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Advances in understanding the genetic architecture of cleft lip and palate disordersLeslie, Elizabeth Jane 01 December 2012 (has links)
Orofacial clefts are a heterogeneous group of craniofacial malformations that affect the lip and/or palate and represent the most common craniofacial birth defect in humans. In 30% of patients the cleft is accompanied by additional physical or cognitive abnormalities. Hundreds of these clefting syndromes have been described, many of which have Mendelian inheritance patterns. The most common of these is Van der Woude syndrome (VWS), caused by mutations in the transcription factor IRF6 (Kondo et al. 2002). The other 70% of patients lack additional features and are considered nonsyndromic. The etiology of nonsyndromic clefts is complex and involves the combined action of multiple genetic variants interacting with environmental factors.
A common approach for identifying genetic risk factor for complex disorders such as nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the genome wide association study (GWAS). We pursued a locus on 1p22 shown to be associated with NSCL/P by Beaty et al. (2010). Through a combination of expression studies in a mouse model and mutation screening in NSCL/P patients, we identified ARHGAP29 as a novel gene for NSCL/P and the likely etiologic gene at this locus. We identified eight rare variants in NSCL/P patients absent in controls including a nonsense and a frameshift mutation. These rare variants are reminiscent of previous resequencing studies that reported rare coding mutations in 20 different candidate genes for NSCL/P. We reviewed these variants and compared them with variants found in over 7000 exomes from the 1000 Genomes Project (1kGP) and NHLBI Exome Sequencing Project (ESP) to identify the variants and genes most likely to contain etiologic rare variants. We found good support for a role for rare variants in NSCL/P, particularly for MSX1 and genes of the FGF signaling pathway.
We next performed several studies to understand the genetic architecture of syndromic forms of clefting, focusing on VWS and popliteal pterygium syndrome (PPS), which is allelic to VWS. We compiled all of the nearly 300 published IRF6 mutations and compared the distribution of these mutations with IRF6 variants obtained from the 1kGP and ESP exomes. We found that mutations causing VWS were significantly over-represented in the DNA-binding domain and for the most part were absent from control exomes, indicating that they are likely to be truly causative for VWS or PPS. These mutations in VWS and PPS only account for 70% of VWS and 97% of PPS. We next hypothesized that mutations in RIPK4, which causes an autosomal recessive pterygia syndrome, could underlie the remaining VWS and/or PPS cases. We found novel homozygous mutations in RIPK4 in two PPS patients. This result has significant clinical ramifications, as counseling of recurrence risk is very different for PPS patients whose disease is caused by dominant IRF6 mutations compared to recessive RIPK4 mutations.
Finally, to understand the variable expressivity of VWS and PPS we performed an association study to identify genetic modifiers. We also looked for genotype-phenotype correlations between the type and location of IRF6 mutations. Although we did not find strong evidence that the candidate genes we selected from GWAS of NSCL/P or other clefting syndromes are modifiers of the VWS or PPS phenotypes, several marginal associations suggest that members of the IRF6 gene regulatory network could act as modifiers. Finally, we found evidence of a larger genotype-phenotype correlation by demonstrating that mutation-negative VWS families have a deficiency of cleft lip phenotypes. Together this work has advanced our understanding of the genetic basis of this diverse set of cleft lip and palate disorders, informing both the biology of craniofacial development and the clinical care of patients affected by these disorders.
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Examining cleft lip and palate as a lifelong disease: genetic investigation of causes and outcomesDavidson, Beth Noelle 01 May 2012 (has links)
Nonsyndromic cleft lip and/or palate (NS CL/P) is a common birth defect with estimated birth prevalence of 1/1000 worldwide. NS CL/P etiology may be explained by the action of as few as two or as many as 14 different genes (Schliekelman et al. 2002) as well as several environmental factors (e.g. smoking and folic acid) (Shi et al. 2008; Wehby et al. 2010). Convincing genetic and/or biologic evidence exists for the contribution of many genes: IRF6, 8q24, FGFR2, FOXE1, BMP4, TGFβ3, MSX1, MAFB , PAX7, ABCA4, and VAX1, to NS CL/P (Dixon et al. 2011). Clefts place substantial burdens on families and society with the estimated costs of cleft care and surgical repair around $100,000 in the United States (Jugessur et al. 2009). The health burden of NS CL/P does not end after the last surgery - impaired social development, surgical morbidity, and cancer are all reported in older children and adults with NS CL/P. Genes involved in clefting during development may be involved in other processes throughout life. We hypothesize that non-coding variation of the FGFR2 gene is associated with NS CL/P and these variants correlate with levels of gene expression. We investigate links between clefting, wound healing, and genes implicated in cancer in NS CL/P families.
Analysis of family genotype data with the Transmission Disequilibrium Test (TDT), demonstrated suggestive association for two non-coding SNPs, rs2912770 with CL/P (p = 0.002 -USA) and rs2114684 with cleft palate (p = 0.002 - USA and all populations) but not for SNPs located within intron 2 - where genome wide association (GWA) signals overlap in both NS CL/P and breast cancer studies. Studies of foreskin tissue supported correlation of rs2912770 genotype with level of FGFR2 expression, though the magnitude of the effect was modest and did not remain significant after correction for multiple comparisons. Transcriptome array analysis suggested novel regions of regulated transcription, but their function as novel exons was not validated by real-time PCR (RT-PCR). As we expanded our focus from FGFR2, we examined association of cleft candidate genes with wound healing complications (WHC) with case-control and TDT analysis. Allelic and genotypic case-control analysis suggests association of rs2981582 with WHCs (p < 0.08). TDT analysis revealed WHC potential association with rs6478437 located upstream of the ( FOXE1) gene (p = 0.04). This study has medical implications, as the identification of children at high-risk for WHCs prior to surgical treatment and interventions may prevent post-surgical wound healing complications. We finally examined NS CL/P association with genes that had prior evidence for a role in clefting and cancer. In this analysis, we observed TDT association of rs4746409, located in intron 4 of the zinc finger 365 ( ZNF365) gene (p = 0.0003). Interestingly, this gene and SNP were tested due to suggestive association with breast cancer (Turnbull et al. 2010) and NS CL/P from GWA analyses (Beaty et al. 2010), which strengthens the connection between NSCL/P and breast cancer risk. Identification of NS CL/P patients at increased cancer risk could save lives and extend healthy life for current cleft patients as the field continues to seek ways to intervene and prevent cleft lip and palate from occurring.
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Expanding the dental phenotype of non syndromic orofacial cleftingHowe, Brian James 01 December 2013 (has links)
No description available.
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Nasality in the Malay language: development of an assessment protocol for Malay speaking children with cleft lip and/or palateMohd Ibrahim, Hasherah January 2009 (has links)
The need for a standard approach for the diagnosis of speech disorders, in particular resonance disorders associated with cleft lip and/or palate, has been recognised. A reliable and valid measure of nasality is important, because it not only affects clinical decision making but is also essential for the evaluation of treatment outcomes. In order to allow cross-linguistic comparisons of the assessment of resonance, language specific stimuli developed according to a common set of guidelines have been recommended. The aim of this thesis was to contribute to the development of an assessment protocol for use in Malay speaking individuals with clefts of the lip and/or palate, specifically focusing on the detection of nasality. A series of four studies were completed which systematically developed and then validated a set of stimuli in the Malay language using both perceptual and instrumental measures. / In the first study, three stimuli were developed for the assessment of nasality based on both the proportion of nasal phonemes in typical conversation samples in Malay and guidelines from the current international literature. The phonetic content of the stimuli were comparable to similar passages used in English and comprised of an Oral Passage, a Nasal Passage and a Set of Sentences. / In the second study, the stimuli constructed were tested in a large number of typically developing (non-cleft) Malay speaking children using both instrumental and perceptual methods of assessment. The results of this study provide the first set of normative data of nasalance scores for the three newly developed stimuli. The mean nasalance score for the Oral Passage was 13.86% (SD = 5.11, 95% CI = 13.04–14.68), 60.28% (SD = 6.99, 95% CI = 59.15–61.41) for the Nasal Passage, and 27.72% (SD = 4.74, 95% CI = 26.96–28.49) for the Set of Sentences. These scores were significantly different from each other suggesting that they can be used to detect the different types of resonance disorder in speech (e.g. hypernasality and/or hyponasality). / In the third study, the stimuli were validated in a sample of Malay speaking children with cleft of the lip and/or palate and compared with a control population. Nasality was measured using perceptual evaluation and nasometry. The results suggested that the Oral Passage and Set of Sentences developed in Malay were valid measures for detecting hypernasality for both perceptual evaluation of nasality, and for nasometry. Due to the small number of participants that were hyponasal, the validity of the Nasal Passage could not be determined. / For nasometry to be clinically relevant threshold values that indicate abnormal nasality are required. The threshold values for each of the stimuli were first ascertained after obtaining typical nasality levels from a group of healthy Malay speaking children and then tested in a sample of cleft and non-cleft Malay speaking children. In contrast to the nasalance cutoffs obtained from typical Malay speaking children, the cutoffs obtained from the cleft children yielded better outcomes for detecting resonance disorders. The cutoffs were: ≥ 22% for the Oral Passage (sensitivity = 0.91, specificity = 0.93, overall efficiency = 0.92), ≥ 30% for the Set of Sentences (sensitivity = 0.96, specificity = 0.85, overall efficiency = 0.88) and ≤ 39 on the Nasal Passage (sensitivity = 1.00, specificity = 0.99, overall efficiency = 0.99). / Finally, the fourth study explored the application of recently developed techniques for assessing nasality using spectral voice analysis and compared these results with nasometry using a sub-sample of Malay speaking children from the third study. The participants were children with cleft lip and/or palate with perceived hypernasality and a group of healthy controls perceived to have normal resonance. The potential of assessing nasality using vowels, which ideally can be an easier option to administer clinically and have minimal impact on language and literacy skills, were investigated. / The findings showed that only the one-third-octave analysis method could be successfully used to detect hypernasality in the cleft population compared to the VLHR method. Using the one-third-octave analysis, the spectral characteristics of nasalised vowel /i/ taken from /pit/ and /tip/ showed an increase in amplitude in F1, between F1 and F2 regions. The amplitude of the formants at F3 region was lower in the cleft group but did not differ from the control group as reported in previous studies. Although, the one-third-octave analysis has some potential in detecting hypernasality, the accuracy of the analysis compared to perceptual ratings of nasality was only moderate. Compared to nasometry, the diagnostic value of the one-third-octave analysis in detecting hypernasality was lower. / The overall findings suggest that, except for the Nasal Passage, the Oral Passage and the Set of Sentences developed in Malay using this systematic approach were culturally appropriate and valid for the assessment of nasality. Furthermore, by comparing two instrumental methods (nasometry and spectral analysis) with perceptual evaluation in a large number of cleft and typically developing children, the present thesis was able to demonstrate the clinical benefits of two recently proposed methods of spectral voice analyses and compare them to existing methods. Compared to spectral analysis, nasometry remains a superior method for assessing nasality. Threshold values that indicate abnormal nasality levels for the newly developed stimuli in Malay have been recommended.
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Hur föräldrar till barn med läpp- käk- och gomspalt upplever beskedet samt bemötande från vårdpersonal : -en litteraturstudieHallqvist, Carola, Gustavsson, Nina January 2008 (has links)
<p>Syftet med denna studie var att, utifrån vetenskaplig litteratur, beskriva hur föräldrar till barn med läpp-, käk- och gomspalt (LKG) upplevde beskedet och den första tiden efter barnets födelse, samt hur de bemöttes av vårdpersonalen. Litteratursökningen genomfördes i Medline och totalt valdes 15 vetenskapliga artiklar ut till föreliggande studies resultat. Många föräldrar till barn med LKG befinner sig den första tiden efter beskedet i en utsatt situation, deras funderingar kan vara många och behovet av stöd kan vara stort. Föreliggande studie visade att en viktig faktor för föräldrarnas upplevelse och välmående var grundlig information och stöd till föräldrarna, givna av välutbildad och erfaren vårdpersonal och att de inte enbart såg till barnets missbildning utan även till barnets hälsa. Vid sjukhusvistelse borde vårdpersonalen uppmärksamma föräldrars eventuella behov av att få känna sig delaktiga i vården av sitt barn. Prenatal diagnos visade sig ha en positiv inverkan på föräldrarnas upplevelse av att få ett barn med LKG. Betydande för hur föräldrarna upplevde sin nya situation var vårdpersonalens attityd och ordval gentemot dem. Möjlighet till kontakt med psykolog eller kontakt med andra föräldrar till barn med LKG visade sig också betyda mycket för föräldrarna.</p> / <p>The aim of this study was to, from scientific articles, illustrate how parents with children born suffering from cleft lip and palate (CLP) reacted when informed of their childs diagnosis, how they experienced the first time period after the birth and the attitude and support from the caregivers. The 15 scientific articles used were found in Medline. Parents with children with CLP are at first in a vulnerable situation beacuse of their many questions and need of support. The result of this study showed that an important factor for the well-being of the parents was profound information and support from well-educated personnel which not only focused on the malformation of the child but also their health. During the hospitalization the caregivers should observe the possible needs the parents could have and how they could be involved in the care of their own child. Further, the result found that prenatal diagnosis had a positiv affect on the parents experience when having a child with cleft lip and palate. The result also proved that the caregivers attitude and their selection of words towards the parents was very important of how the parents experienced the situation. Another important aspect for the parents experience was the possibilty of contact with psychologist and other parents with children with CLP.</p>
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Hur föräldrar till barn med läpp- käk- och gomspalt upplever beskedet samt bemötande från vårdpersonal : -en litteraturstudieHallqvist, Carola, Gustavsson, Nina January 2008 (has links)
Syftet med denna studie var att, utifrån vetenskaplig litteratur, beskriva hur föräldrar till barn med läpp-, käk- och gomspalt (LKG) upplevde beskedet och den första tiden efter barnets födelse, samt hur de bemöttes av vårdpersonalen. Litteratursökningen genomfördes i Medline och totalt valdes 15 vetenskapliga artiklar ut till föreliggande studies resultat. Många föräldrar till barn med LKG befinner sig den första tiden efter beskedet i en utsatt situation, deras funderingar kan vara många och behovet av stöd kan vara stort. Föreliggande studie visade att en viktig faktor för föräldrarnas upplevelse och välmående var grundlig information och stöd till föräldrarna, givna av välutbildad och erfaren vårdpersonal och att de inte enbart såg till barnets missbildning utan även till barnets hälsa. Vid sjukhusvistelse borde vårdpersonalen uppmärksamma föräldrars eventuella behov av att få känna sig delaktiga i vården av sitt barn. Prenatal diagnos visade sig ha en positiv inverkan på föräldrarnas upplevelse av att få ett barn med LKG. Betydande för hur föräldrarna upplevde sin nya situation var vårdpersonalens attityd och ordval gentemot dem. Möjlighet till kontakt med psykolog eller kontakt med andra föräldrar till barn med LKG visade sig också betyda mycket för föräldrarna. / The aim of this study was to, from scientific articles, illustrate how parents with children born suffering from cleft lip and palate (CLP) reacted when informed of their childs diagnosis, how they experienced the first time period after the birth and the attitude and support from the caregivers. The 15 scientific articles used were found in Medline. Parents with children with CLP are at first in a vulnerable situation beacuse of their many questions and need of support. The result of this study showed that an important factor for the well-being of the parents was profound information and support from well-educated personnel which not only focused on the malformation of the child but also their health. During the hospitalization the caregivers should observe the possible needs the parents could have and how they could be involved in the care of their own child. Further, the result found that prenatal diagnosis had a positiv affect on the parents experience when having a child with cleft lip and palate. The result also proved that the caregivers attitude and their selection of words towards the parents was very important of how the parents experienced the situation. Another important aspect for the parents experience was the possibilty of contact with psychologist and other parents with children with CLP.
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Burden of Care Analysis of Presurgical Infant Orthopedics for Improvement of Nasolabial Aesthetics in CUCLPSinger, Emily 27 November 2012 (has links)
The purpose of this study was to evaluate the burden of care (BOC) of two presurgical infant orthopedic (PSIO) protocols used for complete unilateral cleft lip and palate (CUCLP), and to compare aesthetic outcomes with centres not utilizing PSIO. Four samples were collected. Two from the same centre that underwent either traditional infant orthopedics (TIO) or nasoalveolar molding (NAM) and two from centres not employing PSIO. BOC data were collected for the PSIO groups and photos at age 5 were collected for ratings of nasolabial aesthetics. The BOC of NAM was found to be significantly greater than IO for number of visits (9.9 vs. 6.6, (p<0.001)) and days wearing the appliance (127 vs. 112, (p<0.05)). Significant differences in aesthetic ratings were noted amongst the three centres but not between the NAM and TIO groups. Overall, an increased burden of NAM over TIO was detected, without an observable aesthetic improvement.
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Burden of Care Analysis of Presurgical Infant Orthopedics for Improvement of Nasolabial Aesthetics in CUCLPSinger, Emily 27 November 2012 (has links)
The purpose of this study was to evaluate the burden of care (BOC) of two presurgical infant orthopedic (PSIO) protocols used for complete unilateral cleft lip and palate (CUCLP), and to compare aesthetic outcomes with centres not utilizing PSIO. Four samples were collected. Two from the same centre that underwent either traditional infant orthopedics (TIO) or nasoalveolar molding (NAM) and two from centres not employing PSIO. BOC data were collected for the PSIO groups and photos at age 5 were collected for ratings of nasolabial aesthetics. The BOC of NAM was found to be significantly greater than IO for number of visits (9.9 vs. 6.6, (p<0.001)) and days wearing the appliance (127 vs. 112, (p<0.05)). Significant differences in aesthetic ratings were noted amongst the three centres but not between the NAM and TIO groups. Overall, an increased burden of NAM over TIO was detected, without an observable aesthetic improvement.
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Central auditory impairment in children with nonsyndromic cleft lip and/or palateYang, Feng, Frank., 杨峰. January 2011 (has links)
Auditory impairment in patients with craniofacial clefts has been well studied for
decades. However, most previous research has only focused on middle ear disorders
and related auditory consequences in this group. Studies of higher level auditory
status and central auditory processing abilities of this group—particularly in
children—have been unsystematic and have significant limitations, while the
potentially negative impact of central auditory impairment on children should not be
ignored. One important area which needs further research is the status of the central
auditory nervous system (CANS) in children with non-syndromic cleft lip and/or palate (NSCLP). In order to objectively investigate possible central auditory
impairment in children with NSCLP, the present research programme was initiated.
Firstly, two major studies aimed to provide anatomical structural analysis and
functional evaluation of the auditory structures of CANS in a group of infants with
NSCLP, and compare the results to those of normal controls (Studies 1 and 2).
Secondly, a pilot study (Study 3) was conducted to provide preliminary data and
suggest methodology to support a major, future research programme to
comprehensively investigate central auditory processing abilities in children with
NSCLP.
A multi-disciplinary approach that included brain magnetic resonance image
(MRI) scanning, auditory evoked potentials (AEP) recording, and a central
behavioural auditory test battery assessment protocol, was applied in the present
research programme. Based on the results of the studies and data analysis, it was
concluded that: (1) Structural abnormalities of CANS in infants with NSCLP may be
primarily located in the left cerebral hemisphere and cortical abnormalities were more
marked compared with those in other subcortical locations. The development and
maturation of the auditory cortex in infants with NSCLP may be abnormal, compared
with that in normal children; (2) Infants with NSCLP might have normal auditory
sensory function at brain stem and subcortical levels, yet this group may have
significant impaired auditory discriminatory function at cortical level; (3) Children with NSCLP may show normal auditory processing abilities in a quiet listening
environment. However, they may be more vulnerable to background noise and have
impaired auditory processing abilities in areas such as monaural low redundancy and
temporal resolution ability.
In summary, combining the results of MRI, AEP and behavioural measurements
in the present research programme, it is suggested that children with NSCLP are at
potential risk of both structural abnormalities and functional disorders of the CANS,
particularly at auditory cortical level. In addition, this group might also be at risk of
auditory processing impairments to some degree, particularly in noisy environments.
The present research programme has made a contribution to our understanding of the
central auditory status of children with NSCLP, which was not systematically
investigated in previous studies, and provided information on which to base further
research. The research findings should draw the attention of researchers and clinicians
to improving auditory assessment and intervention for patients with craniofacial cleft
disorders. Further efforts in this field in the long-term may help to develop a more
sophisticated audiological evaluation and intervention approach for this population. / published_or_final_version / Speech and Hearing Sciences / Doctoral / Doctor of Philosophy
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Untersuchung zum Gesichtswachstum von Patienten mit Lippen-Kiefer-Gaumenspalten operiert nach dem Leipziger Konzept zur funktionellen Rehabilitation von Lippen-Kiefer-GaumenspaltenTzeuschner, Dominique 06 May 2014 (has links) (PDF)
In der vorliegenden Dissertation wurde anhand von 1042 extraoralen Fotos im Profil und en face untersucht, wie sich das Wachstum longitudinal bei 166 gesunden Kindern, je zehn Kindern mit isolierter Gaumenspalte, einseitiger Lippen-Kiefer-Gaumenspalte sowie doppelseitiger Lippen-Kiefer-Gaumenspalte operiert nach dem Leipziger Konzept entwickelt, sowie inwiefern sich die einzelnen Gruppen in verschiedenen Altersstufen voneinander unterscheiden. Dazu wurden pro Gruppe jeweils fünf Jungen und fünf Mädchen kaukasischer Herkunft, geboren in den Jahren 1994 bis 2001, mit einer nichtsyndromalen Spalte ausgewählt, die ab der Geburt über mehrere Jahre hinweg fotografiert wurden. Diese Fotos wurden digitalisiert und denen von Kontrollpatienten gegenüber gestellt. Anhand von Winkeln der klassischen Morphometrie und Grafiken und Statistiken der geometrischen Morphometrie wurden die Veränderungen im Wachstum analysiert und die Kontrollpatienten mit dem Leipziger OP-Konzept verglichen. Es konnte gezeigt werden, dass die geometrische Morphometrie durchaus geeignet ist, das Gesichtswachstum anhand von extraoralen Fotos zu beurteilen. Weiterhin konnte bestätigt werden, dass mit dem Leipziger Konzept zur funktionellen Rehabilitation von Patienten mit Lippen-Kiefer-Gaumenspalten sehr gute Operationsergebnisse und vor allem Langzeitergebnisse erzielt werden können.
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