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- Pegelow, Marie
(author)
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Genomic and dental investigations of individuals and families with non-syndromic cleft lip and/ or cleft palate, Van der Woude and popliteal pterygium syndromes
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Van der Woude syndrome (VWS) is the most common oral cleft syndrome, accounting for two percent of all cleft lip and/or cleft palate (CL/P) cases. The main characteristics of VWS are lip pits (LP), cleft lip (CL), cleft lip and palate (CLP), cleft palate (CP) and/or hypodontia (H). Popliteal pterygium syndrome (PPS) has the same orofacial characteristics as VWS, combined with systemic anomalies. In 2002, the gene responsible for VWS/ PPS was found to be the interferon regulatory factor 6 gene (IRF6), located on chromosome 1, regio q32.2 The gene encodes for a transcription factor containing both a DNA binding domain and a protein binding domain. Non-syndromic (NS) cleft lip with or without cleft palate (CL±P) occurs without associated malformations in any other organs in approximately 70% of the affected subjects. The inheritance pattern for NSCL/P is complex, with a probable co-segregation of several genes and environmental factors. The IRF6 gene has been proposed to be part of the cause of NSCL/P. The aim of this thesis was to investigate individuals and families, mostly of Swedish and Finnish origin, with NSCL/P, VWS and PPS, with regard to their phenotypes, including dental anomalies, to detect mutations of the IRF6 gene in the syndromic cases and to investigate whether the IRF6 gene is responsible for the cleft phenotype in the nonsyndromic individuals. In Study I, 129 individuals affected with NS unilateral (U) CL±P were analysed for dental characteristics. Malformed lateral incisors were common in NSUCL, while hypodontia was more common in the NSUCLP phenotype. In the total material, hypodontia was found in 29.5% inside and in 15.5% outside the region of the cleft. Most of the existing lateral incisors were positioned distal to the cleft in both the primary and the permanent dentition. Study II revealed IRF6 gene mutation in 59% of the 17 VWS/ PPS families studied using direct sequencing of all exons of the gene. In Study III, the IRF6 gene was investigated in 17 Swedish NSCL/P families, using direct sequencing of the gene, in one affected and one healthy individual of each family. We could not detect any mutation in the protein-coding region of the gene. However, two noncoding SNPs – rs861019, a non-coding polymorphism in exon 2, and rs7552506, located in intron 3 – showed an association with the NSCLP phenotype. In Study IV, we tested two SNPs of IRF6, rs642961 in the promoter and rs2235371 in exon 7 (Val274Ile), for association with our entire sample set of NSCL/P, VWS and PPS families (119 families). In all but the Finnish VWS/ PPS families, the “A” allele of rs642961 was identified as a risk allele; transmission to an affected child occurred in a large majority on the same chromosome as the detected IRF6 mutation. The SNP rs642961, located in the AP-2a binding site in the promoter of the IRF6 gene, has previously been shown to be associated with NSCL±P but our results do not support this. However, we did find a significant risk (p=0.013) for transmission of the G-C haplotype (rs642961-rs2235371) to affected individuals in the NSCP subgroup of Swedish families. Of the 16 VWS/ PPS families found to have a mutation in IRF6 (Studies II and IV), 31% had a de novo mutation, that is, a mutation occurring in the proband only and not in the healthy parents. To conclude, NSCL/P is a complex anomaly, where disturbed dental development is a frequent finding. NSCL/P is not dependent on a single gene, as in Mendelian inherited VWS. Dividing our material into sub-phenotypes resulted in rather small groups, but we did find a significant risk with a haplotype of IRF6 in the NSCP group, and also an association for two SNPs of the IRF6 gene with NSCLP. Our results on NSCL/P emphasize the need for additional evaluation of the IRF6 gene and other genes/modifiers, to further clarify their roles in the development of the NSCL/P phenotype.
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| 2. |
- Pegelow, Marie, et al.
(author)
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The prevalence of various dental characteristics in the primary and mixed dentition in patients born with non-syndromic unilateral cleft lip with or without cleft palate
- 2012
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In: European Journal of Orthodontics. - : Oxford University Press (OUP). - 0141-5387 .- 1460-2210. ; 34:5, s. 561-570
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Journal article (peer-reviewed)abstract
- This retrospective study was carried out on consecutively collected dental casts, x-rays, and photos of 129 Swedish children who had been born with non-syndromic unilateral (U) cleft lip (CL), cleft lip and alveolus (CLA), or cleft lip and palate (CLP). The following dental characteristics were investigated in the primary and permanent dentitions: 1. the presence, eruption, position, and shape of the lateral incisor; 2. the prevalence of rotation and enamel hypoplasia of the permanent central incisor; 3. the occurrence of hypodontia outside the cleft region; and 4. the transition from the primary to the succeeding permanent lateral incisor in the cleft region. Patients with clefts involving the palate (UCLP) exhibited a high frequency of hypodontia. In patients with clefts, which did not include the palate, malformed lateral incisors were a common finding. In the primary and permanent dentition, the lateral incisor had erupted distal to the cleft in 31.8 and 24.8 per cent of the UCLA and UCLP patients, respectively. No significant pattern was seen regarding the transition from the primary to the succeeding permanent lateral incisor (P = 0.15). The central incisor was rotated in 55 per cent of the patients and this positional deviation was particularly frequent in cases where the lateral incisor was missing in the premaxilla (P < 0.05). Hypodontia outside the cleft region was recorded in 15.5 per cent of the patients. Patients with UCLP had more often crossbite than patients with a UCL or a UCLA phenotype (P < 0.001).
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| 3. |
- Peyrard-Janvid, Myriam, et al.
(author)
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Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:1, s. 23-32
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Journal article (peer-reviewed)abstract
- Mutations in interferon regulatory factor 6 (IRF6) account for similar to 70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.
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| 4. |
- Savchenko, Julia, et al.
(author)
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Key outcomes in childbirth : Development of a perinatal core outcome set for management of labor and delivery at or near term
- 2023
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In: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley-Blackwell. - 0001-6349 .- 1600-0412. ; 102:6, s. 728-734
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Journal article (peer-reviewed)abstract
- Introduction: Consistency and relevance of perinatal outcome measures are necessary basics for obstetric research, audit, and clinical counseling. Still, there is an unwarranted variation in reported perinatal outcomes, which impairs research synthesis, validity, and implementation, as well as clinical benchmarking and longitudinal comparisons. The aim of this study was to develop a short-term perinatal (fetal and neonatal) Core Outcome Set to be used in research and quality assurance of management of labor and delivery at or near term.Material and methods: The methods were guided by the Core Outcome Measures in Effectiveness Trials Initiative Handbook. The project was prospectively registered on July 2, 2020 in the Core Outcome Measures in Effectiveness Trials (COMET) data base (reference number 1593). A list of potential outcomes was created based on a systematic review of studies evaluating interventions for peripartum management at or near term (>= 34 weeks of gestation), including decisions regarding timing and type of onset of labor, intrapartum care, and mode of delivery. The list was entered into a two-round Delphi survey with predefined consensus criteria. Participants (n = 67) included clinicians, researchers, lay persons with experience of childbirth (patient representatives), and other stakeholders. A consensus meeting was held to reach a final agreement.Results: Response rates were 82.1% (55/67) and 92.7% (51/55) for the first and second Delphi rounds, respectively. In total, 17 outcomes were included in the final core outcome set, reflecting mortality, health or morbidity, including asphyxia, central nervous system status, infection, neonatal resuscitation and admission, breastfeeding and mother-infant interaction, operative delivery due to fetal distress, as well as birthweight and gestational age. Two of these outcomes were suggested by patient representatives.Conclusions: The Swedish Perinatal Core Outcome Set (SPeCOS) study involved a broad circle of relevant stakeholders and reached consensus on a minimal set of perinatal outcomes that should be collected and reported in a standardized way in all future studies on management of labor and delivery at or near term, regardless of the specific population or condition studied. This could improve obstetric research, evidence synthesis, uptake, implementation, and adherence, as well as clinical practice, audit, and comparisons in childbirth care.
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| 5. |
- Sörensen, Caroline, et al.
(author)
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Comparing oral health-related quality of life, oral function and orofacial aesthetics among a group of adolescents with and without malocclusions
- 2022
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In: Acta Odontologica Scandinavica. - Abingdon, Oxfordshire, United Kingdom : Taylor & Francis. - 0001-6357 .- 1502-3850. ; 80:2, s. 99-104
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim was to analyze how malocclusion relates to perception of oral health-related quality of life (OHRQOL), oral function and orofacial aesthetics among a group of adolescents in Sweden.MATERIAL AND METHODS: Thirty patients with a need for orthodontic treatment (IOTN-DHC grade 4 and 5) and 30 patients with normal occlusion (IOTN-DHC grade 1), aged 13-17 years, were included in the study. A questionnaire containing three parts was used; The Oral Health Impact Profile (OHIP-S14), Jaw Functional Limitational scale (JFLS-20) and Orofacial Aesthetic scale (OES). Malocclusions, orthodontic treatment need and confounders, such as earlier dental treatment and temporomandibular disorders, were registered.RESULTS: Adolescents with malocclusions were more often embarrassed by their mouth and teeth compared to controls (p < .05). Aesthetically, adolescents with malocclusions were more negatively affected by the appearance of the mouth and teeth as well as the over-all facial appearance (p < .05).CONCLUSIONS: Malocclusions clearly affects the adolescents with need for orthodontic treatment in this study. It influences their OHRQOL in the psychosocial impact dimension. Aesthetically they perceive their oral and facial appearance as worse compared to controls. Although embarrassed and unpleased with their oral appearance they still rate themselves as having a good oral health with low jaw function limitations.
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