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

Abstract

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.

Review and case report of the treatment in a young girl with primary failure of eruption

“…9,31 A classic diagnostic feature proposed by Rhoads et al 32 is the frequent involvement of the first molar along with the adjacent teeth in an unusual supracrestal position. A recent systematic review by Hanisch et al 9 identified bilateral infraocclusion of the posterior teeth as a hallmark According to the diagnostic rubrics, 12,33 our patient had the following radiological/clinical signs:…”

“…According to the diagnostic rubrics, 12,33 our patient had the following radiological/clinical signs: The teeth of the posterior region are affected more frequently (first and second molars more often than premolars or canines) Affected teeth were resorbing the alveolar bone coronal but do not erupt totally or erupt incomplete Mostly the clinical findings were asymmetric, which means there was a bilaterally unbalanced eruption of the teeth. Vertically, there is was an impairment of growth of the alveolar bone in the affected region A severe lateral open bite in the affected region …”

“…Most of the research pertain to assessment of specific genes involved. Many studies indicate mutation in the PTH1R gene, and about 51 mutations of the PTH1R gene have been reported till date 9,12‐18 …”

“…The characteristic features of this condition are as follows [6][7][8][9][10][11][12] • History-Familial involvement is one of the signs, but it is not always present and sometimes it follows an incomplete penetrance pattern. However, mutation in parathyroid hormone receptor 1 (PTH1R) has been strongly associated.…”

“…Many studies indicate mutation in the PTH1R gene, and about 51 mutations of the PTH1R gene have been reported till date. 9,[12][13][14][15][16][17][18] Several genes have been identified that play a role in odontogenesis including PAX9, MSX1, PTH1R, and AXIN2. Strong evidence exists that, in most of the cases, PFE is an autosomal dominant heterogeneous condition associated with mutations in PTH1R gene and the genes involved in activation of cAMP/PKA pathway in tooth eruption.…”