Craniofacial growth and development

The dynamic development of orbital shape and volume during childhood creates several challenges for health professionals. There is a close relation with stomatognathic system formation. During prenatal development, the maxilla starts off as two centers of ossification: the premaxilla and the palatal process of the maxilla. They fuse at the premaxillary suture and superiorly up, around, the nasal cavity terminating on the frontal process, forming part of orbita floor. Beside bone relation that is also a strict connection between trigeminal and oculomotor systems. These interrelationship makes patients that present malocclusions more prone to specific ophthalmological problems. On this mini-review we intend to draw the attention of health professionals to the necessity of further investigations on the multidisciplinary approach when treating malocclusion and/or visual problems.

This project investigates different aspects of craniofacial phenotypes exhibited in individuals with Down syndrome (DS), siblings of individuals with DS, and typically developing sibling pairs. A human sample (4-12 yrs.) consisting of 3D facial surface images (n = 55 for four separate samples: i.e. n = 220 overall) was used to explore developmental instability of the face and patterns of facial covariation between individuals with DS, their siblings, and typically developing sibling pairs. Morphometric analyses were used to infer how gene-dosage imbalance, caused by trisomy 21, is affecting DS craniofacial development. Overall we found increased fluctuating asymmetry in the faces of individuals with DS, which provides evidence for the "amplified developmental instability" model put forth by Shapiro (1975, 1983). However, the patterns of differences that we found suggest specific disruptions to regions of the face during craniofacial development rather than the generalized disruptions described by Shapiro under the amplified developmental instability model. Additionally, the results of our investigation found that covariation of facial metrics is different in DS individuals and in DS siblings relative to typically developing siblings. Based on differences in the pattern and strength of integration within and between facial regions in the DS and DS sibling samples, we put forth an "aneuploid conception model" to explain why facial integration is lowest in DS siblings and strengthened in DS relative to DS siblings.

In addition to the human-based analyses, micro-computed tomography (µCT) scans and morphometric analysis were employed to evaluate a complete genetic mouse model for DS - the Ts1Yey mouse. Morphometric comparison of craniofacial measures for Ts1Yey mice and euploid littermates (n = 12 for each sample) was done to determine if this model exhibits craniofacial differences similar to differences seen in humans with DS and in previously established DS mouse models. Overall, our results validate this mouse model for use in craniofacial DS investigations.

Following the invention of the first computed tomography (CT) scanner in the early 1970s, many innovations in three-dimensional (3D) diagnostic imaging technology have occurred, leading to a wide range of applications in craniofacial clinical practice and research. Three-dimensional image analysis provides superior and more detailed information compared with conventional plain two-dimensional (2D) radiography, with the added benefit of 3D printing for preoperative treatment planning and regenerative therapy. Current state-of-the-art multidetector CT (MDCT), also known as medical CT, has an important role in the diagnosis and management of craniofacial injuries and pathology. Three-dimensional cone beam CT (CBCT), pioneered in the 1990s, is gaining increasing popularity in dental and craniofacial clinical practice because of its faster image acquisition at a lower radiation dose, but sound guidelines are needed to ensure its optimal clinical use. Recent innovations in micro-computed tomography (micro-CT) have revolutionized craniofacial biology research by enabling higher resolution scanning of teeth beyond the capabilities of MDCT and CBCT, presenting new prospects for translational clinical research. Even after four decades of refinement, CT technology continues to advance and broaden the horizons of craniofacial clinical practice and phenomics research.

Introduction: Solitary median maxillary central incisor (SMMCI) syndrome is a rare and complex disorder that occurs in 1:50,000 live births. The developmental defects are mainly located in the craniofacial midline, namely: the midline cleft lip palate or congenital nasal malformation. Some of the associated anomalies belong to the holoprosencephaly (failure of the prosencephalon to laterise) spectrum but associated anomalies outside the holoprosencephaly spectrum have also been described. In most severe phenotypes the survival rate is low. Genetic and environmental factors acting between the 35th and 38th day of pregnancy are associated with the anomaly. The relationship of SMMCI to genes implicated in the pathogenesis of holoprosencephaly is still discussed controversially. A SHH missense mutation identified 2001 by Nanni et al. may be associated with SMMCI. SMMCI is characterized by a mostly symmetric central incisor of normal size, located exactly in the midline of the maxilla.
Case report: A 9.5-year-old girl was presented at the Department of Orthodontics, Dentofacial Orthopedics and Pedodontics of Charité Berlin by her father, who was concerned about the single maxillary central incisor. The patient had a non-contributory history. A traumatic loss of one central incisor was ruled out, but a solitary median maxillary central incisor was present in the primary dentition, too. Clinical examination showed dolichofacial, symmetric face with mild hypotelorism, indistinct philtrum and hypoplastic nose. The most striking finding was the presence of a single central incisor that was located in the midline of the maxilla. Additional intraoral findings were the "V"-shaped high palate with an unusual prominent midpalatal ridge and the absence of labial frenulum and incisive papilla. The patient was also evaluated by a geneticist and no mutations of the SHH gene could be identified. According to the CBCT-findings, the midline maxillary suture was fused and therefore rapid maxillary expansion is not a treatment option for this patient. Extractions of the solitary median maxillary central incisor and of 2 mandibular incisors and subsequent orthodontic space closure was the orthodontic approach followed for this patient.
Conclusion: For the clinician, it is important to assure an early detection of SMMCI syndrome with consideration of the patient’s needs in term of dental and medical care. Moreover, a multidisciplinary pedodontic, orthodontic and prothodontic treatment plan is necessary to ensure a successful dental treatment. Patients’ and parents’ perception, treatment needs and concerns should be evaluated carefully. In addition, SMMCI is considered one of the microforms of the holoprosencephaly spectrum and it can be associated with more severe anomalies or with a more severe phenotype of holopros- encephaly in the next generation. Therefore, we would like to underline the fundamental role of the dentist in the early diagnosis by identifying and referring these patients to the clinical geneticist for further evaluation.

RESUMO Existem vários parâmetros que podem ser usados para avaliar o padrão de crescimento mandibular. O objetivo principal deste estudo é determinar se as diagonais: facial, do ramo e mandibular mudam significativamente, segundo a oclusopatia, mesio ou disto, para daí servir como método preditivo de terapêutica. Com os resultados desse estudo, pôde-se concluir que as diferenças das diagonais nos pacientes classe III não se mostram diferentes quando comparado com os de Classe II entre 6 e 10 anos. ABSTRACT There are many parameters that can be used to evaluate mandibular growth pattern. The main objective of this work is to determine if the the following diagonal: facial, ramus and mandibular, show signifcant changes according to the occlusopathy: mesio or distocclusion, and allow predictive evaluation for therapeutic method. The results showed that the diferences of the diagonal mesurements between classII and ClassIII patients were not significant when analyzed on children with age ranged from 6 to 10 years old.

During the development of the vertebrate feeding apparatus, a variety of complicated cellular and molecular processes participate in the formation and integration of individual skeletal elements. The molecular mechanisms regulating the formation of skeletal primordia and their development into specific morphological structures are tightly controlled by a set of interconnected signalling pathways. Some of these pathways, such as Bmp, Hedgehog, Notch and Wnt, are long known for their pivotal roles in craniofacial skeletogenesis. Studies addressing the functional details of their components and downstream targets, the mechanisms of their interactions with other signals as well as their potential roles in adaptive morphological divergence, are currently attracting considerable attention. An increasing number of signalling pathways that had previously been described in different biological contexts have been shown to be important in the regulation of jaw skeletal development and morphogenesis. In this review, I provide an overview of signalling pathways involved in trophic skeletogenesis emphasizing studies of the most species-rich group of vertebrates, the teleost fish, which through their evolutionary history have undergone repeated episodes of spectacular trophic diversification.

Background: The developmental basis of craniofacial morphology hinges on interactions of numerous signalling systems. Extensive craniofacial variation in the polymorphic Arctic charr, a member of the salmonid family, from Lake Thingvallavatn (Iceland), offers opportunities to find and study such signalling pathways and their key regulators, thereby shedding light on the developmental pathways, and the genetics of trophic divergence. Results: To identify genes involved in the craniofacial differences between benthic and limnetic Arctic charr, we used transcriptome data from different morphs, spanning early development, together with data on craniofacial expression patterns and skeletogenesis in model vertebrate species. Out of 20 genes identified, 7 showed lower gene expression in benthic than in limnetic charr morphs. We had previously identified a conserved gene network involved in extracel-lular matrix (ECM) organization and skeletogenesis, showing higher expression in developing craniofacial elements of benthic than in limnetic Arctic charr morphs. The present study adds a second set of genes constituting an expanded gene network with strong, benthic–limnetic differential expression. To identify putative upstream regulators, we performed knowledge-based motif enrichment analyses on the regulatory sequences of the identified genes which yielded potential binding sites for a set of known transcription factors (TFs). Of the 8 TFs that we examined using qPCR, two (Ahr2b and Ap2) were found to be differentially expressed between benthic and limnetic charr. Expression analysis of several known AhR targets indicated higher activity of the AhR pathway during craniofacial development in benthic charr morphotypes. Conclusion: These results suggest a key role of the aryl hydrocarbon receptor (AhR) pathway in the observed crani-ofacial differences between distinct charr morphotypes.

Objectives: Neandertals and humans are closely related but differ noticeably in adult morphology. Previous work has been equivocal as to the contribution of postnatal growth and development to these differences. Due to disparate preservation, most analyses focus on specific anatomies, reconstructed fossils, or limited sample sizes. The objective of this research is to highlight the importance of postnatal growth in expressing Neandertal-human distinctions in the craniofacial skeleton, using a large and unreconstructed Neandertal sample.
Materials/Methods: A resampling approach is utilized to compare relative size change in 20 craniofacial dimen-sions between Neandertals (n = 42) and humans (n = 262). The large number of immature Neandertal sampleswithin and between dental stages provides the necessary variation to test for growth differences. Nested resampling using human-human comparisons assesses the likelihood of observing human-Neandertal growth differences under the null hypothesis of similar ontogenetic variation.
Results: Humans and Neandertals undergo comparable levels of overall size change. However, we identify growth differences for a number of traits, helping explain some of the unique features of this fossil taxon. Nested resampling shows it is unlikely that a Neandertal-like maturation would be observed in a random ontogenetic sample of humans.
Discussion: Growth during adolescence appears to be fundamental in the expression of some Neandertal anatomies. Neandertal upper facial and nasal breadths appear to have expanded rapidly after puberty to account for differences between preadolescents and adults, and Neandertals and humans. Mandibular growth differences may relate to anterior tooth use to process foods and paramastication during Neandertal maturation.

Las órbitas de los primates Haplorrhini son particulares dentro de los mamíferos por estar completamente separadas de la fenestra temporal y rodeadas por hueso, ser convergentes, estar frontalizadas y proveer la base para el desarrollo de un notorio torus supraorbitario. Estas características han sido descriptas, algunas como adaptaciones al hábito de vida y otras como resultado de reacomodaciones estructurales de las matrices funcionales del cráneo. El objetivo de este trabajo es analizar los cambios morfológicos de las órbitas en una muestra ontogenética transversal de Pan troglodytes y su asociación con estructuras adyacentes a fin de discutir implicancias estructurales y funcionales. Se utilizaron 52 imágenes de tomografías computadas de cráneos de Pan troglodytes desde 8 meses de vida postnatal hasta adultos. Se registraron landmarks y se tomaron medidas volumétricas y lineales que permitieron extraer variables angulares y proporciones. Se realizó ANOVA, regresiones lineales y ...

In the head of an embryo, a layer of mesenchyme surrounds the brain underneath the surface ectoderm. This cranial mesenchyme gives rise to the meninges, the calvaria (top part of the skull), and the dermis of the scalp. Abnormal development of these structures, especially the meninges and the calvaria, is linked to significant congenital defects in humans. It has been known that different areas of the cranial mesenchyme have different fates. For example, the calvarial bone develops from the cranial mesenchyme on the baso-lateral side of the head just above the eye (supraorbital mesenchyme, SOM), but not from the mesenchyme apical to SOM (early migrating mesenchyme, EMM). However, the molecular basis of this difference is not fully understood. To answer this question, we compared the transcriptomes of EMM and SOM using high-throughput sequencing (RNA-seq). This experiment identified a large number of genes that were differentially expressed in EMM and SOM, and gene ontology analyses found very different terms enriched in each region. We verified the expression of about 40 genes in the head by RNA in situ hybridization, and the expression patterns were annotated to make a map of molecular markers for 6 subdivisions of the cranial mesenchyme. Our data also provided insights into potential novel regulators of cranial mesenchyme development, including several axon guidance pathways, lectin complement pathway, cyclic-adenosine monophosphate (cAMP) signaling pathway, and ZIC family transcription factors. Together, information in this paper will serve as a unique resource to guide future research on cranial mesenchyme development.

Secretory otitis media (SOM) is a disease of childhood, and this period is characterized by active growing of the craniofacial skeleton (CFS). In this study, we purposed to answer the question ‘how deviations in CFS play a role in ethiopathogenesis of SOM’? Therefore, we evaluated the ‘mastoid-middle ear-Eustachian tube (M-ME-ET) system’ in 30 SOM cases and 30 healthy children by using lateral cephalographies on which reference points and one line related to CFS and ‘M-ME-ET system’ were pointed. The results disclosed that the bony Eustachian tube, the vertical portion of the tensor veli palatini (TVP) muscle and the mastoid air cell system were smaller in SOM cases. In the view of the statements of Enlow (1990) on craniofacial growth, we suggest that the deviations in the growth process of the nasomaxillary complex lead to corresponding imbalances in the bony tube and vertical portion of the TVP. However, since regional imbalances often tend to compensate for one another to provide functional equilibrium (Enlow, 1990), improvement of the tubal function occurs with age.

Growth patterns of the human facial skeleton have been of great interest and importance for biological anthropologists, forensic scientists, craniofacial surgeons, and orthopedists. Nevertheless, growth trends of the facial skeleton in infancy and early childhood are still poorly known and clinical CT data have been insufficiently used for studying craniofacial ontogeny. The purpose of this study was to provide a comprehensive quantitative description of human midfacial ontogeny in infancy and early childhood, and to contribute to debates regarding the role of modularity vs. integration in shaping the human face.

La transformación morfológica extrínseca del neurocráneo se produce no por la retracción pasiva de los tejidos cefálicos sino por su expansión compensatoria. Durante este proceso, el cerebro y la bóveda craneal se expanden hacia las zonas no oprimidas. Este capítulo examinaalgunas nociones básicas de la expansión neuro- y craneológica humanadurante el crecimiento infantil natural. Igualmente recurrimos a la información anatómica y fisiopatológica para explicar luego las alteraciones operantes en la dinámica del creciemiento cefálico durante el proceso de compression externa. Especialmente la embriología craneana y lafisiología del desarrollo postnatal proporcionan valiosos puntos de partida para explorar y discutir las limitaciones naturales en los cambios inducidos ala forma de la bóveda craneal y sus efectos secundarios en la base y en la cara. Llegamos a confirmar que el modelado cefálico solo es posible durante los primeros años de vida y que los cambios en la formación del basi-y esplacnocráneovan en función del momento postnatal, del grado, la duración y de las técnicas del modelado. Su implementación cultural también puede tener implicaciones estéticas para el portador, como son la asimetríacefálicaconcomitante a la compression en cuna y una serie de riesgos para la saluden formade hemorragias, hipertensiónintracraneana, infecciones locales o la necrosis del tejido comprimido.

Mandible condyle remodeling is a great challenge on craniofacial growth studies. The great majority of the reports deals with growing period. However , there is a great necessity to clarify the importance of functional stimulation on adult mandible condyle remodeling. By using an adult mouse model, we investigated the influence of mandible forwarding on condyle remodeling and gene expression by bone forming cells. Tomographic and scintigraphic evaluations showed sagittal growth and cell activity enhancement. RT-PCR showed that Type I collagen, osteocalcin and osteonectin expression level can be altered. We showed that functional stimulation is necessary to maintain the regular gene expression by condyle bone forming cells in adult mice. It opens new frame for further investigations aiming new clinical approaches to temporomandibular joint problems treatment, as well as mandible retrusion treatment .

Objective: growth and development of the anatomic region where the Eustachian tube (ET) is located are associated with the parameters related to other parts of the craniofacial skeleton (CFS). It has been suggested that ET dysfunction is as an important factor in pathogenesis of otitis media in childhood which is associated with its postnatal growth and development process. The purpose of this study was to evaluate associations of length of the ET with various craniofacial parameters. Methods: on lateral cephalometric radiographs of 50 Japanese adult (25 male and 25 female), the dimension of the region where the ET is located (‘length of the ET’) and 22 (15 linear and seven angular) craniofacial parameters were measured by using a digitiser and computer. Correlation and regression analyses were performed between this dimension and other craniofacial parameters. Results: it was found that the dimension of the region in which the ET is located (‘length of the ET’) was associated with many craniofacial parameters belonging to different subunits of the CFS. However, the stepwise regression analysis showed that total cranial base length, posterior upper face height and maxillary depth had determinative effects on this dimension. Conclusion: development of the ET was associated with development of the cranial base and nasomaxillary complex. Therefore, it could be hypothesised that any cessation or aberration in these parts of the CFS cause corresponding imbalances in the ET, which may predispose to otitis media.

Organism size is controlled by interactions between genetic and environmental factors mediated by hormones with systemic and local effects. As changes in size are usually not isometric, a considerable diversity in shape can be generated through modifications in the patterns of ontogenetic allometry.  In this study we evaluated the role of timing and dose of growth hormone (GH) release on growth and correlated shape changes in craniofacial bones. Using a longitudinal study design, we analyzed GH deficient mice treated with GH supplementation commencing pre- and post-puberty. We obtained 3D in vivo micro-CT images of the skull between 21 and 60 days of age and used geometric morphometrics to analyze size and shape changes among control and GH deficient treated and non-treated mice. The variable levels of circulating GH altered the size and shape of the adult skull, and influenced the cranial base, vault, and face differently. While cranial base synchondroses and facial sutures were susceptible to either the direct or indirect effect of GH supplementation, its effect was negligible on the vault. Such different responses support the role of intrinsic growth trajectories of skeletal components in controlling the modifications induced by systemic factors. Contrary to the expected, the timing of GH treatment did not have an effect on catch-up growth. GH levels also altered the ontogenetic trajectories by inducing changes in their location and extension in the shape space,  indicating that differences arose before 21 days and were further accentuated by a truncation of the ontogenetic trajectories in  GHD groups.