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. 2023 Mar 23;13(7):1214.
doi: 10.3390/diagnostics13071214.

Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas

Piranit Nik Kantaputra  1   2 , Kanich Tripuwabhrut  3 , Robert P Anthonappa  4 , Kanoknart Chintakanon  3 , Chumpol Ngamphiw  5 , Ploy Adisornkanj  1   2   6 , Nop Porntrakulseree  7 , Bjorn Olsen  8 , Worrachet Intachai  1 , Raoul C Hennekam  9 , Alexandre R Vieira  10 , Sissades Tongsima  5
Affiliations

Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas

Piranit Nik Kantaputra et al. Diagnostics (Basel). .

Abstract

Background: Supernumerary teeth refer to extra teeth that exceed the usual number of dentitions. A mesiodens is a particular form of supernumerary tooth, which is located in the premaxilla region. The objective of the study was to investigate the genetic etiology of extra tooth phenotypes, including mesiodens and isolated supernumerary teeth.

Methods: Oral and radiographic examinations and whole-exome sequencing were performed on every patient in our cohort of 122 patients, including 27 patients with isolated supernumerary teeth and 94 patients with mesiodens. A patient who had multiple supernumerary teeth also had odontomas.

Results: We identified a novel (c.8498A>G; p.Asn2833Ser) and six recurrent (c.1603C>T; p.Arg535Cys, c.5852G>A; p.Arg1951His, c.6949A>T; p.Thr2317Ser; c.1549G>A; p.Val517Met, c.1921A>G; p.Thr641Ala, and c.850G>C; p.Val284Leu) heterozygous missense variants in FREM2 in eight patients with extra tooth phenotypes.

Conclusions: Biallelic variants in FREM2 are implicated in autosomal recessive Fraser syndrome with or without dental anomalies. Here, we report for the first time that heterozygous carriers of FREM2 variants have phenotypes including oral exostoses, mesiodens, and isolated supernumerary teeth.

Keywords: Fraser syndrome; dental anomalies; extra teeth; mesiodens; mesiodentes; supernumerary tooth; tooth formation.

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Sequence chromatograms of patients with heterozygous missense variants in FREM2 gene. Six variants are recurrent and two are novel.
Figure 2
Figure 2
(A) Patient 1. Mesiodens (arrow). Torus palatinus (arrowhead). (B) Patient 1. Periapical radiograph showing an unerupted mesiodens (arrow). (C) Patient 2. Extracted double mesiodens. (D) Patient 3. Periapical radiograph showing an unerupted mesiodens (arrow).
Figure 3
Figure 3
(A) Patient 4. A periapical radiograph showing an inverted mesiodens (arrow). (B) Patient 5. An occlusal radiograph showing a supernumerary mandibular right premolar (arrow).
Figure 4
Figure 4
Patient 6. Panoramic radiograph showing agenesis of the maxillary permanent third molars (asterisks). Taurodontism of the left maxillary permanent second molar (arrow).
Figure 5
Figure 5
Patient 7. (A) Torus palatinus (arrow). (B) Torus mandibularis (arrowheads). Supernumerary left mandibular premolar (arrow). (C) Panoramic radiograph showing supernumerary mandibular premolars (arrows). Maxillary permanent molars with unseparated roots (asterisks). Short roots of the mandibular right second permanent molar (star).
Figure 6
Figure 6
Patient 8. Panoramic radiograph showing multiple supernumerary teeth and multiple odontomas (arrows).
Figure 7
Figure 7
Hypothetical flowchart shows pathogenetic pathway as a result of FREM2 mutations. Heterozygous missense variants in FREM2 result in alterations of FRAS1-FREM2-FREM1 complex, disruption of basement membrane assembly of nephronectin, abnormal expression of SOX2, overactivation of WNT/β-catenin signaling, and subsequent formation of supernumerary teeth [26,29,33,34,35,36].
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