The etiology of eruption disorders - further evidence of a 'genetic paradigm'

Abstract

The clinical spectrum of tooth eruption disorders includes both syndromic and non-syndromic problems ranging from delayed eruption to a complete failure of eruption. A defect in the differential apposition/resorption mechanism in alveolar bone can cause conditions such as tooth ankylosis, primary failure of eruption, failure of eruption due to inadequate arch length and canine impaction. As our knowledge of the molecular events underlying normal tooth eruption has increased, so too has our understanding of clinical eruption disorders. The recent finding that one gene, parathyroid hormone receptor 1 (PTH1R), is causative for familial cases of primary failure of eruption (PFE) suggests that other disturbances in tooth eruption may have a genetic etiology. In this report, we evaluated the current terminology (ankylosis, PFE, secondary retention, etc.) used to describe non-syndromic eruption disorders, in light of this genetic discovery. We observed that some individuals previously diagnosed with ankylosis were subsequently found to have alterations in the PTH1R gene, indicating the initial misdiagnosis of ankylosis and the necessary re-classification of PFE. We further investigated the relationship of the PTH1R gene, using a network pathway analysis, to determine its connectivity to previously identified genes that are critical to normal tooth eruption. We found that PTH1R acts in a pathway with genes such as PTHrP that have been shown to be important in bone remodeling, hence eruption, in a rat model. Thus, recent advances in our understanding of normal and abnormal tooth eruption should allow us in the future to develop a clinical nomenclature system based more on the molecular genetic cause of the eruption failures versus the clinical appearance of the various eruption disorders.

Figure 1

(A) Clinical presentation of PFE in an individual with a lateral posterior open bite, characterized by supraosseous eruption failure and as shown in the lower right posterior quadrant of the panoramic radiograph (B) intraosseous eruption failure of the lower right second molar. The radiograph also well demonstrates the failure of the second molar to erupt despite a clear eruption pathway.

Figure 1

(A) Clinical presentation of PFE in an individual with a lateral posterior open bite, characterized by supraosseous eruption failure and as shown in the lower right posterior quadrant of the panoramic radiograph (B) intraosseous eruption failure of the lower right second molar. The radiograph also well demonstrates the failure of the second molar to erupt despite a clear eruption pathway.

Figure 2

The gene identifiers for PTH and PTH1R were uploaded into the application, Ingenuity Pathway Analysis. Each gene identifier was mapped to its corresponding gene object in the Ingenuity Pathways Knowledge Base. These genes, called focus genes, were overlaid onto a global molecular network developed from information contained in the Ingenuity Pathways Knowledge Base. Networks of these focus genes were then algorithmically generated based on their connectivity. NOTE: PTHLH in the diagram above is another gene name for PTHrP.