Evolutionary history of Mammalia provides strong evidence that the morphology of skull and brain change jointly in evolution. Formation and development of brain and skull co-occur and are dependent upon a series of morphogenetic and patterning processes driven by genes and their regulatory programs. Our current concept of skull and brain as separate tissues results in distinct analyses of these tissues by most researchers. In this study, we use 3D computed tomography and magnetic resonance images of pediatric individuals diagnosed with premature closure of cranial sutures (craniosynostosis) to investigate phenotypic relationships between the brain and skull. It has been demonstrated previously that the skull and brain acquire characteristic dysmorphologies in isolated craniosynostosis, but relatively little is known of the developmental interactions that produce these anomalies. Our comparative analysis of phenotypic integration of brain and skull in premature closure of the sagittal and the right coronal sutures demonstrates that brain and skull are strongly integrated and that the significant differences in patterns of association do not occur local to the prematurely closed suture. We posit that the current focus on the suture as the basis for this condition may identify a proximate, but not the ultimate cause for these conditions. Given that premature suture closure reduces the number of cranial bones, and that a persistent loss of skull bones is demonstrated over the approximately 150 million years of synapsid evolution, craniosynostosis may serve as an informative model for evolution of the mammalian skull.

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Computed tomography (CT) has brought to the craniofacial surgeon a three-dimensional representation of internal structures. CT scans provide visualization of anatomy for preoperative planning and postoperative evaluation. Beyond visualization, however, a CT scan enables assessment of measurements useful to clinicians and basic scientists. All measurement systems used with CT require the ability to accurately locate regions of interest on the image (i.e., areas, volumes, outlines, curves, surfaces, points). This study evaluates the precision and repeatability of locating anatomic landmarks in three dimensions on CT slice images, and validates these locations using an established measurement system. The average error of landmark position is always less than 0.5 mm and for some landmarks error is negligible. Repeatability studies show that less than 2% of the total variance in our data is due to measurement inaccuracy. Although data collected from CT scans are internally consistent, validation results caution the use of CT data In combination with data collected using calipers or other direct means of measurement.

BackgroundDifferences in cranial morphology arise due to changes in fundamental cell processes like migration, proliferation, differentiation and cell death driven by genetic programs. Signaling between fibroblast growth factors (FGFs) and their receptors (FGFRs) affect these processes during head development and mutations in FGFRs result in congenital diseases including FGFR-related craniosynostosis syndromes. Current research in model organisms focuses primarily on how these mutations change cell function local to sutures under the hypothesis that prematurely closing cranial sutures contribute to skull dysmorphogenesis. Though these studies have provided fundamentally important information contributing to the understanding of craniosynostosis conditions, knowledge of changes in cell function local to the sutures leave change in overall three-dimensional cranial morphology largely unexplained. Here we investigate growth of the skull in two inbred mouse models each carrying one of two gain-of-function mutations in FGFR2 on neighboring amino acids (S252W and P253R) that in humans cause Apert syndrome, one of the most severe FGFR-related craniosynostosis syndromes. We examine late embryonic skull development and suture patency in Fgfr2 Apert syndrome mice between embryonic day 17.5 and birth and quantify the effects of these mutations on 3D skull morphology, suture patency and growth.ResultsWe show in mice what studies in humans can only infer: specific cranial growth deviations occur prenatally and worsen with time in organisms carrying these FGFR2 mutations. We demonstrate that: 1) distinct skull morphologies of each mutation group are established by E17.5; 2) cranial suture patency patterns differ between mice carrying these mutations and their unaffected littermates; 3) the prenatal skull grows differently in each mutation group; and 4) unique Fgfr2-related cranial morphologies are exacerbated by late embryonic growth patterns.ConclusionsOur analysis of mutation-driven changes in cranial growth provides a previously missing piece of knowledge necessary for explaining variation in emergent cranial morphologies and may ultimately be helpful in managing human cases carrying these same mutations. This information is critical to the understanding of craniofacial development, disease and evolution and may contribute to the evaluation of incipient therapeutic strategies.

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Computed tomography (CT) has brought to the craniofacial surgeon a three-dimensional representation of internal structures. CT scans provide visualization of anatomy for preoperative planning and postoperative evaluation. Beyond visualization, however, a CT scan enables assessment of measurements useful to clinicians and basic scientists. All measurement systems used with CT require the ability to accurately locate regions of interest on the image (i.e., areas, volumes, outlines, curves, surfaces, points). This study evaluates the precision and repeatability of locating anatomic landmarks in three dimensions on CT slice images, and validates these locations using an established measurement system. The average error of landmark position is always less than 0.5 mm and for some landmarks error is negligible. Repeatability studies show that less than 2% of the total variance in our data is due to measurement inaccuracy. Although data collected from CT scans are internally consistent, validation results caution the use of CT data in combination with data collected using calipers or other direct means of measurement.

Anatomical landmarks are defined as biologically meaningful loci that can be unambiguously defined and repeatedly located with a high degree of accuracy and precision. The neurocranial surface is characteristically void of such loci. We define a new class of landmarks, termed fuzzy landmarks, that will allow us to represent the form of the neurocranium. A fuzzy landmark represents the position of a biological structure that is precisely delineated, but occupies an area that is larger than a single point in the observer's reference system. In this study, we present a test case in which the cranial bosses are evaluated as fuzzy landmarks. Five fuzzy landmarks (the cranial bosses) and three traditional landmarks were placed repeatedly by a single observer on three-dimensional (3D) computed tomography (CT) surface reconstructions of pediatric dry skulls and skulls of pediatric patients, and directly on four of the same dry skulls using a 3Space digitizer. Thirty landmark digitizing trials from CT scans show an average error of 1.15 mm local to each fuzzy landmark, while the average error for the last ten trials was 0.75 mm, suggesting a learning curve. Data collected with the 3Space digitizer was comparable. Measurement error of fuzzy landmarks is larger than that of traditional landmarks, but is acceptable, especially since fuzzy landmarks allow inclusion of areas that would otherwise go unsampled. The information obtained is valuable in growth studies, clinical evaluation, and volume measurements. Our method of fuzzy landmarking is not limited to cranial bosses, and can be applied to any other anatomical features with fuzzy boundaries.