The "Down syndrome critical region" (DSCR) is a chromosome 21 segment purported to contain genes responsible for many features of Down syndrome (DS), including craniofacial dysmorphology. We used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the DSCR and assessed dysmorphologies of the craniofacial skeleton that show direct parallels with DS in mice with a larger segmental trisomy. The DSCR genes were not sufficient and were largely not necessary to produce the facial phenotype. These results refute specific predictions of the prevailing hypothesis of gene action in DS.

The genetic basis for complex phenotypes is currently of great interest for both clinical investigators and basic scientists. In order to acquire a thorough understanding of the translation from genotype to phenotype, highly precise measures of phenotypic variation are required. New technologies, such as 3D photogrammetry are being implemented in phenotypic studies due to their ability to collect data rapidly and non-invasively. Before these systems can be broadly implemented the error associated with data collected from images acquired using these technologies must be assessed. This study investigates the precision, error, and repeatability associated with anthropometric landmark coordinate data collected from 3D digital photogrammetric images acquired with the 3dMDface System. Precision, error due to the imaging system, error due to digitization of the images, and repeatability are assessed in a sample of children and adults (N=15). Results show that data collected from images with the 3dMDface System are highly repeatable and precise. The average error associated with the placement of landmarks is sub-millimeter; both the error due to digitization and to the imaging system are very low. The few measures showing a higher degree of error include those crossing the labial fissure, which are influenced by even subtle movement of the mandible. These results suggest that 3D anthropometric data collected using the 3dMDface System are highly reliable and therefore useful for evaluation of clinical dysmorphology and surgery, analyses of genotype-phenotype correlations, and inheritance of complex phenotypes.

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SummaryAbnormalities in cartilage and bone development in the Apert syndrome FGFR2 +/S252W

Down syndrome (DS) is the most common genetic cause of mental retardation and affects many aspects of brain development. DS individuals exhibit an overall reduction in brain size with a disproportionately greater reduction in cerebellar volume. The Ts65Dn mouse is segmentally trisomic for the distal 12-15 Mb of mouse chromosome 16, a region that shows perfect conserved linkage with human chromosome 21, and therefore provides a genetic model for DS. In this study, high resolution magnetic resonance imaging and histological analysis demonstrate precise neuro- anatomical parallels between the DS and the Ts65Dn cerebellum. Cerebellar volume is significantly reduced in Ts65Dn mice due to reduction of both the internal granule layer and the molecular layer of the cerebellum. Granule cell number is further reduced by a decrease in cell density in the internal granule layer. Despite these changes in Ts65Dn cerebellar structure, motor deficits have not been detected in several tests. Reduction in granule cell density in Ts65Dn mice correctly predicts an analogous pathology in humans; a significant reduction in granule cell density in the DS cerebellum is reported here for the first time. The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS. The application of this model for analysis of developmental perturbations is extended by the accurate prediction of DS cerebellar phenotypes.

Nontraditional or geometric morphometric methods have found wide application in the biological sciences, especially in anthropology, a field with a strong history of measurement of biological form. Controversy has arisen over which method is the "best" for quantifying the morphological difference between forms and for making proper statistical statements about the detected differences. This paper explains that many of these arguments are superfluous to the real issues that need to be understood by those wishing to apply morphometric methods to biological data. Validity, the ability of a method to find the correct answer, is rarely discussed and often ignored. We explain why demonstration of validity is a necessary step in the evaluation of methods used in morphometrics.Focusing specifically on landmark data, we discuss the concepts of size and shape, and reiterate that since no unique definition of size exists, shape can only be recognized with reference to a chosen surrogate for size. We explain why only a limited class of information related to the morphology of an object can be known when landmark data are used. This observation has genuine consequences, as certain morphometric methods are based on models that require specific assumptions, some of which exceed what can be known from landmark data. We show that orientation of an object with reference to other objects in a sample can never be known, because this information is not included in landmark data. Consequently, a descriptor of form difference that contains information on orientation is flawed because that information does not arise from evidence within the data, but instead is a product of a chosen orientation scheme.To illustrate these points, we apply superimposition, deformation, and linear distance-based morphometric methods to the analysis of a simulated data set for which the true differences are known. This analysis demonstrates the relative efficacy of various methods to reveal the true difference between forms. Our discussion is intended to be fair, but it will be obvious to the reader that we favor a particular approach. Our bias comes from the realization that morphometric methods should operate with a definition of form and form difference consistent with the limited class of information that can be known from landmark data. Answers based on information that can be known from the data are of more use to biological inquiry than those based on unjustifiable assumptions.

The brain originates relatively early in development from differentiated ectoderm that forms a hollow tube and takes on an exceedingly complex shape with development. The skull is made up of individual bony elements that form from neural crest- and mesoderm-derived mesenchyme that unite to provide support and protection for soft tissues and spaces of the head. The meninges provide a protective and permeable membrane between brain and skull. Across evolutionary and developmental time, dynamic changes in brain and skull shape track one another so that their integration is evidenced in two structures that fit soundly regardless of changes in biomechanical and physiologic functions. Evidence for this tight correspondence is also seen in diseases of the craniofacial complex that are often classified as diseases of the skull (e.g., craniosynostosis) or diseases of the brain (e.g., holoprosencephaly) even when both tissues are affected. Our review suggests a model that links brain and skull morphogenesis through coordinated integration of signaling pathways (e.g., FGF, TGFβ, Wnt) via processes that are not currently understood, perhaps involving the meninges. Differences in the earliest signaling of biological structure establish divergent designs that will be enhanced during morphogenesis. Signaling systems that pattern the developing brain are also active in patterning required for growth and assembly of the skull and some members of these signaling families have been indicated as causal for craniofacial diseases. Because cells of early brain and skull are sensitive to similar signaling families, variation in the strength or timing of signals or shifts in patterning boundaries that affect one system (neural or skull) could also affect the other system and appropriate co-adjustments in development would be made. Interactions of these signaling systems and of the tissues that they pattern are fundamental to the consistent but labile functional and structural association of brain and skull conserved over evolutionary time obvious in the study of development and disease.

Coronavirus disease 2019 (Covid‐19) created unparalleled challenges to anatomy education. Gross anatomy education has been particularly impacted given the traditional in‐person format of didactic instruction and/or laboratory component(s). To assess the changes in gross anatomy lecture and laboratory instruction, assessment, and teaching resources utilized as a result of Covid‐19, a survey was distributed to gross anatomy educators through professional associations and listservs. Of the 67 survey responses received for the May–August 2020 academic period, 84% were from United States (US) institutions, while 16% were internationally based. Respondents indicated that in‐person lecture decreased during Covid‐19 (before: 76%, during: 8%, P < 0.001) and use of cadaver materials declined (before: 76 ± 33%, during: 34 ± 43%, P < 0.001). The use of cadaver materials in laboratories decreased during Covid‐19 across academic programs, stand‐alone and integrated anatomy courses, and private and public institutions (P ≤ 0.004). Before Covid‐19, cadaveric materials used in laboratories were greater among professional health programs relative to medical and undergraduate programs (P ≤ 0.03) and among stand‐alone relative to integrated anatomy courses (P ≤ 0.03). Furthermore, computer‐based assessment increased (P < 0.001) and assessment materials changed from cadaveric material to images (P < 0.03) during Covid‐19, even though assessment structure was not different (P > 0.05). The use of digital teaching resources increased during Covid‐19 (P < 0.001), with reports of increased use of in‐house created content, BlueLink, and Complete Anatomy software (P < 0.05). While primarily representing US institutions, this study provided evidence of how anatomy educators adapted their courses, largely through virtual mediums, and modified laboratory protocols during the initial emergence of the Covid‐19 pandemic.