Dissertations / Theses on the topic 'Dysplasie osseuse'

Les ostéoclastes sont des cellules multinucléées capables de résorber le tissu osseux, elles se différencient à partir de la lignée hématopoïétique en présence de Receptor Activator of Nuclear Factor NF-kB (RANK-L) et M-CSF (Macrophage-Colony Stimulating Factor). Les récepteurs RANK et M-CSFR relaient et amplifient le signal de leurs ligands en activant de multiples voies de signalisation intracellulaire dont l’intégration aboutira à l’intégration de NFATc1, facteur de transcription essentiel pour la différenciation des ostéoclastes. Les protéines adaptatrices, du fait de leur structure, jouent un rôle crucial dans cette signalisation. De nombreuses études ont montré que la protéine adaptatrice 3BP2/ SH3BP2, initialement identifiée comme une protéine interagissant avec la kinase c-Abl puis comme partenaire des kinases de la famille Src et Syk, joue un rôle important dans la signalisation et l’activation des leucocytes. Des études génétiques ont montré que des mutations du gène 3bp2 chez l’homme sont associées à une dysplasie osseuse génétique « Chérubinisme » et à un phénotype ostéopénique inflammatoire chez la souris. Ces observations laissent entrevoir un rôle additionnel de 3BP2 dans la régulation des cellules du système osseux et particulièrement la différenciation des ostéoclastes. Dans le but d’étudier le rôle de 3BP2 dans la différenciation des ostéoclastes, nous avons utilisé la lignée RAW264. 7, une lignée myélo-monocytaire murine capable de se différencier en ostéoclaste en présence de RANK-L. Avec la méthode d’interférence ARN, nous avons développé des modèles cellulaires « perte de fonction » n’exprimant plus 3BP2. Ces modèles nous ont permis de montrer que l’expression de 3BP2 est essentielle pour la différenciation des ostéoclastes et que son absence altère la différenciation de ces cellules en ostéoclastes. Nous avons ainsi montré que l’effet de l’absence de 3BP2 est restreint à la voie de signalisation RANK sans aucune conséquence sur la voie de signalisation GM-CSF et la différenciation des cellules dendritiques. Dans un premier temps, nous avons montré que cet effet « perte de fonction » est lié à un défaut de polymérisation d’actine et d’activation de la protéine tyrosine kinase Src et des voies de signalisation MAPKs (MEK, ERK, JNK) contrôlées par RANK-L. Nous avons observé également une inhibition de l’induction de NFATc1 et AP-1, des facteurs de transcription essentiels à la différenciation des ostéoclastes. Par la suite, l’analyse transcriptionnelle de différentes protéines impliquées dans la différenciation des ostéoclastes (CaR, TRAP, Cathépsine K) a révélée une inhibition significative de leur induction dans les cellules déficients en 3BP2. Nous avons finalement montré que la reconstruction avec des molécules Src et NFATc1 constitutivement actives restaure la différenciation des ostéoclastes dans les cellules déficients en 3BP2. En conclusion, notre étude a montré que la protéine 3BP2, via la protéine tyrosine kinase Src, joue un rôle central au cours de la différenciation des ostéoclastes en contrôlant les voies de signalisation RANK, impliquées dans l’activation de NFATc1, facteur de transcription clé de la différenciation ostéoclastique
Osteoclasts are multinucleated bone-resorbing cells, which derived from hematopoietic cells of the monocyte/macrophage lineage following stimulation with two essential cytokines, RANK-L and M-CSF. The molecular pathways involved in osteoclast formation involve complex network of signaling molecules, including adaptor proteins kinases, which ultimately lead to the activation of a transcriptional program in which NFATc1 plays a pivotal role. The adaptor protein 3BP2, originally identified as a c-Abl binding protein, and a partner of Src and Syk kinases families, has been involved in leucocytes signaling and activation? Genetic studies have further associated mutations of the 3BP2 gene of the human bone disease Cherubism and to inflammation and bone dysfunction in mouse. However, how wild-type 3BP2 exactly functions in osteoclast differentiation has yet been elucidated. In this study, we have investigated the role of endogenous 3BP2 exactly functions in osteoclast differentiation using siRNA-mediated silencing of 3BP2 expression in the RAW264. 7 monocyte/macrophage cell line. We show here that 3BP2 was required for RANK-L-induced differentiation of RAW264. 7 cells was associated with reduced RANK-L-induced actin reorganization and Src, ERK, JNK, IKKα/β, but not p38 phosphorylation. Following RANK-L stimulation, the 3BP2-deficient cells exhibited impaired up-regulation of Src, c-fos and NFATC1 mRNA expression, whereas NFATc2 and NFATc3messengers were not significantly affected. Compared to control cells, 3BP2-knockdown cells induced to osteoclast by RANK-L displayed no up-regulation of Src and NFATc1 proteins? In addition, the introduction of constitutively active mutants of Src and NAFTc1 in 3NP2 deficient cells restored osteoclast differentiation. Finally, we provide evidence that enhanced osteoclast differentiation triggered by a 3BP2 Cherubism mutant also required NFAT activity in RAW264. 7 cells. Together, this study demonstrates that 3BP2 is a key regulator of RANK-mediated osteoclastogenesis through Src and NFATc1 activation

La pratique du mariage entre apparentés au sein de la population libanaise, favorisée par des raisons sociales, religieuses, géographiques et aussi politiques, a vu apparaître des sous-groupes de populations de taille plus ou moins réduite, parfois à la limite d’isolats génétiques. Ceci a engendré une augmentation de la prévalence des maladies autosomiques récessives fréquentes mais aussi et surtout rares. Parmi ces dernières, les chondrodysplasies ont retenu notre attention. Elles sont caractérisées par un retard statural dû à un défaut du processus d’ossification endochondale, qui est responsable de la croissance des os longs. Au cours de ces dernières décennies, plus de 230 gènes responsables d’environ 400 maladies osseuses constitutionnelles ont été identifiés. Cependant, les bases moléculaires d'une centaine de dysplasies osseuses restent, à ce jour, inconnues. L’identification de gènes codant pour des protéines de nature extrêmement variée a contribué à la compréhension du mécanisme complexe d’ossification endochondrale. Mon travail de thèse, réalisé en cotutelle entre l’équipe de recherche « Bases moléculaires et physiopathologiques des chondrodysplasies » de l’hôpital Necker enfants-malades, à Paris en France et l’Unité de Génétique Médicale (UGM) de l’Université Saint-Joseph au Liban, a consisté à identifier des gènes impliqués dans des dysplasies osseuses autosomiques récessives dans quatre familles libanaises consanguines. Dans ce cadre, différentes stratégies ont été adoptées. La première a été une stratégie d’intersection des variations détectées par le séquençage de l’exome de deux patients, atteints d’une forme sévère de dysplasie spondylodysplastique létale et issus de deux familles libanaises consanguines et non apparentées (Familles A et B). Nous avons identifié une mutation homozygote du gène MAGMAS (NM_016069, p.Asn76Asp) (Mitochondria-associated granulocyte macrophage CSF-signaling molecule) à l’origine de la maladie dans les deux familles A et B. MAGMAS est une protéine associée à la mitochondrie et impliquée dans la régulation de l’import actif des protéines vers la matrice mitochondriale. Par immunohistochimie, nous avons montré que MAGMAS est spécifiquement exprimée au niveau de l’os et de la zone hypertrophique du cartilage. MAGMAS, ayant une fonction cruciale pour la survie, est très conservé entre les espèces. Après avoir généré des souches de levures exprimant une copie normale ou mutée du gène humain MAGMAS, nous avons validé l’effet délétère de la mutation p.Asn76Asp, i) sur la croissance des levures, en montrant que les souches portant le gène humain muté présentent un caractère thermosensible, ii) sur la fonction d’import des protéines vers la matrice mitochondriale, qui est altérée dans les souches mutées et iii) sur la stabilité de la protéine. Nous avons également observé un effet de la mutation sur la morphologie des mitochondries et des peroxysomes des cellules de levures, suggérant une induction de l’autophagie dans les souches de levures portant la mutation p.Asn76Asp. L’identification de mutations de MAGMAS dans une dysplasie osseuse sévère, permet d’attribuer à cette protéine un rôle spécifique dans le processus complexe d’ossification endochondrale. La deuxième stratégie a été une combinaison, au sein d’une même famille, d’une stratégie de cartographie par homozygotie et du séquençage de l’exome d’un seul patient. Cette approche a été utilisée dans une famille consanguine avec 3 enfants atteints porteurs d’une dysplasie rhizomélique (Famille C). Nous avons identifié une mutation homozygote du gène NWD1 (NACHT and WD repeat domain containing 1) (NM_001007525, p.Cys1376Tyr) responsable de la maladie dans cette famille C. Ce gène code pour une protéine ayant des domaines WD répétés qui lui confèrent un rôle dans divers mécanismes comme la transduction de signal, la régulation de la transcription, le transport vésiculaire et le contrôle du cycle cellulaire. (...)
Social, religious, geographic and political reasons have favored the consanguineous marriage in the Lebanese population. This led to an increase in the prevalence of autosomal recessive disorders, especially the rare entities including chondrodysplasias. This group of diseases is due to an impairment of the endochondral ossification process. Causative mutations have now been identified in over 230 different genes in more than 400 unique skeletal phenotypes. However, the genetic basis of over 100 different entities remains to be determined. My PhD research project, held between the research group « Bases moléculaires et physiopathologiques des chondrodysplasies » of Necker enfants-malades hospital (INSERM U781, PARIS, France) and the Medical Genetics Unit of Saint-Joseph University (Lebanon), aims to identify genes involved in autosomal recessive skeletal dysplasias in four consanguineous Lebanese families. Different strategies were carried out: the first consists in overlapping data from whole exome sequencing of two patients affected by a new lethal type of spondylodysplastic dysplasia and issued from two consanguineous unrelated Lebanese families (Families A and B). Here, we report a homozygous missense mutation in the Mitochondria-associated granulocyte macrophage CSF-signaling gene (MAGMAS: NM_016069, p.Asn76Asp) in this severe skeletal dysplasia. MAGMAS, also referred to as PAM16, is a mitochondria-associated protein, involved in pre-proteins import into mitochondria and essential for cell growth and development. We demonstrate that MAGMAS is expressed in trabecular bone and cartilage at early developmental stages underlining its specific role in skeletogenesis. We also give strong evidence of the deleterious effect of the identified mutation on the stability of the protein, its in-vivo activity and the viability of yeast strains. We also show that the mutation is able to induce autophagy in yeast cells. Reporting deleterious MAGMAS mutation in a skeletal dysplasia supports a key and specific role for this mitochondrial protein in ossification. Additional studies would be of interest to further understand the specific role of magmas in ossification. The second strategy was to combine, in a consanguineous family, homozygosity mapping with whole exome sequencing of one of the patients. This strategy was undertaken in family C with 3 patients affected by a rhizomelic dysplasia. It allowed us to identify a homozygous missense mutation in the NWD1 gene (NACHT and WD repeat domain containing 1: NM_001007525, p.Cys1376Tyr) as responsible for the skeletal dysplasia in this family. NWD1 belongs to a large group of WD-repeat domain-containing proteins that are involved in different physiological mechanisms such as signal transduction, transcription regulation, vesicular transport and cell cycle control. (...)

La Dysplasie Ectodermique Hypohidrotique liée à l'X (DEX) est une maladie génétique liée à une mutation du gène EDA. Le phénotype exprimé par le modèle murin Tabby est l'équivalent de celui observé dans l'espèce humaine et présente des anomalies dentaires, cranio-faciales, vertébrales et des défauts de trabéculation osseuse. Dans ce contexte, une cartographie de ces anomalies chez le mutant Tabby était nécessaire et l'analyse de l’impact de la mutation Eda/Ta sur la croissance du squelette crânien et post-crânien a été étudiée. Un suivi longitudinal d'une cohorte d'individus murin Tabby (5 mâles hémizygotes EdaTa/Y, 6 femelles hétérozygotes EdaTa/+) et sauvages (n=12) a été réalisé à partir d’une succession d’acquisitions TDM pendant plus de 2 ans. L'observation des profils de croissance et de leurs paramètres a montré des anomalies de croissance du complexe crânio-facial, de la base du crâne (hypo-développement crânien) et un déficit de croissance relatif des os longs (fémur et humérus) chez les souris hémizygotes EdaTa/Y. Ces résultats mettent pour la première fois en évidence des anomalies de développement des os longs et confirment le rôle d’EDA-A dans la formation normale du squelette. Ces données constituent un pré-requis essentiel pour tester l’efficacité de tentatives de réversion phénotypique à partir de protéines recombinantes
X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) is a genetic disorder due to a mutation of the EDA gene. The phenotype expressed by Tabby mice, murine model of XLHED, is equivalent to that observed in humans including dental anomalies, craniofacial and vertebral trabecular bone defects. In this context, a mapping of these anomalies in Tabby mice was necessary and the impact of the EdaTa mutation on cranial and post -cranial skeletal growth was studied. A 2 years (112 weeks) μCT follow-up of Tabby mice (5 hemizygous males EdaTa/Y, 6 heterozygous females EdaTa/+) and Wild Type group (n = 12) hasbeen performed. The observation of growth patterns and parameters showed a relative cranial hypodevelopment, abnormal growth of the craniofacial complex and a relative hypo-development of appendicular skeleton (femur and humerus) in Tabby mice. These results allowed for the first time to highlight appendicular developmental abnormalities, confirming the role of EDA-A in the normal formation of the skeleton. While enriching the phenotypic picture of this syndrome, in a therapeuticperspective, all of these data are an essential prerequisite to test the effectiveness of attempts to phenotypic reversion from recombinant proteins

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystemic disorder characterized by disproportionate short stature due to skeletal dysplasia, renal disease due to focal segmental glomerulosclerosis (FSGS), T-cell immunodeficiency, and vascular disease. SIOD is caused by mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene, which encodes for a DNA annealing helicase with roles in DNA replication, DNA repair, and gene expression. Although SMARCAL1 functions to maintain genomic integrity, it is not known how SMARCAL1 deficiency leads to the various clinical features of SIOD. My aim was therefore to characterize the molecular pathogenesis of the dental, vascular, renal, and immune features. Given that SMARCAL1 has a role in modulating gene expression and that phenotypic changes are typically preceded by changes in gene expression, I hypothesized that SMARCAL1 deficiency pathologically alters the expression of key genes that lead to the clinical features of SIOD. To test this, SIOD patient tissues were studied using molecular biological analyses. With respect to vascular disease, an SIOD aorta had decreased expression of elastin, and both transcriptional and post-transcriptional mechanisms contributed to the elastin deficiency. Elastin is critical for the structural integrity of the arteries and its deficiency is a known cause of vascular disease. With respect to renal disease, SIOD glomeruli have increased expression and activation of the Wnt and Notch signaling pathways. Wnt and Notch signaling are required for kidney development and the postnatal reactivation of these pathways is an established cause of FSGS. With respect to immune disease, SIOD T cells have decreased mRNA and protein expression of interleukin 7 receptor alpha chain (IL7R). IL7R is critical for T-cell development and its deficiency is a known cause of T-cell immunodeficiency. In conclusion, the gene expression alterations detected are known causes of disease and differ among the tissues studied. These findings suggest that SMARCAL1 deficiency may cause each disease feature by tissue-specific gene expression changes. Further studies are required to define the mechanism of how SMARCAL1 deficiency alters the expression of these genes.
Medicine, Faculty of
Medical Genetics, Department of
Graduate

La dysplasie ectodermique hypohidrotique (DEH) liée à l’X (DEX) est une maladie caractérisée par des anomalies ectodermiques. La DEX résulte d’une mutation du gène EDA, codant pour l’Ectodysplasine. La DEH autosomique récessive est la conséquence d’une mutation du gène EDAR ou EDARADD. L’EDA est exprimée au niveau des structures ectodermiques et au niveau des ostéoblastes. Nous avons étudié les conséquences de la DEH au niveau dentaire et osseux chez l’homme et la souris Ta. Nous avons montré que la sévérité de l’oligodontie ne permet pas de distinguer la DEX de la DEH autosomique récessive contrairement à la distribution des agénésies dentaires. Les mutations EDA, TNF, furine, tronquantes et non-tronquantes ont une expression variable. Nous avons identifié une hyperdensité médullaire et une hypercorticalisation au niveau mandibulaire chez l’homme. La souris Ta présente une réduction du volume osseux trabéculaire et de la densité osseuse. Ces modifications osseuses incluent des changements dans la composition matricielle
X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) is a disease characterized by ectodermal anomalies ascribed to a mutation of EDA gene, encoding EDA. Ectodysplasin Receptor (EDAR) and Ectodysplasin Receptor Associated Death-Domain (EDARADD) genes are both mutated in autosomal HED. Dental and bone manifestations in HED were studied in human and in the Ta mouse. XLHED and autosomal recessive HED showed similar severity in oligodontia, with a differential distribution of dental agenesis in primary dentition. Mutations in the TNF or furine sites and truncating or non-truncating EDA mutations were similar. Bone phenotypic manifestations were detected in XLHED patients with mandibular medullary hypermineralization and hypercorticalization. Reductions in Ta mouse mandibular trabecular bone volume and bone density were described. Structural bone alterations in adult Ta mouse consisted in bone matrix changes (collagen and osteopontin)

Die Radiologie fungiert als wesentliches Instrument in der Diagnostik und Nachsorge fibro-ossärer Läsionen (FOL). Hierbei gewinnen überlagerungsfreie, dreidimensionale Aufnahmen aufgrund der im Kopf-Halsbereich vorhandenen hohen Dichte und Vielfalt anatomischer Strukturen und der damit einhergehenden Fülle von Differentialdiagnosen an Bedeutung. Anhand der Studie wurden die röntgenologischen Charakteristika von ossären Dysplasien (OD) und ossifizierenden Fibromen (OF) im dentalen Volumentomogramm herausgestellt, sowie diagnostische und therapeutische Vorteile der dentalen Volumentomographie (DVT) im Vergleich zur Orthopantomographie (OPG) und Computertomographie (CT) ermittelt und gegenübergestellt. Zu diesem Zwecke wurden anhand eines Fragebogens 18 Röntgenbildpaare (OPG-DVT) von FOL durch zehn Betrachter auf (A) deren röntgenologische Eigenschaften sowie Metallartefakte befundet und (B) deren Abbildungsqualität von sehr gut (1) bis schlecht (5) bzw. nicht beurteilbar bewertet. Insgesamt wurden 360 Analysebögen ausgewertet. Entitäts- und röntgentechnikspezifische Unterschiede wurden statistisch ermittelt. Die Abbildungsqualitäten der DVT und CT wurden auf Grundlage einer intensiven Literaturrecherche verglichen. Die Ergebnisse dieser Studie stellten signifikante Unterschiede in den röntgenologischen Eigenschaften von OD und OF heraus. Acht von zehn Strukturen zeigten in den DVT-Aufnahmen eine signifikant bessere Abbildungsqualität im Vergleich zu den OPG-Aufnahmen. Die teilweise gravierenderen Befunde in den DVT-Aufnahmen deuteten auf eine Unterinterpretation dieser Befunde im OPG hin. Die Literaturrecherche zu Gegenüberstellungen der Abbildungsqualitäten in CT und DVT wies nahezu ausnahmslos auf eine Überlegenheit der DVT hin.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an incompletely penetrant autosomal recessive multisystem disorder characterized by dysmorphic facies, short stature, renal failure, and T-cell immunodeficiency. Biallelic loss-of-function mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response enzyme with annealing helicase activity, are associated with SIOD. My studies focused on further delineation of the molecular basis of SIOD by assessing the contribution of defective DNA repair to the pathophysiology of SIOD and a mechanism by which SMARCAL1 can modulate trait penetrance. Through collaborative analyses of the clinical data and molecular studies of SIOD patients, my coworkers and I observed that SIOD patients have a high frequency of non-Hodgkin lymphoma and showed that despite similarities among SIOD and other DNA repair diseases, SMARCAL1-deficient cells do not have increased baseline DNA breaks detectable by comet assay. Additionally, SIOD patients do not have a detectable defect of nucleotide excision repair (NER), homologous recombination (HR) or nonhomologous end joining (NHEJ) to explain their ectodermal or immunological features, although Smarcal1-deficient mice are hypersensitive to several DNA damaging agents. Furthermore, my colleagues and I found that SMARCAL1 orthologues localize to transcriptionally active chromatin and modulate gene expression, that deficiency of the SMARCAL1 orthologues alone is insufficient to cause disease in fruit flies and mice, that SMARCAL1 deficiency causes modest diffuse alterations in gene expression, and that SMARCAL1 deficiency causes disease via interaction with genetic and environmental factors that further alter gene expression. In summary, our findings provide guidance for clinical management of SIOD and suggest that alterations in the variance of gene expression levels contribute to the penetrance of SIOD.

Magister Scientiae Dentium - MSc(Dent)
Ossifying fibroma (OF) is the most frequent of the three fibro-osseous lesions of the jaws. It occurs mostly in patients between the age of 20 and 40 years. Females are more commonly affected than males. Clinically, OF usually presents as a painless expansive intra-bony mass. Swelling and pain may be present in some cases while some lesions are discovered incidentally. Radiographically, OF is usually well-defined and unilocular or multilocular. Early lesions present as well-defined radiolucency that are small in size. Over time, the lesions tend to enlarge in size and become mixed radiolucent-radiopaque and finally become completely radiopaque. The aim of this study was to determine the clinical and radiological features of ossifying fibroma presenting at the Departments of Maxillo-Facial and Oral Surgery and Diagnostics and Radiology, University of the Western Cape Oral Health Centre as well as to assess its management and recurrence patterns. A retrospective case series analysis was performed of all histopathologically diagnosed ossifying fibroma cases available at the Departments of Maxillo-Facial and Oral Surgery and Diagnostics and Radiology at the Faculty of Dentistry, University of the Western Cape from 1976-2014. Patient's age, gender and ethnicity were recorded. The clinical presentation of the lesion as well as the history was analyzed. Radiographic features including density, size, shape, location, locularity and its effect on adjacent structures was noted. Management of each case and follow-up was also documented. A total 61 cases were included in the study. The majority of patients were females (63.9%) and below 40 years of age (73.9%). Few cases were symptomatic (29.5%) with an average period 22 months from first symptoms to presentation. The mandibular posterior region was most affected (55.5%) while larger lesions occurred more frequently in younger patients. Majority of lesions were radiopaque (49.2%) and had well-defined margins (93.6%). Most cases were managed by surgical curettage (68.2%). Following an average follow-up period of 20 months only one case recurred (recurrence rate =6.7%). In conclusion, the majority of the clinical and radiographic findings of ossifying fibroma were similar in South African patients as those of other populations. Differences include that the lesions in this population were more radio-opaque and larger in size than in the reported literature. Surgical curettage is an acceptable management protocol with low rate of recurrence.

Le syndrome de Dyggve-Melchior-Clausen (DMC) et la dysplasie de Smith-McCort (SMC) sont deux maladies génétiques rares qui se manifestent par des anomalies squelettiques identiques. Les patients DMC développent, en plus, une microcéphalie associée à un retard mental. Le gène impliqué dans ces deux dysplasies, DYM, a été identifié en 2003 et code la DYMECLINE, une protéine golgienne, capable de s'échanger entre l'appareil de Golgi et le cytosol dont la fonction est inconnue. Les objectifs de ce travail ont été de valider la souris déficiente pour Dym comme modèle de Patteinte cérébrale du syndrome DMC et d'exploiter ce modèle afin d'avancer dans la compréhension du rôle de la Dymecline dans le cerveau. Nous avons montré que, comme chez l'homme, la perte de fonction de la Dymecline entraine le développement d'une microcéphalie progressive. Nous n'avons pas décelé d'anomalies majeures de la structure corticale ni de diminution du potentiel prolifératif des progéniteurs neuraux ou d'augmentation de l'apoptose. En revanche nous avons mis en évidence une réduction de la surface de la substance blanche associée à une hypomyélinisation centrale. Au niveau cellulaire, les neurones présentent une fragmentation de l'appareil de Golgi et des anomalies de marqueurs vésiculaires. Par ailleurs, nous avons identifié une mutation de RAB33B chez un patient SMC. RAB33B code également une protéine golgienne qui jouerait un rôle régulateur dans le transport vésiculaire. Cette étude montre la pertinence de notre modèle pour étudier la microcéphalie associée au syndrome DMC et suggère un rôle de la Dymecline dans l'organisation du Golgi et le trafic vésiculaire
Dyggve-Melchior-Clausen syndrome (DMC) and Smith-McCort dysplasia (SMC) are rare autosomal recessive growth retardation disorders, which share identical skeletal features. DMC is systematically associated with microcephaly and mental retardation whereas SMC is not. A common responsible gene, DYM, was identified in 2003 and encodes DYMECLIN, a highly conserved protein that localizes to the Golgi apparatus and is able to shuttle between the Golgi and the cytoplasm but its biological function is unclear. The present work aims to determine whether the murine model deficient for Dym gene is relevant to study microcephaly in DMC and to provide insights into the function of Dymeclin in the brain. Results indicate that, as in humans, loss of Dymeclin function leads to progressive microcephaly. Although no major alteration in cortical organization was detected, we found a reduction of both the frontal cortex and the white matter. Proliferation and apoptosis were found normal in neural progenitors, but differentiated neurons display a fragmented Golgi apparatus and synaptic vesicles anomalies. In addition, we observed a reduced thickness of myelin sheaths in the corpus callosum. We have also identified a homozygous loss of function mutation in RAB33B in a SMC patient with no mutation in DYM, showing that SMC may be caused by mutations in either gene. Of interest, RAB33B is a small GTP-binding protein localized to the Golgi apparatus and known to play important roles in vesicular transport. This study indicates that the Dym mouse is a relevant model for studying the DMC microcephaly and suggests a role for DYMECLIN in Golgi homeostasis and vesicular trafficking

As lesões fibro-ósseas da região maxilomandibular constituem um grupo heterogêneo de patologias que incluem lesões de desenvolvimento, reativas (displásicas) e neoplásicas, sendo que as duas principais entidades incluídas neste grupo são a displasia fibrosa e o fibroma ossificante. Devido a grande similaridade histológica entre estas patologias a avaliação das características clínicas e imaginológicas, juntamente com os aspectos histopatológicos, são o principal método de diagnóstico diferencial, porém devido a presença de diferentes níveis de maturidade destas patologias, em diversos casos os componentes histológicos assim como seu ordenamento são muito semelhantes. A busca por um processo de diagnóstico histológico mais fundamentado, hoje inexistente, é justificada pela diferença do curso clínico assim como pela eleição do tratamento entre a displasia fibrosa e o fibroma ossificante. Desta forma o propósito deste trabalho foi realizar uma análise retrospectiva descritiva das características clínico-demográficas e histopatológicas, e estabelecer um critério de diagnóstico diferencial que associe algumas características histopatológicas padronizadas juntamente com uma análise imunoistoquímica dos fatores de atividade de remodelação óssea destas lesões. Desta forma foram aplicados diferentes marcadores proteicos e moleculares em casos previamente diagnosticados de displasia fibrosa e fibroma ossificante, objetivando direcionar um critério de diagnóstico mais preciso. Nesse estudo retrospectivo foram avaliados 54 casos, sendo 30 casos de displasia fibrosa e 24 casos de fibroma ossificante, definidos após uma revisão nas análises das lâminas seguindo um padrão com algumas particularidades histomorfológicas para o diagnóstico diferencial. As características histológicas utilizadas para essa diferenciação, baseadas na revisão da literatura, foram: 1- limite entre a lesão e o tecido ósseo adjacente; 2- depósitos esféricos basofílicos (calcificações cementóides); 3- espaços negativos limítrofes entre o tecido ósseo e o tecido conjuntivo; 4- intensidade da celularidade do estroma e; 5- paralelismo das trabéculas ósseas lesionais. Após a reavaliação das lâminas seguindo a padronização de diferenciação com os cinco critérios histológicos mencionados anteriormente, foram reconsiderados os diagnósticos de 7 lâminas, ou seja 12,96% das amostras apresentaram alteração no diagnóstico anatomopatológico inicial. Posteriormente foram utilizados os seguintes imunomarcadores proteicos e moleculares do metabolismo ósseo em 9 lâminas de fibroma ossificante e em 7 lâminas de displasia fibrosa: interleucina 6 (IL-6), osteoprotegerina (OPG), osteocalcina (OCN) e o ligante do receptor do ativador do fator nuclear Kappa B (RANKL). A imunoexpressão destes marcadores foi observada nos seguintes locais: osteócitos, osteoblastos, osteoclastos e no estroma. Apenas a osteoprotegerina apresentou significância estatística nos osteócitos, osteoblastos e osteoclastos. A osteoprotegerina no estroma e os demais marcadores não apresentaram significância estatística em nenhum dos locais.
The fibro-osseous lesions of the maxillomandibular region constitute a heterogeneous group of pathologies that include developmental, reactive (dysplastic) and neoplastic lesions, and the two main entities included in this group are fibrous dysplasia and ossifying fibroma. Due to the great histological similarity between these pathologies the evaluation of the clinical and imaging characteristics, together with the histopathological aspects, are the main method of differential diagnosis, however due to the presence of different levels of maturity of these pathologies, in several cases the histological components as well as their arrangement are very similar. The search for a more substantiated histological diagnosis process, which does not exist today, is justified by the difference in the clinical course as well as by the choice of treatment between fibrous dysplasia and ossifying fibroma. Therefore, the purpose of this study was to perform a descriptive retrospective analysis of the clinical-demographic and histopathological characteristics and to establish a differential diagnosis criterion that associates some standard histopathological characteristics together with an immunohistochemical analysis of the bone remodeling activity factors of these lesions. In this way different molecular and protein markers were applied in previously diagnosed cases of fibrous dysplasia and ossifying fibroma, aiming at directing a more precise diagnosis criterion. In this retrospective study, 54 cases were evaluated, 30 cases of fibrous dysplasia and 24 cases of ossifying fibroma, defined after a review in the analysis of the slides following a pattern with some histomorphological peculiarities for the differential diagnosis. The histological characteristics used for this differentiation, based on the literature review, were: 1- border between the lesion and the adjacent bone tissue; 2- basophilic spherical deposits (cementoid calcifications); 3 - borderline negative spaces between the bone tissue and connective tissue; 4- intensity of stroma cellularity; 5- parallelism of lesionous trabeculae. After the reassessment of the slides following the standardization of differentiation with the five histological criteria mentioned above, the diagnoses of 7 slides were reconsidered, that is, 12.96% of the samples presented alterations in the initial anatomopathological diagnosis. Subsequently, the following protein and molecular biomarkers of bone metabolism were used on 9 ossifying fibrous slides and on 7 fibrous dysplasia slides: interleukin 6 (IL-6), osteoprotegerin (OPG), osteocalcin (OCN) and the activator receptor ligand Of nuclear factor Kappa B (RANKL). Immunoexpression of these markers was observed at the following sites: osteocytes, osteoblasts, osteoclasts and in the stroma. Only osteoprotegerin presented statistical significance in osteocytes, osteoblasts and osteoclasts. The osteoprotegerin in the stroma and the other markers did not present statistical significance in any of the sites.

A research report submitted to the Faculty of Health sciences, University of the Witwatersrand, In conformity with the requirements for the degree of Master of Science in the branch of Oral Pathology School of Oral Health Science, Faculty of Health Sciences University of the Witwatersrand, South Africa Johannesburg, 2018.
Background: Cemento-osseous dysplasia (COD) is a non-neoplastic fibro-osseous lesion which occurs in the tooth-bearing regions of the jaw bones. In many instances the diagnosis of COD is based on the distinctive clinical and radiographic features of this disease. Since the affected bone in COD progressively becomes poorly vascularized, dental prophylaxis is of paramount importance to prevent pulpal and periodontal infection which typically trigger sequestrum formation in the affected bone. The aim of this study was to determine the clinico-pathological characteristics of COD in a South African population sample and to relate this to findings in the literature. Materials and methods: The study comprised a retrospective record review of archived documentation of COD. The histopathology reports of patients diagnosed with COD over the period spanning 1996 to 2015 were reviewed from the files of the Department of Oral Pathology, School of Oral Health Sciences, University of the Witwatersrand, Johannesburg. Results: Of the 23, 288 specimens submitted for histopathological examination 237 (1.02%) cases of COD were found. The mean age of the patients were 53.4 years ± 14.2 years with a 93.2% female predilection. COD mainly affected the mandible (62.4%), followed by involvement of both the maxilla and the mandible (24.5%), and maxilla (13.1%). Of the 143 patients with known COD subtypes florid COD predominated (65%) showing a clear trend of increasing with age, peaking in the 51-60 year age group and then decreasing thereafter. Cases of infected COD comprised 73.8% (174/237) of the COD study sample. Further 33% of all cases of chronic suppurative osteomyelitis (CSOM) in this study were seen in patients with COD. There was no significant association between any of the COD subtypes and CSOM (p > 0.05). Simple bone cysts presented as a complication of COD in 4.6% of cases. Conclusion: This study comprises the largest sample of COD cases thus far reported from South Africa. It showed a higher frequency of CSOM occurring as a complication of COD compared to earlier studies. No significant association was shown between any of the COD subtypes and CSOM.
LG2018

Objectives: This project explores the demographic and clinical presentation of cemento-osseous dysplasia (COD), and their pathognomonic radiographic features. Methods: Demographic and clinical data were collected from the charts of 118 subjects with COD from the Oral Radiology archives. Using a systematic objective survey instrument, 3 general dentists (GP) and 3 oral radiologists (RG) reviewed 50 image sets of COD and similarly-appearing entities. Participants were asked to identify radiographic features and to make a diagnosis based on the images provided. Results: The majority of cases occurred in clinically asymptomatic females in their fifth decade. RGs identified a well-defined border, radiolucent periphery, bilateral occurrence, mixed radiolucent/radiopaque internal structure, and association with anterior and posterior teeth as key features, correctly interpreting 79.3% of COD cases. The absence of root resorption and an association with anterior and posterior teeth were the only key features that guided GPs to correctly interpret 38.7% of COD cases.

Die Radiologie fungiert als wesentliches Instrument in der Diagnostik und Nachsorge fibro-ossärer Läsionen (FOL). Hierbei gewinnen überlagerungsfreie, dreidimensionale Aufnahmen aufgrund der im Kopf-Halsbereich vorhandenen hohen Dichte und Vielfalt anatomischer Strukturen und der damit einhergehenden Fülle von Differentialdiagnosen an Bedeutung. Anhand der Studie wurden die röntgenologischen Charakteristika von ossären Dysplasien (OD) und ossifizierenden Fibromen (OF) im dentalen Volumentomogramm herausgestellt, sowie diagnostische und therapeutische Vorteile der dentalen Volumentomographie (DVT) im Vergleich zur Orthopantomographie (OPG) und Computertomographie (CT) ermittelt und gegenübergestellt. Zu diesem Zwecke wurden anhand eines Fragebogens 18 Röntgenbildpaare (OPG-DVT) von FOL durch zehn Betrachter auf (A) deren röntgenologische Eigenschaften sowie Metallartefakte befundet und (B) deren Abbildungsqualität von sehr gut (1) bis schlecht (5) bzw. nicht beurteilbar bewertet. Insgesamt wurden 360 Analysebögen ausgewertet. Entitäts- und röntgentechnikspezifische Unterschiede wurden statistisch ermittelt. Die Abbildungsqualitäten der DVT und CT wurden auf Grundlage einer intensiven Literaturrecherche verglichen. Die Ergebnisse dieser Studie stellten signifikante Unterschiede in den röntgenologischen Eigenschaften von OD und OF heraus. Acht von zehn Strukturen zeigten in den DVT-Aufnahmen eine signifikant bessere Abbildungsqualität im Vergleich zu den OPG-Aufnahmen. Die teilweise gravierenderen Befunde in den DVT-Aufnahmen deuteten auf eine Unterinterpretation dieser Befunde im OPG hin. Die Literaturrecherche zu Gegenüberstellungen der Abbildungsqualitäten in CT und DVT wies nahezu ausnahmslos auf eine Überlegenheit der DVT hin.