Syndromic craniosynostosis is most commonly associated with mutations in Fibroblast Growth Factor Receptor genes (FGFR)-1, 2 and 3. Clinical and animal reports suggest a link between FGFR-associated craniosynostosis and defects in the gastrointestinal tract (GIT). Objective: to determine whether GIT malformations occur more frequently in the craniosynostosis population with a known FGFR mutation when compared to the general population. Methods: A retrospective chart review of patients diagnosed with Crouzon, Pfeiffer or Apert syndromes between 1990 and 2011 was performed at the Hospital for Sick Children in Toronto. Thirty-two charts meeting inclusion criteria were analyzed for any history of GIT abnormalities. Results: Three out of 32 patients had documented intestinal/bowel malrotations while 7 had gastroesophageal reflux disease. All patients had documented FGFR2 mutations, a finding in line with previous studies and published case reports. Conclusions: Results suggest an association between FGFR-associated craniosynostosis and GIT malformations.

Syndromic craniosynostosis is most commonly associated with mutations in Fibroblast Growth Factor Receptor genes (FGFR)-1, 2 and 3. Clinical and animal reports suggest a link between FGFR-associated craniosynostosis and defects in the gastrointestinal tract (GIT). Objective: to determine whether GIT malformations occur more frequently in the craniosynostosis population with a known FGFR mutation when compared to the general population. Methods: A retrospective chart review of patients diagnosed with Crouzon, Pfeiffer or Apert syndromes between 1990 and 2011 was performed at the Hospital for Sick Children in Toronto. Thirty-two charts meeting inclusion criteria were analyzed for any history of GIT abnormalities. Results: Three out of 32 patients had documented intestinal/bowel malrotations while 7 had gastroesophageal reflux disease. All patients had documented FGFR2 mutations, a finding in line with previous studies and published case reports. Conclusions: Results suggest an association between FGFR-associated craniosynostosis and GIT malformations.

In the BDAS project one of the goals is to create a new solution for monitoring bone healing to complement current techniques. Data have been collected in clinical trials from infants treated for Craniosynostosis by a craniotomic surgery. The data are collected with a biomedical sensor based in microwave technology. This sensor could be able to sense changes in the composition of the different tissues in the upper hemisphere of the head, by noticing a difference in the propagation of the microwaves, as the bone injury from the craniectomy heals over time. In this thesis I analyze the validity of a proposed analytical model for the biosensor and extend the clinical data analysis in BDAS project. The validity of the model is analyzed by comparing its outcomes to available measurements from phantoms mimicking living tissues and to numerical simulations. In the data analysis two hypotheses are formulated and tested regarding the location of the measurement points with respect to a positioning grid and the healing over time too. By deriving a set of parameters for each collected dataset in the clinical trials, a distinct pattern was found which shows visible changes over the course of the healing process with this technique.

A expansão craniana com o uso de molas tem demonstrado eficácia no tratamento das anormalidades craniofaciais, tais como as craniossinostoses. A ação expansora exercida pelas molas tem sido observada tanto quando colocadas entre as margens parietais dos ossos do crânio, como quando lateralmente à sutura sagital, principalmente nas escafocefalias. No presente estudo foi criado um modelo experimental com coelhos, e feita uma avaliação descritiva do comportamento da calota craniana e das suturas sob ação de molas. Foram utilizados 13 coelhos Nova Zelândia com quatro semanas de vida, divididos em quatro grupos: grupo I, foram implantados no crânio marcadores de amálgama para controle; no grupo II, marcadores de amálgama e osteotomia da sutura sagital; no grupo III, marcadores de amálgama, osteotomia da sutura sagital e colocação de uma mola expansora na região interparietal e, no grupo IV, marcadores de amálgama, craniotomia parassagital linear com colocação da mola. Os animais foram sacrificados com duas, quatro, oito e doze semanas. Foi realizado controle radiológico com avaliação do afastamento dos marcadores de amálgama, da variação dos ângulos cefalométricos e das medidas da base do crânio, bem como um estudo histopatológico da região de colocação das molas. Nos grupos com o uso de molas a separação dos bordos da craniotomia foi maior do que naqueles sem a utilização de mola. Houve ossificação em todos os grupos, com maior rapidez no grupo II. O crescimento ósseo deu-se a partir dos bordos e da profundidade. Não foram observadas diferenças significativas no padrão histopatológico da regeneração óssea entre os grupos com colocação de mola na região interparietal e parassagital. O modelo experimental com coelhos se mostrou adequado às análises propostas pelo estudo. Concluiu-se que houve osteogênese por distração nos grupos III e IV e que apresentaram uma expansão craniana semelhantes. / Spring-mediated skull expansion has proven to be effective in the treatment of craniofacial abnormalities, such as craniosynostosis. The use of springs in cranial expansion has been studied both in the sagittal and in parasagittal regions, especially in scaphocephaly. A rabbit model was used in the present study to analyze the effects of springs on the cranial vault and sutures. Thirteen 4-week-old New Zealand rabbits were used and divided into 4 groups: group I, amalgam markers were used as control; in group II, amalgam markers and osteotomy of the sagittal suture; in group III, amalgam markers and osteotomy of the sagittal suture with implant of an expansible spring in the interparietal region and in group IV, amalgam markers and linear parasagittal craniectomy with springs. Animals were sacrificed after 2, 4 and 12 weeks. Radiological control with assessment of the amalgam markers, variation of cephalometric angles and cranial base measurements, as well as the histopathological analysis of the spring implant area were carried out. In the groups using springs distraction of the craniectomy borders was greater than in those that did not use springs. Ossification was observed in all of the groups and was faster in group II. Bone growth started from the borders and depth. There were no significant differences in the histopathological pattern of bone regeneration between the groups with spring implant in the interparietal and parasagittal region. The rabbit model proved to be adequate for the analysis proposed by the study. It was concluded that there was osteogenesis caused by distraction in groups III and IV, with similar skull expansion rates.

A distração osteogênica tem sido extensamente empregada na correção da grave hipoplasia do terço médio da face de portadores de craniossinostose sindrômica. Contudo, poucos estudos têm apresentado os resultados da distração do terço médio da face através de avaliação cefalométrica. O objetivo do presente estudo foi o de avaliar os resultados obtidos com o avanço ósseo do terço médio da face após osteotomia tipo Le Fort III ou frontofacial em monobloco seguida da utilização de dispositivo rígido externo de distração (RED), em portadores de craniossinostose sindrômica, em termos de quantidade de alongamento ósseo, estabilidade esquelética e crescimento facial. Onze pacientes submetidos aos procedimentos de distração, de fevereiro de 2002 a janeiro de 2006, na unidade de cirurgia plástica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, foram avaliados retrospectivamente. Seis pacientes eram portadores da síndrome de Crouzon, quatro da síndrome de Apert, e um da síndrome de Saethre-Chotzen. Onze pacientes foram submetidos ao procedimento de alongamento ósseo do terço médio da face através do uso de dispositivo externo rígido (RED), após osteotomias tipo Le Fort III (N = 4) ou frontofacial monobloco (N = 7). Foram avaliadas retrospectivamente três telerradiografias de face em norma lateral de cada paciente (T1- préoperatório; T2 - pós-operatório recente, logo após a remoção do distrator; T3 - pós-operatório tardio, obtida com um intervalo mínimo de 12 meses após cirurgia). Três cefalogramas foram obtidos de cada paciente, através da direta sobreposição das três telerradiografias, tomado como referência reparos anatômicos do crânio e da porção anterior da fossa craniana. Desta forma, os três traçados cefalométricos foram obtidos no mesmo papel acetato, o qual foi digitalizado. Utilizando o programa de computação gráfica de domínio público Image J, várias mensurações foram realizadas com a intenção de determinar a extensão do avanço sofrido pelos segmentos ósseos na direção do vetor do movimento esquelético, assim como de seus componentes horizontal e vertical, tomando como referência pontos A e orbitário. Pacientes foram ainda divididos em dois grupos (G 1 - pacientes submetidos à osteotomia tipo Le Fort III; G 2 - pacientes submetidos à osteotomia frontofacial em monobloco), e os dados obtidos a partir mensurações de ambos os grupos foram comparados. Avanço significativo do terço médio da face foi obtido com os procedimentos. O componente horizontal do movimento esquelético predominou ao componente vertical. A taxa de reposicionamento posterior horizontal tardio (perda de resultado) foi mínima. Quando comparados os dois procedimentos, foi observada uma diferença significativa entre os grupos Le Fort III e monobloco. A quantidade de avanço obtido foi maior no grupo monobloco que no grupo Le Fort III. Em termos perda de resultado, o grupo Le Fort III foi mais estável que o grupo monobloco. Foi observada uma evidente alteração vertical no posicionamento dos pontos de referência no pós-operatório tardio, se comparado ao pós-operatório recente, evidenciando crescimento na vertical da face, ao contrário do que ocorre na direção horizontal, onde existiu um pequeno reposicionamento posterior e nenhuma evidência de crescimento. / Distraction osteogenesis has been applied extensively to correct the severe midface hipoplasia in syndromic craniosynostosis patients. However few studies have reported midface distraction outcomes through cephalometric evaluation. The purpose of the present study was to evaluate outcomes with midface distraction after Le Fort III and frontofacial monobloc osteotomy using a rigid external device (RED) in patients with syndromic craniosynostosis, in terms of quantity of bone lengthening, skeletal stability and facial growth. Eleven patients underwent to midface distraction from February of 2002 to January of 2006 at the plastic surgery unit of The \'Hospital das Clínicas\' of the Medical School of The University of São Paulo were retrospectively evaluated. Six patients had Crouzon, four had Apert, and one had Saethre-Chotzen syndrome. The patients were submit to bone lengthening procedure of the midface using a rigid external device (RED) after osteotomy type Le Fort III (n=4) and frontofacial monobloc osteotomy (n=7). Three teleradiography were retrospectively evaluated of each patient (T1 - before surgery; T2- after surgery, rigth after distractor removal; T3 - after surgery, obtained with a minimal interval of 12 months after surgery). The three lateral cephalograms were obtained from each patient by direct teleradiography superimposition taken as references the anatomic repairs in the cranium and anterior skull base. This way the three cephalometric tracings were obtained in the same acetate paper which was digitalized. Utilizing a public domain program Image J, various mensurations were accomplished with intension of determine the extent of advancement suffered by the bone segments in the direction of vector skeletal movement and its horizontal and vertical components as well, as taken as references point A and orbitale. Patients still were divided between two groups (G 1- patients submitted to an osteotomy type Le Fort III; G 2- patients submitted to monobloc frontofacial osteotomy), and the data obtained from mensurations from both groups were compared. Significant midface advancement was achieved with the procedures. The horizontal component of the movement was predominant if compared to vertical. The rate of horizontal relapse was minimal. When compared the two procedures was noted a significant difference between Le Fort III and monobloc groups. The advancement rate was greater in monobloc than Le Fort III group. In terms of relapse Le Fort III group was more stable than monobloc group. In vertical direction was noted an evident altered position of the reference points at late postoperative period if compared with recent postoperative period given evidence of facial vertical direction growth, contrary from what occurred in horizontal direction where existed a small relapse and no growth.

To facilitate examination for osteogenesis and follow up after craniotomy similar head models called phantoms are made. The head phantom should emulate the tissues from a real head. This requires that the realistic head phantom have the same electrical properties as relative permittivity (dielectric constant) and conductivity. Both must be validated and matched for right frequency spectrum. Validation measurements are performed by a coaxial slim probe connected to an Agilent Technologies E8364B network analyzer. The range of frequency measured is from 1 to 50 GHz, but matching will only be processed for 1 to 10 GHz. The resonance frequency for the antenna or sensor, which later will be used, is 2.4 GHz. The end results of the head phantom consists of three different tissues or layers (skin, bone and brain). Cavities will be created in the bone and will act as different defects or stages of re-growing bone. Phantom cube is done for examining the influence of implant in bone. Insertions of cube samples are made to emulate intermediates between implant and bone. Keywords: agar, BMP, body morphogenetic protein, bone implant, brain phantom, craniosynostosis, craniotomy, cube phantom, phantom, re-growing bone, skin phantom, skull phantom, tissue.

A distração osteogênica tem sido extensamente empregada na correção da grave hipoplasia do terço médio da face de portadores de craniossinostose sindrômica. Contudo, poucos estudos têm apresentado os resultados da distração do terço médio da face através de avaliação cefalométrica. O objetivo do presente estudo foi o de avaliar os resultados obtidos com o avanço ósseo do terço médio da face após osteotomia tipo Le Fort III ou frontofacial em monobloco seguida da utilização de dispositivo rígido externo de distração (RED), em portadores de craniossinostose sindrômica, em termos de quantidade de alongamento ósseo, estabilidade esquelética e crescimento facial. Onze pacientes submetidos aos procedimentos de distração, de fevereiro de 2002 a janeiro de 2006, na unidade de cirurgia plástica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, foram avaliados retrospectivamente. Seis pacientes eram portadores da síndrome de Crouzon, quatro da síndrome de Apert, e um da síndrome de Saethre-Chotzen. Onze pacientes foram submetidos ao procedimento de alongamento ósseo do terço médio da face através do uso de dispositivo externo rígido (RED), após osteotomias tipo Le Fort III (N = 4) ou frontofacial monobloco (N = 7). Foram avaliadas retrospectivamente três telerradiografias de face em norma lateral de cada paciente (T1- préoperatório; T2 - pós-operatório recente, logo após a remoção do distrator; T3 - pós-operatório tardio, obtida com um intervalo mínimo de 12 meses após cirurgia). Três cefalogramas foram obtidos de cada paciente, através da direta sobreposição das três telerradiografias, tomado como referência reparos anatômicos do crânio e da porção anterior da fossa craniana. Desta forma, os três traçados cefalométricos foram obtidos no mesmo papel acetato, o qual foi digitalizado. Utilizando o programa de computação gráfica de domínio público Image J, várias mensurações foram realizadas com a intenção de determinar a extensão do avanço sofrido pelos segmentos ósseos na direção do vetor do movimento esquelético, assim como de seus componentes horizontal e vertical, tomando como referência pontos A e orbitário. Pacientes foram ainda divididos em dois grupos (G 1 - pacientes submetidos à osteotomia tipo Le Fort III; G 2 - pacientes submetidos à osteotomia frontofacial em monobloco), e os dados obtidos a partir mensurações de ambos os grupos foram comparados. Avanço significativo do terço médio da face foi obtido com os procedimentos. O componente horizontal do movimento esquelético predominou ao componente vertical. A taxa de reposicionamento posterior horizontal tardio (perda de resultado) foi mínima. Quando comparados os dois procedimentos, foi observada uma diferença significativa entre os grupos Le Fort III e monobloco. A quantidade de avanço obtido foi maior no grupo monobloco que no grupo Le Fort III. Em termos perda de resultado, o grupo Le Fort III foi mais estável que o grupo monobloco. Foi observada uma evidente alteração vertical no posicionamento dos pontos de referência no pós-operatório tardio, se comparado ao pós-operatório recente, evidenciando crescimento na vertical da face, ao contrário do que ocorre na direção horizontal, onde existiu um pequeno reposicionamento posterior e nenhuma evidência de crescimento. / Distraction osteogenesis has been applied extensively to correct the severe midface hipoplasia in syndromic craniosynostosis patients. However few studies have reported midface distraction outcomes through cephalometric evaluation. The purpose of the present study was to evaluate outcomes with midface distraction after Le Fort III and frontofacial monobloc osteotomy using a rigid external device (RED) in patients with syndromic craniosynostosis, in terms of quantity of bone lengthening, skeletal stability and facial growth. Eleven patients underwent to midface distraction from February of 2002 to January of 2006 at the plastic surgery unit of The \'Hospital das Clínicas\' of the Medical School of The University of São Paulo were retrospectively evaluated. Six patients had Crouzon, four had Apert, and one had Saethre-Chotzen syndrome. The patients were submit to bone lengthening procedure of the midface using a rigid external device (RED) after osteotomy type Le Fort III (n=4) and frontofacial monobloc osteotomy (n=7). Three teleradiography were retrospectively evaluated of each patient (T1 - before surgery; T2- after surgery, rigth after distractor removal; T3 - after surgery, obtained with a minimal interval of 12 months after surgery). The three lateral cephalograms were obtained from each patient by direct teleradiography superimposition taken as references the anatomic repairs in the cranium and anterior skull base. This way the three cephalometric tracings were obtained in the same acetate paper which was digitalized. Utilizing a public domain program Image J, various mensurations were accomplished with intension of determine the extent of advancement suffered by the bone segments in the direction of vector skeletal movement and its horizontal and vertical components as well, as taken as references point A and orbitale. Patients still were divided between two groups (G 1- patients submitted to an osteotomy type Le Fort III; G 2- patients submitted to monobloc frontofacial osteotomy), and the data obtained from mensurations from both groups were compared. Significant midface advancement was achieved with the procedures. The horizontal component of the movement was predominant if compared to vertical. The rate of horizontal relapse was minimal. When compared the two procedures was noted a significant difference between Le Fort III and monobloc groups. The advancement rate was greater in monobloc than Le Fort III group. In terms of relapse Le Fort III group was more stable than monobloc group. In vertical direction was noted an evident altered position of the reference points at late postoperative period if compared with recent postoperative period given evidence of facial vertical direction growth, contrary from what occurred in horizontal direction where existed a small relapse and no growth.

Abstract This work evaluated the safety and effectiveness of operative techniques used in cranioplastic surgery and outcomes of these surgical methods. In study I the feasibility of endocranial fixation in frontal remodeling surgery for metopic and coronal synostosis was established. Good to excellent aesthetic results were seen in 96% of cases evaluated by a surgeon at the time of follow-up. Three patients out of 27 had complications requiring revisions. No mortality or permanent morbidity, nor complications related to endocranial placement of the plates were seen. Thus it was verified that placing resorbable material intracranially reduces the aesthetic impact without hindering the final result. Study II found that posterior cranial vault distraction procedures produced a mean increase of 25% in intracranial volume. This proved to be an effective technique for treating a variety of craniosynostosis with significant shortage of intracranial volume. 3D photogrammetric imaging was found to be a suitable non-ionizing method for evaluation of cranial volume increase following distraction. In study III a new tool was developed and successfully used for the intraoperative guidance of distractor device placement to ensure congruent vectors and thus reduced complications of these surgical procedures. In study IV long-term functional and aesthetic outcomes of the surgical treatment for sagittal synostoses in patients reaching adulthood was examined. The mean follow-up time was 26.5 years and the patients were 18 to 41 years old at the time of follow-up. The patients treated for sagittal synostosis were equally satisfied with their facial appearance as were their age and gender matched controls. Independent panels found patients’ appearance to be slightly less attractive, but the difference was less than 10 mm on a 100 mm Visual Analogue Scale, representing a low clinical significance. Patients’ socioeconomic situation such as education, housing, employment and marital status equaled controls with similar frequencies of headaches, mental problems or health issues as the controls. / Tiivistelmä Tässä tutkimuksessa selvitettiin kallon saumojen ennenaikaisen luutumisen (kraniosynostoosi) leikkausmenetelmien tehokkuutta ja turvallisuutta sekä pitkäaikaisia tuloksia. Leikkausmenetelmä, jossa epämuotoinen kallo uudelleenmuotoillaan ja luiset osat kiinnitetään toisiinsa kallon sisäpuolelle asennettavilla ja kudokseen hajoavilla levyillä oli tehokas ja luotettava (N=27). Jälkitarkastuksessa tulos arvioitiin erinomaiseksi tai hyväksi 96 %:lla tapauksista. Leikkaushoitoa vaativia ongelmia tai komplikaatioita esiintyi kolmella, mutta pysyvää haittaa ei jäänyt. Komplikaatiot eivät johtuneet levyjen sijainnista kallon sisällä. Saumojen ennenaikaisesta luutumisesta johtuvaa kallon tilavuuden alenemaa hoidettiin venytyshoidolla (N=30). Menetelmällä saavutettiin keskimäärin 25 %:n lisääntyminen tilavuudessa, ja se soveltuukin erityisen hyvin potilaille, joilla tarvitaan suuri tilavuuden lisääntyminen. Leikkaustekniikkaan ei liittynyt isoja komplikaatioita. Tulosta arvioitiin osalla potilaista kolmiulotteisella valokuvauksella, joka perinteisistä seurantamenetelmistä poiketen ei altista ionisoivalle säteilylle, ja se osoittautui käyttökelpoiseksi seurantamenetelmäksi. Venytyshoitoa varten kallon pintaan kiinnitettävät pidennyslaitteet tulee asettaa yhdensuuntaisesti, ja se on teknisesti haasteellista. Työssä kehitettiin kirurginen instrumentti, jolla venyttimet voidaan luotettavammin asetella samansuuntaisiksi. Uusi tekniikka ehkäisee mekaanisia ongelmia, joita muuten voisi ilmetä erisuuntaisten venyttimien välillä pidennyksen edetessä. Lapsuudessa venekallon johdosta leikattujen potilaiden (N=40) pitkäaikaiset hoitotulokset sekä selviytyminen elämässä 26.5 vuoden seuranta-ajan jälkeen olivat hyviä. Heidän taloudellinen ja sosiaalinen tilanne (koulutus, asumismuoto, työllistyminen, siviilisääty ym.) ei eronnut ikä- ja sukupuolivakioitujen vertailuhenkilöiden (N=40) tilanteesta. Yleisessä terveydentilassa, päänsärkyjen esiintymisessä ja mielenterveysongelmissa ei ollut eroa. Potilaiden tyytyväisyys omaan ulkonäköönsä oli samankaltainen kuin vertailuhenkilöillä. Ulkopuolisen asiantuntijapaneelin tekemän arvion perusteella potilaiden kasvojen ulkonäkö oli vähemmän miellyttävä kuin vertailuhenkilöillä, mutta ero oli vähäinen (<10 % ero visual analogue scale, VAS, asteikolla). Asiantuntijapaneeli teki arvionsa tietämättä onko arvioitava henkilö potilas vai vertailuhenkilö.

This thesis further delineates the molecular genetic basis of a relatively common craniofacial condition, coronal craniosynostosis. It used whole-exome sequencing to identify novel disease genes in patients with non-syndromic coronal synostosis and negative genetic testing. Initially, 2 patients were identified with damaging, frameshift mutations in a gene not previously linked with craniosynostosis – Transcription Factor 12 (TCF12). A further intronic mutation was identified in a third patient. This gene encodes a transcription factor that dimerises with TWIST1, mutations of which cause Saethre-Chotzen syndrome, also associated with coronal synostosis. Screening 344 undiagnosed patients identified 35 further mutations, all with coronal synostosis with 14 cases arising de novo. This work was published and testing for TCF12-related craniosynostosis was translated clinically. Significant non-penetrance (60%) was identified in mutation-positive relatives and the genetic background was investigated. Firstly, analysis of parental origins of de novo mutations identified 6 of paternal origin and helped refine haplotype assignment. Secondly, haplotype analysis of TCF12-mutation carriers revealed modest correlation with phenotypic status, but this was insufficient to be useful in clinical testing. Thirdly, TCF12 haplotypes were analysed for association with non-syndromic coronal synostosis, but no significant association was found. Further exome sequencing revealed a de novo frameshift mutation in Transcription Factor 20 (TCF20) in a patient with coronal synostosis and autism, although the mutation only correlated with the latter phenotype. Analysis of 5 trios revealed a novel variant in myosin heavy chain 4 (MYH4) in 1 family, although its role in suture development is uncertain. Reviewing pooled exome data from 19 mutation-negative patients revealed no further disease genes. In summary, this thesis describes novel gene discovery, defines a new clinical entity and investigates genetic background of penetrant and non-penetrant individuals. Further exome sequencing identified another disease gene, a de novo mutation and compiled lists of damaging variants to allow future work.

Une craniosynostose est une pathologie caractérisée par la fusion prématurée d'une ou plusieurs sutures crâniennes. C'est un défaut de naissance assez fréquent (1/2500 naissances) qui résulte en une forme anormale du crâne et qui peut être accompagné d'une déficience mentale dans certains cas. Des mutations du gène TWIST1, qui encode un facteur de transcription basique Helix-Loop-Helix (bHLH) de classe II, causent le syndrome de Saethre-Chotzen qui est associé à une synostose de la suture coronale (El Ghouzzi et al. 1997; Howard et al. 1997). Un nouveau gène a récemment été découvert comme étant une nouvelle cause du syndrome Saethre-Chotzen ainsi que de synostose coronale asyndromique (Sharma, Fenwick, Brockop, et al., 2013): il s'agit du gène TCF12, qui encode un facteur de transcription bHLH de classe I.Nous démontrons qu'une reduction de l'expression génique de Twist1 et Tcf12 chez la souris cause une synostose coronale, et nous suggérons que les protéines bHLH Twist1 et Tcf12 forment des hétérodimères dont le dosage est critique pour le développement de la suture coronale.Nous nous concentrons aussi sur Twist1 et prouvons que son expression est requise dans les tissus dérivant du mésoderme ainsi que ceux dérivant des crêtes neurales pour le développement normal de la suture coronale.De plus, nous notons que dans la suture coronale, Twist1 exclut Notch2 afin de garder la suture ouverte, et beta-catenin joue un rôle dans la maintenance de l'ouverture de la suture en ciblant Jagged1 lors du développement de la suture coronale chez la souris.Enfin, nous mentionnons de nouveaux gènes qui pourraient avoir un impact sur le développement normal de la suture coronale: Aggrecan, Goosecoid, Gucy1a3 et Gucy1b3. / Craniosynostosis, the premature fusion of one or more cranial sutures, is a common birth defect (1/2500 live births) that results in abnormalities in skull shape and sometimes in neurological deficiencies (Wilkie, 1997; Wilkie and Morriss-Kay, 2001). Mutations in TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, cause Saethre-Chotzen syndrome, associated with coronal synostosis (El Ghouzzi et al. 1997; Howard et al. 1997). We recently discovered a new craniosynostosis gene, TCF12, which encodes a class I bHLH transcription factor. Tcf12 causes.Saethre-Chotzen syndrome and asyndromic coronal synostosis. (Sharma, Fenwick, Brockop, et al., 2013). We show that a reduction in the dosage of Twist1 and Tcf12 in mouse causes coronal synostosis, and we suggest that the Twist1 and Tcf12 form heterodimers whose dosage is critical for coronal suture development. We also demonstrate that Twist1 is required in both neural-crest and mesoderm-derived tissues for the normal coronal suture development. Moreover, we show that in the coronal suture, Twist1 excludes Notch2 thus maintaining suture patency. and we show that beta-catenin also plays a role in the maintenance of suture patency by regulating Jagged1. Finally, we identified Aggrecan, Goosecoid, Gucy1a3 and Gucy1b3 as Twist1-regulated genes that could have an impact on the normal development of the coronal suture.