the gap to be bridged is so great that the time window for developing sutural interdigitations may have closed. Other sutures, such as the lambdoid, squamosal, and sphenotemporal, develop with normal interdigitations because abutting bone margins are in close enough proximity to permit suture formation. © 1996 Wiley-Liss, Inc.     

Breaking Symmetry: A Quantitative Analysis of Facial Skeleton Disharmony in Children Born with Bilateral Cleft Lip and Palate

Bilateral cleft lip and palate (BCLP) occurs when craniofacial precursors fail to form or fuse properly during development. The aim of this retrospective, cross-sectional investigation was to quantify directional asymmetry (DA) of the facial skeleton of children born with Veau Class IV nonsyndromic BCLP. To accomplish this goal, coordinate values of anatomical landmarks were acquired from three-dimensional cone beam computed tomographic images of the craniofacial skeleton of middle- to late-aged children born with BCLP and age- and sex-matched controls and used to compare patterns of asymmetry variation. Multivariate analyses revealed different patterns of DA variation across samples and identified approximately 30% of DA measures as significantly different. Magnitudes of statistically significant linear distances differ in the craniofacial region, with most smaller DA differences located near the orbits and frontal bone, while larger differences were localized mostly to the midface, alveolar ridge, and nasal borders. Generally, areas of the craniofacial skeleton derived from the maxillary and nasal prominences demonstrated the highest magnitudes of DA. The methods and results presented will be useful to biomedical researchers when identifying the extent to which patients with BCLP diverge from typical developmental expectations. Quantifying DA and assessing local differences across the craniofacial complex can aid medical practitioners when developing treatments to improve BCLP surgical algorithms and outcomes. Anat Rec, 302:1726–1732, 2019. © 2019 American Association for Anatomy     

Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross

Using eight inbred founder strains of the mouse Collaborative Cross (CC) project and their reciprocal F1 hybrids, we quantified variation in craniofacial morphology across mouse strains, explored genetic contributions to craniofacial variation that distinguish the founder strains, and tested whether specific or summary measures of craniofacial shape display stronger additive genetic contributions. This study thus provides critical information about phenotypic diversity among CC founder strains and about the genetic contributions to this phenotypic diversity, which is relevant to understanding the basis of variation in standard laboratory strains and natural populations. Craniofacial shape was quantified as a series of size‐adjusted linear dimensions (RDs) and by principal components (PC) analysis of morphological landmarks captured from computed tomography images from 62 of the 64 reciprocal crosses of the CC founder strains. We first identified aspects of skull morphology that vary between these phenotypically ‘normal’ founder strains and that are defining characteristics of these strains. We estimated the contributions of additive and various non‐additive genetic factors to phenotypic variation using diallel analyses of a subset of these strongly differing RDs and the first eight PCs of skull shape variation. We find little difference in the genetic contributions to RD measures and PC scores, suggesting fundamental similarities in the magnitude of genetic contributions to both specific and summary measures of craniofacial phenotypes. Our results indicate that there are stronger additive genetic effects associated with defining phenotypic characteristics of specific founder strains, suggesting these distinguishing measures are good candidates for use in genotype–phenotype association studies of CC mice. Our results add significantly to understanding of genotype–phenotype associations in the skull, which serve as a foundation for modeling the origins of medically and evolutionarily relevant variation.     

Cranial growth in isolated sagittal craniosynostosis compared with normal growth in the first 6 months of age

Sagittal craniosynostosis (SCS), the most common type of premature perinatal cranial suture fusion, results in abnormal head shape that requires extensive surgery to correct. It is important to find objective and repeatable measures of severity and surgical outcome to examine the effect of timing and technique on different SCS surgeries. The purpose of this study was to develop statistical models of infant (0–6 months old) skull growth in both normative and SCS subjects (prior to surgery). Our goal was to apply these models to the assessment of differences between these two groups in overall post-natal growth patterns and sutural growth rates as a first step to develop methods for predictive models of surgical outcome. We identified 81 patients with isolated, non-syndromic SCS from Seattle Children's Craniofacial Center patient database who had a preoperative CT exam before the age of 6 months. As a control group, we identified 117 CT exams without any craniofacial abnormalities or bone fractures in the same age group. We first created population-level templates from the CT images of the SCS and normal groups. All CT images from both groups, as well as the canonical templates of both cohorts, were annotated with anatomical landmarks, which were used in a growth model that predicted the locations of these landmarks at a given age based on each population. Using the template images and the landmark positions predicted by the growth models, we created 3D meshes for each week of age up to 6 months for both populations. To analyze the growth patterns at the suture sites, we annotated both templates with additional semi-landmarks equally spaced along the metopic, coronal, sagittal and lambdoidal cranial sutures. By transferring these semi-landmarks to meshes produced from the growth model, we measured the displacement of the bone borders and suture closure rates. We found that the growth at the metopic and coronal sutures were more rapid in the SCS cohort than in the normal cohort. The antero-posterior displacement of the semi-landmarks also indicated a more rapid growth in the sagittal plane in the SCS model than in the normal model. Statistical templates and geometric morphometrics are promising tools for understanding the growth patterns in normal and synostotic populations and to produce objective and reproducible measurements of severity and outcome. Our study is the first of its kind to quantify the bone growth for the first 6 months of life in both normal and sagittal synostosis patients.     

Study of Metopic Suture in the Adult Human Skulls of North India

The Metopic or Frontal Suture is formed at the meeting of the two halves of Frontal bone, in the midline. Normally it starts to close in the second year of life and within a short duration, gets completely obliterated. At times there may be a partial or complete failure of this obliteration- so when a complete metopic suture is present from Nasion to Bregma, it is known as Metopism.The present study was undertaken to observe the incidence of Metopic suture and Metopism in the adult human skulls of North India. For this purpose, 1020 skulls were observed, belonging to the Anthropology Museum of Department of Anatomy, GSVM Medical College Kanpur. Metopic suture was found to be present in the midline, in altogether 184 skulls (18.04%); out of which complete persistent Metopic suture (or Metopism) was reported in 36 skulls (3.5%) and partially obliterated suture in 148 skulls (14.6%)- it was present in the lower part of Frontal bone in 142 skulls (14%), in the upper part in 4 skulls (0.38%) and in the middle part in 2 skulls (0.19%). The upper end of Metopic suture was observed to meet the median sagittal suture, end-to-end, at Bregma in 6 skulls (15%) while in the rest of 34 skulls (85%), the upper end of Metopic suture failed to meet the anterior end of median sagittal suture and the deflection ranged between 12 mm to 2 mm. Mean suture length was computed to be 128 mm.