The genetic basis of hemifacial microsomia.

The aetiology of hemifacial microsomia is uncertain vascular, metabolic, teratogenic and genetic factors have been proposed as aetiological influences. The evidence for a genetic basis comes from observations of the phenotype in individuals carrying chromosomal rearrangements, and from a small number of studies involving families in whom the condition appeared to be transmitted in a Mendelian fashion. Malformations reminiscent of hemifacial microsomia have also been seen in knockout and mutant animal models, and these have given rise to a number of candidate genes for the disease. Two main objectives were defined at the start of this project. The first of these was to expand upon the currently available clinical data by interviewing and examining patients with hemifacial microsomia or isolated microtia who presented to two specialist treatment centres in London, Great Ormond Street Hospital and Mount Vernon Hospital. Alongside this a genome scan was performed on a family in which hemifacial microsomia appeared to be segregating in an autosomal dominant manner. Whilst definite linkage to a single locus could not be inferred from the results of the genome scan, a few regions of interest were identified, and linkage to a large proportion of the genome was excluded. One area of particular interest, 2q32 - 2q37, was analysed in greater detail, and other regions together with their potential disease genes have been highlighted

Study of a possible genetic cause of CHARGE association

CHARGE association, or syndrome as it is now known, is a condition where a number of congenital malformations are non-randomly associated in a recognizable pattern. There are two sets of diagnostic criteria for CHARGE syndrome which are in common usage at present (Blake et al., 1998; Verloes, 2005). The etiology of CHARGE syndrome was unknown. We identified twin girls with CHARGE syndrome and a de novo apparently balanced chromosome translocation 46,XX,t(8;13)(q11.2;q22). By mapping the chromosome translocation breakpoints we found that the gene chromodomain-helicase-DNA-binding protein 7 (CHD7) located at 8q12 was disrupted in these girls. CHD7 has a genomic length of 188kb with 9000 coding bases over 37 exons. It has a putative function as a transcription factor which makes it a good candidate gene for a condition which affects multiple body systems. Concurrently with this study Vissers et al (2004) identified CHD7 as a cause of CHARGE syndrome. They found two individuals with CHARGE syndrome with overlapping microdeletions detected by array CGH. By sequencing the 9 genes in this region in a cohort of 17 cases they identified a mutation in CHD7 in 10 cases. We ascertained a cohort of 45 patients with a diagnosis of CHARGE syndrome or possible CHARGE syndrome by scrutinizing the clinical genetics databases in Glasgow and Sheffield. Part of the cohort was accessed by receipt of samples from clinical genetics departments elsewhere in the U.K. and in Lisbon. Clinical information was acquired on this cohort either by examination and review of the clinical notes by the author or by completion of a proforma by the referring clinician. Sequencing in this cohort of 45 patients was successful in 43 individuals. We identified 28 mutations; 16 nonsense, 10 frameshift and 2 splice site mutations. 20 of the mutations were novel, 8 had been reported in other studies. The mutations were found throughout the gene with no particular hotspots. No genotype/phenotype correlations were found either in relationship to the position of the mutation within the gene or with regards to the type of mutation. I have analyzed the phenotype in our cohort and compared it with the cases of CHARGE association reported prior to the availability of mutation analysis. I have also compared the phenotype in our mutation positive cases with those reported in other studies which were mutation-positive. We report two individuals with rare findings in CHARGE syndrome; one with a palsy of the twelfth cranial nerve reported anecdotally only once before (Blake et al., 2008), and another child with a limb reduction defect which has been reported in five other cases (Aramaki et al., 2006; Asamoah et al.,2004; Van de Laar et al., 2007). Our notes review ascertained an incidence of CHARGE syndrome of 1/10,000

Craniofacial and dental anomalies in Van der Woude and Blepharocheilodontic syndromes

Background and objectives: Cleft lip and/or palate (CL/P) is the most common orofacial birth defect, which may either be associated with other abnormalities or occur as an isolated condition. The most common syndromic form of orofacial clefting is the Van der Woude Syndrome (VWS), Blepharocheilodontic (BCD) syndrome is a rare condition characterised by eye, lip and dental developmental orofacial clefting abnormalities. The aim of this thesis was to analyse BCD syndrome phenotypes and the associated dental and craniofacial anomalies and compare it with non-syndromic bilateral cleft lip and palate (NSBCLP) and non-cleft) (study I), the prevalence, pattern and severity of taurodontism (study II), as well as the dental maturity (DM) and anomalies in individuals with VWS exhibiting cleft palate, were analyzed and compared with non-syndromic cleft palate (NSCP) and non-cleft controls (study III). Materials and methods: In study I, cephalometric radiographs of BCD syndrome patients, 20 NSBCLP and 20 non-cleft, were analysed. The clinical records, photographs, dental study casts and dental radiographs were also assessed to determine the tooth agenesis extent and pattern, dental morphology and malocclusion. For study II, one hundred and seventy-eight dental panoramic tomographs (DPTs) consisting of 42 VWS patients, 42 NSCP patients and 94 normative non-cleft children were assessed, and their first permanent molars evaluated. Measurement 3 of the taurodontism index. Prevalence, pattern, and severity were compared between groups. For study III, 204 dental panoramic tomographs (DPTs) consisted of 51 VWS patients, 51 NSCP patients and 102 normative non-cleft children were collected. Dental stages were assessed by Demirjian’s method, with the Finnish dental maturity reference values. Dental anomalies included tooth agenesis and taurodontism. Results: The results of study I revealed that BCD syndrome patients had a maxillary–mandibular sagittal discrepancy (very severe skeletal III malocclusion) and decreased anterior lower face height compared to NSBCLP and non-cleft controls (P = 0.001, P = 0.027). All patients had oligodontia (mean number of missing permanent teeth 13.7). All patients exhibited missing upper central and lateral incisors, upper canine and premolar teeth. In study II, the prevalence of taurodontic molars in children with VWS was higher than in the other groups (59.5% compared to 45.2% in the NSCP group, and 26.6% in non-cleft controls). The prevalence and severity of taurodontism in VWS and NSCP were significantly higher than in non-cleft children in all first permanent molars, while the difference between VWS and NSCP groups was not significant. Children in VWS group were approximately twice more likely to have taurodontism compared to NSCP group. Hypotaurodontism was the most frequent type in taurodontic molars. In study III, the differences between dental age (DA) and chronological age (CA) of VWS group and NSCP group were significantly lower than the difference in the non-cleft group (P= 0.002). There was no significant difference between VWS and NSCP groups (P= 0.817). Hypodontia prevalence in the non-cleft group (5.88 %) was significantly lower than both VWS group (37.25 %) (P= 0.0001) and NSCP group (19.6 %) (P= 0.035). Conclusions: The craniofacial skeletal defects in the BCD syndrome group were more severe than in patients with NSBCLP. The pattern of tooth agenesis is unusual as it included teeth that are normally highly resistant to agenesis. In VWS and NSCP we observed a high prevalence of taurodontism. Most taurodontic molars are hypotaurodontic. Dental maturity was delayed in both the VWS and NSCP groups compared to the non-cleft control. Hypodontia prevalence was significantly high in both VWS and NSCP groups compared to the non-cleft control. This thesis will provide an insight into these diseases and help clinicians develop a proper guideline for treatment protocol.Tiivistelmä ei ole saatavilla

The construction of 'self' in individuals with congenital facial palsy; A grounded theory exploration

Background: Developmental and psychoanalytic research findings suggest that early face to face interactions with caregivers play a significant role in the construction of an individual’s sense of self and that disruptions to these interactions can have negative consequences for social and emotional development. However, there is currently a significant gap in the research literature regarding how the sense of self is constructed in individuals who have limited or no facial expression due to conditions such as congenital facial palsy. Consequently, little is known about how the sense of self develops in these individuals. The aims of this study were twofold: to explore the construction of ‘self’ in individuals living with this condition and to construct a grounded theory of this process. It is hoped that these findings will add to the limited literature in this area and be used to develop specialist psychotherapeutic interventions for those living with this condition.Method: A constructivist Grounded Theory methodology was adopted, and a purposive sampling strategy used to recruit the initial sample. Semi structured interviews were conducted with fourteen adults (8 male and 6 female) with a diagnosis of congenital facial palsy; eight interviews were conducted face to face with participants in the USA and six via Skype with participants in the UK. In the final stages of the analysis theoretical sampling was used to recruit two parents of children with congenital facial palsy. Participants were asked about their experiences across the lifespan of living with congenital facial palsy and their constructions of self were explored.Findings: Participants’ retrospective accounts suggest that living with congenital facial palsy negatively influences communications with caregivers and others across the lifespan. Participants’ accounts suggest that two separate self-states were constructed through their interactions with others; a ‘“defective me”’ and a “validated me”. Participants described how the ‘“defective me”’ self-state was constructed through the following relational processes; ‘struggling to make connections’, ‘experiencing invalidation,’ and ‘struggling with affect regulation’. Conversely, several participants described how the construction of a “validated me’’ self-state occurred through; ‘making validating connections’. Those participants who described the ability to move more fluidly between self-states described better psychosocial outcomes as they recovered more quickly from negative interactions with others.Conclusion: The findings of this study highlight the central role that the face occupies in the construction of the ‘self’ and the unique challenges those with congenital facial palsy are likely to experience in constructing a validated self-state. It is suggested that psychotherapies which focus on healing the non-verbal sense of self may be one effective approach to working clinically with this population

A Survey of Speech-Language Pathologists\u27 Academic Preparation in Craniofacial Anomalies

Craniofacial anomalies occur in 1 of 750 newborns a year with the three main types being cleft lip, cleft palate, and cleft lip and/or cleft palate. There are six main factors that affect craniofacial anomalies that are focused on in this research, including genetics, environmental factors, medications, diet, health risks, and surgical procedures/surgeons. The research found that there is a lot of information on craniofacial anomalies and speech-language pathologists need to learn about as much as possible. The lack of knowledge and academic preparations speech-language pathologists have in craniofacial anomalies has decreased their awareness in the birth defect and has also caused a lack of confidence in their practices to properly treat these patients. In conclusion, there needs to be an improvement in the academic preparation in the CSD undergraduate and graduate programs in craniofacial anomalies

Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome

CHARGE syndrome [coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities (including deafness)] is a genetic disorder characterized by a specific and a recognizable pattern of anomalies. De novo mutations in the gene encoding chromodomain helicase DNA binding protein 7 ( CHD7 ) are the major cause of CHARGE syndrome. Here, we review the clinical features of 379 CHARGE patients who tested positive or negative for mutations in CHD7 . We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals. We also highlight recent genetic and genomic studies that have provided functional insights into CHD7 and the pathogenesis of CHARGE syndrome. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65049/1/33323_ftp.pd