Objective: To investigate the association of previously reported single nucleotide polymorphisms (SNPs) in relation to orofacial clefts and assess their interaction with environmental factors. Methods: Genome-wide SNP genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate SNPs were selected from a previous genome-wide association study (Shi et al., 2012) along with surrounding SNPS for a total of 2142 genotyped and imputed SNPs. A total of 411 case-parent triads and 25 case-parent dyads were analyzed using log-linear models to test for maternal and parent-of-origin effects along with their interaction with maternal smoking and maternal folic acid consumption. Results: A significant association (q = 0.025) was detected for a region in the ATXN3 gene. This significance refers to the interaction between maternal periconceptional smoking and maternal genetic effects. Nominally significant associations in genes relating to the brain were also detected. Conclusion: SNPs in the ATXN3 region warrant further investigation.

Orofacial clefts (OFCs) are among the most common structural birth defects and a public health problem. Several studies suggest that maternal obesity pre-existing diabetes mellitus (DM), and the underlying metabolic abnormalities, may be involved in the pathogenesis of cleft lip (CL) and cleft palate (CP) birth defects. Although hypertension and gestational diabetes mellitus (GDM) have been associated in a few studies with congenital birth defects, studies examining the risk associated with OFCs are limited. The overall objective of this dissertation was to examine the association between maternal obesity, DM, GDM, and hypertension and the risk of OFCs in case-control studies. Analyses of data from an international consortium revealed that maternal obesity (pre-pregnancy BMI >30), compared to normal weight (18.525), was associated with an increased risk of cleft palate with or without cleft lip (CP/L) (adjusted odds ratio (aOR) =1.13 [95% confidence intervals (CI) 1.01-1.25]). We also found a marginal association between maternal underweight and CP/L (1.0 [reference]; aOR=1.14 [0.97-1.34]. CL only was not associated with maternal bodyweight. Interestingly, among college-graduates, there was no increased risk of CP, but mothers with less than a completed college education had an increased risk of CP for underweight and obesity. Investigation of the Utah OFC data provided evidence that maternal GDM is significantly associated with isolated (aOR=2.63 [1.30-5.34]) and non-isolated clefts (aOR=2.66 [1.02-6.97]). Maternal hypertension is significantly associated with non-isolated clefts (aOR=6.56 [2.18-19.77]). We found a further elevated risk of OFCs among GDM mothers and those with hypertension who were also obese. The analyses of data from an international consortium revealed significant associations between maternal diabetes and the risk of OFCs. The estimated relative risk of DM for isolated OFCs was 1.33 [1.14-1.54] and was slightly higher for multiple OFCs (aOR=1.86 [1.44-2.40]). Diabetic mothers with abnormal body-mass-index had an increased risk for having inborn with OFCs. Throughout the dissertation, we demonstrated the extent in which maternal obesity, pre-existing DM, GDM, and maternal hypertension may increase the risk of OFC birth defects. The results highlight the need for pre-conceptional program planning for the prevention of OFCs with screening for abnormal glucose tolerance and hypertension.

Association of type and severity of nonsyndromic OROFACIAL CLEFTS with combined genotypes of RFC1 80 GA, MTHFR 677 CT, IRF6 rs642961 and rs2235371 gene polymorphisms in an Indian population Abstract By Chantal Hakim University of the Pacific. Arthur Dugoni School of Dentistry 2020 Introduction. Genetic etiology of nonsyndromic orofacial clefts comprises many genes acting together. However, little is known about their interactions. The purpose of our study was to analyze associations of phenotypic subtypes of nonsyndromic orofacial clefts with combinations of four genotypes involving candidate gene polymorphisms. Materials and Methods. We analyzed a large dataset of cases and controls collected in one location (Karaikal in India) and genotyped for four gene polymorphisms: RFC1 G80A, MTHFR C677T, IRF6 GA rs642961 and IRF6 CT rs2235371 (IRB approval Nr. 17-118 for existing data). The samples were tested for Hardy-Weinberg genetic equilibrium. Combinations of genotypes in cleft subsamples were compared with controls using Odds Ratio and Confidence Interval (95% significance level) calculations. Results. The Hardy-Weinberg equilibrium test showed that all samples were in genetic equilibrium. Some combinations of RFC1 G80A, MTHFR C677T, IRF6 GA rs642961 and IRF6 CT rs2235371 yielded increased or decreased Odds Ratio (OR>1 or OR<1).This means that subtypes of orofacial clefts were differentially determined by genotype combinations of four gene polymorphisms. Conclusions. Our results suggest that combinations of gene polymorphisms may modulate genetic risk in subtypes of nonsyndromic orofacial clefts. Such studies seem to be important for development of a general procedure and how a prevention plan for a specific location needs to be prepared, which data needs to be collected and which analyses need to be performed.

No description available.

Hintergrund: Zahlreiche Studien beschreiben weltweit eine Zunahme angeborener Fehlbildungen. Diese sind in Deutschland die häufigste Todesursache im frühen Kindesalter. Die hier vorliegende Studie untersuchte lokale und nationale Trends der Prävalenz von Gastroschisis, Omphalozele, Spina bifida und orofazialen Spaltbildungen von 2000 bis 2010. Methoden: Die Prävalenz der 4 Fehlbildungen wurde im Zeitraum Januar 2000–Dezember 2010 mithilfe von 4 Datenquellen aus Leipzig, Sachsen, Sachsen-Anhalt und Deutschland untersucht. Ergebnisse: Die Prävalenz der Fehlbildungen betrug im Untersuchungszeitraum in Deutschland bzw. in Sachsen 1,97/2,12 (Gastroschisis), 1,63/1,48 (Omphalozele), 5,80/8,11 (orofaziale Spaltbildungen) und 2,92/2,50 (Spina bifida) je 10 000 Lebendgeborene. In Sachsen zeigte sich ein Trendanstieg, dessen Effektstärken jedoch sehr gering sind (OR/Jahr zwischen 1,01–1,09). Auch in Deutschland insgesamt wurde eine signifikante Zunahme der Fehlbildungen beobachtet (OR/Jahr zwischen 1,01–1,04), ausgenommen davon war die Lebendgeborenenprävalenz der Spina bifida, die abzunehmen schien (OR/Jahr 0,986 (0,97–1,0), p-korrigiert = 0,04). Schlussfolgerung: Ob ein tatsächlicher Anstieg der Prävalenzen besteht oder lediglich Artefakte einen Anstieg vortäuschen, ist unklar. Änderungen in der Erfassungs- und Verschlüsselungspraxis, Fehlcodierungen, Doppel- und/oder lückenhafte Erfassung der Fehlbildungen könnten die Daten verfälschen. Da nur in Sachsen-Anhalt und Rheinland-Pfalz das Auftreten von Fehlbildungen prospektiv erfasst wird, könnten im Übrigen auch nur in diesen Bundesländern zeitnah Veränderungen der Fehlbildungsprävalenz erkannt werden. Angesichts der anscheinenden oder scheinbaren Zunahme von Fehlbildungen und der offensichtlich fehlerhaften Datenlage ist ein berücksichbundesweites oder sind weitere regionale Register für eine bessere und zeitnahe Erkennung und Erfassung von Fehlbildungen in Deutschland notwendig.

Introdução - A incidência das fendas lábio – palatinas, é de 1 para cada 700 nascidos vivos na população mundial, trata-se de uma má-formação congênita que pode ocorrer devido a fatores endógenos ou exógenos. Objetivo – Relacionar o índice de massa corporal (IMC) materno com o nascimento de bebês com fendas. Métodos – Trata-se de um estudo tipo caso-controle. Foram incluídas 800 mães com idade entre 18 e 35 anos, que não apresentaram suspeita ou confirmação de diabete mellitus ou gravídica e bebês com peso entre 2.500 e 4.500 gramas nascidos entre a 37ª e a 42ª semana de gestação que não apresentaram nenhum outro tipo de deficiência que não a estudada. Para a coleta dos dados aplicou – se questionários a 400 mães de crianças normais distribuídas em quatro postos de saúde da cidade de Santo André (controles), e 400 mães de bebês com fendas labiais e/ou palatinas que estavam em tratamento no FUNCRAF, que é um centro especializado no tratamento da deformidade estudada, nesta mesma cidade (casos). Resultados - Entre os casos encontrou - se 148 (37,00%) mulheres com IMC acima de 26 e entre os controles foram 132 (33,00%). Com relação ao uso de álcool/drogas observou-se que 82 (20,50%) mulheres entre os casos e 58 (14,50%) no grupo controle eram usuárias. Duzentas e onze (52,70%) mães de bebês com fendas relataram ter histórico de má - formação na família dela ou do pai da criança. Este número foi de 103 (25,70%) no grupo controle. No grupo controle observou-se que 330 (82,50%) eram brancas ou pardas, 43 (10,75%) negras e 27 (6,70%) amarelas, entre os casos foram 294 (73,50%) brancas ou pardas, 65 (16,25%) negras e 40 (10,00%) amarelas. Conclusões - O IMC alto não esteve relacionado ao nascimento de bebês com fendas. Ter sido usuária de álcool/drogas no primeiro trimestre de gestação relacionou-se ao nascimento de crianças com a má-formação. O risco de surgimento desta deformidade foi 3,6 vezes maior quanto existiu histórico de qualquer má-formação familiar; a raça/etnia da mãe também apresentou associação com a presença de fendas, a raça branca é a menos associada seguida pela parda e negra e, finalmente pela amarela que foi a que apresenta maior associação. / Introduction – The incidence of cleft lips and palate is 1 to 700 live births in the world population, it is a congenital malformation that can happens due to endogens or exogenesis factors. Objectives – Association between maternal body mass index (BMI) and the risk of cleft lips or palate. Methods – That is a case – control study. We include 800 mothers between 18 and 35 years old without suspicious of gestational or preexisting diabetes and babies between 2,500 e 4, 000 g was born between the 37 and 42 pregnancy week without other congenital malformation that is not the studied. Some questions were asked for 400 normal children’s mothers from four health centers from Santo André (controls), and 400cleft lips or palate children’s mothers from FUNCRAF that is a health center just to treatment of this malformation, from Santo André (cases). Results – Among the cases we have 148 (37.00%) mothers with BMI above 26 and among the controls it was 132 (33.00%). About alcohol and drugs use we have 82 (20.50%) women among cases and 58 (14.50%) on control group. Two hundred eleven (52.70%) malformations children’s mothers declare to have malformation parental history against 103 (25.70%) on control group. On control group we have 330 (82.50%) white , 43 (10.75%) black and 27 (6.70%) yellow, among the cases 294 (73.50%) white, 65 (16.25%) black and 40 (10.00%) yellow. Conclusions – The increase of BMI is not likely to be a risk factor for clefts, the consumption of alcohol/drugs is a risk factor for this malformation; the risk is 3.6 times highest for clefts when there is malformation history; a racial association with clefts was observed, the white women presents the lowest association and the yellow presents the highest one.

Introdução - A incidência das fendas lábio – palatinas, é de 1 para cada 700 nascidos vivos na população mundial, trata-se de uma má-formação congênita que pode ocorrer devido a fatores endógenos ou exógenos. Objetivo – Relacionar o índice de massa corporal (IMC) materno com o nascimento de bebês com fendas. Métodos – Trata-se de um estudo tipo caso-controle. Foram incluídas 800 mães com idade entre 18 e 35 anos, que não apresentaram suspeita ou confirmação de diabete mellitus ou gravídica e bebês com peso entre 2.500 e 4.500 gramas nascidos entre a 37ª e a 42ª semana de gestação que não apresentaram nenhum outro tipo de deficiência que não a estudada. Para a coleta dos dados aplicou – se questionários a 400 mães de crianças normais distribuídas em quatro postos de saúde da cidade de Santo André (controles), e 400 mães de bebês com fendas labiais e/ou palatinas que estavam em tratamento no FUNCRAF, que é um centro especializado no tratamento da deformidade estudada, nesta mesma cidade (casos). Resultados - Entre os casos encontrou - se 148 (37,00%) mulheres com IMC acima de 26 e entre os controles foram 132 (33,00%). Com relação ao uso de álcool/drogas observou-se que 82 (20,50%) mulheres entre os casos e 58 (14,50%) no grupo controle eram usuárias. Duzentas e onze (52,70%) mães de bebês com fendas relataram ter histórico de má - formação na família dela ou do pai da criança. Este número foi de 103 (25,70%) no grupo controle. No grupo controle observou-se que 330 (82,50%) eram brancas ou pardas, 43 (10,75%) negras e 27 (6,70%) amarelas, entre os casos foram 294 (73,50%) brancas ou pardas, 65 (16,25%) negras e 40 (10,00%) amarelas. Conclusões - O IMC alto não esteve relacionado ao nascimento de bebês com fendas. Ter sido usuária de álcool/drogas no primeiro trimestre de gestação relacionou-se ao nascimento de crianças com a má-formação. O risco de surgimento desta deformidade foi 3,6 vezes maior quanto existiu histórico de qualquer má-formação familiar; a raça/etnia da mãe também apresentou associação com a presença de fendas, a raça branca é a menos associada seguida pela parda e negra e, finalmente pela amarela que foi a que apresenta maior associação. / Introduction – The incidence of cleft lips and palate is 1 to 700 live births in the world population, it is a congenital malformation that can happens due to endogens or exogenesis factors. Objectives – Association between maternal body mass index (BMI) and the risk of cleft lips or palate. Methods – That is a case – control study. We include 800 mothers between 18 and 35 years old without suspicious of gestational or preexisting diabetes and babies between 2,500 e 4, 000 g was born between the 37 and 42 pregnancy week without other congenital malformation that is not the studied. Some questions were asked for 400 normal children’s mothers from four health centers from Santo André (controls), and 400cleft lips or palate children’s mothers from FUNCRAF that is a health center just to treatment of this malformation, from Santo André (cases). Results – Among the cases we have 148 (37.00%) mothers with BMI above 26 and among the controls it was 132 (33.00%). About alcohol and drugs use we have 82 (20.50%) women among cases and 58 (14.50%) on control group. Two hundred eleven (52.70%) malformations children’s mothers declare to have malformation parental history against 103 (25.70%) on control group. On control group we have 330 (82.50%) white , 43 (10.75%) black and 27 (6.70%) yellow, among the cases 294 (73.50%) white, 65 (16.25%) black and 40 (10.00%) yellow. Conclusions – The increase of BMI is not likely to be a risk factor for clefts, the consumption of alcohol/drugs is a risk factor for this malformation; the risk is 3.6 times highest for clefts when there is malformation history; a racial association with clefts was observed, the white women presents the lowest association and the yellow presents the highest one.

Darbe nagrinėjamas kompleksinės pagalbos vaikams su įgimtais lūpos ir / ar gomurio nesuaugimais vertinimas tėvų požiūriu. Atlikta teorinė vaikų, turinčių įgimtą lūpos, alveolinės ataugos, gomurio nesuaugimus pagrindinių aspektų analizė. Tyrimo tikslas - ištirti tėvų požiūrį apie medicininės ir logopedinės pagalbos teikimą vaikams, turintiems įgimtų lūpos, alveolinės ataugos ir/ar gomurio nesuaugimų. Darbe aprašytos kompleksinės pagalbos vaikams su įgimtais lūpos ir / ar gomurio nesuaugimais strategijos, išnagrinėti logopedinės pagalbos ypatumai dirbant su tokiais vaikais. Panaudotas anketinės apklausos metodas, interviu ir atlikta statistinė duomenų analizė. Tyrime dalyvavo 105 tėvai, auginantys vaikus su įgimtais lūpos ir / ar gomurio nesuaugimais: 97 šeimos dalyvavo anketinėje apklausoje ir 8 – interviu. Svarbiausios empirinio tyrimo išvados: 1. Vaikams, turintiems lūpos, alveolinės ataugos ir gomurio nesuaugimų, reikalinga kompleksinė įvairių sričių specialistų pagalba. Tokiems vaikams pagalba teikiama iki 18 m. amžiaus. Visame šiame procese labai svarbu komandinis specialistų darbas ir aktyvus bendradarbiavimas su vaiko šeima. 2. Tėvų, auginančių vaikus su įgimtais lūpos, alveolinės ataugos ir/ar gomurio nesuaugimais, nuomonė apie teikiamą pagalbą jų vaikams yra skirtinga ir prieštaringa. Pagalbos suteikimo informacijos sklaida šeimoms, auginančioms vaikus su lūpos ir/ar gomurio nesuaugimais nėra tiek pakankama mažuose Lietuvos miesteliuose, kiek didžiuosiuose miestuose... [toliau žr. visą tekstą] / In this work, the approach to professional help for children with congenital cleft lip and / or palate was evaluated from the parents’ perspective. There was carried out the theoretical analysis of the main aspects related to children with congenital cleft lip, alveolus and palate. Aim of the study – to research parents’ opinion about the treatment and logopedic help support for children with congenital cleft lip, alveolus and palate. In the work, the strategies of professional help for children with congenital cleft lip and / or palate are described, and the peculiarities of logopedic help in work with such children are researched. It was used the method of questionnaire, interview, and it was performed the analysis of statistical data. In the study, there were involved 105 parents having children with congenital cleft lip and / or palate: 97 questionnaire respondents and 8 interview participants. The main conclusions of the empirical study: 1. For children with congenital cleft lip and / or palate, the complex course for rehabilitation of functions is applied until the age of 18 years. In order to achieve good results, the teamwork of surgeon, orthodontist, speech therapist with other specialists in cooperation together with children parents is useful. 2. The opinion of parents, having children with congenital cleft lip and / or palate, is different and contradictory in terms of the professional help for their children; it was revealed that there is a lack of information... [to full text]

Made available in DSpace on 2016-05-02T13:54:43Z (GMT). No. of bitstreams: 1 Dissertacao completa MarceloReischaves.pdf: 170451 bytes, checksum: 9a30d68fc8fa67a4726688e7834fd8b0 (MD5) Previous issue date: 2006-08-25 / Coordenacao de Aperfeicoamento de Pessoal de Nïvel Superior / Clefts of the lip and/or palate account for 65% of all head and neck anomalies and can be isolated or associated with other features as part of syndromes The etiology and pathogenesis of the oral clefts particularly of the nonsyndromic origin remain poorly understood This is in part a reflection of the complexity and diversity of the molecular mechanisms involved during embryogenesis with both genetic and environmental factors playing an influential role The aim of the present study was to evaluate the occurrence of cleft lip and palate in newborns in Alfenas Minas Gerais The sample was composed by 22 cleft lip and palate patients born in Alfenas from 1986 up to 1998 (first six months) among 15,039 registered births Unilateral left cleft lip and lip-palate were more frequently found in males being the opposite in females It was also noted the highest prevalence of cleft lip-palate in males and the exclusive cleft palate in females New studies are required in other geographic areas in Brazil Van der Woude syndrome is a rare autosomal dominant disorder thought to occur with an incidence of approximately 1 in 60,000 live births and without gender predilection Van der Woude syndrome the most frequent form of syndromic clefting is characterized by the association of pits and/or sinuses of the lower lip and cleft lip and/or cleft palate This second part of this dissertation describes the clinical and genetic features of two large and unrelated families with Van der Woude syndrome in Brazil emphasizing the range of anomalies found within and between the families Van der Woude syndrome is transmitted by an autosomal dominant pattern with variable clinical expressivity high prevalence and equilibrated gender distribution Physicians should be aware of the variety of malformations which can be associated with Van der Woude syndrome Genetic counseling in Van der Woude syndrome affected families is important as a high percentage of descendants can have some kind of clefting / As fissuras de lábio e/ou palato perfazem cerca de 65% de todas as anomalias de cabeça e pescoço e podem ser encontradas de forma isolada ou associadas como parte de uma síndrome A etiologia e patogenia das fissuras orais particularmente as de origem não sindrômica são pouco compreendidas Isto devido em parte à complexidade e diversidade do mecanismo molecular envolvido na embriogênese e influenciadas por fatores tanto genético como ambiental O objetivo deste estudo foi avaliar a ocorrência de fissuras de lábio e/ou palato em recém-nascidos na cidade de Alfenas Minas Gerais A amostra foi composta de 22 pacientes portadores de FLP nascidos em Alfenas no período de 1986 a 1998 (primeiros seis meses) em que foram registrados cerca de 15.039 nascimentos As fissuras de lábio unilaterais e labiopalatais foram mais freqüentes no sexo masculino já no sexo feminino a freqüência das fissuras foram equivalentes Os resultados permitiram concluir que a distribuição das fissuras unilaterais de lábio e labiopalatais no sexo masculino tiveram maior freqüência no lado esquerdo e no sexo feminino no lado direito As fissuras bilaterais foram mais freqüentes que os demais tipos de fissuras (75%) A síndrome de Van der Woude é uma condição autossômica dominante rara que atinge um em cada 60,000 nascidos vivos independente do gênero É a forma mais freqüente de fissura sindrômica caracterizada pela presença de fissuras labiopalatais e fossetas no lábio inferior sendo comum a combinação de ambas as condições A segunda parte desta dissertação descreve os aspectos clínicos e genéticos de duas famílias com a síndrome de Van der Woude no Brasil enfatizando as variações da anomalia entre os familiares A síndrome de Van der Woude é transmitida pelo padrão autossômico dominante com expressão clínica variável alta prevalência e distribuição uniforme entre os gêneros No estudo foram observadas expressividade e prevalência variadas e grande distribuição da síndrome na população estudada

Hintergrund: Zahlreiche Studien beschreiben weltweit eine Zunahme angeborener Fehlbildungen. Diese sind in Deutschland die häufigste Todesursache im frühen Kindesalter. Die hier vorliegende Studie untersuchte lokale und nationale Trends der Prävalenz von Gastroschisis, Omphalozele, Spina bifida und orofazialen Spaltbildungen von 2000 bis 2010. Methoden: Die Prävalenz der 4 Fehlbildungen wurde im Zeitraum Januar 2000–Dezember 2010 mithilfe von 4 Datenquellen aus Leipzig, Sachsen, Sachsen-Anhalt und Deutschland untersucht. Ergebnisse: Die Prävalenz der Fehlbildungen betrug im Untersuchungszeitraum in Deutschland bzw. in Sachsen 1,97/2,12 (Gastroschisis), 1,63/1,48 (Omphalozele), 5,80/8,11 (orofaziale Spaltbildungen) und 2,92/2,50 (Spina bifida) je 10 000 Lebendgeborene. In Sachsen zeigte sich ein Trendanstieg, dessen Effektstärken jedoch sehr gering sind (OR/Jahr zwischen 1,01–1,09). Auch in Deutschland insgesamt wurde eine signifikante Zunahme der Fehlbildungen beobachtet (OR/Jahr zwischen 1,01–1,04), ausgenommen davon war die Lebendgeborenenprävalenz der Spina bifida, die abzunehmen schien (OR/Jahr 0,986 (0,97–1,0), p-korrigiert = 0,04). Schlussfolgerung: Ob ein tatsächlicher Anstieg der Prävalenzen besteht oder lediglich Artefakte einen Anstieg vortäuschen, ist unklar. Änderungen in der Erfassungs- und Verschlüsselungspraxis, Fehlcodierungen, Doppel- und/oder lückenhafte Erfassung der Fehlbildungen könnten die Daten verfälschen. Da nur in Sachsen-Anhalt und Rheinland-Pfalz das Auftreten von Fehlbildungen prospektiv erfasst wird, könnten im Übrigen auch nur in diesen Bundesländern zeitnah Veränderungen der Fehlbildungsprävalenz erkannt werden. Angesichts der anscheinenden oder scheinbaren Zunahme von Fehlbildungen und der offensichtlich fehlerhaften Datenlage ist ein berücksichbundesweites oder sind weitere regionale Register für eine bessere und zeitnahe Erkennung und Erfassung von Fehlbildungen in Deutschland notwendig.:Inhaltsverzeichnis Bibliografische Beschreibung 4 I. Abkürzungsverzeichnis 6 1. Einleitung 7 1.1 Hintergrund 7 1.2 Gastroschisis 8 1.3 Omphalozele 12 1.4 Orofaziale Spaltbildungen 15 1.5 Spina bifida 19 1.6 Fragestellung der Studie 22 2. Publikation 25 3. Zusammenfassung der Arbeit 33 4. Literaturverzeichnis 40 II. Erklärung über die Eigenständigkeit der Arbeit 49 III. Lebenslauf 50 IV. Danksagung 52