Anomalies du développement orbitaire chez l'homme (aspects cliniques et études moléculaires des gènes TWIST, FGFR2 et FOXL2)

Les progrès de la biologie moléculaire permettent d'ébaucher la séquence d'évènements moléculaires complexes conduisant à la constitution de la région craniofaciale. Ce travail est focalisé sur l'étude de gènes impliqués dans des syndromes dysmorphiques craniofaciaux. 1ʿEtude du gène TWIST: du syndrome BPES au syndrome de Saethre-Chotzen Une nouvelle mutation dans le gène TWIST a été mise en évidence au sein d'une famille indienne initialement considérée comme présentant un syndrome BPES (Blépharophimosis, Ptosis Epicanthus Inversus Syndrome). L'étude moléculaire a suggéré le diagnostic de syndrome de Saethre-Chotzen, confirmé par une étude clinique qui a mis en évidence la grande variabilité d'expressivité clinique liée à l'haploinsuffisance à TWIST: Une étude des phénotypes murins de souris twist null/+, effectuée sur divers fonds génétiques, a permis de démontrer des homologies par rapport aux phénotypes humains 2ʿ Etude des gènes FGFR (Fibroblast Growth Factor Receptor) dans des craniosténoses syndromiques Les gènes FGFR ont été récemment identifiés comme responsables de formes syndromiques de craniosténoses. Ce travail comporte l'analyse moléculaire de quatre cas de craniosténoses avec des mutations détectées dans le gène FGFR2. 3ʿ Etude du gène FOXL2 impliqué dans le syndrome BPES. Le gène FOXL2 a été identifié comme étant responsable du syndrome BPES (au locus 3q23). Nous avons identifié des mutations dans ce gène pour deux familles et deux cas sporadiques. L'analyse par IRM a mis en évidence l'absence muscle releveur de la paupière supérieure ou son hypoplasie pour cinq individus mutés dans FOXL2 suggérant un rôle de ce gène dans le développement de ce muscle. Conclusions et perspectives: Les gènes TWIST, FGFR et FOXL2 contribuent au développement orbitaire, des études futures pourront tenter de comprendre leur séquence d'action et la variabilité d'expression clinique observée pour les pathologies humaines.Progresses in molecular biology have enhanced our understanding of the complexe molecular mechanisms underlining the development of the craniofacial region. In this work, genes implied in the development of the orbital region are studied. 1ʿ The TWIST gene: form BPES syndrome to Saethre-Chotzen syndrome A new mutation in the TWIST gene was found in a large Indian family presenting initially as a Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (BPES). The molecular diagnosis has suggested the diagnosis of Saethre-Chotzen syndrome confirmed by a clinical research showing an important variability of the expression of haploinsufficiency for TWIST. Phenotypes of twist null/+ mice, on various genetic backgrounds, showed homologies with the human phenotypes. 2ʿ FGFR (Fibroblast Growth Factor Receptor ) genes and syndromic craniosynostosis. FGFR genes have recently been identified as responsible for a certain number of Syndromic craniostenosis syndromes. Mutations in four cases of syndromic craniostenosis with mutations in FGFR2 are described. 3ʿ The FOXL2 gene implied in the BPES The FOXL2 gene is known to be mutated in the BPES syndrome (locus 3q23). We have identified mutations in this gene for two famillies and two sporadic cases. MRI analysis revealed the absence or hypoplasia of the superior levator muscle raising the hypothesis that this gene is implied in the development of this muscle. Conclusions and perspectives: The TWIST, FGFR and FOXL2 genes contribute to the development of the orbital region. Futures studies may attempt to understand their interactions and the variability of the related human syndromes.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Définition moléculaire de l'origine des alteractions morphologiques liées à la dysfonction de Twist

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Congenitally missing teeth and labio-palatal clefts: keep to the left

Objectives: dental anomalies are more frequent for individuals with clefts than for the general population. Our objective is to evaluate the prevalence of dental ageneses in a sampling from Alsace made up of 124 children with clefts (81 boys and 43 girls, average age 12.5 years old). Method: clinical and radiographic exams make it possible to specify the dental formula as well as the type of clefts that are divided into 4 groups: simple Labial Clefts (LC – 12.9%), Labio-Alveolar Clefts (LAC – 4%), Labio-Palatal Clefts (LPC – 49.2%) and Palatal Clefts (PC – 33.9%). Results: 63% of the patients present one or more ageneses mainly involving the maxillary lateral incisors (54%) and the maxillary or mandibular second premolars (32%). The percentage of children with congenitally missing teeth is, in ascending order, minimal in the case of LC (33%), average in the case of PC (54%) and highest in cases of LPC (79%). The frequency of ageneses increases proportionally with the severity of the cleft. The left side is most affected (p < 0.01) regardless of the side of the cleft. Conclusions: dental ageneses are more frequent on the left side, regardless of the side of the cleft. The greater prevalence on the left side could suggest the intervention of overlapping etiopathogenic factors when clefts and dental ageneses are involved

Agénésies dentaires et fentes labio-palatines : priorité à gauche

Objectifs : les anomalies dentaires sont plus fréquentes chez les individus porteurs de fentes que dans la population générale. Notre objectif est d’évaluer la prévalence des agénésies dentaires dans un échantillon alsacien composé de 124 enfants porteurs de fentes (81 garçons et 43 filles, âge moyen 12,5 ans). Méthode : les examens clinique et radiographique permettent de préciser la formule dentaire ainsi que le type de fentes qui sont classées en 4 groupes : Fente Labiale pure (FL - 12.9%), Fente Labio-Alvéolaire (FLA - 4 %), Fente Labio-Palatine (FLP - 49.2 %) et Fente Palatine (FP - 33.9 %). Résultats : 63 % des patients présentent une ou plusieurs agénésies dentaires touchant essentiellement les incisives latérales maxillaires (54 %) et les secondes prémolaires maxillaires ou mandibulaires (32%). Le pourcentage d’enfants avec agénésies est, par ordre croissant, minimal en cas de FL (33%), moyen en cas de FP (54%) et culmine en cas de FLP (79%). La fréquence des agénésies augmente avec la sévérité de la fente. Le côté gauche est le plus atteint (p <0.01) quel que soit le côté de la fente. Conclusions : les agénésies dentaires sont plus fréquentes du côté gauche, quel que soit le côté de la fente. Cette prévalence à gauche pourrait suggérer l’intervention de facteurs étiopathogéniques communs à la survenue des fentes et des agénésies dentaires

Prise en charge multidisciplinaire des agénésies dentaires multiples associées aux dysplasies ectodermiques hypohidrotiques

Les dysplasies ectodermiques hypohidrotiques (DEH) constituent un groupe hétérogène et complexe de syndromes caractérisés par un phénotype dento-cranio-facial associant une oligodontie sévère, une brachygnathie-endognathie maxillaire et une concavité faciale notamment. Les paramètres céphalométriques sont révélateurs d’une insuffisance de croissance squelettique maxillaire sagittale, d’une position mandibulaire prognathique, d’une réduction des hauteurs ramiques et faciales, ainsi que de modifications basi-crâniennes. Un diagnostic et une prise en charge au sein d’une équipe multi-disciplinaire précoce sont nécessaires. En denture temporaire, un traitement prothétique initial est préconisé, pouvant être associé éventuellement à un traitement interceptif orthopédique. En denture mixte, le traitement de l’insuffisance maxillaire transversale consiste en la mise en place d’un disjoncteur sur gouttière ou d’un quadhélix, dans le cas de phénotypes modérés avec présence de moyens d’ancrage suffisants. Le repositionnement orthopédique antérieur du maxillaire repose sur l’utilisation d’un masque facial. En denture permanente, les étapes essentielles correspondent aux aménagements orthodontiques pré-implantaires et pré-prothétiques, ainsi qu’à la préparation orthodontique pré-chirurgicale avant une éventuelle chirurgie orthognathique mono- ou bi-maxillaire. Les ancrages squelettiques temporaires de type mini-vis ou plaque peuvent être indiqués dans les cas avec déficit d’ancrage

Multidisciplinary treatment plan for multiple dental ageneses associated with hypohidrotic ectodermal dysplasias

Hypohidrotic ectodermal dysplasias (HED) are a heterogeneous and complex group of syndromes characterized by a dental craniofacial phenotype associated with severe oligodontia, maxillary hypoplasia with broad face and most notably facial concavity. Cephalometric analyses show insufficient maxillary sagittal growth, a protruded mandible, reduced facial and ramus heights, as well as basicranial changes. Early diagnosis and care from a multidisciplinary team are essential. In the primary dentition, initial prosthetic treatment is recommended and may possibly be combined with interceptive orthodontic treatment. In the mixed dentition, treatment of a transverse maxillary deficiency consists in installing a removable expander or a quadhelix in the case of moderate phenotypes where there is adequate anchorage support. To achieve mandibular anterior repositioning of the maxilla the patient must wear a facial mask. In the permanent dentition, the important steps are correlated with the pre-implant and pre-prosthetic orthodontic adjustments, as well as the presurgical orthodontic preparation that precedes subsequent single or double jaw orthognathic surgery. Temporary skeletal anchorage with mini-screws or plates can be used in cases of insufficient anchorage

PEEK (polyether-ether-ketone)-coated nitinol wire: Film stability for biocompatibility applications

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Temporospatial gene expression and protein localization of matrix metalloproteinases and their inhibitors during mouse molar tooth development

International audienceThe gene expression and protein distribution of matrix metalloproteinase (MMP) -2, -9, membrane type-1 MMP (MT1-MMP), as well as of TIMP-1, -2, and -3 were analyzed during mouse molar development. Immunohistochemical data demonstrated that all the MMPs investigated were expressed in the dental epithelium and mesenchyme. In contrast, gene and protein expression analysis for TIMPs showed that they were differentially expressed. TIMP-1 was expressed in the dental epithelium and mesenchyme between E13 and E16 and was transiently up-regulated at E14, the cap stage. TIMP-1 expression was also detected in differentiating odontoblasts. TIMP-2 RNA transcripts were found in the peridental and dental mesenchyme, odontoblasts, and ameloblasts. Protein analysis revealed high expression on the lingual side of the dental epithelium and underlying mesenchyme together with transient expression in the enamel knot at E14 and expression in the gingival tissue and enamel matrix postnatally. TIMP-3 RNA transcripts were found in discrete regions of the dental epithelium, including at high levels in the cervical loop at E16. Expression was also detected in preodontoblasts at E16 and transiently during ameloblast differentiation. Analysis of the protein distribution revealed a lower level of TIMP-3 on the lingual side of the dental epithelium at E14. MT1-MMP was expressed in the dental mesenchyme between E13 and E16, at relatively high levels in the cervical loop at E14, and in the odontoblasts and ameloblasts. The distinct temporospatial distribution patterns of the TIMPs suggest that these inhibitors play several intrinsic roles during tooth development

Expression and localization of laminin-5 subunits during mouse tooth development

International audienceTooth morphogenesis is regulated by epithelial-mesenchymal interactions mediated by the basement membrane (BM). Laminins are major glycoprotein components of the BMs, which are involved in several cellular activities. The expression and localization of the alpha3, beta3, and gamma2 laminin-5 subunits have been analyzed by in situ hybridization and immunohistochemistry during mouse molar development. Initially (E12), mRNAs of all subunits were detected in the entire dental epithelium and the corresponding proteins were located in the BM. During cap formation (E13-14), transcripts for the alpha3 and gamma2 subunits were localized in the outer dental epithelium (ODE), whereas the beta3 subunit mRNA was present in the inner dental epithelium (IDE). During the early bell stage (E16), immunoreactivity for all subunits disappeared from the BM along the IDE, although intense signals for beta3 mRNA were detectable in cells of the IDE. Subsequently, when the dentinal matrix was secreted by odontoblasts (E18-19.5), mRNAs of all three subunits were re-expressed by ameloblasts, and the corresponding proteins were detected in ameloblasts and in the enamel matrix. Tissue recombination experiments demonstrated that when E16 IDE or ODE was associated with E18 dental papilla mesenchyme, immunostaining for all laminin-5 subunits disappeared from the BM, whereas when cultured with non-dental limb bud mesenchyme, they remained positive after 48 hr of culture. These results suggest that the temporospatial expression of laminin-5 subunits in tooth development, which appears to be differentially controlled by the dental mesenchyme, might be related to the enamel organ histo-morphogenesis and the ameloblast differentiation

Expression and localization of laminin-5 subunits in the mouse incisor

International audienceLaminin-5 is associated with several epithelial tissues and forms part of the anchoring filaments of hemidesmosomes. Recent data have shown that the expression of laminin-5 subunits is impaired in junctional epidermolysis bullosa (JEB), and, in these patients, enamel hypoplasia is commonly observed. Rodent incisors are continuously growing teeth with an asymmetry between their labial and lingual sides. Enamel matrix formation is restricted to the labial side. We have analyzed the changes in the expression and localization of laminin-5 subunits (alpha3, beta3, and gamma2) in lower incisors of the mouse. The apical loop located at the end of the labial side contained stem cells and showed expression for all laminin-5 subunits. In the anterior direction, the inner dental epithelial cells (IDE) transiently lost the immunoreactivity for all subunits, whereas the transcripts for the beta3 subunit remained in the IDE. All subunit mRNAs and proteins were expressed in ameloblasts facing predentine and also in secretory and maturation stage ameloblasts. Enamel matrix contained laminin-5. On the lingual side, the expression of laminin-5 subunits was continuous from the epithelial root sheath to the epithelial rests of Malassez in the periodontal ligament. These results suggest that spatial and temporal regulation of laminin-5 subunits correlates with the histogenesis of the dental organ, ameloblast differentiation, and enamel formation and also that laminin-5 plays a role in the adhesion between dental epithelial cells and the extracellular matrix (enamel or dentine) in areas where the dental basement membrane is absent