Assessing nasal airway resistance and symmetry: An approach to global perspective through computational fluid dynamics.

This study aimed to explore the variability in nasal airflow patterns among different sexes and populations using computational fluid dynamics (CFD). We focused on evaluating the universality and applicability of dimensionless parameters R (bilateral nasal resistance) and ϕ (nasal flow asymmetry), initially established in a Caucasian Spanish cohort, across a broader spectrum of human populations to assess normal breathing function in healthy airways. In this retrospective study, CT scans from Cambodia (20 males, 20 females), Russia (20 males, 18 females), and Spain (19 males, 19 females) were analyzed. A standardized CFD workflow was implemented to calculate R-ϕ parameters from these scans. Statistical analyses were conducted to assess and compare these parameters across different sexes and populations, emphasizing their distribution and variances. Our results indicated no significant sex-based differences in the R parameter across the populations. However, moderate sexual dimorphism in the ϕ parameter was observed in the Cambodian group. Notably, no geographical differences were found in either R or ϕ parameters, suggesting consistent nasal airflow characteristics across the diverse human groups studied. The study also emphasized the importance of using dimensionless variables to effectively analyze the relationships between form and function in nasal airflow. The observed consistency of R-ϕ parameters across various populations highlights their potential as reliable indicators in both medical practice and further CFD research, particularly in diverse human populations. Our findings suggest the potential applicability of dimensionless CFD parameters in analyzing nasal airflow, highlighting their utility across diverse demographic and geographic contexts. This research advances our understanding of nasal airflow dynamics and underscores the need for additional studies to validate these parameters in broader population cohorts. The approach of employing dimensionless parameters paves the way for future research that eliminates confounding size effects, enabling more accurate comparisons across different populations and sexes. The implications of this study are significant for the advancement of personalized medicine and the development of diagnostic tools that accommodate individual variations in nasal airflow.

A shared pattern of midfacial bone modelling in hominids suggests deep evolutionary roots for human facial morphogenesis.

Midfacial morphology varies between hominoids, in particular between great apes and humans for which the face is small and retracted. The underlying developmental processes for these morphological differences are still largely unknown. Here, we investigate the cellular mechanism of maxillary development (bone modelling, BM), and how potential changes in this process may have shaped facial evolution. We analysed cross-sectional developmental series of gibbons, orangutans, gorillas, chimpanzees and present-day humans (n = 183). Individuals were organized into five age groups according to their dental development. To visualize each species's BM pattern and corresponding morphology during ontogeny, maps based on microscopic data were mapped onto species-specific age group average shapes obtained using geometric morphometrics. The amount of bone resorption was quantified and compared between species. Great apes share a highly similar BM pattern, whereas gibbons have a distinctive resorption pattern. This suggests a change in cellular activity on the hominid branch. Humans possess most of the great ape pattern, but bone resorption is high in the canine area from birth on, suggesting a key role of canine reduction in facial evolution. We also observed that humans have high levels of bone resorption during childhood, a feature not shared with other apes.

Beyond skeletal studies: A computational analysis of nasal airway function in climate adaptation.

OBJECTIVES: Ecogeographic variation in human nasal anatomy has historically been analyzed on skeletal morphology and interpreted in the context of climatic adaptations to respiratory air-conditioning. Only a few studies have analyzed nasal soft tissue morphology, actively involved in air-conditioning physiology. MATERIALS AND METHODS: We used in vivo computer tomographic scans of (N = 146) adult individuals from Cambodia, Chile, Russia, and Spain. We conducted (N = 438) airflow simulations during inspiration using computational fluid dynamics to analyze the air-conditioning capacities of the nasal soft tissue in the inflow, functional, and outflow tract, under three different environmental conditions: cold-dry; hot-dry; and hot-humid. We performed statistical comparisons between populations and sexes. RESULTS: Subjects from hot-humid regions showed significantly lower air-conditioning capacities than subjects from colder regions in all the three conditions, specifically within the isthmus region in the inflow tract, and the anterior part of the internal functional tract. Posterior to the functional tract, no differences were detected. No differences between sexes were found in any of the tracts and under any of the conditions. DISCUSSION: Our statistical analyses support models of climatic adaptations of anterior nasal soft tissue morphology that fit with, and complement, previous research on dry skulls. However, our results challenge a morpho-functional model that attributes air-conditioning capacities exclusively to the functional tract located within the nasal cavity. Instead, our findings support studies that have suggested that both, the external nose and the intra-facial soft tissue airways contribute to efficiently warming and humidifying air during inspiration. This supports functional interpretations in modern midfacial variation and evolution.

Embryonic cranial cartilage defects in the Fgfr3Y367C /+ mouse model of achondroplasia.

Achondroplasia, the most common chondrodysplasia in humans, is caused by one of two gain of function mutations localized in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leading to constitutive activation of FGFR3 and subsequent growth plate cartilage and bone defects. Phenotypic features of achondroplasia include macrocephaly with frontal bossing, midface hypoplasia, disproportionate shortening of the extremities, brachydactyly with trident configuration of the hand, and bowed legs. The condition is defined primarily on postnatal effects on bone and cartilage, and embryonic development of tissues in affected individuals is not well studied. Using the Fgfr3Y367C/+ mouse model of achondroplasia, we investigated the developing chondrocranium and Meckel's cartilage (MC) at embryonic days (E)14.5 and E16.5. Sparse hand annotations of chondrocranial and MC cartilages visualized in phosphotungstic acid enhanced three-dimensional (3D) micro-computed tomography (microCT) images were used to train our automatic deep learning-based 3D segmentation model and produce 3D isosurfaces of the chondrocranium and MC. Using 3D coordinates of landmarks measured on the 3D isosurfaces, we quantified differences in the chondrocranium and MC of Fgfr3Y367C/+ mice relative to those of their unaffected littermates. Statistically significant differences in morphology and growth of the chondrocranium and MC were found, indicating direct effects of this Fgfr3 mutation on embryonic cranial and pharyngeal cartilages, which in turn can secondarily affect cranial dermal bone development. Our results support the suggestion that early therapeutic intervention during cartilage formation may lessen the effects of this condition.

Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.

Quantification of global orbital shape variation.

The complex anatomy of the orbit generates a complex orbital shape that can only be quantified approximatively by classic linear measurements such as maximum width and height. There is no global three-dimensional quantification of variations in orbital shape. The purpose of this study was to develop a method to quantify a global three-dimensional orbital shape variation in a healthy population and to test a series of explanatory factors. We investigated the hypotheses that orbital shape is related to gender(H1), orbital size(H2) and/or age(H3). Medical computed tomography(CT) images of 60 adult individuals were studied. The study sample consisted of 30 males and 30 females with a mean age of 25.1 years. Four anatomical landmarks and 140 semi-landmarks were measured on both positive and negative 3D reconstructed orbits and analyzed with geometric morphometrics. A principal component analysis(PCA) was computed to define a morphological space. Shape variation was visualized using vector distance maps and diagrams. The greatest variation was seen in the length of the superior orbital fissure. There was a gradient in terms of orbital shape ranging from short, wide orbits to tall, narrow orbits. The analysis did not highlight any significant age-, gender- or size-related impact in terms of orbital shape variation. Future avenues to explore include the study of other potential explanatory factors such as the different embryological origins of the orbital bones, the passage of vessels and nerves, and ethnic origins. This method can also be applied to the study of pathological orbits.

New insights into the variability of upper airway morphology in modern humans.

The biological adaptation of the human lineage to its environment is a recurring question in paleoanthropology. Particularly, how eco-geographic factors (e.g., environmental temperature and humidity) have shaped upper airway morphology in hominins have been subject to continuing debate. Nasal shape is the result of many intertwined factors that include, but are not limited to, genetic drift, sexual selection, or adaptation to climate. A quantification of nasal airway (NA) morphological variation in modern human populations is crucial to better understand these multiple factors. In the present research, we study 195 in vivo CT scans of adult individuals collected in five different geographic areas (Chile, France, Cambodia, Russia, and South Africa). After segmentation of the nasal airway, we reconstruct 3D meshes that are analyzed with a landmark-free geometric morphometrics method based on surface deformation. Our results highlight subtle but statistically significant morphological differences between our five samples. The two morphologically closest groups are France and Russia, whose NAs are longer and narrower, with an important protrusion of the supero-anterior part. The Cambodian sample is the most morphologically distinct and clustered sample, with a mean NA that is wider and shorter. On the contrary, the Chilean sample form the most scattered cluster with the greatest intra-population variation. The South African sample is morphologically close to the Cambodian sample, but also partially overlaps the French and Russian variation. Interestingly, we record no correlation between NA volume and geographic groups, which raises the question of climate-related metabolic demands for oxygen consumption. The other factors of variation (sex and age) have no influence on the NA shape in our samples. However, NA volume varies significantly according both to sex and age: it is higher in males than in females and tends to increase with age. In contrast, we observe no effect of temperature or humidity on NA volume. Finally, we highlight the important influence of asymmetries related to nasal septum deviations in NA shape variation.

Processes and patterns: Insights on cranial covariation from an Apert syndrome mouse model.

BACKGROUND: Major cell-to-cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms. FGF/FGFRs are necessary to produce several "vertebrate-specific" structures, including the vertebrate head. Here, we examine the effects of the FGFR2 S252W mutation associated with Apert syndrome on patterns of cranial integration. Our data comprise micro-computed tomography images of newborn mouse skulls, bred to express the Fgfr2 S252W mutation exclusively in either neural crest or mesoderm-derived tissues, and mice that express the Fgfr2 S252W mutation ubiquitously. RESULTS: Procrustes-based methods and partial least squares analysis were used to analyze craniofacial integration patterns. We found that deviations in the direction and degree of integrated shape change across the mouse models used in our study were potentially driven by the modular variation generated by differing expression of the Fgfr2 mutation in cranial tissues. CONCLUSIONS: Our overall results demonstrate that covariation patterns can be biased by the spatial distribution and magnitude of variation produced by underlying developmental-genetic mechanisms that often impact the phenotype in disproportionate ways.

FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model.

Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis.

Facial asymmetry tracks genetic diversity among Gorilla subspecies.

Mountain gorillas are particularly inbred compared to other gorillas and even the most inbred human populations. As mountain gorilla skeletal material accumulated during the 1970s, researchers noted their pronounced facial asymmetry and hypothesized that it reflects a population-wide chewing side preference. However, asymmetry has also been linked to environmental and genetic stress in experimental models. Here, we examine facial asymmetry in 114 crania from three Gorilla subspecies using 3D geometric morphometrics. We measure fluctuating asymmetry (FA), defined as random deviations from perfect symmetry, and population-specific patterns of directional asymmetry (DA). Mountain gorillas, with a current population size of about 1000 individuals, have the highest degree of facial FA (explaining 17% of total facial shape variation), followed by Grauer gorillas (9%) and western lowland gorillas (6%), despite the latter experiencing the greatest ecological and dietary variability. DA, while significant in all three taxa, explains relatively less shape variation than FA does. Facial asymmetry correlates neither with tooth wear asymmetry nor increases with age in a mountain gorilla subsample, undermining the hypothesis that facial asymmetry is driven by chewing side preference. An examination of temporal trends shows that stress-induced developmental instability has increased over the last 100 years in these endangered apes.

Gravettian cranial morphology and human group affinities during the European Upper Palaeolithic.

Archaeologically defined Upper Palaeolithic (UP, 45,000-10,000 years ago) "cultures" are often used as proxies to designate fossil populations. While recent genomic studies have partly clarified the complex relationship between European UP "cultures" and past population dynamics, they leave open numerous questions regarding the biological characterization of these human groups, especially regarding the Mid-UP period (MUP, 33,000-24,000 years ago), which encompasses a pan-European cultural mosaic (Gravettian) with several regional facies. Here, we analyse a large database of well-dated and well-preserved UP crania, including MUP specimens from South-West France (SWF) and Moravia, using 3D geometric morphometrics to test for human group affinities. Our results show that the Gravettian makers from these two regions form a remarkably phenetically homogeneous sample which is different from, and more homogeneous than, the Late UP sample. Those results are congruent with genomic studies indicating a genetic continuity within the Gravettian manufacturers and a discontinuity marked by the Last Glacial Maximum (LGM). Moreover, our study expands the geographical range of the MUP phenetic continuity to SWF, for which aDNA data are scarce, and clarifies the post-LGM European population structure in SWF, with a possible dual ancestry stemming from different LGM refugia.

Early development of the Neanderthal ribcage reveals a different body shape at birth compared to modern humans.

Ontogenetic studies provide clues for understanding important paleobiological aspects of extinct species. When compared to that of modern humans, the adult Neanderthal thorax was shorter, deeper, and wider. This is related to the wide Neanderthal body and is consistent with their hypothetical large requirements for energy and oxygen. Whether these differences were already established at birth or appeared later during development is unknown. To delve into this question, we use virtual reconstruction tools and geometric morphometrics to recover the 3D morphology of the ribcages of four Neanderthal individuals from birth to around 3 years old: Mezmaiskaya 1, Le Moustier 2, Dederiyeh 1, and Roc de Marsal. Our results indicate that the comparatively deep and short ribcage of the Neanderthals was already present at birth, as were other skeletal species-specific traits. This morphology possibly represents the plesiomorphic condition shared with Homo erectus, and it is likely linked to large energetic requirements.

Late subadult ontogeny and adult aging of the human thorax reveals divergent growth trajectories between sexes.

Sexual dimorphism is an important feature of adult thorax morphology, but when and how sex-related differences in the ribcage arise during ontogeny is poorly known. Previous research proposed that sex-related size differences in the nasal region arise during puberty. Therefore, we explore whether ribcage sexual dimorphism also arises at that time and whether this sexual dimorphism is maintained until old age. We measured 526 (semi)landmarks on 80 CT-based human ribcage reconstructions, on individuals ranging from 7 to 65 year-old. The 3D coordinates were submitted to the Procrustes superimposition and analyzed. Our results show that the trajectories of thorax size and shape between sexes diverge at around 12 years of age, and continue slightly diverging until old age. The differential ontogenetic trends cause adult male ribcages to become deeper, shorter, and wider than female. Our results are consistent with the evidence from the cranial respiratory system, with the development of sexual dimorphism probably related to changes in body composition during puberty combined with changes in the reproductive system.

Extraocular muscle positions in anterior plagiocephaly: V-pattern strabismus explained using geometric mophometrics.

INTRODUCTION: Ophthalmological involvement in anterior plagiocephaly (AP) due to unicoronal synostosis (UCS) raises management challenges. Two abnormalities of the extraocular muscles (EOM) are commonly reported in UCS without objective quantification: (1) excyclorotation of the eye and (2) malposition of the trochlea of the superior oblique muscle. Here we aimed to assess the positions of the EOM in AP, using geometric morphometrics based on MRI data. MATERIALS AND METHODS: Patient files were listed using Dr WareHouse, a dedicated big data search engine. We included all patients with AP managed between 2013 and 2018, with an available digital preoperative MRI. MRIs from age-matched controls without craniofacial conditions were also included. We defined 13 orbital and skull base landmarks in order to model the 3D position of the EOM. Cephalometric analyses and geometric morphometrics with Procrustes superimposition and principal component analysis were used with the aim of defining specific EOM anomalies in UCS. RESULTS: We included 15 preoperative and 7 postoperative MRIs from patients with UCS and 24 MRIs from age-matched controls. Cephalometric analyses, Procrustes superimposition and distance computations showed a significant shape difference for the position of the trochlea of the superior oblique muscle and an excyclorotation of the EOM. CONCLUSIONS: Our results confirm that UCS-associated anomalies of the superior oblique muscle function are associated with malposition of its trochlea in the roof of the orbit. This clinical anomaly supports the importance of MRI imaging in the surgical management of strabismus in patients with UCS.

Allometry and advancing age significantly structure craniofacial variation in adult female baboons.

Primate craniofacial growth is traditionally assumed to cease upon maturation or at least be negligible, whereas bony remodeling is typically associated with advanced adult age and, in particular, tooth loss. Therefore, size and shape of the craniofacial skeleton of young and middle-aged adults should be stable. However, research on both modern and historic human samples suggests that portions of the CFS exhibit age-related changes in mature individuals, both related to and independent of tooth loss. These results demonstrate that the age-category 'adult' is heterogeneous, containing individuals demonstrating post-maturational age-related variation, but the topic remains understudied outside of humans and in the cranial vault and base. Our research quantifies variation in a sample of captive adult female baboons (n = 97) in an effort to understand how advancing age alters the mature CFS. Craniometric landmarks and sliding semilandmarks were collected from computed tomography (CT) scans of adult baboons aged 7-32 years old. To determine whether craniofacial morphology is sensitive to aging mechanisms and whether any such effects are differentially distributed throughout the cranium, geometric morphometric techniques were employed to compare the shapes of various cranial regions among individuals of increasing age. Unexpectedly, the biggest form differences were observed between young and middle-aged adults, rather than between adults with full dentitions and those with some degree of tooth loss. Shape variation was greatest in masticatory and nuchal musculature attachment areas. Our results indicate that the craniofacial skeleton changes form during adulthood in baboons, raising interesting questions about the molecular and biological mechanisms governing these changes.

Three-dimensional analysis of sexual dimorphism in ribcage kinematics of modern humans.

OBJECTIVES: Sexual dimorphism is an important biological factor underlying morphological variation in the human skeleton. Previous research found sex-related differences in the static ribcage, with males having more horizontally oriented ribs and a wider lower ribcage than females. Furthermore, a recent study found sex-related differences in the kinematics of the human lungs, with cranio-caudal movements of the caudal part of the lungs accounting for most of the differences between sexes. However, these movements cannot be quantified in the skeletal ribcage, so we do not know if the differences observed in the lungs are also reflected in sex differences in the motion of the skeletal thorax. MATERIALS AND METHODS: To address this issue, we quantified the morphological variation of 42 contemporary human ribcages (sex-balanced) in both maximal inspiration and expiration using 526 landmarks and semilandmarks. Thoracic centroid size differences between sexes were assessed using a t test, and shape differences were assessed using Procrustes shape coordinates, through mean comparisons and dummy regressions of shape on kinematic status. A principal components analysis was used to explore the full range of morphological variation. RESULTS: Our results show significant size differences between males and females both in inspiration and expiration (p < .01) as well as significant shape differences, with males deforming more than females during inspiration, especially in the mediolateral dimension of the lower ribcage. Finally, dummy regressions of shape on kinematic status showed a small but statistically significant difference in vectors of breathing kinematics between males and females (14.78°; p < .01). DISCUSSION: We support that sex-related differences in skeletal ribcage kinematics are discernible, even when soft tissues are not analyzed. We hypothesize that this differential breathing pattern is primarily a result of more pronounced diaphragmatic breathing in males, which might relate to differences in body composition, metabolism, and ultimately greater oxygen demand in males compared to females. Future research should further explore the links between ribcage morphological variation and basal metabolic rate.

Nonsyndromic craniosynostosis: novel coding variants.

BACKGROUND: Craniosynostosis (CS), the premature fusion of one or more neurocranial sutures, is associated with approximately 200 syndromes; however, about 65-85% of patients present with no additional major birth defects. METHODS: We conducted targeted next-generation sequencing of 60 known syndromic and other candidate genes in patients with sagittal nonsyndromic CS (sNCS, n = 40) and coronal nonsyndromic CS (cNCS, n = 19). RESULTS: We identified 18 previously published and 5 novel pathogenic variants, including three de novo variants. Novel variants included a paternally inherited c.2209C>G:p.(Leu737Val) variant in BBS9 of a patient with cNCS. Common variants in BBS9, a gene required for ciliogenesis during cranial suture development, have been associated with sNCS risk in a previous genome-wide association study. We also identified c.313G>T:p.(Glu105*) variant in EFNB1 and c.435G>C:p.(Lys145Asn) variant in TWIST1, both in patients with cNCS. Mutations in EFNB1 and TWIST1 have been linked to craniofrontonasal and Saethre-Chotzen syndrome, respectively; both present with coronal CS. CONCLUSIONS: We provide additional evidence that variants in genes implicated in syndromic CS play a role in isolated CS, supporting their inclusion in genetic panels for screening patients with NCS. We also identified a novel BBS9 variant that further shows the potential involvement of BBS9 in the pathogenesis of CS.

Choanal Atresia and Craniosynostosis: Development and Disease.

A number of textbooks, review articles, and case reports highlight the potential comorbidity of choanal atresia in craniosynostosis patients. However, the lack of a precise definition of choanal atresia within the current craniosynostosis literature and widely varying methods of detection and diagnosis have produced uncertainty regarding the true coincidence of these conditions. The authors review the anatomy and embryologic basis of the human choanae, provide an overview of choanal atresia, and analyze the available literature that links choanal atresia and craniosynostosis. Review of over 50 case reports that describe patients diagnosed with both conditions reveals inconsistent descriptions of choanal atresia and limited use of definitive diagnostic methodologies. The authors further present preliminary analysis of three-dimensional medical head computed tomographic scans of children diagnosed with craniosynostosis syndromes (e.g., Apert, Pfeiffer, Muenke, and Crouzon) and typically developing children and, although finding no evidence of choanal atresia, report the potentially reduced nasal airway volumes in children diagnosed with Apert and Pfeiffer syndromes. A recent study of the Fgfr2c Crouzon/Pfeiffer syndrome mouse model similarly found a significant reduction in nasal airway volumes in littermates carrying this FGFR2 mutation relative to unaffected littermates, without detection of choanal atresia. The significant correlation between specific craniosynostosis syndromes and reduced nasal airway volume in mouse models for craniosynostosis and human pediatric patients indicates comorbidity of choanal and nasopharyngeal dysmorphologies and craniosynostosis conditions. Genetic, developmental, and epidemiologic sources of these interactions are areas particularly worthy of further research.

Developmental and Evolutionary Significance of the Zygomatic Bone.

The zygomatic bone is derived evolutionarily from the orbital series. In most modern mammals the zygomatic bone forms a large part of the face and usually serves as a bridge that connects the facial skeleton to the neurocranium. Our aim is to provide information on the contribution of the zygomatic bone to variation in midfacial protrusion using three samples; humans, domesticated dogs, and monkeys. In each case, variation in midface protrusion is a heritable trait produced by one of three classes of transmission: localized dysmorphology associated with single gene dysfunction, selective breeding, or long-term evolution from a common ancestor. We hypothesize that the shape of the zygomatic bone reflects its role in stabilizing the connection between facial skeleton and neurocranium and consequently, changes in facial protrusion are more strongly reflected by the maxilla and premaxilla. Our geometric morphometric analyses support our hypothesis suggesting that the shape of the zygomatic bone has less to do with facial protrusion. By morphometrically dissecting the zygomatic bone we have determined a degree of modularity among parts of the midfacial skeleton suggesting that these components have the ability to vary independently and thus can evolve differentially. From these purely morphometric data, we propose that the neural crest cells that are fated to contribute to the zygomatic bone experience developmental cues that distinguish them from the maxilla and premaxilla. The spatiotemporal and molecular identity of the cues that impart zygoma progenitors with their identity remains an open question that will require alternative data sets. Anat Rec, 299:1616-1630, 2016. © 2016 The Authors The Anatomical Record Published by Wiley Periodicals, Inc.