Cranial Growth Research Articles

Craniosynostosis Part I: Pathophysiology and Patient Evaluation

Craniosynostosis is the premature fusion and obliteration of one or more cranial sutures. As a result, cranial growth can only occur parallel to the involved suture(s) resulting in predictable head shape morphologies. More importantly, the restricted cranial growth can also have a deleterious effect on the growing brain with increased intracranial pressures leading to abnormal neurocognitive development, blindness, and death. Craniosynostosis can either be syndromic or non-syndromic; and therefore, patient evaluation should be performed in a multi-disciplinary team setting for comprehensive care. Physical exam focuses on head shape morphology, associated anomalies, and signs of intracranial pressure. Imaging with 3D CT is gold standard at confirming diagnosis and extent of suture involvement. Early diagnosis is key for planning optimal intervention. This review contains 14 figures, 4 tables and, 42 references. Keywords: craniosynostosis, virchow’s law, plagiocephaly, trigonocephaly, scaphocephaly, brachycephaly, Apert Syndrome, Crouzon Syndrome, Pfeiffer Syndrome, intracranial pressure

Comparative analysis of cranial vault remodeling versus endoscopic suturectomy in the treatment of unilateral lambdoid craniosynostosis.

Unilateral lambdoid synostosis is the premature fusion of a lambdoid suture or sutures and represents the least common form of craniosynostosis, occurring in 1 in 40,000 births. Cranial vault remodeling (CVR) and endoscopic suturectomy with helmet therapy (ES) are surgical approaches that are used to allow for normal brain growth and improved craniofacial symmetry. The authors conducted a comparative outcomes analysis of patients with lambdoid synostosis undergoing either CVR or ES. The authors conducted a retrospective consecutive cohort study of patients with nonsyndromic lambdoid synostosis who underwent surgical correction identified from a single-institution database of patients with craniosynostosis seen between 2000 and 2018. Cranial growth was measured in head circumference percentile and z score. Nineteen patients (8 female and 11 male) with isolated unilateral lambdoid synostosis were identified (8 right and 11 left). Six underwent CVR and 13 underwent ES. No statistically significant differences were noted between surgical groups with respect to suture laterality, the patient's sex, and length of follow-up. Patients treated with ES presented and underwent surgery at a younger age than those treated with CVR (p = 0.0002 and p = 0.0001, respectively). Operating and anesthesia time, estimated blood loss, and ICU and total hospital days were significantly lower in ES (all p < 0.05). No significant differences were observed in pre- and postoperative head circumference percentiles or z scores between groups up to 36 months postoperatively. No patients required reoperation as of last follow-up. Endoscopic management of lambdoid synostosis is safe, efficient, and efficacious in terms of intraoperative and long-term cranial growth outcomes when compared to CVR. The authors recommend this minimally invasive approach as an option for correction of lambdoid synostosis in patients presenting early in their course.

Significant Factors in Cranial Remolding Orthotic Treatment of Asymmetrical Brachycephaly.

This retrospective chart review focuses on determining the most effective time to begin cranial remolding orthosis (CRO) treatment for infants with asymmetrical brachycephaly. Subjects with asymmetrical brachycephaly started CRO treatment between 3 and 18 months of age. These infants had a cranial vault asymmetry index (CVAI) ≥ 3.5 and a cranial index (CI) ≥ 90. Subjects were excluded if they had any comorbidities affecting growth, dropped out of treatment, were lost to follow-up, or were noncompliant. Factors which were found to statistically influence treatment outcomes were subject initial age, initial CVAI, and initial CI. Overall, younger subjects were more likely to achieve a corrected head shape. The presence of prematurity or torticollis had statistically nonsignificant effects on the success of treatment. Initial CI was found to be a stronger predictor than initial CVAI as to which subjects achieved correction. The less severe the starting CI, the more likely the subject was to achieve full correction. The clinical understanding is that it requires more cranial growth to “round out” a full posterior skull flattening than an asymmetry. Based on the study results, infants with asymmetrical brachycephaly should be treated as early as possible to increase chances of achieving full correction of the deformity.

Craniofacial growth and development in a mouse model of Down syndrome

Down syndrome (DS) is a developmental disorder caused by trisomy of human chromosome 21. Ts65Dn, a widely used mouse model of DS, has facilitated the study of mechanisms underlying the genotypic and phenotypic anomalies associated with DS. Previous studies have shown the adult cranium and brain to be markedly smaller in size in Ts65Dn mice relative to their euploid littermates. To determine how postnatal developmental patterns contribute to cranial variation in trisomic mice, we quantitatively compared growth trajectories from birth (postnatal day 0, P0) to postnatal day 6 (P6) in Ts65Dn and euploid mice. We hypothesized that trisomy affects cranial growth rate in Ts65Dn mice, causing size and shape differences between Ts65Dn and euploid mice. Multivariate regression and principal components analyses of craniofacial shape and size show some subtle differences between the trisomic and euploid mice at P0, but by P6 the trisomic mice are considerably smaller than the euploids. Interestingly, Ts65Dn at P6 are closer in both size and shape to P0 euploid mice than to euploid mice at P6 or newborn Ts65Dn. This could occur through changes in growth rate of Ts65Dn mice, resulting in the trisomic P6 mice retaining features common to younger, typically developing mice. Further research focusing on prenatal ages will provide a better understanding of how differences in timing of developmental events, such as delays in migration and mitosis of cranial neural crest cells in mouse model of DS, contribute to trisomic craniofacial growth and development.Support or Funding InformationR01‐HD038384 (RHR)

CBCT assessment of posterior cranial base and surrounding structures in orthodontically treated adolescents

Understanding craniofacial growth and development is important for accurate diagnosis, treatment planning and post-treatment evaluation of orthodontic cases. Paramount to this is knowledge of the cranial base growth and development, since it is the foundation upon which the remaining facial structures develop. The purpose of this study was to analyse different anatomical structures in the posterior cranial base and determine its changes during the adolescent years (13-15 year of age) using CBCT. Sixty CBCT images of the adolescent population that received orthodontic treatment at two time-points (mean age T1: 13.1 years/T2: 14.6years) were used to assess growth related dimensional changes using 33 selected landmarks. Inter-rater, intra-rater and accuracy of 33 selected landmarks in the posterior cranial base and surrounding area were then evaluated via three-dimensional (3D) cone-beam computed tomography (CBCT). Linear differences were then calculated among the different landmarks to determine the changes present in the sample. The selected landmarks in the posterior cranial base and surrounding area were found to be reliably and accurately located in 3D. Over the growth period studied (17.5months), minor statistically significant changes occurred, but they were deemed clinically irrelevant. The studied landmarks in the posterior cranial base and surrounding area showed minor clinically insignificant changes over the study period. The observed changes could be attributed to measurement error. The posterior cranial base is deemed to be stable in all three dimensions of study during the adolescent growth period studied.

Evaluation of Cranial Base Morphology of Pakistani Population in Skeletal Class I, II and III Malocclusions

Introduction: Cranial Base integrate different patterns of growth in various regions of the skull such as the nasal cavity, the oral cavity, and the pharynx. Anteroposterior jaw position is thought to be affected by cranial base growth. Although scientific literature shows conflicting results regarding both positive and negative correlation between the cranial base and skeletal malocclusions.&#x0D; Materials &amp; Method: 138 patients selected according to the Inclusion criteria were divided into three major categories depending upon ANB angle. Class I, class II group and class III group. Pretreatment lateral cephalometric radiographs were taken. Linear and Angular measurements were measured. All the data was entered in SPSS version 25 and then analyzed by using descriptive statistics including mean, standard deviation and by using inferential statistics including Pearson correlation and ANOVA test.&#x0D; Result: No significant differences were recorded between cranial base deflection angles (N-S-Ar and N-S-Ba) and malocclusions groups while Anterior cranial base length S-N was found to be maximum in class III and posterior cranial base length S-Ba was greater in class I.&#x0D; Conclusion: Cranial base angles N-S-Ar and N-S-Ba did not demonstrate any statistically significant correlation with three malocclusion groups i.e. Class I, Class II and Class III and their correlation was negative.

BDNF and NGF signals originating from sensory ganglia promote cranial motor axon growth.

After exiting the hindbrain, branchial motor axons reach their targets in association with sensory ganglia. The trigeminal ganglion has been shown to promote motor axon growth from rhombomeres 2/3 and 4/5, but it is unknown whether this effect is ganglion specific and through which signals it is mediated. Here, we addressed these questions by co-cultures of ventral rhombomere 8 explants with cranial and spinal sensory ganglia in a collagen gel matrix. Our results show that all cranial sensory ganglia and even a trunk dorsal root ganglion can promote motor axon growth and that ganglia isolated from older embryos had a stronger effect on the axonal growth than younger ones. We found that brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are necessary and sufficient for this effect. Altogether, our results demonstrate that the promoting effect of sensory ganglia on cranial motor axon growth is stage dependent, but not ganglion specific and is mediated by BDNF and NGF signals.

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 (0-6months 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 6months. 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 6months 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 6months of life in both normal and sagittal synostosis patients.

A 3D Follow-Up Study of Cranial Asymmetry from Early Infancy to Toddler Age after Preterm versus Term Birth.

Preterm infants are at higher risk for both symmetrical and asymmetrical head molding. This study involved 3D stereophotogrammetry to assess the cranial growth, molding, and incidence of deformational plagiocephaly (DP) in preterm children compared to term born children. Thirty-four preterm infants and 34 term born controls were enrolled in this study from Oulu University Hospital, Finland. Three-dimensional head images were obtained at the age of 2–4 months (T1), 5–7 months (T2), 11–13 months (T3), and 2.5–3 years (T4) from the term equivalent age (TEA). There was no statistically significant difference in oblique cranial length ratio (OCLR), cephalic index (CI), or weighted asymmetry score (wAS) between the two groups. Occipital flattening, defined by flatness score (FS) was statistically significantly greater in the preterm group than in the term group at T1–T4 (p < 0.05). In both groups, OCLR improved gradually over time. There were no instances, in either group, of severe DP and no moderate DP after T2. Results indicate that DP affects preterm and full-term children almost equally during the first three years of life, and cranial asymmetry resolves at a similar rate in both preterm and term groups after three months of corrected age. Preterm infants present with more occipital flattening than full-term children.

Development and Validation of Novel Three-Dimensional Craniofacial Landmarks on Cone-Beam Computed Tomography Scans.

As cone-beam computed tomography (CBCT) scans become increasingly common, it is vital to have reliable 3-dimensional (3D) landmarks for quantitative analysis of craniofacial skeletal morphology. While some studies have developed and used 3D landmarks, these landmark sets are generally small and derived primarily from previous 2-dimensional (2D) cephalometric landmarks. These derived landmarks lack information in parts of the skull such as the cranial base, which is an important feature for cranial growth and development. The authors see a real need for development and validation of 3D landmarks, particularly bilateral landmarks, across the skull for improved cephalometric analysis. The primary objective of this study is to develop and validate a set of 61 3D anatomical landmarks on the face, cranial base, mandible, and teeth for use in clinical and research studies involving CBCT imaging. Each landmark was placed 3 times by 3 separate trained observers on a set of 10 anonymized CBCT patient scans. Intra-rater and inter-rater estimates of consistency and agreement were calculated using the intraclass correlation coefficient. Measurement error was calculated per landmark and per X, Y, and Z landmark coordinate. The authors had high ICC estimates within rates, indicating high consistency, and high ICC estimates among raters, indicate good agreement across raters. Overall measurement error for each landmark and each X, Y, and Z coordinate was low. Our results confirm the accuracy of novel 3D landmarks including several on the cranial base that will serve researchers and clinicians for use in future studies involving 3D CBCT imaging and craniofacial development.

Ethnic differences in craniofacial and upper spine morphology between European and Asian children with skeletal Class III malocclusion

The aims of this study were to analyze differences in craniofacial and upper cervical spine morphology, including posterior cranial fossa and growth prediction signs between European and Asian skeletal Class III children, and to analyze associations between morphologic deviations in the upper cervical spine and craniofacial characteristics. A total of 60 skeletal Class III children, 19 Danes and 41 Koreans, were included. Upper spine morphology, Atlas dimensions, and craniofacial morphology, including posterior cranial fossa and growth prediction signs, were assessed on lateral cephalograms. Differences and associations were analyzed by multiple linear and logistic regression analyses adjusted for age and gender. In the craniofacial morphology, the inclination of the maxilla (NSL/NL, P<0.05) and the shape of the posterior cranial fossa (s-d, d-p, p-iop; P<0.01 and P<0.0001, respectively) were significantly different between the 2 groups. There was no significant difference in upper cervical spine morphology and Atlas dimensions between the groups. Fusion was significantly associated with the sagittal jaw relationship (P<0.05), and the total upper spine deviations were significantly associated with some growth prediction signs (P<0.05, P<0.01). Atlas dimensions were significantly associated with the prognathia of the mandible (P<0.05), posterior cranial fossa (P<0.01, P<0.0001), and some growth prediction signs (P<0.05, P<0.01). Upper spine morphology and Atlas dimensions may provide valuable information for predicting jaw growth and craniofacial morphology in Class III malocclusion.

Anthropometry before Day 46 and Growth Velocity before 6 Months of Guatemalan Breastfed Infants Are Associated with Subclinical Mastitis and Milk Cytokines, Minerals, and Trace Elements

Subclinical mastitis (SCM) is an inflammatory condition of the mammary gland, but its association with human milk composition and infant growth is not well described. We investigated whether SCM, milk cytokines, and/or estimated intakes of milk minerals and trace elements were associated with infant anthropometry or growth velocity before 6 mo. Breast milk was collected from Mam-Mayan mothers (n=114) at both early (2-46 d) and established (4-6 mo) lactation. Concentrations of 9 elements (sodium, potassium, calcium, magnesium, copper, iron, manganese, selenium, zinc) analyzed by inductively-coupled plasma mass spectrometry were used to estimate infants' daily intakes. Concentrations of 4 cytokines were measured. Milk concentrations and infants' estimated elemental intakes and anthropometric measurements during early and established lactation were compared by SCM status. Multiple regression was used to identify factors associated with infant growth attainment (<46 d) for infant weight- (WAZ), length- (LAZ), and head circumference-for-age (HCAZ) and weight-for-length (WLZ) z scores and with growth velocity (expressed as Δ/d) from early to established lactation. SCM prevalence was higher in early (30%) than established (10%) lactation. Breast milk of SCM mothers had higher cytokine concentrations and higher magnesium in early and higher selenium concentrations in both early and established lactation (Padj<0.0121). At day 46, regression models showed inverse associations of SCM with WLZ and IL-1β with LAZ (Padj<0.0150). In contrast, linear growth velocity was positively associated with IL-1β measured in early lactation (Padj<0.0124), whereas cranial growth velocity was positively associated with IL-8 measured during established lactation ( Padj<0.0124). Despite a high prevalence of inadequate intakes, only infants' intake of milk magnesium during early lactation was associated with linear growth velocity in breastfed infants <6 mo. Evidence shows that SCM, breast-milk cytokines, and infants' estimated intakes of select elements are independently associated with growth attainment and growth velocity during lactation.

Sensitivity and specificity of magnetic resonance imaging and computed tomography for the determination of the developmental state of cranial sutures and synchondroses in the dog

BackgroundDuring skull ontogenesis, growth centers in the skull base and calvarial bones allow gradual expansion of the cranial vault. Premature growth termination of cranial base synchondroses and/or calvarial sutures can result in devastating skull dysmorphologies. There is evidence to believe that a premature closure in one or more cranial growth centers contribute to the brachycephalic skull morphology in dogs. To provide a proof of concept for the non-invasive investigation of ontogenetic changes in cranial sutures and synchondroses in living dogs, we compared magnet resonance imaging (MRI) and computed tomography (CT) with histologic findings. Our aim was to determine the in vitro sensitivity and specificity for conventional clinical imaging methods in the assessment of cranial suture closure and synchondroses ossification in dogs.ResultsThe evaluation of cranial base synchondroses in MRI had a sensitivity of up to 93.1% and a specificity of 72.7% dependent on the observer. The evaluation of cranial base synchondroses in CT had a sensitivity of 92.2% and a specificity of 86.4%. Suture assessment on MRI suture assessment had a sensitivity of 82.1% dependent on the observer and a specificity of 19.3%. CT suture assessment had a sensitivity of 85.1% and a specificity of 40.4% in dependence of the observer.ConclusionConventional cross-sectional imaging techniques (MRI and CT) allow reliable assessment of the open or closed state of synchondroses within the cranial base. In contrast CT and MRI are not suitable for a reliable assessment of the cranial sutures in dogs.

Telescoping With Multiple Revolution Cranial Osteotomies in Patients With Simple Craniosynostosis.

Simple craniosynostosis is a cranial disease characterized by the premature closure of the cranial sutures, it develops during the first years of life and affects 1 in every 2000 to 2500 births worldwide (1). The cranial growth alteration occurs as parallel flattening to the compromised sutured with compensatory bulging in a perpendicular vector. Currently, The Suturectomy is the gold validated surgical treatment, that besides the dynamic Cranioplasties of multiples revolutions allows the design of bone flaps and therefore the correction of the secondary deformities caused by the synostosis. This multicenter descriptive study assessed a 20 series of cases (6 Plagiocephaly, 13 Scaphocephaly, 1 Brachycephaly) obtained in Cali, Colombia, that underwent surgery between January of 2014 and December of 2017, applying a Suturectomy surgery with additional telescoping of multiple revolution cranial osteotomies. The authors observe no clinical complications in the recruited patients regarding postoperative period of the described surgical technique (1, 90, and 180 days), thereby obtaining excellent outcomes on the maintained suture distraction focused on the assessment of the 3D reconstruction computed tomography scans.

Predictive model of cranial growth in infants with cranial deformation

Differences in cranial growth trajectories define morphological variation in both normal and pathological conditions. Predicting divergent trajectories is key to understanding how and when morphological variation is produced. The incidence of cranial deformation in human infants, specifically deformational plagiocephaly and brachycephaly, has increased dramatically with the initiation of the Back to Sleep campaign in the 1990s. Treatment often requires several months of helmet therapy. However, practitioners have no objective means for reliably estimating the necessary duration of therapy. The goal of this study was to develop a model to provide individualized predictions of duration of helmet therapy using cranial growth trajectories.We obtained STARscanner® 3D laser scan images of 541 children seen in clinic for abnormal head shape at their first visit and again at completion of helmet therapy with IRB approval. Measurements obtained from images at both visits included head circumference, cephalic ratio, oblique diameter difference, cranial vault asymmetry index, sex, and age. A Multivariate Random Forest Model was used to fit the model with 200 trees and 441 patients in the training set. A five‐fold cross‐validation was performed to assess accuracy of the model's prediction of cranial measurements with respect to the duration of helmet therapy. Data from the remaining 100 patients were used to validate the resulting model.Our Multivariate Random Forest model predicts accurately cranial growth trajectories during helmet therapy in infants with cranial deformation. The five‐fold cross validation error of our model is more than 22% lower than standard linear models, with average mean squared error of 0.2568. These results demonstrate that necessary duration of helmet therapy can be accurately predicted using our smart machine learning method.Thousands of infants per year are treated for cranial deformation. Using machine learning, we have developed a model that predicts individualized, evidence‐based treatment strategies accurately. The model is incorporated into a web‐based interface that can be used by practitioners in real time. Used in combination with practitioners' expertise, families will be informed about the likely length of treatment and degree of improvement that may be expected for their individual child. Importantly, while the model developed here is specific to infant cranial deformation, the approach is easily translatable to other craniofacial anomalies, as well as to normal patterns of cranial growth.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Exploring Mechanisms of Cranial Vault Development using a Coupled Turing‐Biomechanical Model

Bones of the mouse cranial vault are formed by differentiation of mesenchymal cells into osteoblasts, a process called intramembranous ossification that is primarily thought to be controlled by a cascade of reactions between extracellular molecules and cells that may be significantly guided by mechanical forces. In this study, we use a computational approach and an extensive experimental database to elucidate the role of biomechanics in morphogenesis of the cranial vault. We assume that the biochemical process can be modeled using Turing's reaction-diffusion model, a mathematical model describing the pattern formation controlled by interacting molecules (activators and inhibitors). In addition, we hypothesize that mechanical stimuli of the cells due to growth of the underlying brain contributes significantly to the process of cell differentiation. We have developed a coupled framework that incorporates these modeling constructs. The mathematical formulation was solved using the finite volume method. The computational domain and model parameters are determined using a large collection of experimental data that provides precise three-dimensional measures of mouse cranial geometry and cranial vault bone formation for specific embryonic time points. The results of this study suggest that mechanical strain contributes information to specific aspects of bone formation. Our mechanobiological model predicts some key features of cranial vault bone formation that were verified by experimental observations in normal case, including the relative location of ossification centers of the individual vault bones, the pattern of cranial vault bone growth over time, and the position of cranial vault sutures. Support or Funding Information Computations for this research were performed on the Pennsylvania State University's Institute for Cyber Science Advanced Cyber Infrastructure (ICS-ACI). This work was supported in part through instrumentation funded by a National Science Foundation grant OCI0821527, a Burroughs-Wellcome Fund 2013 Collaborative Research Travel Grant, Pennsylvania Department of Health using Tobacco Cure Funds, and by the National Institutes of Health grants R01DE022988 and P01HD078233. The model predicts the pattern of cranial vault bone growth. a) Computational prediction of the distribution of differentiating osteoblasts and cranial vault bone formation by embryonic day. b) Observed cranial vault bone formation and growth in embryonic mice. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reduced body size of insular black-tailed deer is caused by slowed development.

Adult body size correlates strongly with fitness, but mean body sizes frequently differ among conspecific populations. Ultimate, fitness-based explanations for these deviations in animals typically focus on community-level or physiological processes (e.g., competition, thermoregulation). However, proximate mechanisms underlying adaptive body size adjustments remain poorly understood. Adjustments in adult body size may result from shifts in growth-related life-history traits, such as the length of time to achieve adult body size (i.e., growth period) and how quickly the body increases in size (i.e., growth rate). Since insular populations often demonstrate dramatic shifts in adult body size, island populations represent a natural experiment by which to test the proximate mechanisms of size change. Here, using dental eruption patterns, we show that a dwarfed population of black-tailed deer (Odocoileus hemionus columbianus) experiences significant heterochronic shifts relative to mainland conspecifics. Namely, juvenile development slowed, such that teeth erupted ≥ 1year later, but cranial growth suggested no concurrent adjustments in skeletal growth period. Thus, slowed growth rate, shown here with teeth, combined with unchanged growth period resulted in dwarfism, consistent with ultimate predictions for insular, resource-limited populations. Therefore, selection on body size may act on life-history traits that influence body size, rather than acting on body size directly.

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Jurassic stem-mammal perinates and theorigin of mammalian reproduction and growth.

Transformations in morphology, physiology and behaviour along the mammalian stem lineage were accompanied by profound modifications to reproduction and growth, including the emergence of a reproductive strategy characterized by high maternal investment in a small number of offspring1,2 and heterochronic changes in early cranial development associated with the enlargement of the brain3. Because direct fossil evidence of these transitions is lacking, the timing and sequence of these modifications are unknown. Here we present what is, to our knowledge, the first fossil record of pre- or near-hatching young of any non-mammalian synapsid. A large clutch of well-preserved perinates of the tritylodontid Kayentatherium wellesi (Cynodontia, Mammaliamorpha) was found with a presumed maternal skeleton in Early Jurassic sediments of the Kayenta Formation. The single clutch comprises at least 38 individuals, well outside the range of litter sizes documented in extant mammals. This discovery confirms that production of high numbers of offspring represents the ancestral condition for amniotes, and also constrains the timing of a reduction in clutch size along the mammalian stem. Although tiny, the perinates have an overall skull shape that is similar to that of adults, with no allometric lengthening of the face during ontogeny. The only positive allometries are associated with the bones that support the masticatory musculature. Kayentatherium diverged just before a hypothesized pulse of brain expansion that reorganized cranial architecture at the base of Mammaliaformes4-6. The association of a high number of offspring and largely isometric cranial growth in Kayentatherium is consistent with a scenario in which encephalization-and attendant shifts in metabolism and development7,8-drove later changes to mammalian reproduction.

Effects of the highly COX-2-selective analgesic NSAID etoricoxib on the rate of orthodontic tooth movement and cranial growth

BackgroundNSAID analgesics have found widespread use in the treatment of pain, inflammation and fever. The highly COX-2-selective NSAID etoricoxib has shown a favorable side effect profile and excellent analgesic efficacy, particularly for dental and orthodontic pain, surpassing the current standard analgesic in orthodontics, acetaminophen. However, potential side effects on the rate of orthodontic tooth movement (OTM) and cranial growth, relevant for clinical usability during orthodontic treatment, have not yet been investigated. Material and methods40 male Fischer344 rats were randomly assigned to 4 groups (n=10) — controls receiving only 1.5ml tap water per day by oral gavage for a total of 5 weeks (1) as well as rats receiving an additional daily normal etoricoxib dosage of 7.8mg/kg for 3d (2) and 7d/week (3) and a high dosage of 13.1mg/kg for 7d/week (4) with serum bioavailability assessed by liquid chromatography–mass spectrometry. After one week of premedication, the first upper left molars (M1) were moved orthodontically in anterior direction for 4 weeks using a closed NiTi coil spring (0.25N) and OTM as well as sagittal cranial growth were quantified cephalometrically by CBCT imaging at the start and end of OTM. ResultsOTM, quantified as anterior metric tipping of M1, was significantly inhibited by about 33% only in rats receiving high-dose etoricoxib 7d/week (p=0.046) with a respective, but insignificant tendency also detectable for the normal dosages, whereas sagittal cranial growth was by tendency slightly increased with rising etoricoxib dosages, reflected by corresponding steady-state serum concentrations, confirming etoricoxib bioavailability. ConclusionsAn etoricoxib-induced clinically relevant deceleration of OTM is not to be expected at dosage regimens used in clinical practice to treat dental or orthodontic pain in contrast to a continuously administered high dosage. Due to its favorable side effect profile and higher analgesic efficiency regarding dental and orthodontic pain, etoricoxib should be a clinically valid alternative to the current standard orthodontic analgesic acetaminophen with its associated higher risk profile.