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Genetics of Malocclusion

2959 words (12 pages) Essay in Biology

08/02/20 Biology Reference this

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Epidemiology.

Alhammadi et al performed a review of the literature to determine the distribution of malocclusion across the world, both in permanent and mixed dentitions (Alhammadi et al., 2018). From a pool of 53 studies (they retrieved 2977 from an electronic search), they estimate that the prevalence of Class I type of occlusion is 74.7%, Class II is 19.56% and Class III is 5.93% in permanent dentition. In mixed dentition the prevalence of Class I were 73%, Class II 23% and Class III 4%.

Embryology and postnatal development of the maxilla and mandible

Both the maxilla and the mandible are derived from the first pharyngeal arch (Nanci, 2017) Moreover they develop from paired prominences composed of mesenchyme that can be identified in a 42 days old embryo (Sadler, 2019). The growth of the mandible is assisted by the cartilage of the first pharyngeal arch, the Meckel’s cartilage. This structure has a close positional relationship with the mandible however it does not give rise to bone in the mandible. Instead, the mandible develops from intramembranous ossification and Meckel’s cartilage disintegrate and largely disappear, forming only a portion of the malleus and incus, but not contributing into a significant part of the mandible (Proffit et al., 2018). The process of intramembranous formation of the mandible starts at the sixth week with a condensation of the mesenchyme in the division of the inferior alveolar nerve in the incisor and mental branches (Nanci, 2017). Later, the ossification starts at this condensation, spreading anteriorly towards the midline and posteriorly to the point where the mandibular never divides. The anterior ossification takes place along the lateral aspect of Meckel’s cartilage which leads to the formation of a trough or channel that consist of two plates (one medial and one lateral) that join each other beneath the incisor nerve. This trough of bone extends to the midline where it gets close to the contralateral trough of the contralateral mandibular process. These two ossification centers do not fuse with each other until shortly after birth. Later the through of bone is converted into a canal because of the formation of bone above the nerve. The posterior ossification also takes place along the lateral aspect of Meckel’s cartilage. It extends toward the division of the mandibular nerve into the inferior alveolar and lingual nerve. Moreover, medial and lateral plates of bones develop in relation to teeth germs, starting at the point of division of the mandibular nerve. This phenomenon allows the division of the trough of bone in compartments occupied by teeth germs which are going to be completely surrounded by bone (Nanci, 2017). The ramus of the mandible is also formed by intramembranous ossification of the mesenchyme of the first pharyngeal arch.

In contrast to the embryonic period, postnatally the mandible growths by endochondral activity in the condyle at the temporomandibular joint where hypertrophy, hyperplasia and endochondral replacement occurs in the cartilage that covers the surface of the condyle. The rest of the mandible growth by direct apposition on its surface. Vital staining studies indicate that the principal sites of growth of the postnatal mandible are the posterior surface of the ramus (which allows an increase in the length of the mandible) and the condylar and coronoid process with minimal changes in the body and chin area. When considering this as the frame of references it looks like the mandible is translated downward and forward. However, it grows upward and backward maintaining its contact with the skull.

The maxilla develops entirely intramembranous ossification of the mesenchyme of the maxillary process (Proffit et al., 2018). Its center of ossification appears where the inferior orbital nerve gives the anterosuperior dental nerve. Bone formation spreads from this center posteriorly toward the zygoma, anteriorly toward the incisor region and superiorly to form the frontal process of the maxillary bone. This pattern of bone deposition allows the formation of another trough in relationship with the infraorbital nerve. In addition, bone in relationship with the tooth germs arises from two plates: one medial and one lateral. They are named medial and lateral alveolar plates. The lateral alveolar plate arises from a downward extension of the trough of the infraorbital nerve. The medial alveolar plate forms from the union between the palatal process and the main body of the maxilla. Both, the medial and the lateral alveolar plates will give rise to another trough of bone surrounding tooth germs. Like in the mandible, the tooth germs will be enclosed in bone (Nanci, 2017).

Postnatally the growth of the maxilla is the result of a process of translation of the position of the mandible relative to the cranium and the cranial base and a simultaneous phenomenon of bone surface modelling. The position translation is due to forces arising from the cranial base growth that pushes the maxilla and from bone apposition in the sutures that connect the maxilla to the cranial base and cranium. The modelling process consists of resorption of the anterior surface of the maxilla with apposition of bone in the opposite direction (Proffit et al., 2018).

Syndromes that present malocclusion

A classical syndrome that present malocclusion as a clinical feature is the Crouzon Syndrome (OMIM # 123500) (Glaser et al., 2000). These patients often present hypoplastic maxilla and exophthalmia (Neville et al., 2016). Crouzon syndrome is considered an autosomal dominant disorder that presents craniosynostosis (premature closure of cranial sutures) and it is thought to be caused in part by a mutation in the gene encoding the fibroblast growth factor receptor 2 (FGFR2) on the chromosome 10. The FGFR2 genes encode a tyrosine kinase receptor that has three portions(Johnson and Wilkie, 2011). The first region is an extracellular ligand binding portion composed of three immunoglobulins like domains (IgI, IgII and IgIII). The second region is a transmembrane region and the last one is an intracellular kinase domain (Azoury et al., 2017). It has been suggested that most of the mutation that causes Crouzon syndrome occurs in the third extracellular immunoglobulin-like domain encoded by exons IIIa or IIIc, producing constitutive activation of the receptor (Johnson and Wilkie, 2011). The hypoplastic maxilla phenotype arises from a prenatal fusion of the superior and posterior sutures of the maxilla along the wall of the orbit. This premature fusion of these sutures prevents that the maxilla is translated downward and forward producing severe underdevelopment of the maxilla (Proffit et al., 2018).

Another syndrome that presents a malocclusion as a phenotype is the Apert syndrome (OMIM #101200). Patients affected by the Apert Syndrome also present craniosynostosis, cone-shaped calvarium, Midfacial hypoplasia and several other clinical features (Woods et al., 2015). Studies indicate that 98% Apert syndromes are caused by one of two mutations in the exon IIIa of the FGFR2 gene. This mutation cause an amino acid substitution of a Serine for a Tryptophan in the position 252 or a Proline for an Arginine in the position 253. These two mutations produce an increased affinity and altered specificity of FGFR2 for its ligand the fibroblast growth factor (FGF) (Das and Munshi, 2018).

Treacher Collins syndrome (OMIM #154500) is another case of a syndrome that present malocclusion. This disease follows an autosomal dominant pattern of inheritance and presents a variable phenotype that includes bimaxillary micrognathia and retrognathia in 78% of patients (Kadakia et al., 2014). Most of the mutations occur in the gene TCOF1 in around 78 to 93% of the cases but in around 8% of the patients, the mutations are in the genes POLR1C or POLR1D. Several mutations have been associated with Treacher Collins syndrome and most of them are small frameshift mutations yielding a truncated protein. Studies in animals indicate that the protein produced by the gene TCOF1 attenuate the neural crest cell migration into the craniofacial region. Specifically, it is considered that mutations in TCOF1 affect ribosomal biosynthesis in the neural crest cells that are migrating to the craniofacial regions.

Genes associated with non-syndromic malocclusion

In a study published in 2015, da Fontoura et all evaluate the association of several candidate genes and skeletal malocclusion (da Fontoura et al., 2015). Specifically, they evaluated genes that are known to be expressed in the craniofacial complex, have a genetic linkage to malocclusion or a known role in the etiology of syndromes that present malocclusion. They characterized the phenotypes of 269 patients using cephalometric radiograph. The criteria used are the size of the overjet, the ANB angle, molar/canine angle classification, Witt analysis and the lateral profile of the patient. Considering this high number of dimensions in the phenotypes, the authors performed a principal component analysis. This is a mathematical method that allows transforming this high number of dimensions in just a few. This few dimensions act as a summary of features and are named principal components (PC) (Lever et al., 2017). They identified four principal components that in total explained 69% of the variance among the patients. The PC1 represents vertical discrepancies, from skeletal deep bites to skeletal open bites. The PC2 depicts horizontal discrepancies that vary from convex to concave profiles. The PC3 describes the ramus height, mandibular body size and cranial base orientation. The PC4 explain the variation in the condylar inclination and projection of the chin. Then they search for associations between these PC and the genotypes from the patients. In order to do this, they evaluate the degree of association between single nucleotide polymorphisms (SNP) present in the candidate genes of the patients and each of the four PC. They identified two SNP significantly associated with PC3 and PC4, respectively. The first one is near a gene named TWIST1 and was associated with the PC3. This SNP is associated with a shorter ramus, larger body mandibular body length and a steep anterior cranial base orientation. The second SNP was near a gene called SNAI3 and was associated with PC2. Specifically, it is associated with a severe class II phenotype and a convex profile. The role of TWIST1 in the development of the size of the ramus is also sustained by results obtained in mouse. In order to understand the role of Twist1 in mandibular development, Zhang et al used conditional Knock out of Twist1(Zhang et al., 2012) in a mouse where the expression of Cre recombinase is under the control of an enhancer region of Hand2 (Ruest et al., 2003). This last gene is expressed in post-migratory neural crest cells that populate the mandibular pharyngeal arch. Therefore, when this group of cells express Hand2 the Cre enzyme will be active and it is going to induce the recombination event leading to the knockout of Twist1 in the post-migratory neural crest cells in the mandible. When they analyze the phenotype of pups with this conditional knockout out, the authors identified that the ramal region of the mandible was greatly reduced in size.

Several genes have been associated with mandibular prognathism (MIM #176700) (Chen et al., 2015). For instance, a genome-wide association study identified 6 loci as susceptible regions of mandibular prognathism (Saito et al., 2017) suggesting 6 genes as candidates (Table 1).

Current and future therapy

Malocclusion may be treated with orthognathic surgery. This procedure may be defined as “the surgical repositioning of the maxilla and/or mandible with or without orthodontic repositioning of the teeth, in order to improve dentofacial function and aesthetics (in a stable manner) and health-related quality of life” (Naini et al., 2017). Moreover, patients that present malocclusion may be treated with orthodontic therapy (Abreu, 2018). The utility of knowing which genes may help develop a precision orthodontic treatment in which this genetic information can be used to predict, for instance future growth trajectories (Jheon et al., 2017).

Figures.

Table 1

Type of occlusion

Syndromic or non-syndromic

Genetic cause (multi gene, single gene) name of gene

References

 Class III

 Crouzon syndrome

 Mutation in FGFR2

 (Neville et al., 2016)

Class III

Apert syndrome

Mutation in FGFR2

(Johnson and Wilkie, 2011)

Class II

Treacher Collins syndrome

Mutations in TCOF1, POLR1C or POLR1D.

(Kadakia et al., 2014)

Class III

Non syndromic

FGF23

(Chen et al., 2015)

Class II

Non syndromic

ACTN3

(Zebrick et al., 2014)

Class II

Non syndromic

SNAI3 (SNP)

(da Fontoura et al., 2015)

Class III

Non syndromic

TWIST1 (SNP)

(da Fontoura et al., 2015)

Class III

Non syndromic

Loci 1p22.3; gene SSX2IP

(Saito et al., 2017)

Class III

Non syndromic

Loci 1q32.2; gene PLXNA2

(Saito et al., 2017)

Class III

Non syndromic

Loci 3q23; gene RASA2

(Saito et al., 2017)

Class III

Non syndromic

Loci 6q23.2; gene TCF21

(Saito et al., 2017)

Class III

Non syndromic

Loci 7q11.22; gene CALN1

(Saito et al., 2017)

Class III

Non syndromic

Loci 15q22.22; gene RORA 

(Saito et al., 2017)

References

  • Abreu, L.G., 2018. Orthodontics in Children and Impact of Malocclusion on Adolescents’ Quality of Life. Pediatr Clin North Am 65, 995-1006.
  • Alhammadi, M.S., Halboub, E., Fayed, M.S., Labib, A., El-Saaidi, C., 2018. Global distribution of malocclusion traits: A systematic review. Dental Press J Orthod 23, 40.e41-40.e10.
  • Azoury, S.C., Reddy, S., Shukla, V., Deng, C.X., 2017. Fibroblast Growth Factor Receptor 2 (Int J Biol Sci 13, 1479-1488.
  • Chen, F., Li, Q., Gu, M., Li, X., Yu, J., Zhang, Y.B., 2015. Identification of a Mutation in FGF23 Involved in Mandibular Prognathism. Sci Rep 5, 11250.
  • da Fontoura, C.S., Miller, S.F., Wehby, G.L., Amendt, B.A., Holton, N.E., Southard, T.E., Allareddy, V., Moreno Uribe, L.M., 2015. Candidate Gene Analyses of Skeletal Variation in Malocclusion. J Dent Res 94, 913-920.
  • Das, S., Munshi, A., 2018. Research advances in Apert syndrome. J Oral Biol Craniofac Res 8, 194-199.
  • Glaser, R.L., Jiang, W., Boyadjiev, S.A., Tran, A.K., Zachary, A.A., Van Maldergem, L., Johnson, D., Walsh, S., Oldridge, M., Wall, S.A., Wilkie, A.O., Jabs, E.W., 2000. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet 66, 768-777.
  • Jheon, A.H., Oberoi, S., Solem, R.C., Kapila, S., 2017. Moving towards precision orthodontics: An evolving paradigm shift in the planning and delivery of customized orthodontic therapy. Orthod Craniofac Res 20 Suppl 1, 106-113.
  • Johnson, D., Wilkie, A.O., 2011. Craniosynostosis. Eur J Hum Genet 19, 369-376.
  • Kadakia, S., Helman, S.N., Badhey, A.K., Saman, M., Ducic, Y., 2014. Treacher Collins Syndrome: the genetics of a craniofacial disease. Int J Pediatr Otorhinolaryngol 78, 893-898.
  • Lever, J., Krzywinski, M., Altman, N., 2017. Principal component analysis. Nature Methods 14, 641.
  • Naini, F.B., Gill, D.S., Wiley Online Library, 2017. Orthognathic surgery : principles, planning and practice, p. 1 online resource.
  • Nanci, A., 2017. Ten Cate’s oral histology : development, structure, and function, 9th edition. ed.
  • Neville, B.W., Damm, D.D., Allen, C.M., Chi, A.C., ClinicalKey Flex, Oral and maxillofacial pathology, Fourth edition. ed, p. 1 online resource.
  • Neville, B.W., Damm, D.D., Allen, C.M., Chi, A.C., ClinicalKey Flex, 2016. Oral and maxillofacial pathology, Fourth edition. ed, p. 1 online resource.
  • Proffit, W.R., Fields, H.W., Larson, B.E., Sarver, D.M., 2018. Contemporary orthodontics, Sixth edition. ed.
  • Ruest, L.B., Dager, M., Yanagisawa, H., Charité, J., Hammer, R.E., Olson, E.N., Yanagisawa, M., Clouthier, D.E., 2003. dHAND-Cre transgenic mice reveal specific potential functions of dHAND during craniofacial development. Dev Biol 257, 263-277.
  • Sadler, T.W., 2019. Langman’s medical embryology, Fourteenth edition. ed.
  • Saito, F., Kajii, T.S., Oka, A., Ikuno, K., Iida, J., 2017. Genome-wide association study for mandibular prognathism using microsatellite and pooled DNA method. Am J Orthod Dentofacial Orthop 152, 382-388.
  • Woods, E., Parekh, S., Evans, R., Moles, D.R., Gill, D., 2015. The dental development in patients with Aperts syndrome. Int J Paediatr Dent 25, 136-143.
  • Zebrick, B., Teeramongkolgul, T., Nicot, R., Horton, M.J., Raoul, G., Ferri, J., Vieira, A.R., Sciote, J.J., 2014. ACTN3 R577X genotypes associate with Class II and deepbite malocclusions. Am J Orthod Dentofacial Orthop 146, 603-611.
  • Zhang, Y., Blackwell, E.L., McKnight, M.T., Knutsen, G.R., Vu, W.T., Ruest, L.B., 2012. Specific inactivation of Twist1 in the mandibular arch neural crest cells affects the development of the ramus and reveals interactions with hand2. Dev Dyn 241, 924-940.
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