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Cleft palate affects approximately 1 in 2000 live births resulting in considerable morbidity to affected individuals and their families. Evidence that the p63 gene is mutated in at least seven human developmental syndromes which are each characterised by varying extents of orofacial clefting, coupled to the severe facial dysmorphism displayed by the p63 mutant mouse, highlight the need to elucidate the role of the p63 during normal and aberrant palatogenesis. In mice, secondary palate development closely mirrors that occurring in humans; consequently, the mouse is a pre-eminent model organism for studying palatogenesis. In mice, the palatal shelves initiate from the maxillary processes and grow vertically, lateral to the tongue. The shelves re-orientate and make contact above the tongue. The medial edge epithelia (MEE) of the apposed palatal shelves adhere to form a midline epithelial seam (MES). Subsequent degeneration of the MES allows mesenchymal confluence across the palate, at which point palatogenesis is considered complete. The mechanisms underlying degeneration of the MES remain contentious; however, in vivo studies suggest that cessation of proliferation, induction of apoptosis and periderm migration are essential to ensure removal of the midline seam. The data presented in this thesis uncover a key role for p63 in controlling these aspects of cell behaviour during palatal shelf fusion. Tgfb3-/- mice exhibit cleft palate with maintained expression of p63 in the MEE. This thesis reveals that epistatically lowering the dosage of p63 in Tgfb3-/- mice rescues this fusion defect, facilitating periderm cell migration out of the MEE and subsequent MES degradation. Recent research suggests that p63 orchestrates a cell adhesion network in the palate. In this context, this thesis suggests the importance of p63 down-regulation in the MES in compromising adhesion at the basal-periderm border, thereby allowing periderm cell migration out from the midline and subsequent MES degradation. To test the hypothesis that down-regulation of p63 is essential for palatal fusion, tetracycline-inducible transgenic animals in which ΔNp63α is targeted to the MEE of the developing palate have been engineered. ΔNp63α bi-transgenic mice presented with cleft palate in which the MES failed to degenerate. An observed lack of apoptotic activity in the MEE of ΔNp63α bi-transgenic mice suggested a role for p63-mediated apoptosis during MES degradation. Gene ontology analysis of a complete range of ΔNp63α transcriptional targets which have been identified in the secondary palate by ChIP-seq, lent support to this hypothesis. The data indicate that p63 down-regulation in the MES is essential to ensure complete removal of the MES and implicate p63 as a key regulator of apoptosis during this process; thereby building on work which suggests that cell death is the major fate of the MEE. In addition to dissecting a pathway of fundamental importance in secondary palate development, this research provides insights into ectodermal development more generally and has wider significance for the study of many congenital malformations.

Magister Public Health - MPH / Cleft lip and/or palate deformity is the most common facial birth defect with an incidence of 1 in 600 for every live birth worldwide. Despite the availability of specialised cleft care in Nigeria, many cleft patients are not aware that CL±Ps can be repaired and, thus, present late for treatment. As a result, there is a high incidence of unoperated CL±P in the country which has a grim negative health impact on the population. Furthermore, it was noted that the family caregivers including parents and other members of the extended family are crucial in getting early care for these children with CL±P. Therefore, understanding the perception of CL±P, attitude and experience with cleft services would go a long way in reducing the problem of late presentation and under-utilisation of these services. Therefore, the aim of the study was to explore the care givers’ perception and experience in accessing cleft services at Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria. In this study, we employed an exploratory qualitative methodology that gave deep insights and provided clear understanding of the perceptions by caregivers of children with CL±P on the aetiology of cleft, family reactions and their experience in accessing cleft services at our hospital. Data analysis was done following verbatim transcription using thematic analysis. Ethics statement: Before commencement of the study, ethical approval was obtained from the Institutional Review Boards of the University of Western Cape and the Usmanu Danfodiyo University Teaching Hospital Health Research and Ethics Committee. Informed consent was sought from each prospective participant and the signed form appropriately documented.

Introduction: Dento-alveolar anomalies associated with Orofacial clefts (OFCs) can present with a wide range of variation. This vast diversity makes it difficult to pinpoint their specific etiology. For instance, differentiating anomalies that arise as a consequence of the physical effects of the cleft itself or from the same biological processes that result on clefting, from those that likely occur as a sequela from the surgical repair is a challenge. One approach that can aid this differentiation is to study if first degree relatives of children with clefts whom themselves do not have an overt cleft but may carry genetic cleft risk, are more likely to present some of these anomalies. If so, the elevated risk on these seemingly unaffected relatives will indicate that the particular anomaly arises as a consequence of the molecular pathways that give rise to cleft risk rather than from the physical consequences of the cleft or the surgical repairs. Understanding the different etiological factors underlying dental anomalies within the cleft phenotypic spectrum is a fundamental step for prevention and better management of such anomalies. Amongst the most common dento-alveolar anomalies seen in children born with OFC are tooth size-arch length discrepancies and dento-alveolar shape irregularities, mostly studied in the maxillary arches. Such arch irregularities lead to moderate or severe malocclusions. It is not well known if unaffected family members (UFM) of children with clefts are also susceptible to such dento-alveolar shape irregularities and thus their etiology is not well understood. This study aims to characterize 3D variation in dento-alveolar shape as part of the cleft phenotypic spectrum in UFMs of individuals with OFCs compared to controls with no history of OFC. Methods: A total of 760 maxillary and 760 mandibular casts were digitally scanned using a NextEngine Laser scanner and digitized by two raters with 92 landmarks for maxilla and 94 landmarks for mandible, covering gingival margins and occlusal surfaces via Landmark Editor Software. A reliability of 88.15% was obtained for an interrater agreement error of less than 1mm for all landmarks obtained. 3D coordinates were extracted and registered using a Procrustes fit procedure. Procrustes residuals were analyzed via canonical variate analyses to capture differences in 3D shape between cases and controls. Of the 760 maxillary individuals attempted, 535 (Cases N=133, Controls=402) had all 92 landmarks and 688 (Cases=192, Controls496) had at least 40 landmarks in the canine to canine region. Of the 760 mandibular individuals attempted, 434 (Cases N=99, Controls=335) had all 94 landmarks and 611 (Cases=180, Controls=431) had at least 40landmarks in the canine to canine region. Thus analyses were done separately for each subsample. Results: Case-control differences were not significant (P=0.11) for overall maxillary dental arch shape. However, for the maxillary canine to canine dataset, significant differences were found (P=0.02 for raw Procrustes distance, P<0.0001 for Mahalanobis distance). Case-control differences were significant (P=0.02) for overall mandibular dental arch shape. Significant shape differences were also found for the mandibular canine to canine dataset (P=0.01 for raw Procrustes distance, P<0.0001 for Mahalanobis distance). In other words, there is better separation between cases and controls for the mandibular dataset compared to the maxillary dataset (P=0.11 for the maxillary full arch). Cases had maxillary and mandibular anterior dentitions that were overall retrusive, with anterior teeth that significantly tapered towards the incisal third with larger interproximal incisal embrasures and height to width rations that deviate from ideal ratios (i.e. width is ~70% of the height) due to an overall decrease in crown height. Also, incisal edges seem to flare outwards from the arch line when compared to controls. Moreover, case arch forms trend towards a “v” shape, resembling a Bonwill-Hawley arch shape compared to a “u” shape in the controls. Conclusions: Upper anterior, lower anterior and overall arch shape significantly differ between UFM of individuals with OFC and controls. The most significant differences were located in the maxillary and mandibular anterior dentitions, where cases were more retrusive overall with incisal edges that were tapered and flared, displaying large embrasures and tapered and flared, displayed large embrasures when compared to controls. The phenotypic differences identified in this study contribute to the understanding of the cleft phenotypic spectrum aiding future studies of cleft etiology and cleft risk prediction.

Thesis (M. Sc.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis(M.A.)--Case Western Reserve University, 2010 / Title from PDF (viewed on 2010-01-28) Department of Communication Sciences Includes abstract Includes bibliographical references and appendices Available online via the OhioLINK ETD Center

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The genetics and epigenetics of cortisone-induced cleft palate in the mouse have been examined. The SW/Fr strain, in which 6% of newborns have a cleft palate in the absence of treatment, has the greatest reactivity to cortisone of any strain tested so far and closes it palate comparatively late in development. After cortisone treatment, the mean of the distribution on palate closure stage is shifted towards later gestational ages without changing the variance. / The genetic basis for the DBA/2-C57BL/6 difference in susceptibility to cortisone-induced cleft palate is relatively simple. One dominant gene on chromosome 5 contributes predominantly to the strain difference in susceptibility, but the embryonic response appears also to be influenced by genes on the X chromosome. The H-2 haplotype does not affect the cortisone-induced cleft palate response in the two congenic strains C57BL/10 (B10) and B10.A by altering the stage of palate closure.

This retrospective cohort study of 336 lateral cephalometric radiographs from 62 children (34 males and 28 females) with non-syndromic complete unilateral cleft lip and palate from the Hospital for Sick Children and 50 non-cleft children (25 females and 25 males) from the Burlington Growth Centre. Cervical vertebral maturation stages at age 10, 12 and 14 were determined. The cervical vertebral maturation (CVM) was established using the 6-stage method described by Baccetti and coworkers. The reproducibility of classifying CVM stages was high, with an inter-rater reliability (ICC) with the standard (Baccetti et al, 2005) of 80% and intra-rater reliability of 85%. The Cervical vertebral maturation stage for both males and females with UCLP was significantly later than children without a cleft at age 10, 12 and 14. The results suggest that patients with UCLP show delayed skeletal maturation in comparison to non-cleft patients.