Investigating Transcriptomic Changes Associated with Unilateral Condylar Hyperplasia

Abstract

Background: Unilateral condylar hyperplasia (UCH) is a self-limiting condition predominantly affecting females between the ages of 11 and 30 years, characterized by non-neoplastic overgrowth of one mandibular condyle leading to progressive maxillofacial asymmetry and malocclusion. Numerous hypotheses have been proposed to explain the etiology of UCH; however, these theories remain inconclusive, and the underlying molecular mechanisms have not been fully investigated and remain poorly understood. While a limited number of studies have investigated UCH using approaches such as single-cell transcriptomics, the global transcriptomic profile of human UCH condylar tissue has not yet been comprehensively explored. Aims: 1 To investigate the transcriptomic signature of UCH through RNA sequencing. 2. To analyze changes in gene expression patterns in affected subjects. 3. To investigate the correlation between condylar length and the severity of mandibular asymmetry in UCH patients. Materials and methods: Seven patients diagnosed with active UCH scheduled for high condylectomy followed by orthognathic surgery were included in the study. Left over affected condylar tissues and unaffected mandibular tissues were obtained during surgery. For downstream transcriptomic analysis, four patients matched in age, sex, and surgical procedure were selected to minimize variability. Total RNA was extracted from the collected tissues and sequencing was performed on the NextSeq 500 platform (Illumina) using a mid-output flow cell configuration. Targeted gene expression analysis was performed to investigate transcriptomic changes associated with UCH, and radiographic measurements were used to evaluate the relationship between linear and angular mandibular measurements. Results: Seven patients with active UCH were included (mean age 22.07 ± 4.43 years), with a predominance of females (71.4%). Right-sided involvement was observed in four patients (57.1%). Due to sample quality constraints, downstream transcriptomic analysis was ultimately restricted to one matched patient. Targeted gene expression analysis revealed increased expression of genes associated with osteogenic differentiation (RUNX2, SP7, SOX9), extracellular matrix organization and collagen remodeling (COL1A1, COL1A2, COL2A1, COL5A2, COL10A1, ACAN, SPARC, POSTN, LOX, PLOD2, OGN), and growth factor signaling (TGFB2, IGF1), whereas VEGFA, implicated in angiogenic growth signaling, was downregulated. Genes involved in epigenetic regulation and chromatin remodeling demonstrated differential modulation, including increased expression of histone demethylases (JMJD1C) and reduced expression of key transcriptional repressors (DNMT1, HDAC4, PHC2). Within the matrix remodeling pathway, MMP13 was upregulated, whereas inflammatory-associated gene MMP3 was downregulated. In the estrogen signaling pathway, GPER1 was downregulated, while ESR1 and ESR2 showed comparable expression between tissues. Radiographic analysis demonstrated only a statistically significant difference in ramal height (Co–Go) between males and females on both the affected (p = 0.03) and unaffected sides (p = 0.01). Correlation analysis revealed strong bilateral associations among mandibular linear measurements, particularly between condylar length and ramal height on the affected and unaffected sides Conclusion: The findings suggest that UCH is primarily associated with enhanced osteochondral differentiation and extracellular matrix remodeling rather than inflammatory, angiogenic, or estrogen receptor transcription-driven processes. The observed gene expression profile indicates activation of pathways involved in bone formation and matrix organization within the affected condyle, occurring within a transcriptionally permissive epigenetic context. Radiographic evaluation further indicates that skeletal linear mandibular measurements, particularly condylar length and ramal height, are strongly interrelated, whereas incisor tipping likely represents compensatory dentoalveolar adaptations to skeletal asymmetry rather than a direct indicator of its severity. As the transcriptomic analysis was exploratory and limited by sample size, these observations require validation in larger cohorts. These results provide novel transcriptomic insight into the molecular mechanisms underlying condylar overgrowth and highlight potential targets for future investigation.