Supernumerary teeth in patients with cleft lip and palate: the tooth germs do not separate

ABSTRACT Introduction: Supernumerary teeth in cases of cleft lip and palate do not result from the division of normal germs before the formation of hard tissue. Deciduous and permanent teeth odontogenesis begins after the face has formed, either with or without the cleft. Discussion: The most acceptable hypothesis to enable understanding of the presence of supernumerary teeth on one or both sides of the cleft palate is hyperactivity of the dental lamina in its walls. This hyperactivity, with the formation of more tooth germs, must be attributed to mediators and genes related to tooth formation, under strong influence of local epigenetic factors, whose developmental environment was affected by the presence of the cleft. Conclusion: The current concepts of embryology no longer support the fusion of embryonic processes for the formation of the face, but rather the leveling of the grooves between them. All human teeth have a dual embryonic origin, as they are composed of ectoderm and mesenchyme/ectomesenchyme, but this does not make it easy for them to be duplicated to form supernumerary teeth.

The most frequent supernumerary teeth are the mesiodens, mandibular premolars and Bolk's fourth molars. When they resemble the group of origin, they are denominated eumorphic supernumerary teeth, and when they have an undefined shape, they are said to be dysmorphic. In cleft lip and palate patients, the frequency of supernumerary teeth reaches up to 43.5% of cases [1][2][3][4][5] (Fig 1).

FORMATION OF THE FACE DOES NOT OCCUR BY FUSION
The formation of the face does not occur by fusion of embryonic processes, which was an older way of understanding how facial development takes place. All evidence has shown that the face is formed by leveling of the embryonic processes, except at a very specific and central point of the hard palate, from which anterior and posterior leveling is also established. 6 These concepts, of face formation mechanisms, and their evolution -from the fusion to the leveling -have been meticulously reviewed, described and presented in an article published in 2017 6 (Figs 2 and 3).

WHEN THE DENTAL LAMINA AND TOOTH GERMS BEGIN
The anterior part of the primitive mouth, or stomodeum, has an ectodermal lining of the external part that invaginates. This lining joins with the lining at the back of the mouth - which, in the embryo, is called the embryonic pharynx. 12 When the buccopharyngeal membrane is broken, the two cavities join to form the final mouth. The exact site in the oral mucosa where this membrane adheres is still controversial. The first sign of deciduous human dentition occurs around the eighth week of embryonic life, with a linear thickening in the lining and a horseshoe-shaped contour at the location of the future dental arch. 13 This thickening will form the dental lamina that descends vertically as it enters the space that will be the mandible and maxilla. Underlying this thickening, there is an increase in the concentration of mesoderm and ectomesenchymal cells derived from the neural crest, that will later form the dental papilla and dental follicle.
This thickening of the ectodermal lining initially occurs at the region of the incisors and molars in each quadrant, which will unite, as they grow towards the anterior and posterior directions, and become equal in the region that will be the canines.
These two areas are influenced by the same mediators and All these above-mentioned characteristics and occurrences are relative to the deciduous lateral incisor, and not the permanent lateral incisor. From the deciduous lamina, sprouts or buds will form, which will give rise to the germs of the deciduous teeth and to another lamina that arise by lingual, and will give rise to the permanent teeth -which is also called the successional lamina, and is continuous around the entire dental arch.
But there is a most important point: the first signs of formation of this successional lamina that will give rise to permanent teeth only begin to appear after the eleventh week of embryonic life. 6,13 As mentioned before, the deciduous teeth

HYPOTHESES TO EXPLAIN SUPERNUMERARY TEETH, INCLUDING IN CASES WITH CLEFTS
The cause of supernumerary teeth is unknown. There are theories or hypotheses to explain them, highlighting the following: 1. The hyperactivity of the dental lamina, represented by excessive induction for this laminar and continuous tissue to form more tooth buds than the normal number. This can occur due to an excessive quantity of growth factors or mediators, especially in the areas of clefts, which lead to more teeth appearing than were originally programmed by the genes.

Atavism, or phylogenetic reversal, which represents current
manifestations of distant ancestral characteristics - as a possible occurrence of third dentition, which has never been described or observed in primates and predecessors of the human race. This theory represents a theoretical and very imaginative presumption.
3. The sectioning, into two or more parts, of a tooth germ prior to the formation of hard or mineralized tooth tissue, but due to an unknown cause that has never been demonstrated in vivo.

CLEFT LIP AND PALATE DO NOT OCCUR CONCOMITANTLY WITH THE BEGINNING OF ODONTOGENESIS
On the lateral walls of cleft palate, there is frequent presence of supernumeraries in the form of a extra lateral incisor on the side corresponding to the premaxilla or as a tooth similar to the lateral incisor on the maxillary side of the cleft, also identified as precanine. [1][2][3][4][5] These teeth may also be dysmorphic, as they do not have the morphology of the dental group that gave rise to them, but their tissues are microscopically indistinguishable from eumorphic and normal teeth.
An explanation often given for these supernumerary teeth in clefts is that the supposed lack of fusion - an event that could never be demonstrated, even in a rudimentary way -would cleave the tooth germ into two parts, thus giving rise to two independent teeth, with one of them being supernumerary.
In the formation of clefts, no cleavage occurs, and there is no external force that separates the structures, such as the maxilla and the teeth, which have already been formed. In this period, the teeth have not yet been formed.  (Figs 2 and 3). Hyperactivity of the dental lamina is suggested to be the explanation for the supernumerary teeth, which could be increased by the accentuated epigenetic factors in the cleft palate area.

ALL TEETH ARE OF DUAL EMBRYONIC ORIGIN
The formation of sprouts or buds that will form tooth germs at each point corresponding to a tooth occurs by cell differ- In the region of the cleft palate, the two separate parts will continue to receive stimuli from the mediators to give rise to tooth germs. On both sides of the dental lamina and both sides of the future maxillary lateral incisor germ, the embryonic origin is the same. The topography and location of a structure does not determine its embryonic origin, but rather to which embryonic layer those cells belong. All teeth will always have an ectodermal and mesenchymal origin.
The fact that the maxillary lateral incisor is derived from the site where the medial nasal process was leveled, and the canine is derived from the area that was topographically derived from the maxillary process, does not imply that lateral incisor and canine have a distinct or different embryonic origin.
The embryonic origin or nature has to do with being derived from the ectoderm, mesoderm and endoderm, and even being of ectomesenchymal origin, as in the case of all human teeth. The fact that the deciduous maxillary lateral incisor arises from one or another facial embryonic process does not distinguish or modify its embryonic origin or its nature, especially if we consider that the mechanism of fusion of embryonic processes is not scientifically supported: There is no evidence of these fusions, obtained by means of any analysis or methodology. 6 All evidence shows that leveling of embryonic pro-

FINAL CONSIDERATIONS
The location and organization of dental buds in the dental lamina occur by induction of mediators called growth factors, which act and activate the genes of odontogenesis. 14 Hyperactivity represented by more mediators and an increased response to them may plausibly explain the formation of supernumerary tooth buds and germs, irrespective of whether they occur in cleft areas or not.
As the times of formation of the face and the chronology of odontogenesis do not occur concomitantly, this does not allow us to affirm that the formation of a cleft lip and palate cleaves or severs the germ of the maxillary lateral incisor, in order to give rise to supernumerary teeth that are so common in these cases. On both sides of a cleft lip and palate, mediator induction continues normally and may induce supernumerary formation, by local lamina hyperactivity at these separate ends or interfaces.