Differential diagnosis of primary failure of eruption (PFE) with and without evidence of pathogenic mutations in the PTHR1 gene

Background Primary failure of eruption (PFE) may be associated with pathogenic mutations in the PTHR1 gene. It has numerous manifestations and is characterized by severe posterior open bite. However, there are also phenotypically similar types of eruption anomalies not associated with a known pathogenic PTHR1 mutation. The purpose of this study was to evaluate whether a distinction can be made between PTHR1-mutation carriers and noncarriers based on clinical and radiological findings. Patients and methods A total of 36 patients with suspected PFE diagnoses were included and analyzed in accordance with specific clinical and radiographic criteria. In addition, all patients underwent Sanger DNA sequencing analysis of all coding sequences (and the immediate flanking intronic sequences) of the PTHR1 gene. Results Of these patients, 23 exhibited a heterozygous pathogenic mutation in the PTHR1 gene (PTHR1-mutation carriers), while molecular genetic analysis revealed nosequence alteration in the other 13 patients (non-PTHR1-mutation carriers). Relevant family histories were obtained from 5 patients in the carrier group; hence, this group included a total of 13 familial and 10 simplex cases. The group of noncarriers revealed no relevant family histories. All patients in the carrier group met six of the clinical and radiographic criteria explored in this study: (1) posterior teeth more often affected; (2) eruption disturbance of an anterior tooth in association with additional posterior-teeth involvement; (3) affected teeth resorbing the alveolar bone located coronal to them; (4) involvement of both deciduous and permanent teeth; (5) impaired vertical alveolar-process growth; and (6) severe subsequent finding of posterior open bite. None of the analyzed criteria were, by contrast, met by all patients in the noncarrier group. All patients in the carrier group could be assigned to one of three classifications indicating the extent of eruption disturbance, whereas 4 of the 13 noncarriers presented none of these three patterns. The clinical and radiographic criteria employed in this study would have correctly identified 10 of the 13 PFE patients in the noncarrier group as possessing no detectable PTHR1 mutation. Conclusion The evaluation of clinical and radiographic characteristics can heighten the specificity of ruling out suspected PTHR1 involvement in PFE patients. A hereditary element of PTHR1-associated PFE is clearly identifiable. More studies with more patients are needed to optimize the sensitivity of this preliminary approach on the differential identification of PTHR1-mutation carriers versus noncarriers by multivariate analysis

Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

OBJECTIVES: Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases. MATERIALS AND METHODS: Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases. RESULTS: We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms. CONCLUSIONS: Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function. CLINICAL RELEVANCE: Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options

Primary failure of eruption (PFE)--clinical and molecular genetics analysis

Background: The term "primary failure of eruption" (PFE) refers to the complete or partial failure of a primary non-ankylosed tooth to erupt due to a disturbance of the eruption mechanism. Up to now, the molecular basis for this failure was unknown. Patients and Methods: Four families were studied in whom at least two members were affected by non-syndromic PFE as part of a clinical and molecular genetics study. Radiological diagnostics (OPTs) were carried out in all patients and their unaffected relatives (control group). The genetic analysis included a genomewide linkage analysis followed by direct DNA sequencing of positional candidate genes. Results: Starting from the index patients, we were able to reconstruct pedigrees over two and/or three generations in the families that indicated an autosomal-dominant mode of inheritance of non-syndromic PFE. Fifteen patients were diagnosed with PFE. Gender distribution was nearly equal (7 female, 8 male). Molecular genetic analysis of the PTHR1 gene revealed three distinct heterozygous mutations (c.1050-3C>G; c.543+1G>A; c.463G>T). Unaffected persons exhibited no mutations. Conclusions: Knowledge of the genetic causes of non-syndromic PFE can now be used for the differential diagnosis of eruption failure. It permits affected family members to be identified early and may lead to new treatment possibilities in the long term. The genetically-verified diagnosis of "primary failure of eruption" can protect patients and orthodontists from years of futile treatment, because orthodontic treatment alone does not lead to success. Moreover, it has a negative influence on unaffected teeth and areas of the jaw

[Primary failure of eruption (PFE). Clinical and molecular genetics analysis] Article in French

Background: The term “primary failure of eruption” (PFE) refers to the complete or partial failure of a primary non-ankylosed tooth to erupt due to a disturbance of the eruption mechanism. Up to now, the molecular basis for this failure was unknown. Patients and Methods: Four families were studied in whom at least two members were affected by non-syndromic PFE as part of a clinical and molecular genetics study. Radiological diagnostics (OPTs) were carried out in all patients and their unaffected relatives (control group). The genetic analysis included a genomewide linkage analysis followed by direct DNA sequencing of positional candidate genes. Results: Starting from the index patients, we were able to reconstruct pedigrees over two and/or three generations in the families that indicated an autosomal-dominant mode of inheritance of non-syndromic PFE. Fifteen patients were diagnosed with PFE. Gender distribution was nearly equal (7 female, 8 male). Molecular genetic analysis of the PTHR1 gene revealed three distinct heterozygous mutations (c.1050-3C>G; c.543 + 1G>A; c.463G>T). Unaffected persons exhibited no mutations. Conclusion: Knowledge of the genetic causes of non-syndromic PFE can now be used for the differential diagnosis of eruption failure. It permits affected family members to be identified early and may lead to new treatment possibilities in the long term. The genetically-verified diagnosis of “primary failure of eruption” can protect patients and orthodontists from years of futile treatment, because orthodontic treatment alone does not lead to success. Moreover, it has a negative influence on unaffected teeth and areas of the jaw