A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family

ObjectivesThe present study aimed to identify the genetic cause of non-syndromic primary failure of tooth eruption in a five-generation consanguineous Saudi family using whole-exome sequencing (WES) analysis.DesignThe family pedigree and phenotype were obtained from patient medical records. WES of all four affected family members was performed using the 51Mb SureSelect V4 library kit and then sequenced using the Illumina HiSeq2000 sequencing system. Sequence alignment, variant calling, and the annotation of single nucleotide polymorphisms and indels were performed using standard bioinformatics pipelines. The genotype of candidate variants was confirmed in all available family members by Sanger sequencing.ResultsPedigree analysis suggested that the inheritance was autosomal recessive. WES of all affected individuals identified a novel homozygous variant in exon 8 of the parathyroid hormone 1 receptor gene (PTH1R) (NM_000316: c.611T>A: p.Val204Glu).ConclusionTo the best of our knowledge, this is the first report of primary failure of eruption caused by a homozygous mutation in PTH1R. Our findings prove the application of WES as an efficient molecular diagnostics tool for this rare phenotype and further broaden the clinical spectrum of PTH1R pathogenicity.     

原发性牙齿萌出障碍的研究进展

原发性牙齿萌出障碍（PFE）是一种十分罕见的疾病,它并非由临床检查可发现的局部或全身因素所致,而是由牙齿萌出机制本身出现异常导致的牙齿萌出障碍。PFE常影响恒磨牙,造成严重的后牙开,其诊断和治疗均较为困难。本文就PFE的临床特征、发病机制、临床诊断和治疗等方面的研究进展作一综述。     

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.     

Traumatic intrusion of primary tooth: follow up until eruption of permanent successor tooth

Abstract –  This paper presents a clinical case of a 2½-year-old boy who suffered dental trauma because of a fall from a bike. His father thought that the boy's central upper left incisor had been fractured. The clinical exam showed laceration of the upper maxillary frenum and a possible intrusion of the tooth, as the area was swollen. An upper maxillary occlusal X-ray confirmed the intrusion of the incisor. The procedure adopted was to wait for the re-eruption of the tooth. It was recommended that the boy stop using a pacifier and feeding bottle. The necessity of keeping the affected area clean was also emphasized. The patient was observed and, within 6 months, the central upper left incisor was found in occlusion. The successor permanent tooth was normal after 6 years.     

CSF-1 regulation of osteoclastogenesis for tooth eruption

The dental follicle regulates the alveolar bone resorption needed for tooth eruption. In the rat first mandibular molar, a decrease in the expression of osteoprotegerin (OPG) in the dental follicle at day 3 enables the osteoclastogenesis needed for eruption to occur. Because colony-stimulating factor-1 (CSF-1) is maximally expressed in the dental follicle at day 3, it was hypothesized that CSF-1 down-regulates OPG gene expression in the dental follicle in vivo. To test this, we compared the expression of OPG in osteopetrotic toothless (tl/tl) rats deficient in CSF-1 with expression in their normal littermates for given ages. OPG gene expression was found to be higher in the dental follicle of the tl/tl mutants than in normals. Transfecting short interfering RNA specific for CSF-1 mRNA into dental follicle cells resulted in an up-regulation of OPG expression. Thus, these studies support our hypothesis that the down-regulation of OPG needed for tooth eruption is mediated by CSF-1.     

Familial primary failure of eruption of permanent teeth

A son and his mother presented with features consistent with a diagnosis of primary failure of eruption. The features of this condition are described together with some aspects of treatment. The impact of the condition on vertical facial growth is discussed.     

Effects of antiresorptive medications on tooth root formation and tooth eruption in paediatric patients

Tooth eruption is a pivotal milestone for children's growth and development. This process involves with the formation of the tooth root, the periodontal ligament (PDL) and the alveolar bone, as the tooth crown penetrates the bone and gingiva to enter the oral cavity. This review aims to outline current knowledge of the adverse dental effects of antiresorptive medications. Recently, paediatric indications for antiresorptive medications, such as bisphosphonates (BPs), have emerged, and these agents are increasingly used in children and adolescents to cure pathological bone resorption associated with bone diseases and cancers. Since tooth eruption is accompanied by osteoclastic bone resorption, it is expected that the administration of antiresorptive medications during this period affects tooth development. Indeed, several articles studying human patient cohorts and animal models report the dental defects associated with the use of these antiresorptive medications. This review shows the summary of the possible factors related to tooth eruption and introduces the future research direction to understand the mechanisms underlying the dental defects caused by antiresorptive medications.     

Biostatistical proof of retarded tooth eruption in the permanent dentition of patients with clefts]

It is evidenced biostatistically that the eruption of the permanent teeth is retarded in cleft patients. This retardation concerns both the maxillary and mandibular teeth. Both sexes are involved. In female cleft patients the change to the permanent dentition occurs earlier than in male cleft patients. There is no sidedness.     

Influence of metabolic-linked early life factors on the eruption timing of the first primary tooth

Aim

Early eruption of permanent teeth has been associated with childhood obesity and diabetes mellitus, suggesting links between tooth eruption and metabolic conditions. This longitudinal study aimed to identify pre-, peri- and postnatal factors with metabolic consequences during infancy that may affect the eruption timing of the first primary tooth (ETFT) in children from an ethnically heterogeneous population residing within the same community.

Material and methods

Participants were recruited (n = 1033) through the GUSTO (Growing Up in Singapore Towards healthy Outcomes) birth cohort (n = 1237). Oral examinations were performed at 3-month intervals from 6 to 18 months of age. Crude and adjusted analyses, with generalized linear modelling, were conducted to link ETFT to potential determinants occurring during pregnancy, delivery/birth and early infancy.

Results

Overall mean eruption age of the first primary tooth was 8.5 (SD 2.6) months. Earlier tooth eruption was significantly associated with infant’s rate of weight gain during the first 3 months of life and increased maternal childbearing age. Compared to their Chinese counterparts, Malay and Indian children experienced significantly delayed tooth eruption by 1.2 and 1.7 months, respectively.

Conclusions

Infant weight gain from birth to 3 months, ethnicity and maternal childbearing age were significant determinants of first tooth eruption timing. Early life influences can affect primary tooth development, possibly via metabolic pathways.

Clinical relevance

Timing of tooth eruption is linked to general growth and metabolic function. Therefore, it has potential in forecasting oral and systemic conditions such as caries and obesity.

     

原发性萌出障碍1例

对1例青少年不明原因的牙齿萌出障碍的患者进行临床和影像学检查,原发性萌出障碍、不明确萌出障碍和机械性牙齿萌出障碍进行鉴别诊断。通过实验性拔牙、临床检查及锥形束CT（CBCT）观察,确诊为原发性萌出障碍。原发性萌出障碍是一种口腔罕见疾病,在没有遗传病史的情况下很难与其他类型的萌出障碍鉴别,实验性拔牙可以是很好的辅助手段。