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As craniossinostoses são malformações craniofaciais caracterizadas pelo fechamento precoce de uma ou mais suturas cranianas. Elas são doenças congênitas e são causadas por mutações em diversos genes devido ao grande número de vias envolvidas na formação e manutenção das suturas cranianas. Embora mutações em 53 genes já tenham sido descritas o conhecimento da genética e da patofisiologia das craniossinostoses ainda é incompleto. Nesse trabalho tivemos como objetivo a identificação de novas mutações associadas às craniossinostoses bem como o aprofundamento do conhecimento sobre a atuação dessas mutações em células humanas por meio de estudos funcionais. Para identificarmos novas mutações utilizamos metodologias de sequenciamento em larga escala conhecidas como sequenciamento de noiva geração (NGS). Identificamos a mutação causal em uma paciente proveniente de um casamento consanguíneo portadora da síndrome de Raine (p.P496L em FAM20C). Também delimitamos a poucas mutações candidatas outros onze casos atípicos de craniossinostose. Por fim estudamos os efeitos de diferentes FGFs sobre o comportamento de células com a mutação mais comum causadora da S. de Apert, p.S252W em FGFR2. Descobrimos que os FGFs10 e 19 têm ações distintas sobre o perfil transcricional e sobre a taxa de proliferação de células mutantes. Também descobrimos que as células tronco mesenquimais e as células fibroblastóides têm comportamentos distintos ao serem tratadas com FGF19. Os resultados aqui apresentados serão de grande serventia para o melhor delineamento da biologia das suturas cranianas e da patofisiologia das craniossinostoses / Craniosynostosis are craniofacial malformations defined by early closure of the cranial sutures. They are congenital diseases caused by mutations in several genes due to the diversity of pathways involved in the development and maintenance of the cranial sutures. Even though 53 genes have already been linked to various forms of craniosynostosis, the knowledge about the genetics and pathophysiology is incomplete. In this work we aimed to identify new mutations associated with craniosynostosis as well as to further the knowledge of how those mutations act in human cells. To identify new variants associated with craniosynostosis we used large scale sequencing techniques known as next generation sequencing (NGS). We were able to identify the causal mutation in one patient from a consanguineous marriage with Raine syndrome (p.P496L in FAM20C). We also were able to elect candidate mutations in other eleven cases of atypical craniosynostosis. Lastly, we studied the effects of different FGFs over the behavior of human cells harboring the most common Apert syndrome mutation, p.S252W in FGFR2. We discovered that FGFs 10 and 19 have different effects over the transcriptional profile and proliferation rate of mutant cells. We also found that FGF19 have opposite effects in mesenchymal stem cells and fibroblastoid cells osteogenic differentiation. The results shown here will be of great service to better understand the biology of cranial suture and the pathophysiology of craniosynostosis

Sutures are the joints between the bones of skull, a tiny amount of movement is permitted at sutures, which contributes to the compliance of skull. Craniosynostosis is a disease in which some or all of the sutures in the skull of an infant close too early, causing problems with normal growth of brain and/or skull. Craniosynostosis can only be cured with operation, but someone has try to use helmet to adjust this condition. This study uses cranial from 2-month-old mice with shadow Moiré to measure its 3-D profile, and use this result to build ANSYS model, and to simulate the condition of Craniosynostosis with ANSYS. The results are then compared with existed symptom of Craniosynostosis.

Craniosynostosis is a common developmental disorder characterised by premature, pathological fusion of one or more of the fibrous connections, or sutures, that normally separate the bony plates of the skull during early development. Premature sutural fusion, typically occurring in utero, results in anomalous skull growth, and may have consequences for the developing brain. Most cases of single-suture craniosynostosis (SSC) require surgery, preferentially performed within the first year of life, to release the fused suture and reshape the deformed skull and improve brain growth potential. The exact mechanisms by which brain development is disrupted in SSC are uncertain. Research suggests that children with all forms of SSC are at heightened risk for neuropsychological problems; however, the nature, extent and risk factors (e.g., genetic, environmental, severity of skull deformity) for these disturbances, are yet to be established. The aim of this study was to examine the impact that SSC may have on neurodevelopmental skills during infancy and to use a theory-driven approach to explore the possible contributory factors to developmental progression during infancy. / Participants included 30 infants with SSC (16 metopic, 14 sagittal). Participants were assessed on the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) during early infancy when they were between 5 and 15 months of age. Fifty-three percent (n=16) of these infants were also assessed in late infancy when they were between 17 and 33 months of age and at least six months post-surgical intervention. During both early and late infancy, children with craniosynostosis demonstrated significantly poorer gross motor skills compared to the normative sample, but other skills were in line with normal population expectations. Factors including subtype of craniosynostosis, severity of deformity, social risk and age at surgery, were not shown to be significantly associated with developmental level during early or late infancy. The impact of genetic variables on early development was unclear in the current sample. / This study has provided important insights into the functional significance of disruption to typical brain growth in infants with SSC. Findings indicate that SSC is a condition associated with developmental delay during early infancy prior to surgical intervention, with developmental concerns remaining evident post-surgically in late infancy. Findings support recommendations for the close monitoring of the development of these children during early life.

As craniossinostoses são malformações craniofaciais caracterizadas pelo fechamento precoce de uma ou mais suturas cranianas. Elas são doenças congênitas e são causadas por mutações em diversos genes devido ao grande número de vias envolvidas na formação e manutenção das suturas cranianas. Embora mutações em 53 genes já tenham sido descritas o conhecimento da genética e da patofisiologia das craniossinostoses ainda é incompleto. Nesse trabalho tivemos como objetivo a identificação de novas mutações associadas às craniossinostoses bem como o aprofundamento do conhecimento sobre a atuação dessas mutações em células humanas por meio de estudos funcionais. Para identificarmos novas mutações utilizamos metodologias de sequenciamento em larga escala conhecidas como sequenciamento de noiva geração (NGS). Identificamos a mutação causal em uma paciente proveniente de um casamento consanguíneo portadora da síndrome de Raine (p.P496L em FAM20C). Também delimitamos a poucas mutações candidatas outros onze casos atípicos de craniossinostose. Por fim estudamos os efeitos de diferentes FGFs sobre o comportamento de células com a mutação mais comum causadora da S. de Apert, p.S252W em FGFR2. Descobrimos que os FGFs10 e 19 têm ações distintas sobre o perfil transcricional e sobre a taxa de proliferação de células mutantes. Também descobrimos que as células tronco mesenquimais e as células fibroblastóides têm comportamentos distintos ao serem tratadas com FGF19. Os resultados aqui apresentados serão de grande serventia para o melhor delineamento da biologia das suturas cranianas e da patofisiologia das craniossinostoses / Craniosynostosis are craniofacial malformations defined by early closure of the cranial sutures. They are congenital diseases caused by mutations in several genes due to the diversity of pathways involved in the development and maintenance of the cranial sutures. Even though 53 genes have already been linked to various forms of craniosynostosis, the knowledge about the genetics and pathophysiology is incomplete. In this work we aimed to identify new mutations associated with craniosynostosis as well as to further the knowledge of how those mutations act in human cells. To identify new variants associated with craniosynostosis we used large scale sequencing techniques known as next generation sequencing (NGS). We were able to identify the causal mutation in one patient from a consanguineous marriage with Raine syndrome (p.P496L in FAM20C). We also were able to elect candidate mutations in other eleven cases of atypical craniosynostosis. Lastly, we studied the effects of different FGFs over the behavior of human cells harboring the most common Apert syndrome mutation, p.S252W in FGFR2. We discovered that FGFs 10 and 19 have different effects over the transcriptional profile and proliferation rate of mutant cells. We also found that FGF19 have opposite effects in mesenchymal stem cells and fibroblastoid cells osteogenic differentiation. The results shown here will be of great service to better understand the biology of cranial suture and the pathophysiology of craniosynostosis

Craniosynostosis is a disorder characterized by the premature fusion of one or more cranial sutures in the infant skull, resulting in an abnormal shape of the cranium. An effective surgical procedure for treatment of this disorder has been developed and is currently use called "Dynamic Spring Mediated Craniofacial Reshaping." This technique involves surgical removal of the fused suture and insertion of springs to expand the gap created by the suture removal in order to gradually reshape the skull to a more desirable shape. There were three primary objectives of this research: develop a device that could fabricate type 316 stainless steel wireform springs having consistent mechanical characteristics, evaluate the performance of the device, and develop a mathematical model to predict the mechanical characteristics of the fabricated springs. Use of the mathematical model facilitates further research to be performed that could determine the most effective use of the "Dynamic Spring Mediated Craniofacial Reshaping" surgical procedure. / Master of Science

Craniosynostosis is a disorder characterized by the premature fusing of cranial sutures in an infant. Premature closure of these sutures can lead to detrimental consequences on the development of a child. The two broad categories of craniosynostosis are classified as syndromic and nonsyndromic. Nonsyndromic craniosynostosis involves only the fusion of one or more sutures, whereas syndromic craniosynostosis involves other abnormalities throughout the body of the affected individual. Two of the families analyzed in this study were of the syndromic nature, and known FGFR mutations were discovered. However, phenotypical features documented in association with these mutations differed from our individuals. Two families affected with nonsyndromic sagittal synostosis were also analyzed. Within one of these families, three candidate mutations were identified as possible disease causing mutations. These mutations were found in the genes ITGAV, SLC30A9, and BAMBI. Here we analyze the function of these proteins and determine the significance of the role they may play in nonsyndromic craniosynostosis.

A Síndrome de Apert é caracterizada por craniossinosteses e sindactilia dos dedos das mãos e dos pés. Essas malformações causam diminuição do crescimento da base do crânio com hipoplasia da face associada a severa retrusão maxilar e podem impor um imenso sofrimento tanto à função quanto à estética da pessoa afetada. O tratamento inclui vários procedimentos cirúrgicos que são adaptados às necessidades do indivíduo afetado. O objetivo desse estudo foi avaliar a morfologia craniofacial e os arcos dentários de adolescentes e adultos jovens com Síndrome de Apert comparando-os com um grupo controle. Foram avaliados 22 indivíduos que foram submetidos ao exame de tomografia computadorizada de feixe cônico (TCFC) para avaliação e diagnóstico e também foram obtidos modelos digitalizados. A amostra foi composta por um grupo de estudo (G1) e um grupo controle (G2). No grupo G1 foram incluídos 11 indivíduos com síndrome de Apert com idade entre 11 e 22 anos. No grupo G2 foram incluídos indivíduos pareados por gênero e idade ao grupo G1 e com equilíbrio das relações faciais e oclusão classe I. Foram realizadas medidas cefalométricas e análise de modelos no software Dolphin 3D para análise descritiva da norma frontal e lateral, formato da base craniana, análise estrutural dos componentes verticais e horizontais, tegumentos e dentes. Foram calculadas as correlações intraclasses para avaliação de concordância e a comparação entre os grupos foi aplicado o teste t de student, teste Mann-Whitney e o nível de significância adotado foi de 5%. Na comparação entre os grupos ,foram observadas diferenças significativas (p <= 0,05) , sendo que o grupo do indivíduos com síndrome de Apert apresentaram aumento da altura facial inferior, rotação horária da mandíbula associada a maior inclinação do corpo e ramo da mandíbula, ângulo da base do crânio diminuído, alteração entre a porção posterior e média da face, porém não existem muitas compensações dentárias, mas a maxila apresentou-se com dimensões menores que os indivíduos não sindrômicos . / Apert syndrome is characterized by craniosynostosis and syndactyly of the fingers and toes. These malformations cause a decrease in the growth of the skull base with facial hypoplasia associated with severe maxillary retrusion and can impose immense suffering on both the function and the aesthetics of the affected person. The treatment includes several surgical procedures that are tailored to the needs of the affected individual. The aim of this study was to evaluate the craniofacial morphology and dental arches of adolescents and young adults with Apert\'s Syndrome comparing them with a control group. Twenty-two patients who underwent concomitant computed tomography (CBCT) examination and evaluation were evaluated. The sample consisted of one study group (G1) and one control group (G2). In the G1 group, 11 individuals with Apert syndrome were included between 11 and 22 years of age. In the G2 group, individuals were paired by gender and age to the G1 group and with balance of facial relations and class I occlusion. Cephalometric measurements and model analysis were performed in Dolphin 3D software for descriptive analysis of frontal and lateral norm, cranial base shape, structural analysis of vertical and horizontal components, integuments and teeth. Intraclass correlations were calculated for concordance evaluation and the comparison between the groups was applied the t student test, Mann-Whitney test and the level of significance was 5%. In the comparison between the groups, significant differences were observed (p <= 0.05), and the group of individuals with Apert syndrome presented lower facial height increase, hourly rotation of the mandible associated with greater inclination of the body and branch of the mandible, decreased cranial base angle, favoring a more vertical position, there was alteration between the posterior and middle portion of the face, however there are not many dental compensations, but the maxilla presented smaller dimensions than the non-syndromic individuals that can favor several alterations dental changes.