Literatura científica selecionada sobre o tema "Malformations du crâne"

Background:Women with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) have greater risk of adverse obstetric and birth outcomes than women without these conditions. Infant outcomes are less well-studied. It is unknown whether re-hospitalization after delivery occurs more often for affected mothers and their infants.Objectives:We compared obstetric outcomes among women with and without RA or SLE, and birth outcomes among their infants. Maternal and infant rehospitalizations <2 years of delivery were also compared.Methods:This population-based cohort study used linked birth-hospital discharge data from Washington State for 1987-2014. International Classification of Disease 9th revision (ICD9) codes identified all women with RA (ICD9 714.X, 725.X) and SLE (ICD9 710, 710.0, 710.1) in the hospital discharge record at delivery, and a 10:1 comparison group of women without these codes. Analyses were restricted to singleton live births (1,223 RA; 1,354 SLE). Poisson regression with robust standard errors estimated relative risks (RR) and 95% confidence intervals (CI) for selected outcomes, accounting for delivery year, maternal age, and parity.Results:Many adverse outcomes were more common among RA and SLE cases than among comparison women. Preeclampsia occurred more often during pregnancies of women with RA (RR 1.42, 95% CI 1.17-1.71) or SLE (RR 2.33, 95% CI 2.01-2.70), as did preterm rupture of membranes (PROM, RR 2.85, 95% CI 2.20-3.72 for RA; RR 3.28, 95% CI 2.54-4.23 for SLE). Cesarean deliveries were more common among nulliparous women in both groups (RR 1.32, 95% CI 1.18-1.48 for both conditions). Infants of women with RA or SLE were more likely to weigh <2500 g (RR 2.08, 95% CI 1.72-2.52 for RA; RR 4.88, 95% CI 4.27-5.58 for SLE), be small for gestational age (RR 1.25, 95% CI 1.07-2.50; RR 2.30; 2.04-2.59, respectively), delivered at <32 weeks gestation (RR 1.83, 95% CI 1.13-2.97; RR 5.13, 95% CI 3.75-7.01, respectively), and require neonatal intensive care unit admission (NICU, RR 1.89, 95% CI 1.56-2.30; RR 2.71, 95% CI 2.25-3.28, respectively). Infants of women with SLE were more likely to have a malformation (RR 1.46, 95% CI 1.21-1.75) or die within 2 years (RR 2.11, 95% CI 1.21-3.67). Rehospitalization levels among both women with RA (RR 2.22; 1.62-3.04) and SLE (RR 2.78, 95% CI 2.15-3.59) were greatest <6 months of delivery and declined over time. Infants of women with SLE had increased rehospitalization <6 months (RR 1.64, 95% CI 1.36-1.98).Conclusion:Consistent with prior literature, we found women with RA or SLE experienced many adverse outcomes. In our data, these included preeclampsia, PROM, and cesarean deliveries, with increased risks more notable among women with SLE. Infants of women with either condition were more likely to weigh <2500g, be <32 weeks gestation, small for gestational age, and require NICU admission than infants of comparison women. Only infants of women with SLE had increased malformations. Maternal rehospitalization after delivery was more common in both groups; most marked at <6 months. Infant rehospitalizations were increased in both cohorts to a lesser extent. Close follow-up during this time period is crucial to minimize adverse outcomes.Disclosure of Interests:Julianna Sabo: None declared, Namrata Singh: None declared, Deborah A. Crane: None declared, David R. Doody: None declared, Melissa A. Schiff: None declared, Beth A. Mueller Shareholder of: Household owns shares in AstraZeneca

Abstract Vascular anomalies (VA), comprised of tumors and malformations, are a spectrum of disorders including benign and malignant lesions characterized by abnormal growth or development of vascular and/or lymphatic vessels that can affect any organ. If left untreated VA can be associated with substantial morbidity and mortality through disfiguration, organ dysfunction, hemorrhage, infection, and/or thrombosis. Correct diagnosis is critical to provide optimal management recommendations but is often challenging due to the phenotypic heterogeneity of these lesions. The biomarker angiopoietin-2 (ang-2), a member of a family of growth factors that regulate blood vessel growth and development, has previously been reported to be elevated in certain VA associated with coagulopathy, including Kaposiform hemangioendotheliomas (KHE) and Kaposiform lymphangiomatosis (KLA) (Le Cras TD, Angiogenesis 2017). Ang-2 levels have been reported to decrease in some patients in response to treatment with sirolimus (Le Cras TD, Angiogenesis 2017; Crane J, Pediatr Blood Cancer 2020). Based upon the published methodology, a clinical serum ang-2 assay was developed that employs a quantitative sandwich enzyme immunoassay technique using a monoclonal antibody specific for human ang-2. Age specific normal ranges for serum ang-2 were determined and were congruent with those first reported for the research assay (range: 1,434-4,141 pg/mL). Here we describe two VA cases in which the clinical ang-2 assay was utilized to aid diagnosis and to detect treatment response, replacing or limiting more invasive, expensive, and high-risk evaluations such as sedated imaging or surgical biopsy. Patient 1 presented at birth with a large purpuric tumor of the right leg associated with thrombocytopenia and hypofibrinogenemia concerning for Kasabach-Merritt phenomenon (KMP). MRI imaging was suggestive of KHE, and the diagnosis was confirmed by biopsy. He was started on methylprednisolone 0.8mg/kg q12h for 1 week and then tapered over 2 months. He was also started on sirolimus 0.4mg/m 2 q12h. His ang-2 serum level was elevated at diagnosis (23,674 pg/mL) and showed reductions over time (graph 1). His ang-2 level continued to decrease as steroids were weaned despite initially having increased swelling and discoloration of the tumor. His steroid wean was slowed; however, therapy was not escalated due to continued decreases in ang-2 levels. Clinically the patient is doing well 1-year post-diagnosis, with improvement in appearance of the tumor and without recurrence of KMP. Patient 2 is a 13-year-old male initially diagnosed at 5 years of age with generalized lymphatic anomaly (GLA) after presenting with acute respiratory failure secondary to significant pleural effusions, bony lesions, and splenic involvement. Prior attempts to classify his diagnosis by histology were inconclusive. He was treated with sirolimus, intermittent pulse steroids, celecoxib, and zoledronic acid, with suboptimal response to therapy. During puberty he presented with significantly increased coagulopathy (D-dimer 32,815 ng/mL and fibrinogen 62 mg/dL: ranges <500ng/mL and 150-400mg/dL respectively) and worsening pericardial and pleural effusions. The lesion was not clinically behaving as expected for GLA, with features suggestive of KLA. Serum ang-2 was measured as an additional diagnostic aid and was elevated at 8,903 pg/mL. GLA has not been reported to be associated with elevations in ang-2. Based on this new information his diagnosis was re-classified as KLA. He was started on weekly vincristine and trametinib, a mitogen activated protein kinase (MEK) inhibitor, with reported efficacy in treatment of KLA, replacing his sirolimus. After 2 months, there were improvement in coagulopathy (D-Dimer 23,306ng/mL and fibrinogen 154mg/dL) and decreasing ang-2 levels (graph 2). These cases demonstrate the potential utility of serum ang-2 as a diagnostic tool and biomarker to monitor response to treatment in selected patients with VA. Next steps are to evaluate ang-2 levels in an expanded group of VA to understand which diagnoses can be distinguished by elevated levels at baseline and how treatment impacts ang-2 over time. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Objective To determine whether children born with a cleft palate ± lip (CP ± L) and additional congenital differences (ACDs – including ‘Congenital malformations and deformations’ as coded in ICD-10), are less likely to meet the three national speech outcome standards at age five compared to children with CP ± L and no ACDs. Design An observational study, utilizing national data from the UK Cleft Registry and Audit NEtwork (CRANE) Database linked to national administrative data of hospital admissions. Setting National Health Service, England. Patients 2191 children (993 female, 1198 male) with CP ± L, born 2006-2012 in England, with complete speech data and consent to data linkage. Outcome Measure Perceptual speech analysis utilised the Cleft Audit Protocol for Speech – Augmented (CAPS-A) rating and United Kingdom National Speech Outcome Standards (Speech Standard 1 (SS1), Speech Standard 2a (SS2a) and Speech Standard 3 (SS3)). Results Of 2191 children, 759 (35%) had at least one ACD. Presence of one ACD did not significantly impact speech outcomes but two or more ACDs reduced the odds of achieving all three speech standards: SS1 aOR 0.602 (CI 0.45-0.82, P = .002), SS2a aOR 0.563 (CI 0.41-0.77, P = .001), SS3 aOR 0.606 (0.43-0.84, P = .003). When exploring ACDs by ICD-10 groupings, congenital malformations of the ‘Eye, ear, face and neck’, ‘Circulatory system’, ‘Digestive system’, ‘Musculoskeletal system’ and ‘Other congenital malformations’ reduced a child's odds of achieving the speech standards. Conclusions ACDs, in the absence of a known syndrome, have a significant impact on speech outcome at age five. Incorporating these factors into risk-adjustment models for service level outcome reporting is recommended.

Introdução: O recém-nascido (RN) é classificado como prematuro quando apresenta idade gestacional inferior a 37 semanas e peso de nascimento igual ou abaixo de 2.550g. Devido à imaturidade do sistema respiratório, o neonato está sujeito a apresentar diversas complicações, dentre elas, as respiratórias, o que ocasiona o seu prolongamento na unidade de terapia intensiva neonatal (UTIN). A fisioterapia respiratória é de grande importância no tratamento e recuperação do RN através da aplicação de técnicas de higiene brônquica (HB). O estudo teve como objetivo investigar os efeitos da fisioterapia respiratória no recém-nascido prematuro publicados na literatura científica. Materiais e Métodos: Trata-se de um a revisão integrativa realizada nas bases de dados Biblioteca Virtual em Saúde, LILACS, Medline, SciELO, SCOPUS e ISI Web of Knowledge, incluindo artigos publicados no período de 2007 a 2015. Oito artigos foram incluídos nesta revisão. Resultados e Discussão: A atuação da fisioterapia respiratória foi analisada mediante os efeitos da aplicação das técnicas de HB mais utilizadas no recém-nascido pré-termo (RNPT), podendo destacar a tapotagem, vibrocompressão, drenagem postural e aspiração. Foram realizadas comparações para comprovar a eficácia e os possíveis efeitos colaterais que pudessem alterar o funcionamento da mecânica respiratória do RN. Os estudos mostraram a efetividade da fisioterapia respiratória e os efeitos das manobras na condição respiratória do neonato de risco. Conclusão: A fisioterapia tem um papel importante no cuidado ao recém-nascido pré-termo, mas necessita de mais estudos que comprovem sua eficácia e sua importância na melhora da condição de vida do neonato.Descritores: Recém-Nascido; Nascimento Prematuro; Fisioterapia.ReferênciasNikolovi V. Congenital malformations and perinatal mortality at the Saint Antoine University Obstetric. Gynecologic Clinic. 1989;28(1):36-4.Oliveira RMS, Franceschini SCC, Priore SE. Avaliação antropométrica do recém-nascido prematuro e/ou pequeno para a idade gestacional. Rev Bras Nutr Clín. 2008;23(4):298-30.Calafiori L. Taxa de prematuridade no Brasil. 2014. Disponível em: <http://www.uicamp.br/ unicamp/noticias/2014/11/14/brasil-tem-40-partos -prematuros-por-hora>. Acesso em: 17 de mai.2016.Benício MHD, Monteiro CA, Souza JMP, Castilho EA, Lamonica IMR. Análise de fatores de risco para o baixo peso ao nascer em nascidos vivos do município de São Paulo. Rev Saúde Pública. 1985;19(4):311-20. Ramos HAC, Cuman RKN. Fatores de risco para prematuridade: pesquisa documental. Rev Enferm. 2009;13(2):297-304.Carvalho ML, Silver LD. Confiabilidade da declaração da causa básica de óbitos neonatais: implicações para o estudo da mortalidade prevenível. Rev Saúde Pública 1995;29(5):342-48.Mendonça EF, Goulart EMA, Machado JAD. Confiabilidade da declaração de causa básica de mortes infantis em região metropolitana do sudeste do Brasil. Rev Saúde Pública 1994;28(5):385-91.Ferrari LSL, Brito ASJ, Carvalho ABR, Gonzáles MRC. Mortalidade neonatal no município de Londrina, Paraná, Brasil, nos anos 1994,1999 e 2002. Cad Saúde Pública 2006; 22(5):1063-71.Ministério da Saúde. Atenção à saúde do recém-nascido. Guia para os profissionais de saúde. 2. ed. Brasília-DF; 2012. p.11-38.Lewis JA, Lacey JL, Henderson-Smart DJ. A review of chest physiotherapy in neonatal intensive care units in Australia. J Paediatr Child Health. 1992;28(4):297-300.Graziela MM, Abreu CF, Miyoshi MH. Papel da fisioterapia respiratória nas doenças respiratórias neonatais. Clin Perinatol. 2010;1(1):145.Etches PC, Scott B. Chest physiotherapy in the newborn: effect on secretions removed. Pediatrics. 1978;62(5):713-15.All-Alaiyan S, Dyer D, Khan B. Chest physiotherapy and pós-extubation atelectasis in infants. Pediatric Pulmonol. 1996;21(4):227-30.Azeredo CAC. Fisioterapia respiratória atual. Rio de Janeiro: Edusuam; 1986.Azeredo CAC. Fisioterapia respiratória moderna. São Paulo: Editora Manole; 1993.Costa D. Fisioterapia respiratória básica. São Paulo: Editora Atheneu; 1999.Flenady VJ, Gray BH. Chest physiotherapy for preventing morbidity in babies being extubated from mechanical ventilation. Cochrane Database Syst Rev 2000;(2):CD000283. Guy P. Groupe d´ Étude Pluridisciplinaire Stéthacoustique. Novas técnicas de fisioterapia. 2013. Available from:<http://www.postiaux.com/pt/methode.html>. Acesso em 17 de mai.2016.Nicolau CM, Lahóz AL. Fisioterapia respiratória em terapia intensiva pediátrica e neonatal: uma revisão baseada em evidências. Pediatria. 2007;29(3):216-21.Barbosa LR, Melo MRAC. Relações entre qualidade da assistência de enfermagem: revisão integrativa da literatura. Rev Bras Enferm. 2012;61(3):366-70.Souza MT, Silva MD, Carvalho R. Revisão integrativa: o que é e como fazer. Einstein. 2010;8(1):102-6.Piva JP, Garcia PCR. Insuficiência Respiratória Aguda. IN: Piva JP, Carvalho P, Garcia PCR. Terapia Intensiva em Pediatria. Medsi: Rio de Janeiro; 2009.p.163.Nicolau CM, Falcão MC. Influência da fisioterapia resiratória sobre a função cardiopulmonar em recém-nascido de muito baixo peso. Rev Paul Pediatr. 2010; 28(2):170-75.Souza JAQ, Moran CA. Fisioterapia respiratória em recém-nascidos pré-termo: ensaio clínico randomizado. Rev Bras Med. 2013;49(11):434-38.Antunes LCO, Silva EG, Bocardo P, Daher DR, Faggiotto RD, Rugolo LMSS. Efeitos da fisioterapia convencional versus aumento do fluxo expiratório na saturação de O2, freqüência cardíaca e freqüência respiratória em prematuro no período pós-extubação. Rev bras fisioter. 2006; 10(1):97-103.Nicolau CM, Falcão MC. Efeitos da fisioterapia respiratória em recém-nascidos: análise crítica da literatura. Rev Paul Pediatria. 2007;25(1):72-5.Santos MLM, Souza LA, Batiston AP, Palhares DB. Efeitos de técnicas de desobstrução brônquica na mecânica respiratória de neonatos prematuros em ventilação pulmonar mecânica. Rev. bras. ter. intensiva . 2009;21(2):183-89. Martins AP, Segre CAM. Fisioterapia respiratória em neonatologia: importância e cuidados. Pediatr mod. 2010;46(2):56-60.Johnston C, Zanetti NM, Comaru T, Ribeiro SNS, Andrade LB, Santos SLL. I Recomendação brasileira de fisioterapia respiratória em unidade de terapia intensiva pediátrica e neonatal. Rev bras ter intensiva. 2012;24(2):119-29.De Paula LC, Ceccon ME. Análise comparativa randomizada entre dois tipos de sistema de aspiração traqueal em recém-nascidos. Rev Assoc Med Bras. 2010;56(4):434-39.Gonçalves RL, Tsuzuki, LM, Carvalho, MGS. Aspiração endotraqueal em recém-nascidos intubados: uma revisão integrativa da literatura. Rev bras ter intensiva. 2015;27(3):284-92.American Association for Respiratory Care. AARC Clinical Practice Guidelines. Endotracheal suctioning of mechanically ventilated patients with artificial airways. Respir care. 2010;55(6):758-64.Rosa FK, Roese CA, Savi A, Dias AS, Monteiro MB. Comportamento da mecânica pulmonar após a aplicação de protocolo de fisioterapia respiratória e aspiração traqueal em pacientes com ventilação mecânica invasiva. Rev bras ter intensiva. 2007;19(2):170-75.Pederson CM, Rosendahl-Nielsen M, Hjermind J, Egerod I. Endotracheal suctioning of the adult intubated patiente—what is the evidence? Intensive Crit Care Nurs. 2009;25(1):21-30Gonçalves RL, Tsuzuki LM, Carvalho MGS. Aspiração endotraqueal em recém-nascidos intubados: uma revisão integrativa da literatura. Rev bras ter intensiva. 2015;27(3):284-92.Selsby DS. Chest physiotherapy. BMJ. 1989; 298(6673):541-42.Ferreira ACL, Troster EJ. Atualização em terapia intensiva pediátrica. Rio de Janeiro: Interlivros; 1996.Holloway R, Adams EB, Desai SD, Thambiran AK. Effect of chest physiotherapy on blood gases of neonates treated by intermittent positive pressure respiration. Thorax. 1996;24(4):421-26.Wood BP. Infant ribs: gereralized periosteal reaction resulting from vibrator chest physiotherapy. Radiology. 1987;162(3):811-12.Raval D, Yeh TF, Mora A. Chest physiotherapy in preterm infants wih RDS in the first 24 hours of life. J Perinatol. 1987;7(4):301-4.Juliani RCTP, Lahóz ALC, Nicolau CM, Paula LCS, Cunha MT. Fisioterapia nas unidades de terapia intensiva pediátrica e neonatal. Programa Nacional de educação continuada em Pediatria. PRONAP 2003/2004; 70: 9-24.Gava MV, Picanço PSA. Fisioterapia pneumológica. São Paulo: Manole; 2007.Figueira F. Pediatria. 3. ed. Rio de Janeiro: Guanabara Koongan; 2004.Crane LD, Zombek M, Krauss NA, Auld PA. Comparison of chest physiotherapy techniques in infants with RDS. Pediatr Res.1978;12:559A.Duara S, Bessard K, Keszler L. Evaluation of different percussion time intervals at chest physiotherapy on neonatal pulmonary function parameters. Pediatr Res. 1983;17:310A.Tudehope DI, Bagley C. Techniques of physiotherapy in intubated babies with the respiratory distress syndrome. Aust Paediatr J. 1980;16(4):226-28.Selestrin CC, Oliveira AG, Ferreira C, Siqueira AAF, Abreu LC, Murad N. Avaliação dos parâmetros fisiológicos em recém-nascidos pré-termo em ventilação mecânica após procedimentos de fisioterapia neonatal. Rev bras crescimento desenvolv hum. 2007;17(1):146-55.Nicolau CM. Estudo das repercussões da fisioterapia respiratória sobre a função cardiopulmonar em recém-nascido pré-termo de muito baixo peso [dissertação]. São Paulo: Faculdade de Medicina USP; 2006.Cuelo AF, Arcodaci CS, Feltrim MIZ. Broncoobstrução. São Paulo: Panamericana. 1987.Curran LC, Kachoyeanos MK. The effects of neonates of two methods of chest physical therapy. Mothercraft Nursing. 1979;4:309-13.Oliveira LRC. Padronização do desmame da ventilação mecânica em Unidade de Terapia Intensiva: resultados após um ano. Rev bras ter intensiva. 2006;18(2):131-36.Finer NN, Boyd J. Chest physiotherapy in the neonate: a controlled study. Pediatrics. 1978; 61(2):282-85.Alcântara PC, Filho JOS, Lima TCP. Atuação da fisioterapia respiratória em recém-nascido com a síndrome do desconforto respiratório. Revisão da literatura. EFDeportes.2015;19(202).Goto K, Maeda T, Mirmiram M; Ariagno R. Effects of prone and supine position on sleep characteristics in preterm infants. Psychiatry Clin Neurosci. 1999, 53(2):315-17.Lanza FC, Gazzotti MR, Luque A, Cadrobbi C, Faria R, Solé D. Fisioterapia respiratória em lactantes com bronquiolite: realizar ou não? Mundo Saúde. 2008;32(2):183-88.Haddad ER, Costa LCD, Negrini F, Sampaio LMM. Abordagens fisioterapêuticas para remoção de secreções das vias aéreas em recém-nascidos: relato de casos. Pediatria. 2006;28(2):135-40.

Les rétrognathies avec ou sans séquence de Pierre Robin sont des malformations rares de la face associant une sysmorphie faciale et des troubles fonctionnels. Le diagnostic prénatal reste difficile malgré le développement de l'échographie. La céphalométrie radiologique est l'outil de référence pour le diagnostic des dysmorphies faciales et l'étude de la croissance. Pour être appliquée au prénatal elle doit être adaptée à l'échographie et tenir compte de la croissance fœtale de la face. Notre étude a consisté à modéliser la croissance fœtale des trois composantes fonctionnelles du développement craniofacial : base du crâne, massif facial et cavité nasale, mandibule et cavité orale. Le travail anatomique a étudié la croissance et les rapports maxillo-mandibulaires dans le plan sagittal chez 18 fœtus répartis sur la période fœtale. La partie préchordale de la base du crâne et le massif facial ont une vitesse de croissance constante alors que la croissance verticale de la cavité orale s'accélère à la fin du troisième trimestre. Le décalage maxillo-mandibulaire tend à augmenter pour être de 7° en fin de troisième trimestre. Les principaux repères anatomiques de la céphalométrie sont retrouvés sur la coupe sagittale de l'échographie morphologique. Le décalage maxillo-mandibulaire échographique était de 8° en moyenne (n=52). A partir de nos données nous proposons une étude clinique pour valider la céphalométrie échographique fœtale et la comparer avec les données fonctionnelles postnatales. Nous pensons que notre modèle fonctionnel permettra de mieux articuler les différentes explications de la croissance faciale et de comprendre le rôle de la fonction sur la morphologie faciale

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<br>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

FOXL2 est un facteur de transcription à domaine forkhead de liaison à l’ADN. Chez l’homme, les mutations de FOXL2 sont responsables du syndrome du Blépharophimosis-Ptôsis-Epicantus-inversus (BPES), pathologie génétique à transmission autosomique dominante caractérisée par des malformations cranio-faciales et parfois par une insuffisance ovarienne prématurée (IOP). Le gène FOXL2 s’exprime dans les cellules de la granulosa, il est un des marqueurs précoces du développement ovarien. Il semble jouer un rôle majeur dans la mise en place et le maintien du stock de follicules disponibles. De plus, il est exprimé dans les tissus péri-oculaires, expliquant les malformations palpébrales observées chez les patients. De plus, FOXL2 possède une répétition de 14 alanines conservée chez les mammifères. Dans un premier temps, nous avons montré que la taille de la polyalanine influait sur la localisation subcellulaire de la protéine, sa solubilité et son activité. Nous avons mis en évidence que les conséquences cellulaires étaient dépendantes de la taille de l’expansion de la polyalanine. Enfin, nous avons montré que les promoteurs cibles de FOXL2 présentaient des sensibilités différentes aux expansions. Dans un second temps, nous nous sommes intéressés au fait qu’à l’heure actuelle lorsqu’une jeune patiente se présente avec un BPES il est impossible de prédire les risques d’IOP encourus. Nous avons développé une méthode d’analyse permettant de prédire le type de BPES connaissant la mutation portée par la patiente. Ces études ont non seulement permis de mieux comprendre la physiopathologie moléculaire de la maladie mais aussi permis une avancée dans la prise en charge des malades<br>FOXL2 is a transcription factor with a forkhead DNA binding domain. In humans, mutations of FOXL2 are responsible for the Blepharophimosis-Ptosis-Epicantus-inversus syndrome (BPES), characterized by craniofacial abnormalities and sometimes premature ovarian failure (IOP). The FOXL2 gene is expressed in granulosa cells, it is an early marker of ovarian development. It seems to play a major role in the establishment and maintenance of ovarian follicles stock. Moreover, it is expressed in eyelids, explaining the malformations observed in patients. Furthermore, FOXL2 has a repetition of 14 alanines conserved in mammals. Initially, we showed that the size of the polyalanine affected the subcellular localization of the protein, its solubility and its activity. We have demonstrated that the cellular effects were dependent on the size of the polyalanine expansion. Finally, we showed that the FOXL2 target promoters showed different sensitivities to expansions. In a second step, we are interested in the fact that currently when a young patient presents with BPES it is impossible to predict the risk of IOP incurred. We have developed an analytical method to predict the type of BPES knowing the mutation carried by the patient. These studies have not only helped to better understand the molecular pathophysiology of the disease but also enabled a breakthrough in the care of patients

L’apparition de la tête au cours de l’évolution des chordés semble coïncider avec l’émergence d’une population cellulaire embryonnaire propre aux vertébrés, les cellules dérivées de la crête neurale céphalique (CCNC). Au cours du développement, ces cellules contribuent à la formation des structures squelettiques des mâchoires au sein du 1er arc pharyngé (AP1). Les muscles qui permettent la mastication dérivent, par contre, d’une autre population cellulaire de l’AP1, les cellules du mésoderme myogénique céphalique (CMMC). Des travaux précédant le début de ma thèse avaient montré le rôle central des CCNC dans la détermination, l’arrangement et la différenciation des CMMC en muscles crâniofaciaux. Pourtant la nature de la communication entre les CCNC et les CMMC restait à élucider. Le but de mes travaux était donc de comprendre comment les CCNC et les CMMC interagissent et parviennent à se coordonner de manière harmonieuse pour générer le système squeletto-musculaire qui assure la fonctionnalité des mâchoires. Les gènes à homéoboîte Dlx5 et Dlx6 sont exprimés par les CCNC et déterminent l’identité squelettique maxillo-mandibulaire; leur activation dépend du signal endothéline-1 (Edn1) via son récepteur EdnRA. Afin de comprendre les mécanismes par lesquels les CCNC orchestrent la myogenèse crâniofaciale des vertébrés, j’ai analysé l’effet de l’inactivation des gènes Dlx5/6 et EdnRA chez la souris sur la muscularisation des mâchoires. Mes résultats démontrent que l’expression de Dlx5/6 dans les CCNC est essentielle au maintien du programme myogénique des CMMC à l’origine de la formation des muscles masticateurs. Les gènes Dlx5/6 ont donc un rôle crucial dans la coordination du développement des structures squelettiques et musculaires des mâchoires. L’expression des gènes Dlx au sein de l’AP1 aurait pu être à l’origine de l’apparition de mâchoires fonctionnelles chez les vertébrés. La genèse d’une bouche muscularisée sous le contrôle des gènes Dlx aurait permis la transition d’un mode de nutrition passif par filtration à un mode de nutrition plus actif de prédation au cours de l’évolution des chordés. Les syndromes du premier arc sont un large spectre d’anomalies congénitales de la face issues d’un défaut de développement des CCNC de l’AP1. Chez les patients, les malformations squelettiques mandibulaires observées à la naissance sont accompagnées d’hypoplasies ou agénésies des muscles masticateurs. Pourtant, aucune explication n’a été proposée pour cette association entre anomalies osseuses et musculaires. En extrapolant les résultats obtenus chez la souris, je propose que les malformations des muscles masticateurs observés chez ces patients dérivent de défauts de communication entre les CCNC et les CMMC au cours du développement embryonnaire précoce. En conclusion, l’ensemble de mes travaux a permis de mettre en lumière le rôle organisateur des CCNC dans la muscularisation des mâchoires. J’ai pu proposer de nouvelles hypothèses sur l’implication de l’interaction CCNC-CMMC pour l’origine de la prédation chez les chordés et pour l’étiologie de certaines malformations de la face chez l’enfant<br>The appearance of the head during chordate evolution seems to coincide with the emergence of an embryonic cellular population specific to vertebrates, the cephalic neural crest cells (CNCCs). During development, CNCCs give rise to the skeletal structures of the jaws within the 1st pharyngeal arch (PA1). In contrast, masticatory muscles derive from another PA1 cellular population, the cephalic myogenic mesodermal cells (CMMCs). A study appeared before the beginning of my thesis had shown that CCNCs play a central role in the determination, the patterning and the differentiation of CMMCs in craniofacial muscles. However, the nature of the communication between CCNCs and CMMCs remained still obscure. The aim of my work was to understand how CCNCs and CMMCs interact to generate the functional skeletomuscular system of the jaws. The two homeobox genes Dlx5 and Dlx6 are expressed by CCNCs and determine maxillomandibular skeletal identity; their activation depends on endothelin-1 signaling (Edn1) via its EdnRA receptor. In order to elucidate the mechanisms by which CCNCs orchestrate head myogenesis in vertebrates, I analyzed the effects of Dlx5/6 and EdnRA inactivation on jaw muscularization in the mouse. My results show that the expression of Dlx5/6 in CCNCs is crucial to maintain the CMMCs myogenic program at the origin of the masticatory muscle formation. Therefore, the expression of Dlx5 and Dlx6 seem to be essential to coordinate the development of skeletal and muscular structures of the jaws. Dlx expression within the PA1 could have been at the origin of the appearance of functional jaws during vertebrate evolution and would have allowed the transition from passive filter feeding to active predation in chordates. First arch syndromes are a broad spectrum of craniofacial congenital anomalies resulting from a defect of CCNC development in the PA1. In these patients, the mandibular skeletal malformations observed at birth are accompanied by hypoplasia or agenesis of masticatory muscles, however no explanation has been proposed for the association between bone and muscular anomalies. Extrapolating the results obtained in the mouse, I propose that the masticatory muscle malformations observed among these patients derive from communication defects between CNCCs and CMMCs during early embryonic development. In conclusion, my work permits to shed new light on the organizing role of CCNCs in the muscularization of jaws. These findings led me to propose new hypotheses on the importance of CNCCs-CMMCs interaction for the origin of predation in chordates and for the etiology of certain craniofacial congenital malformations

Le rat Dumbo présente un aspect malformatif évoquant certains syndromes crânio-faciaux humains. La compréhension du phénotype Dumbo pourrait expliquer les événements cellulaires et moléculaires à l’origine de ces syndromes. Le données recueillies chez le rat Dumbo et comparées à celles du rat Wistar sont susceptibles de constituer de précieuses informations éventuellement transposables à l’espèce humaine.<p><p>La première étape de cette étude a consisté en des analyses morphologiques et morphométriques afin de vérifier les perturbations morphologiques communes entre les rats Dumbo et les syndromes malformatifs humains :la brièveté des os zygomatique, maxillaire, mandibulaire et la position basse des oreilles. Ces analyses ont été réalisées sur les squelettes embryonnaires âgés de 16 jours à 21 jours de rats Dumbo et Wistar à l’aide d’une coloration in toto au Bleu Alcian – Alizarine. La deuxième étape de cette étude consistait en une analyse cytogénétique. Pour ce faire, nous avons établi le caryotype du rat Dumbo et nous l’avons comparé avec le caryotype du rat Wistar. L’étape suivante fut de procéder à l’analyse histologique des malformations crânio-faciales chez le rat Dumbo en observant la chondrogenèse pendant la morphogenèse crânio-faciale. Enfin, l’examen de l’expression des gènes Msx1 sens (S) ,Msx1 antisens (AS) et Dlx1 dans l’extrémité céphalique des rats Dumbo a été réalisé par les techniques de RT–PCR (Reverse Transcription Polymerase Chain Reaction method). Des estimations semi-quantitatives ont été validées en utilisant des dilutions ADNc du rat Wistar. Des densitométries de la densité d’amplicons fluorescence ont été réalisées à l’aide du logiciel VilberLourmat Bio1D software.<p><p>Les résultats obtenus ont permis de caractériser de manière précise les malformations crânio-faciales chez le rat Dumbo.<p> <p>1-\<br>Doctorat en Sciences biomédicales et pharmaceutiques<br>info:eu-repo/semantics/nonPublished

Aujourd’hui, les modèles numériques sont couramment utilisés dans le monde de la recherche, mais aussi de l’industrie, de la santé, de la finance, etc… La qualité du résultat sera toujours liée à la finesse et à la précision avec laquelle l’ingénieur est capable de formaliser les phénomènes physiques rencontrés. Dans le cadre plus spécifique de la modélisation biomécanique, énormément de paramètres rentrent en compte, rendant très compliquée la standardisation des modèles. Cette thèse s’inscrit donc dans une démarche d’amélioration de la qualité des modèles numériques du crâne humain au travers de plusieurs études ayant pour objectif d’analyser les paramètres morphologiques du crâne et de les utiliser pour la personnalisation d’un modèle morpho-mécanique. La méthode de scan par micro-tomographie a été utilisée pour scanner plus de 360 échantillons prélevé sur 10 crânes, puis des essais mécaniques de compression quasi-statiques et dynamiques ont été menés sur une partie de ces échantillons. Les résultats obtenus ont permis de développer une carte d’évolution d’un certain nombre de paramètres morphologiques du crane basés sur un modèle polynomiale. Une étude comparative statistique a permis de mettre en évidences les liens existants entre la morphologie et le comportement mécanique de ces échantillons. Au final, la liaison de ces deux études a permis de proposer un modèle morpho-mécanique personnalisable, puis de le valider pour différentes simulations éléments finis sur des échantillons osseux et sur une voute crânienne complète<br>Today, the digital models are usually used in the world of research, but also in industry, health, finance, etc.… The quality of the results will always be connected to the accuracy with which the engineer is able of formalizing the physical phenomena. More specifically in the biomechanical modelling, working with a high number of parameters, making very complicated the standardization of the models. This thesis has an approach of improvement in the quality of the digital models of the human skull through several studies having for aim the analysis of the morphological parameters of the skull and their use for the personalization of a morpho-mechanical model.The method of scan by micro-tomography was used to scan more than 360 samples taken from 10 skulls, and then mechanical tests of compression in quasi-statics and dynamics were led on a part of these samples. The results we obtained allowed us to develop a card of evolution of a number of morphological parameters of the skull based on a polynomial model. A statistical comparative study allowed to highlight the existing links between the morphology and the mechanical behaviour of these samples. Finally, the connection of these two studies allowed to propose a customizable morpho-mechanical model, and to validate it for various finite elements simulations on bones samples and on complete human skull

Le syndrome de Hallermann-Streiff (HSS) est un trouble du développement extrêmement rare qui se caractérise par un vieillissement prématuré, une microcéphalie, une microphtalmie, des cataractes congénitales, un nez en bec et une petite taille harmonieuse. Jusqu’à présent, aucune étude n’a pu mettre en évidence la survenue de cette pathologie ainsi quelles mutations intervenant dans l’apparition de HSS demeurent inconnues. Mon projet de thèse avait pour but de découvrir de nouveaux gènes chez des patients HSS n’ayant aucun défaut génétique connu. J’ai pu mettre en évidence quatre variants de novo dans les gènes COL3A1, MYH4, SUCNR1 et UGT2B4 chez un patient HSS et j’ai également détecté une mutation de novo dans le gène SCAF1 chez un autre patient. A l’exception de COL3A1, les gènes identifiés n’ont été associés à aucun défaut de développement et les variants retrouvés ont été prédits comme bénins par les outils in sillico. Cependant, il semble toutefois très probable que le variant de COL3A1 soit impliqué dans l’apparition de HSS, c’est pourquoi des recherches plus approfondies seront nécessaires pour confirmer sa pathogénicité. Récemment, des analyses de séquençage complet de l’exome ont révélé, chez quatre patients HSS non apparentés, les premiers variants candidats au niveau des gènes SMC2, SMC4, CHD6 et FAM111. Mon travail a eu pour but de prouver l’implication de ces gènes dans l’étiologie de HSS. J’ai démontré que ces gènes candidats étaient co-régulés aux niveaux transcriptionnel et traductionnel. De plus, j’ai établi le fait que la plupart des gènes dérégulés dans HSS avaient un rôle dans des processus liés à l’ADN, dont la ségrégation des chromosomes sœurs et la réplication de l’ADN. Mes résultats obtenus au cours de ma thèse, renforcent fortement l’implication de ces gènes dans la pathologie ainsi que la probabilité que cette dernière soit liée à la chromatine. Par ailleurs, j’ai pu montr que la diminution de la longueur des télomères ainsi que des défauts de prolifération cellulaire étaient associés à HSS, en accord avec l’aspect progéroïde du syndrome. L’ensemble de mes résultats, ont permis de mettre en évidence et pour la première fois les dérégulations génétiques survenus chez tous les patients HSS ainsi que les mécanismes physiologiques pathogènes qui sont à l’origine de son apparition<br>Hallermann-Streiff syndrome (HSS) is an extremely rare developmental disorder characterized by premature aging, microcephaly, microphtamia, congenital cataracts, beaked nose, and proportionate short stature. Until now, the causative mutations in HSS remain unknown. My PhD work aimed to unravel novel genes in the HSS patients with unknown molecular basis. I revealed four de novo variants in the COL3A1, MYH4, SUCNR1, and UGT2B4 in one HSS patient. In another HSS patient, I detected a de novo mutation in the SCAF1 gene. Except for COL3A1, the identified genes have never been associated any developmental disorder and the variants were predicted as benign by the in silico tools. The null COL3A1 variant however seems most likely to be involved in HSS. Further investigations are required to confirm the pathogenicity of the detected variant in HSS. Recently, trio-based whole exome sequencing (WES) revealed the first candidate variants in the SMC2, SMC4, CHD6, and FAM111A genes in four unrelated HSS patients. My PhD work aimed to investigate the actual involvement of the genes in the etiology of HSS. I demonstrated that the candidate genes co-regulate at the transcriptional and protein levels. Furthermore, I established that most genes dysregulated in HSS are involved in DNA related process including sister chromosome segregation and DNA replication. My findings strongly reinforce the involvement of the genes in the disorder and point to the likelihood of HSS as a chromatin-related disease. Moreover, I revealed that telomere length attrition and impaired cellular proliferation are associated to HSS, consistently with the progeroid features present in the disorder. Altogether, my work revealed the first common features in HSS and shed light onto the pathogenic mechanisms that account for the disease

Arnold Chiari type I malformation (CM-I) is a genetic disease first described in 1891 by Hans Chiari (SCHIJMAN, 2004). CM-I is characterized by the descent of the cerebellar tonsils more than 5 mm from the lower margin of the foramen magnum, which can impede the flow of cerebrospinal fluid (CSF) and is often associated with syringomyelia (BALL; CRONE, 1995; ROMERO-LUNA et al., 2022), generating great clinical neurological interest due to the difficulty in diagnosis (MORO et al., 1999).

Arnold Chiari type I malformation (CM-I) is a genetic disease first described in 1891 by Hans Chiari (SCHIJMAN, 2004). CM-I is characterized by the descent of the cerebellar tonsils more than 5 mm from the lower margin of the foramen magnum, which can impede the flow of cerebrospinal fluid (CSF) and is often associated with syringomyelia (BALL; CRONE, 1995; ROMERO-LUNA et al., 2022), generating great clinical neurological interest due to the difficulty in diagnosis (MORO et al., 1999).