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WIREs Dev Biol
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Diseases of the tooth: the genetic and molecular basis of inherited anomalies affecting the dentition

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Abstract In humans, inherited variation in the number, size, and shape of teeth within the dentitions are relatively common, while rarer defects of hard tissue formation, including amelogenesis and dentinogenesis imperfecta, and problems associated with tooth eruption are also seen. In many cases, these anomalies occur in isolation, but they can also present as a feature of numerous well‐characterized developmental syndromes. Complex reiterative signaling between the epithelium and mesenchyme is a feature of normal tooth development in the embryo, occurring from early patterning through morphogenesis, hard tissue formation and during root development. Significant events also occur during postnatal development of the dentition, including hard tissue maturation and tooth eruption. In the last decade, advances in human and mouse genetics have meant that in many cases candidate genes have been identified for these anomalies. These genes have provided a useful platform for developmental biologists, allowing them to begin elucidating how these signals interact to generate a functional dentition and understand the mechanisms underlying many of the anomalies that are seen in human populations. In this article, we review current concepts relating to the developmental biology of tooth number, size, and shape, formation of the dental hard tissues and eruption of the tooth into the oral cavity. We will focus on the molecular mechanisms underlying these processes in both health and disease. WIREs Dev Biol 2013, 2:183–212. doi: 10.1002/wdev.66 This article is categorized under: Birth Defects > Craniofacial and Nervous System Anomalies

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The primary (deciduous), mixed and secondary (permanent) dentitions. (a) The primary dentition of a 4‐year old boy; (b) Panoramic radiograph of the mixed dentition in a 10‐year old girl. There is symmetry of development within the dental arches, with the exception of a solitary, early developing third molar in the subject's upper left jaw quadrant (red arrow). On the left, the secondary (permanent) successional teeth are identified in white and the secondary (permanent) accessional teeth in red. The primary (deciduous) teeth are identified on the right in pale blue (note that all the premolars [tooth number 4/5], the upper permanent canines [tooth number 3] and all second permanent molars [tooth number 7] are unerupted and that the lower primary canines [tooth letter C] have been exfoliated; (C) Permanent dentition in a 30‐year old woman with a normal occlusion.

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Primary failure of eruption. (a–c) Serial panoramic radiographs of a male subject affected by generalized primary failure of eruption (PFE). (a) At 10 years of age the lower left, upper and lower right first molars have failed to erupt (*); (b) At 11 years of age, and (c) 13 years of age there is a lack of eruptive development of the affected teeth (*). (d–i) Localized PFE. At 12 years of age, there is a lack of occlusal development associated with the lower right first permanent molar (*), which has completely failed to erupt, although development of the remaining dentition appears normal.

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Osteogenesis imperfecta affecting the primary dentition. (a–c) Intra‐oral appearance; (d) Radiographic appearance. Note the loss of coronal tooth tissue, pulp canal obliteration, and opalescent appearance of the teeth. Courtesy of Dr. Mike Harrison.

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Amelogenesis imperfecta. The wide spectrum of appearance associated with amelogenesis imperfecta (AI) in both dentitions (a–d) Hypoplastic AI (in d, autosomal recessive AI with a severe and generalized enamel hypoplasia and open bite malocclusion); (e and f) Hypomineralized AI (in e, mixed hypomature/hypocalcified AI and in f, Hypomature AI). Courtesy of Dr, Mike Harrison.

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Anomalies of tooth size and form. (a) Megadont upper left secondary central incisor; (b) Microdont upper left secondary lateral incisor; (c) Double tooth in the primary dentition (*); (d) Talon cusp on the upper right secondary central incisor; (e) Cusp of Carabelli (arrowed); (f) Taurodont first permanent molars (*).

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Cleidocranial dysplasia. (a) Classic presentation of cleidocranial dysplasia in an adult patient. There has been progressive loss of the retained primary dentition but failure of eruption of the secondary dentition. (b) Panoramic radiograph of the subject in (a) reveals multiple unerupted secondary teeth, many of which are supernumerary (*). (c) Cone Beam Computerized Tomographic (CBCT) scan of a 10‐year‐old child with cleidocranial dysplasia. There are multiple unerupted supernumerary teeth (red arrows).

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Supernumerary teeth. Supernumerary teeth affecting the secondary dentition (a) Erupted mesiodens in the midline of the anterior maxilla (arrowed); (b) Erupted tuberculate supernumerary preventing eruption of the maxillary secondary central incisors (arrowed); (c) Supplemental lateral incisor tooth [S] erupted between the secondary lateral incisor [2] and canine [3] teeth.

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Nonsyndromic selective tooth agenesis (STHAG). Clinical appearance (left panels) and accompanying panoramic radiographs (right panels) demonstrating nonsyndromic STHAG of the secondary dentition (a, a′) Incisor‐premolar hypodontia (the upper lateral incisors, lower second premolars and lower third molars are absent); (b, b′) Hypodontia (the upper first and second premolars, lower second premolars and all third molars are absent); (c, c′) Oligodontia (a combination of 10 incisor and premolar teeth, and all the third molars are absent). (*) Identifies absent teeth.

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EDA signaling in tooth development (a, b) Eda (formerly known as downless) and (c, d) Edar (formerly known as tabby) expression is localized to the epithelium of developing mouse teeth in a complementary and overlapping pattern.12 In the early thickening, these genes are restricted to lateral (a) and medial (c) regions (white arrows), respectively; while later, Eda is highly expressed in the enamel knot (blue arrows) and Edar is seen in the epithelial collar of the cap stage tooth germ (yellow arrows). Analysis of Eda and Edar mutant mice has demonstrated that tooth development is grossly normal until the cap stage of development. However, the Eda mutant has an absent enamel knot, with those cells that are present arranged in a rope‐like structure, while the Edar mutant does have an enamel knot present, it is smaller, with the secondary enamel knots that form later, fused. These mutants all demonstrate varying levels of tooth agenesis, a reduced number of cusps with abnormal morphogenesis and microdontia11,12; with morphological differences existing between them63 and a phenotype directly dependent upon signal level.4,6,7 Indeed, overexpression of Eda in the epithelium can induce the formation of supernumerary teeth in the mouse.4,6 In situ hybridization courtesy of Dr. Abigail Tucker.

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Msx1 and Pax9 are key players during early tooth development. Msx1 and Pax9 encode homeodomain and paired‐domain transcription factors, respectively and were among the first genes to be identified in the developing mouse tooth. (a) Msx1 and (b) Pax9 are both strongly expressed in the early mesenchyme of the bud stage tooth germ (a, b).47,48 Msx1−/− and Pax9−/− mice have tooth development that arrests at the bud stage49,50 with both genes involved in reiterative signaling during early odontogenesis. A key role appears to be during the transition from bud to cap stage and in the molar tooth germ at least; both are important in mediating BMP4 signaling, being initially downstream of this protein and then maintaining Bmp4 expression in the dental mesenchyme at (c) Bud and (e) Cap stages.49,51 Mesenchymal BMP4 plays an important role inducing formation of the primary enamel knot and the expression of enamel knot signaling proteins, including Shh in the (d) Bud and (f) Cap stages. Msx1 and Pax9 interact genetically, individual heterozygous mice are normal, but Msx1+/−; Pax9+/− mice have oligodontia; which interestingly, can be rescued by transgenic expression of (human) BMP4.52 Pax9 is able to directly activate the Msx1 promoter and acts synergistically with MSX1 to induce Bmp4 in odontogenic mesenchyme.53,54 In situ hybridization courtesy of Dr Isabelle Miletich.

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