Introduction
Introduction:

Autosomal dominant primary failure of tooth eruption is a rare genetic disorder that disrupts the normal eruption of permanent teeth. The significance of this condition lies not only in its rarity but also in the absence of standardized treatments, making management challenging.

Case Presentation
Case Presentation:

A 19-year-old female presented with multiple unerupted teeth with small, irregular roots. On clinical examination, no other features indicative of dysmorphology were identified. The patient’s family history was notable for a maternal history of unerupted and malformed teeth.

Diagnostic Workup
Diagnostic Workup:

The patient's panoramic dental x-ray showed several unerupted/malformed teeth in 3/4 quadrants of her mouth. The remaining teeth have small, irregular roots. Some of the unerupted teeth also do not have lamina dura, which could suggest ankylosis. A comprehensive ectodermal dysplasia and related disorders panel was performed, which revealed an intronic variant in the PTH1R gene (c.543+5G>A). This variant was classified as a variant of uncertain significance (VUS). Pathogenic variants in PTH1R are associated with autosomal dominant primary failure of tooth eruption or metaphyseal chondrodysplasia Jansen-type.

To further elucidate the clinical relevance of this variant, targeted genetic testing was conducted on the patient’s mother, who presented with a similar dental phenotype. The mother was found to carry the same PTH1R gene variant.

Treatment and Management
Treatment and Management:

Patient is in the process of comprehensive treatment with extracting and implant-replacing missing teeth.  

Outcome and Follow-Up
Outcome and Follow-up:

Patient's current treatment is to continue to restore the normal teeth function.

Discussion
Discussion:

The patient has a clinical phenotype consistent with primary failure of tooth eruption and genetic testing revealed an intronic variant in the PTH1R gene (c.543+5G>A). This variant is present at an extremely low frequency in all databases and gnomAD nonfounder subpopulation frequency is 0.003%. It has not been reported in PTH1R gene-related conditions. 

This is a splice region mutation which is not within 2-bp of splicing junction. Predictive algorithms suggest that this variant can disrupt the consensus splicing sites.

There is significant evidence in the literature regarding association of heterozygous loss of function in the PTH1R gene and failure of tooth eruption phenotype. Despite classification of this gene as a VUS, given the phenotypic concordance between mother and daughter, this intronic variant likely contributes to their shared dental phenotype.

It is also worth mentioning that the patient does not have a phenotype consistent with metaphyseal chondrodysplasia Jansen-type which also is associated with PTH1R gene mutation.

Conclusion
Conclusion:

This case highlights the importance of detailed family history and targeted testing in the evaluation of genetic variants associated with isolated dental anomalies.