Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic ...review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects:
MSX1
,
PAX9
,
IRF6
,
TP63, KMT2D
,
KDM6A
,
SATB2
,
TBX22
,
TGFα
,
TGFβ3
,
TGFβR1
,
TGFβR2
,
FGF8
,
FGFR1
,
KISS1R
,
WNT3
,
WNT5A
,
CDH1
,
CHD7
,
AXIN2
,
TWIST1
,
BCOR
,
OFD1
,
PTCH1
,
PITX2
, and
PVRL1
. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the
GOTermMapper
(Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The aim of this study was to determine the amount of deviation in nasolabial shape in patients with a cleft compared with an average non-cleft face, and to assess whether this difference is related ...to nasolabial aesthetics. Three-dimensional stereophotogrammetric images of 60 patients with a unilateral cleft were used. To quantify shape differences, four average non-cleft faces were constructed from stereophotogrammetric images of 141 girls and 60 boys. Three-dimensional shape differences were calculated between superimposed cleft faces and the average non-cleft face for the same sex and age group. Nasolabial aesthetics were rated with the modified Asher-McDade Aesthetic Index using a visual analogue scale (VAS). Mean VAS scores ranged from 51.44 to 60.21 for clefts, with lower aesthetic ratings associated with increasing cleft severity. Shape differences were found between cleft faces and the average non-cleft face. No relationship was found for the VAS, age, and sex, except that a lower VAS was related to a higher nose and lip distance between the superimposed cleft and average non-cleft faces for nasal profile (P= 0.02), but the explained variance was low (R2=0.066). In conclusion, except for nasal profile, nasolabial aesthetics were not influenced by the extent of shape differences from the average non-cleft face.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purpose of this study was to evaluate the accuracy of Demirjian's dental age estimation in children in a Belgian Caucasian population and to adapt the scoring system in case of a significant ...overestimation as frequently reported. We selected 2523 orthopantomograms of 1265 boys and 1258 girls, of which 2116 (1029 boys and 1087 girls) were used for estimating the dental age with the Demirjian's technique. The 407 other orthopantomograms were beyond the original age limit. A second sample of 355 orthopantomograms was used to evaluate the accuracy of the original method and the adapted method. A signed-rank test was performed to search for significant age differences between the obtained dental age and the chronological age. A weighted ANOVA was performed in order to adapt the scoring system for this Belgian population. The overestimation of the chronological age was confirmed. The adapted scoring system resulted in new age scores expressed in years and in a higher accuracy compared to the original method in Belgian Caucasians.
Hemifacial microsomia (HFM) is a congenital disorder marked by facial asymmetry. Whether facial asymmetry accounts for asymmetrical dental development is unknown. There are few data on dental ...development relative to mandibular development or severity of HFM, or on development over time. We hypothesized that when mandibular development was severely disturbed, local dental development was also affected. We compared dental development scores between affected and non-affected mandibular sides in patients with HFM (n = 84) and compared these data with those collected from Dutch control children (n = 451). Logistic functions were constructed for dental age over time for all four Pruzansky/Kaban types. The results showed a tendency toward delayed dental development in Pruzansky/Kaban types IIb and III at younger ages. The temporary delay of tooth formation in patients with severe forms of HFM and the distribution of agenic teeth suggest an interaction between mandibular and dental development.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Common variants in interferon regulatory factor 6 (IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants ...contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal ...anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene.
We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones.
Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity.
Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.
Craniofacial development is tightly regulated and therefore highly vulnerable to disturbance by genetic and environmental factors. Fibroblast growth factors (FGFs) direct migration, proliferation and ...survival of cranial neural crest cells (CNCCs) forming the human face. In this study, we analyzed bone and cartilage formation in the head of five dpf
zebrafish larvae and assessed gene expression levels for 11 genes involved in these processes. In addition,
hybridization was performed on 8 and 24 hours post fertilization (hpf) larvae (
,
,
,
). A significant size reduction of eight out of nine craniofacial cartilage structures was found in homozygous mutant (6-36%,
<0.01) and heterozygous (7-24%,
<0.01) larvae. Also, nine mineralized structures were not observed in all or part of the homozygous (0-71%,
<0.0001) and heterozygous (33-100%,
<0.0001) larvae. In homozygote mutants,
and
expression was upregulated compared to wild type, presumably to compensate for the reduced bone formation. Decreased
expression may compromise cartilage formation. Upregulated
in homozygotes indicates impaired CNCC function.
expression was reduced in the first and second stream of CNCCs in homozygous mutants at 24 hpf, as shown by
hybridization. This indicates an impairment of CNCC migration and survival by
mutation.
The 22q11.2 deletion syndrome (22q11.2DS) is one of the most frequent microdeletion syndromes and presents with a highly variable phenotype. In most affected individuals, specific but subtle facial ...features can be seen. In this observational study, we aim to investigate the craniofacial and dental features of 20 children with a confirmed diagnosis of 22q11.2DS by analyzing 3-dimensional (3D) facial surface scans, 2-dimensional (2D) clinical photographs, panoramic and cephalometric radiographs, and dental casts. The 3D facial scans were compared to scans of a healthy control group and analyzed using a spatially dense geometric morphometric approach. Cephalometric radiographs were digitally traced, and measurements were compared to existing standards. Occlusal and dental features were studied on dental casts and panoramic radiographs. Interestingly, a general trend of facial hypoplasia in the lower part of the face could be evidenced with the 3D facial analysis in children with 22q11.2DS compared to controls. Cephalometric analysis confirmed a dorsal position of the mandible to the maxilla in 2D and showed an enlarged cranial base angle. Measurements for occlusion did not differ significantly from standards. Despite individual variability, we observed a retruded lower part of the face as a common feature, and we also found a significantly higher prevalence of tooth agenesis in our cohort of 20 children with 22q11.2DS (20%). Furthermore, 3D facial surface scanning proved to be an important noninvasive, diagnostic tool to investigate external features and the underlying skeletal pattern.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The aim of this longitudinal study was to monitor patients' microbiological and clinical parameters from bracket placement up to 3 months post-treatment. Twenty-four patients (10 males and 14 ...females, aged 14.6 ± 1.0 years) were included in this investigation. Microbiology (sub- and supragingival), periodontal probing depth (PPD), bleeding on probing (BOP), and gingival crevicular fluid (GCF) flow were assessed at baseline (T1), at bracket removal (T2), and 3 months post-treatment (T3). A statistical comparison was made over time and between the banded, bonded, and control sites. Repeated measurements on patients were taken into account by modelling the patients as a random factor. Except for PPD and BOP, values were log-transformed before analysis. Corrections for simultaneous hypothesis testing were performed via simulation. The results demonstrated that sub- and supragingival colony-forming units ratio (CFU ratio aerobe/anaerobe) decreased significantly (relatively more anaerobes) at T2 compared with T1. Between T2 and T3 no significant increase in CFU ratio was seen, resulting in a significantly lower CFU ratio at T3 compared with T1 for subgingival plaque. The difference concerning supragingival plaque between T3 and T1 was not significant. Clinical parameters PPD, POB, and GCF flow showed a significant increase between T1 and T2. Between T2 and T3 these variables decreased significantly but remained significantly higher than at T1 except for BOP values at the bonded sites (P = 0.0646). Placement of fixed orthodontic appliances has an influence both on microbial and clinical periodontal parameters, which were only partly normalized, 3 months following the removal of the appliances.
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