Mechanisms of primary failure of eruption: a new model of multidimensional framework

Primary failure of eruption (PFE) is an uncommon autosomal dominant disorder predominantly defined by an impaired tooth eruption mechanism. It is characterized by a unilateral or bilateral open bite in the posterior area and incomplete or absent tooth eruption. Nonetheless, its etiology remains unclear. Current studies indicate that PFE may be directly associated with mutations in several genes, including parathyroid hormone receptor 1 (PTH1R), lysine (K)-specific methyltransferase 2 C (KMT2C), and transmembrane protein 119 (TMEM119). Despite the growing research on PFE genetics, no cohesive conceptual framework exists to integrate the known genetic information. This review seeks to address this gap and introduce a novel pathogenic model. The model posits that the normal eruption of teeth relies on the precise equilibrium between "The Pro-Eruptive Axis" and "The Anti-Resistance Axis," with the Dental Follicle (DF) serving as the central regulatory hub of this mechanism. This research will systematically categorize PFE-related genes and classify their pathogenic mechanisms as "insufficient motivation" or "excessive resistance" in eruption. On this basis, this review will analyze in depth the crosstalk of key signaling pathways (such as PTH, Wnt, TGF-β, and RANKL/OPG), investigate the complexity of genetic influences and temporal factors in elucidating phenotypic variability, enhance the existing classification framework into a dynamic, multi-dimensional comprehensive network, and ultimately suggest precise diagnostic approaches and prospective therapeutic targets based on pathogenic mechanisms from a translational medicine perspective. By constructing this integrated pathophysiological model, we aim to establish a robust theoretical framework for investigating molecular mechanisms and clinical diagnosis and formulating novel individualized treatment options for PFE.