Fibroblast Dysregulation in Multiple Idiopathic External Cervical Resorption: Laboratory Investigation From a Rare Case of 13 Affected Teeth

Introduction: Multiple idiopathic external cervical resorption (MIECR) is a rare and aggressive form of external resorption with an unclear aetiology. This study reports and investigates a unique case of extensive MIECR, potentially associated with chemotherapy exposure. The patient, a pharmacist responsible for preparing chemotherapy drugs, developed external cervical resorption affecting 13 teeth, with rapid progression occurring within just one year after starting her occupation. Notably, following local surgical treatment and cessation of high-risk work, the progression of MIECR was temporarily controlled.

Methods: Whole-exome Sequencing was conducted to identify potential genetic contributors. Granulation tissue removed from the tooth cavity, along with extracted teeth obtained during surgery, was collected for histopathological analysis to characterise the pathological features of MIECR. Single-cell RNA Sequencing was performed on granulation tissue and healthy gingival tissue to explore the molecular basis of MIECR. Fibroblast-like cells were isolated from granulation tissue and subjected to in vitro experiments to validate their role in MIECR pathogenesis. Statistical analyses were conducted using Student's t-test or one-way analysis of variance (ANOVA), with a p-value of less than 0.05 considered statistically significant.

Results: Whole-exome Sequencing suggested a pivotal role for a GNAS missense mutation in disease pathogenesis. Histopathological analysis revealed extensive fibroblast proliferation and invasiveness within the lesion tissue. Moreover, single-cell RNA Sequencing and in vitro experiments demonstrated abnormal fibroblast activity characterised by excessive proliferation and osteoclastic traits, implicating fibroblasts in MIECR progression. Importantly, the inhibition of the PI3K/Akt signalling pathway significantly reduced fibroblast invasion and osteoclastogenesis.

Conclusions: This study offers novel insights into the pathogenesis of MIECR, paving the way for more effective diagnostic and therapeutic strategies.

GNAS; PI3K/Akt signalling pathway; fibroblast; multiple idiopathic external cervical resorption.