Severe Posterior Infra-occlusion on a Young Girl Posing a Diagnostic Challenge- Review and Report of a Case of Primary Failure of Eruption

Primary failure of eruption is characterized by a non-syndromic eruption failure of permanent teeth in the absence of any mechanical obstruction. Applying orthodontic traction to teeth affected by PFE will not be successful and may cause ankylosis. This correspondence reviews and demonstrates the treatment of a case of PFE.

Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants

Background Primary failure of eruption (PFE) is a hereditary condition, and linkage with variants in the PTH1R gene has been demonstrated in many cases. The clinical severity and expression of PFE is variable, and the genotype–phenotype correlation remains elusive. Further, the similarity between some eruption disorders that are not associated with PTH1R alterations is striking. To better understand the genotype–phenotype correlation, we examined the relationship between the eruption phenotype and PTH1R genotype in 44 patients with suspected PFE and 27 unaffected relatives. Sanger sequencing was employed to analyze carefully selected PFE patients. Potential pathogenicity of variants was evaluated against multiple genetic databases for function prediction and frequency information. Results Mutational analysis of the PTH1R coding sequence revealed 14 different variants in 38 individuals (30 patients and 8 first-degree relatives), 9 exonic and 5 intronic. Their pathogenicity has been reported and compared with the number and severity of clinical signs. In 72.7% of patients with pathogenic variants, five clinical and radiographic criteria have been found: involvement of posterior teeth, involvement of the distal teeth to the most mesial affected, supracrestal presentation, altered vertical growth of the alveolar process and posterior open-bite. In cases with mixed dentition (3), the deciduous molars of the affected quadrant were infraoccluded. Discussion The probability of an affected patient having a PTH1R variant is greater when five specific clinical characteristics are present. The likelihood of an eruption defect in the absence of specific clinical characteristics is rarely associated with a PTH1R mutation. Conclusions We report here that systematic clinical and radiographic observation using a diagnostic rubric is highly valuable in confirming PFE and offers a reliable alternative for accurate diagnosis.

The Orthodontic Treatment Scheme for Primary Failure of Eruption Patient without PTH1R Mutation

Primary failure of eruption (PFE) is observed as a defect in the tooth eruption mechanism with the heterozygous mutations of parathyroid hormone receptor gene (PTH1R). The present study reported 2 families suffered from nonsyndromic tooth eruption disorder in successive generations. Genetic analysis and standardized assessments, including clinical and radiographic examinations, of the dental condition of all patients were performed to give a clear understanding of the disease. The mutation of PTH1R was detected in patient II-1 (Family I) by PCR and sanger sequencing. Sequencing analysis reviewed heterozygous presence of c.439C>T in exon 2 of PTH1R. According to the UniprotKB database, PTH1R is highly conserved among several mammalian species. RNA-seq was performed to further analyze the role of PTH1R in tooth development and eruption. It showed that during tooth development, the expression of PTH1R decreased in the early stage of tooth development in rat and mouse. However, the mutations of PTH1R were not detected in 2 patients from family II. With extensive analysis of the radiographs and physical examination, we attempted to use orthodontic methods to create enough room for tooth eruption, which shows therapeutic result to the submerged tooth. The results suggested new orthodontic scheme for the PFE patient without PTH1R mutation. Both clinical and genetic diagnosis should be considered in the treatment planning.

Replacing buried teeth: A Review of primary failure of eruption of permanent teeth and case report

Primary failure of eruption is a condition that has variable presentation and can be difficult to diagnose. This article provides an overview of the condition and discusses the management of an unusual case of primary failure of eruption of permanent teeth in a 37-year-old adult. CPD/Clinical Relevance: Where surgical and orthodontic options are unpredictable, restorative management alone may achieve successful functional and aesthetic outcomes for cases involving primary failure of eruption of permanent teeth.

Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption

Although many variants of the parathyroid hormone 1 receptor (PTH1R) gene are known to be associated with primary failure of eruption (PFE), the mechanisms underlying the link remains poorly understood. We here performed functional analyses of PTH1R variants reported in PFE patients—namely, 356C>T (P119L), 395C>T (P132L), 439C>T (R147C), and 1148G>A (R383Q)—using HeLa cells with a lentiviral vector-mediated genetic modification. Two particular variants, P119L and P132L, had severe reduction in a level of N-linked glycosylation when compared with wild-type PTH1R, whereas the other 2 showed modest alteration. PTH1R having P119L or P132L showed marked decrease in the affinity to PTH1-34, which likely led to severely impaired cAMP accumulation upon stimulation in cells expressing these mutants, highlighting the importance of these 2 amino acid residues for ligand-mediated proper functioning of PTH1R. To further gain insights into PTH1R functions, we established the induced pluripotent stem cell (iPSC) lines from a patient with PFE and the heterozygous P132L mutation. When differentiated into osteoblastic-lineage cells, PFE-iPSCs showed no abnormality in mineralization. The mRNA expression of RUNX2, SP7, and BGLAP, the osteoblastic differentiation-related genes, and that of PTH1R were augmented in both PFE-iPSC-derived cells and control iPSC-derived cells in the presence of bone morphogenetic protein 2. Also, active vitamin D3 induced the expression of RANKL, a major key factor for osteoclastogenesis, equally in osteoblastic cells derived from control and PFE-iPSCs. In sharp contrast, exposure to PTH1-34 resulted in no induction of RANKL mRNA expression in the cells expressing P132L variant PTH1R, consistent with the idea that a type of heterozygous PTH1R gene mutation would spoil PTH-dependent response in osteoblasts. Collectively, this study demonstrates a link between PFE-associated genetic alteration and causative functional impairment of PTH1R, as well as a utility of iPSC-based disease modeling for future elucidation of pathogenesis in genetic disorders, including PFE.

A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report

Background Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant. Case presentation The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE. Conclusions In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients.

Multiple unerupted teeth – an interesting challenge

This paper describes primary failure of eruption and presents some of the theories about the aetiology of this clinical condition. It also covers single ankylosed teeth as well as cases that present with multiple unerupted teeth. The various approaches to the clinical management of this not uncommon problem are discussed, along with the pros and cons of some of these techniques. One difficult clinical challenge is documented, where a 14-year-old patient presented with 19 unerupted permanent teeth and, with the help of rare-earth magnets and upper and lower fixed appliances, within a two-year period a good result was achieved. CPD/Clinical Relevance: Clinicians encounter teeth that have failed to erupt on a regular basis. Appropriate diagnosis and treatment planning of these cases, and subsequent effective clinical management, is imperative to ensure the most favourable outcome for our patients.