Clinical Characteristic Of Congenital Agenesis And Study Of Distribution And Significance Of PAX9 In Dental Development

Background:The tooth is one of the vertebrate organs in which molecularregulation has been actively studied in recent years, mostly with mouse molarteeth as a model system. The development of teeth is regulated by inductiveinteractions between epithelial and mesenchymal cells and is under strict geneticcontrol. More than 200 genes are known to be expressed during toothdevelopment.Agenesis of one or more permanent teeth occurs in about 1.6-9.6% of thepopulation, excluding third molar agenesis, which is more prevalent . Most often,1 or 2 second premolars or lateral maxillary incisors are missing. The term'hypodontia' is defined as the congenital absence of fewer than 6 teeth, whereas'oligodontia' designates the congenital absence of 6 or more permanent teeth,excluding the third molars. Oligodontia is a rare condition that can occur inassociation with genetic syndromes, or as a non-syndromic isolated familial trait,or as a sporadic finding.Non-syndromic familial oligodontia has, in most cases, been shown to beinherited as an autosomal-dominant trait. Several cases where a single genemutation is associated with oligodontia have been described in recent years. So far,mutations in MSX1 and PAX9 have been shown in families with non-syndromicfamilial oligodontia. Furthermore, agenesis of a few teeth to the entire set of teethin one large Chinese kindred has been mapped to a locus on chromosome 10q11.MSX1 and PAX9 are both transcription factors expressed in the dentalmesenchyme at the stage of initiation of tooth development, in both the dentalpapilla and the dental follicle.PAX9 is situated on chromosome 14 and belongs to the PAX gene family,which encodes a group of transcription factors that play a role in earlydevelopment. PAX proteins are defined by the presence of a DNA-binding domain,the 'paired-domain', which makes sequence-specific contact with DNA. Pax9expression has a highly specific pattern during mouse embryogenesis, inderivatives of the foregut endoderm, somites, limb mesenchyme, midbrain, andthe cephalic neural crest. Homozygous Pax9-deficient mice die shortlyafter birth,most likely as a consequence of cleft of the Secondary palate;they lackpharyngeal pouch derivatives, and craniofacial/visceral skeletogenesis is disturbed.Heterozygous Pax9 mutant mice exhibit no obvious abnormalities. PAX9 isexpressed in the dental mesenchyme prior to the first morphological manifestationof odontogenesis. As in Msx1 knockout mice, the tooth development inhomozygous Pax9-deficient mouse embryos is arrested at the bud stage, indicatingthat Pax9 is required for tooth development to proceed beyond this stage.So far, the literature reports some families in whom PAX9 mutations segregatewith non-syndromic autosomal-dominant inherited oligodontia. The eight familieshave all shown different kinds of mutations in the PAX9 coding region. Thepurpose of the present study was to screen a family with non-syndromicoligodontia for mutations in MSX1 and PAX9. The phenotype correlated wellwith reports on families described earlier in the literature, and the oligodontia wasinherited as anautosomal-dominant trait.Objective: One aim is to explore effective method for preventing and curingcongenital agenesis, to find out the condition and rules of clinical congenitalagenesis. The other aim is to ensure the time andlocation of Pax9 expression in dental development, to search after its function andinteraction between Pax9 and congenital agenesis.Material and method: We selected the congenital teeth agenesis patients fromSchool of Stomatology, Jilin University during 2003,1-2005,12. First, we recordedthe disease history, excluding the history of teeth extraction. For those patientsbeing up to the mustard and their families, we first gave them careful oralexamination and systemic examination, and then took panoramic radiograph andorthopantomographic radiograph. The family tree was also determined forancestry analysis. Nine pregnant Kunming mice aging 10.5-18.5days was madeslices for HE staining and PAX9 goat anti-mouse antibosy SPimmunohistochemical staining. The result was analysed by the image analysissystem and taken pictures for recording.Results: 9 congenital teeth agenesis families and 11 sporadic patients had beencollected. From these data, we found that congenital teeth agenesis was not asimple agenesis of tooth, but could combine with other congenital abnormity(mostly the skin and its pertained tissue, eye etc.), or only the simple teethagenesis. There are all kinds of clinical manifestation and its reason is complextoo. Some of them had family history, while others didn't have. At the same time,some agenesis patients have obvious abnormity conformation of their teeth. Insome ancestry, congenital teeth agenesis is the indication of system diseases. Sothe oral cavity is the "window" of other systemic diseases, especially for thosehaving syndromes, the systemic examination is especially important.The hereditary mode of ancestry congenital teeth agenesis are mostlyautosomal-dominant manner accompanied with incompleted dominant,autosomal-dormant manner, X-linked, multi-factors and multi-gene hereditarymode. The ancestry we investigated are all autosomal-dominant manneraccompanied with incompleted dominant, that is the traditional mode of agenesis.The possible reasons which we did not find other mode of hereditary are thelimited number or area (mainly Jilin and Inner Mongolia Provinces).The sporadic patients were often lack of anterior teeth or bi-cusp teeth, withthe wisdom teeth missing in one or two. We did not find other molars missing, thenumber of missed teeth was usually from 1to5, and we did not find the typical"peg shaped" teeth.The congenital teeth agenesis is always accompanied by skull-jaw abnormity,class â…¢ dental malocclusion mal-occlusion, part of them had delayed permanentteeth eruption.The patients of congenital teeth agenesis are often found when they are treatedbecause of deciduous teeth-permanent teeth substitution problems or otherdiseases. Since most of them are found late, and the mechanism of congenitalteeth agenesis is not clear, we can only try to find and diagnose them as early aspossible and give them proper treatment, so that we can save the healthy milkteeth and maintain the completeness of dentition. If the teeth can not bemaintained, it should be extracted as early as possible, and make them a gapmaintainer. Then , they should be checked periodically for adjustment of themaintainer to fit the development of jaw bone. Only in this way, can we improvetheir mastication efficiency and facilitate the development of soft and hard tissue.Or we can close the dispersed gaps between teeth, and make temporal denture forthem until their adulthood for the permanent denture.Dental germs in all development stages might be observed in HE stainingsections. In the immunohistochemical staining sectionsPAX9 was localized in cell plasm. The localization and positive degreechanged in different development stages. There was no expression of PAX9 in theodontogenic epithelia and the mesenchymal cells in dental lamina and bud stage.In cap stage, there was the expression of PAX9 in the papillas and little expressionin inner, outer enamel epithelia and stellate reticula. In the early bell stage strongstaining was observed in odontoblasts or preodontoblasts, weak staining in innerenamel epithelia and papillas. In the late bell stage PAX9 was localized inodontoblasts , ameloblasts and the enamelo-dentinal junction. The degree ofexpression was lower in preodontoblasts, new enamel and predentin. There wasalso staining in dentinal tube and enamel matrix , but the degree was decreasingwith the distance to the enamelo-dentinal junction.The expression of PAX9 is the signal of tooth formation, and the appearanceof the signal is earlier than any morphology signals.PAX9 is involved in theinitiation of the signals of the tooth development. But the initiation of the dentaldevelopment is not determined by the only PAX9 gene. In this experiment theexpression of PAX9 was not observed in the dental lamina stage and bud stage.The reason may be that the sensitivity of the immunohistochemical method is lowor that PAX9 gene is only transcribed but not translated.PAX9 takes the role in theregulation of the dental germ development during the transitional period from thebud stage to cap stage.The degree of PAX9 expression changed in different germ stages. There is noexpression in epithelia and mesenchymal cells of bud stage. PAX9 begins to beexpressed in papilla cells of cap stage. Strong staining is observed in odontoblastsand preodonblasts of the bell stage.The expression is weakened in theodontoblasts and ameloblasts after the matrix secretion. The change of the PAX9expression illustrates that PAX9 may be involved in the differentiation, maturationof the odontoblasts and ameloblasts and the secretion of the dentine and enamelmatrix.After the differentiation of the odontoblasts, the staining of PAX9 is strong inthe place where the enemalo-dentinal junction will be developed. It suggests thatPAX9 as a signal molecule could participate in the interaction between theepithelial tissue and mesenchymal tissue in order to form the dental hard tissueorderly and coordinately. The expression of PAX9 was fairly strong in newenamel and predentin and was localized along the odontoblast process in thedentinal tube. There is a decreasing tendency away from the basal membrane. Itmay be supposed that PAX may be playing a role in the dentin and enamelbiomineralization process, that with the mineralization PAX9 may be degradedand absorbed to provide the place for the further mineralization.Conclusions:1.The congenital teeth agenesis is autosomal dominant inheritant diseaseaccompanying incomplete penetrance.2.The inheritant appearance include the deleted tooth number, crown shape anderupting procedure.3.The manifestation is serious if the individual is combined with environmentalfactor. there are many sorts of absent tooth.4.The anterior teeth and premolar are involved in sporadic cases. The occlusionof the remaining teeth is normal. There are many interspaces in the anterior teeth.The third molar develops well.5.There is an interaction between the development of maxillofacialhard tissue and formation of the teeth.6.The therapy to the congenital teeth agenesis is to treat the symptom and torestore the defect of dentition.7. PAX9 enforces the transform from bud stage to cap stage and the furtherdevelopment of dental germ.8.PAX9 regulates the differentiation of odontoblasts, ameloblasts and the matrixsecretion in the bell stage.9.PAX9 is involved in the biomineralization process of the dentine and enamel.