EtiologyBased Dental and Craniofacial Diagnostics

38 Chapter 3 Figure 3.1 Developmental fields in the cranium. Schematic illustration of Figure 3.3 Cranial fields marked on profile and frontal radiographs. The fields in the craniofacial region based on insight into cell migration to fields marked in Figure 3.1 are transferred to radiographs because specific regions in the head (green arrows). Fetal pathology cases have also radiographs are used for diagnostics. Furthermore, the theca field is supported the field concept. There are bilateral frontonasal fields (fused marked (purple). Notice in the profile radiograph to the left how all the midaxially) and bilateral maxillary, palatine, and mandibular fields. Within craniofacial fields converge toward the sella turcica. This is useful in the fields there are minor subfields. The fields stretch from the surface of clinical evaluations concerning craniofacial malformations. Malformations the head or from the skin to the sella turcica region. Tissues within a field in different craniofacial fields are associated with certain malformation have the same etiological background. Furthermore, an occipital, axial field types in the sella turcica. Source: Kjær (2010). is marked. This field is formed from the notochord. It is not a bilateral field but there can be bilateral differences due to deviation in the body axis the external nose, and the interocular distance (Figure 3.7). The signaling to the left and right sides. Source: Kjær (2010). field includes the maxillary incisors and extends posteriorly to the incisive papilla and incisive foramen. Figure 3.2 A detailed overview of the frontonasal field demonstrating that there is a left and a right component of the field. The bilateral field arises Malformations in the face which can be traced back to the anteriorly from the neural crest from a right and left area of cell migration. frontonasal field are wide and short interocular distance, a tubular nose, and an abnormal philtrum and lip contour. frontonasal field is also missing. Figure 3.6 also contains two histological sections from fetuses with cleft lip condition which is Cleft lip can occur at the borderlines between the frontonasal a borderline defect between the frontonasal field and the maxil­ field and the maxillary field (Figure 3.8). This borderline can also lary field. Of these two cleft lip conditions, the left is a unilateral be demonstrated in intraoral radiographs of the incisors and the cleft lip case and the right is a bilateral cleft lip case. In the alveolar process (see Chapter 13). bilateral case, it can be observed how the frontonasal field contains the nasal septum and the maxillary incisors. Congenital skin abnormalities may also indicate the border­ Clinical relevance line between the frontonasal and maxillary field. The borderline When observing a normal face in the clinic, it is important to between the fields can be very sharp, as in Sturge–Weber notice the frontonasal field with special focus on the philtrum, syndrome (port wine stain syndrome). It can be presumed that the face in this characteristic syndrome expresses involve­ ment not only of the skin but also of the underlying connective tissue and bone, but this has not been proven. Maxillary field and palatine field The maxillary field is located posteriorly to the frontonasal field. Included in the field are the sphenoid corpora and part of the palate as illustrated in Figure 3.5. In the dentition, the canines and the premolars mark the maxillary field. The palatine field stretches from the floor of the sella turcica and includes parts of the sphenoid bone, part of the palatal bone and presumably a part of the zygomatic bone (see Figure 3.5). In the dentition, the maxillary molars mark the palatine field. Fetal pathology In cases where the frontonasal field is abnormally developed, the maxillary and palatine fields may also be irregular. This can be expressed, for example, by a circular palate in the cyclopia condition and by cleft lip and palate cases (Figure 3.9).

Developmental fields in the cranium and alveolar process 39 Figure 3.5 This figure demonstrates the different origins of the human palate from different areas of the neural crest. (Left) Occlusal view of the palate and alveolar process from a human cranium. The blue line indicates the midpalatine suture. This suture connects the right and left hemimaxillae. The yellow lines mark the anterior triangle of the palate which arises from the frontonasal neural crest cells. The red line indicates the border between the maxillary fields from the maxillary neural crest cells, and the palatine fields from the palatine neural crest cells. The figure shows that the incisors occur in the frontonasal field, canines and premolars in the maxillary field, and the molars in the palatine field. (Right) A schematic drawing of the human palate. The yellow area marks the frontonasal fields, the red area marks the maxillary fields, and the orange marks the palatine fields. Figure 3.4 Illustration of the frontonasal field marked on three Figure 3.7 Photograph demonstrating a normally developed infant. On photographs of human crania. The two upper crania are from adults, and the face of the infant are green and yellow lines. The midaxial line (dark the lower cranium is from a child. The crania are viewed from three green) indicates the axial area where the bilateral frontonasal fields meet. different angles: upper – axial, center – frontal, lower – occlusal level. It The light green and yellow lines indicate how far the field reaches laterally appears that the field stretches from between the eyes and posteriorly to from the midline. The field includes the lower part of the forehead. (Inset) the sella turcica in the shape of a fan. In the palate, only the anterior part A figure demonstrating the extent of the frontonasal field into the child’s including the incisors is a part of the frontonasal field. palate. Figure 3.6 Demonstration of different fetal pathological aspects within the frontonasal fields. (Left) Two fetuses. One at GA 18 weeks with an oroocular cleft (left) and a total absence of the lower part of the frontonasal field, and one at GA 12 weeks with cyclopia (right) including a proboscis above the eye balls. In cyclopia, the frontonasal field has not developed. The nasal septum is absent and the distance from the sella turcica to the eyes is very short (for more information see Chapter 13). (Right) Two histological sections demonstrating unilateral cleft lip (left) and bilateral cleft lip (right). The right figure demonstrates the interrelationship between the nasal septum and the frontonasal segment of the maxilla, including the central incisors.Part of one lateral incisor can also be observed in this section.

40 Chapter 3 Figure 3.8 Schematic drawing of a child with unilateral cleft lip (marked Figure 3.10 A schematic drawing of the bony components of the palate black in the upper lip). Note the asymmetry of the nose and the broad seen in an occlusal view. The midpalatal suture is marked by three stars, distance between the eyes. This cleft condition involves only the the incisive fissures are marked by arrows. The posterior part of the palate frontonasal field. See Chapter 13 for more information. is marked orange. The horizontal part of the palatine bone has a darker orange color to indicate the normal position of these bony components. The black contours laterally in these orange areas represent pathological development of the horizontal part of the palatine bone. In this condition, the axial component of the palatine bone structures are lacking, creating a cleft-like condition in the posterior palate. This often occurs in human fetuses with Down’s syndrome. horizontal portion of the palatine bone is underdeveloped (Figure 3.10). Clinical relevance Isolated cleft palate is a condition in which the maxillary field and the palatine field do not fuse midaxially. For dental abnormalities associated with the different fields, see Chapter 13. In Down’s syndrome, it has been demonstrated that the palatine cleft often observed is due to malformations and underdevelopment of the horizontal components of the palatine bone (see Figure 3.10). Figure 3.9 Intraoral photographs of different prenatal palatal Mandibular field malformations. (Upper left) A cyclopic, human fetus. The palate is circular. The mandibular field stretches from the articular mandibular (Upper right) A palatal cleft extending to the incisive foramen. (Lower left) fossa in the temporal bone anteriorly to the symphysis menti A complete midline cleft including the frontonasal field. (Lower right) This region. Prenatally, the two hemimandibles are separate and is a midline cleft between the palatine and maxillary fields extending to the connected by the mental symphysis at the midline. Within the left where the cleft continues between the frontonasal field and maxillary first few years of postnatal life, the symphysis menti disappears field. Note the Simonart’s band indicated by an arrow. and the hemimandibles are united to form a single bone. In very rare cases, this uniting of the bilateral mandibular fields fails, resulting in persistence of the symphysial structures in the bone or in a mandibular midaxial cleft (see Figure 1.32). The mandibular field can be subdivided according to inner­ vation paths as demonstrated in Figure 2.29. How this field is interrelated to fields in the cranial base is still not known. A total absence of the bilateral mandibular fields is called agnathia (Figure 3.11). A midpalatine cleft located midaxially is a cleft between the Fetal pathology palatine shelves in a case with absence of the frontal nasal field. Malformations in the mandible are rarely observed prenatally. Significant mandibular retrognathia is observed in trisomy 18 A cleft in the posterior part of the palate can be due to and even more extreme retrognathia is observed in triploidy. abnormal development of the palatine field in which the

Developmental fields in the cranium and alveolar process 41 Fetal pathology The most severe defect in the thecal field is the total absence of the thecal bone (the uppermost part of the frontal squama, the parietal bone, the upper part of the temporal and occipital squama). This is observed in anencephaly in which the hemi­ spheres of the cerebrum have not developed, as illustrated in Figure 2.5. Different openings and holes in the theca field can also occur in association with encephaloceles. Parietal foraminae have been described in relation to abnormal development of the hemispheres in holoprosencephaly. Figure 3.11 A schematic drawing of a newborn with absence of the Clinical relevance mandibular field. This rare condition is called agnathia. As a consequence The thickness of the theca is measured frontally, parietally, to this lethal malformation, the mouth opening does not develop and the and occipitally (occipital squama) by cephalometric analysis ears appear below the face. (Figure 3.12). Standard measurements for these regional, age- dependent thicknesses exist. In different skeletal malocclusion cases and in different pathological cases, the theca thickness may vary from normal standards. However, all bone components of the mandible are present in Occipital field these cases. In Figure 1.30, two examples of prenatally malformed This midaxial occipital field could also be named the notochordal mandibles are shown in which different mandibular regions are field because the notochord runs through the vertebral bodies to absent. the posterior wall of the sella turcica. The occipital field is the uppermost field in the body axis, including the cervical spine and Clinical relevance the posterior cranial fossa. The field is a cartilage-formed, funnel- Congenital mandibular asymmetry can be caused by a unilateral shaped field which includes the cerebellum and the cervical spine underdevelopment which might be due to abnormal cell types – it is also known as the cerebellar field. Cranially, it stretches from the neural crest or as a result of a deviant migration pattern from the posterior wall of the pituitary gland along the tentorium of the cells from the neural crest. If this malformation involves cerebelli to the occipital squama, and from there caudally the condylar cartilage, then the asymmetry will be accentuated through the cervical vertebral column. during growth. In patient cases, it is important to notice the mandibular midline. A minor mandibular midline cleft may be a sign of nonfusion of the bilateral mandibular fields. Also late traces of nonclosure of a symphysis menti can be observed and is con­ sidered a midline defect (see Figure 1.32). Condylar ankylosis is a rare but severe, often unilateral malformation in which ossification occurs between the mandib­ ular condyle and external cranial fossa. This results in abnormal, unilateral arrest of mandibular growth and loss of the mandibu­ lar chewing function. The etiology behind condylar ankylosis can be an infection or a physical trauma. Condylar aplasia or hypoplasia can also be observed anthro­ pologically (see Figure 1.31). Furthermore, conditions such as juvenile arthritis may disturb condylar growth, resulting in asymmetry with varying degrees of severity. Mandibular mal­ formations have also been observed in cases with absence of the mandibular canal and abnormal innervation pattern. Theca field Figure 3.12 A profile radiograph (Turner’s syndrome) with cephalometric The osseous theca field covers the cerebrum. It is composed of the lines inserted. The lines demonstrate various cephalometric measurements cranial part of the frontal squama, the parietal bone, and the of the thickness of the neurocranium. The measurements of the uppermost cranial part of the occipital squama. The theca of the temporal cervical vertebra (atlas) are also depicted. Source: M Lindroos, University bone is also a part of this field. of Copenhagen, Copenhagen, Denmark. Reproduced with kind permission of M Lindroos.

42 Chapter 3 Fetal pathology Figure 3.14 (Left) Frontal view of a human fetus with Turner’s syndrome The occipital field is involved in different fetal pathological cases. GA 17 weeks. Note the broad neck with nuchal fluid accumulation. (Right) In Figure 3.13, rachischisis, a verteberal clefting (occipital cele) of A frontal radiograph from the same fetus with Turner’s syndrome. Note the occipital field is demonstrated. In this condition, the cranial the bilateral, cervical ribs in the region of the C7 vertebra. base angle is greatly diminished. The most common deviations in the occipital field are seen in fetuses with a broad neck. Examples are Down’s syndrome and Turner’s syndrome (Figure 3.14). Prenatally, Turner’s syndrome fetuses often have an extra rib rudiment located at C7 (seventh cervical vertebra). These fetuses have large, fluid-filled cavities in the lateral neck region (see Chapter 13). These cavities are localized to the cervical region and do not extend further through the body. Clinical relevance How can craniofacial fields be proven? Recently, the occipital field has been analyzed cephalometrically in genotypically normal individuals, in Down’s syndrome, and in The fields were originally observed experimentally and micro­ Turner’s syndrome patients. In these syndromal cases, this field scopically. Now fetal pathological and clinical cases as demon­ deviates in shape from the normal standards. It has also been strated above have supported the existence of these fields. observed in Down’s and Turner’s syndrome that the thickness of Anthropological material from pathological crania from new­ the endochondral squama belonging to the occipital field varies borns has meanwhile provided a convincing visual overview. significantly from standard thickness. This is demonstrated in Figures 3.15–3.20. When observing a profile radiograph in the clinic, it is Frontonasal field important to notice the thickness of the squama and possible In one figure (Figure 3.15), a cranium appears without the lower malformations in the cervical vertebrae. It is equally important to component of the frontonasal field. This is also called a midline assess the cranial base angle, the length of the basilar part of the cleft. Another cranium (Figure 3.16) demonstrates the existence occipital bone or clivus, the posterior sella wall morphology, and of only the bilateral frontonasal fields and the nonexistence of the the sphenooccipital synchondrosis. In several conditions, all of bilateral maxillary and palatine fields. these components in the occipital field may be affected. Maxillary and palatine field Absence of the two fields is demonstrated in Figure 3.16 and absence/malformation of the palatine field is shown in Figure 3.17. In Figure 3.17, the zygomatic arch is also missing which may indicate a connection between the palatine field and the zygomatic bone or between the mandibular field (mandible not available in this anthropological case) and the zygomatic bone. Midaxial clefting between the bilateral palatine and max­ illary fields is demonstrated in Figure 3.18. This midaxial cleft is combined with a paraaxial cleft between the frontonasal field and Figure 3.13 A profile radiograph of a human fetus GA 20 weeks with Figure 3.15 Photos of a human cranium from a newborn, demonstrating rachischisis (occipital cleft). Note the diminished cranial base angle. (Inset) median cleft in the maxilla. The frontonasal field has not developed to its A photograph of the fetus viewed from behind. The defect is limited to the full extent. This is part of the holoprosencephalic syndrome. Note the cervical spinal region. diminished frontal fontanelle. Source: T Söderqvist, Medicinsk Museion, Copenhagen, Denmark. Reproduced with permission of T Söderqvist.

Developmental fields in the cranium and alveolar process 43 Figure 3.16 Photos of a human cranium lacking the maxillary and palatine neural crest fields. The frontonasal field between the eyes including the nose region and incisive alveolar process has developed. When the maxillary and palatine field does not develop, then the margo infraorbitalis, the inferior border of the orbita, does not develop. Note that the anterior fontanelle appears normal. Source: T Söderqvist, Medicinsk Museion, Copenhagen, Denmark. Reproduced with permission of T Söderqvist. the right maxillary field. Isolated clefting between the frontonasal Figure 3.18 This part of a cranium from a newborn demonstrates a field and maxillary field is demonstrated in Figure 3.19. The complete cleft lip and palate condition from an occlusal view. Source: T cranium in Figure 3.17 demonstrates the absence of a region Söderqvist, Medicinsk Museion, Copenhagen, Denmark. Reproduced with covering the posterior part of the palatine field and the zygomatic permission of T Söderqvist. arch. This field has not yet been named but the zygoma field is suggested. the theca appears different in different craniofacial malforma­ tions (see Figure 1.35). Mandibular field The extremely rare absence of the mandibular field is seen in the Occipital field lethal condition agnathia which has been demonstrated in The occipital field is almost completely absent in the cranium Figure 3.11. demonstrated in Figure 3.20. An occipital encephalocele is the presumed cause of the malformation. Severe malformations in Theca field The theca field can be proven by the lethal condition called anencephaly in which the theca is not formed (see Figure 2.5). There are sharp borderlines between the thecal fields and the caudally located fields. The pattern of sutures and fontanelles in Figure 3.17 Photographs of a human cranium lacking the development of the palatine neural crest field. The posterior part of the margo infraorbitalis is lacking, and so is the posterior part of the palate and the zygomatic arch. The frontonasal and maxillary fields are apparently normally developed. The mandible was not present in this case. Source: T Söderqvist, Medicinsk Museion, Copenhagen, Denmark. Reproduced with permission of T Söderqvist.

44 Chapter 3 Figure 3.19 Part of a cranium from a newborn with bilateral cleft lip. The Figure 3.21 (Left) Diagram demonstrating how the cranial fields are occlusal view (left) and frontal view (right) demonstrate a cleft occurring at interrelated with development of the alveolar process and the teeth. the borders between the frontonasal and the maxillary neural crest fields. Accordingly, a malformation in teeth within a developmental field can be The lower part of the frontonasal field appears isolated – this part was interrelated with abnormal bone development in the corresponding cranial formerly named the premaxilla. Source: T Söderqvist, Medicinsk Museion, field. (Right) Intraoral photograph of a child with a malformation of the Copenhagen, Denmark. Reproduced with permission of T Söderqvist. teeth in the left frontonasal field. The etiology behind this condition depends on actual jaw bone development and on the anamnesis. These aspects are highlighted in the text. Source: Kjær (2012). fetal pathology cases such as iniencephaly also demonstrate the The upper jaw and the dentition occipital field. The developmental fields in the upper jaw are composed of the frontonasal field, which includes the maxillary incisors, and Developmental fields in the alveolar the maxillary field, which includes the canines and premolars process (see Figure 3.21). Finally, there are palatine fields which include the molars. These fields are all bilateral and stretch to the palate. The dental arches in the upper and lower jaw can be separated The innervation marks and limits the fields – the nasopalatine into segments with different innervations according to corre­ nerve marks the frontonasal field, the maxillary nerve marks the sponding craniofacial fields. The segments are called fields and maxillary field, and the palatine nerve marks the palatine field are illustrated in Figure 3.21. (see Figure 3.21). Clinical relevance Diagrams illustrating the peripheral nerves with ectomesen­ chyme from the same neural crest region appear in Figure 3.21. In cases of localized malformations in the dental arch, it is important to consider whether the deviation is within a field or whether it crosses into other fields. If it is congenital, it must be considered whether the condition can be traced back to an ectomesenchymal or nervous origin in the affected field. Figure 3.20 Photographs of a cranium lacking development of the The lower jaw and the dentition occipital field. All bony parts belonging to the occipital field are absent, The inferior mandibular nerve in the mandibular canal is com­ including the basilar part of the occipital bone, and the posterior part of posed of several nerve branches approaching different regions of the sphenoid bone corpus with the posterior wall of the sella turcica. The the alveolar process. Compared to the innervation of the maxilla, lateral parts of the occipital bone bordering the foramen magnum and the there are separate nerve branches in the mandible and accordingly, lower, cartilaginously formed part of the occipital squama have not separate mandibular fields. Branches including the incisors are formed. All structures have formed by signaling from the rostral part of located in the lowest part of the mandibular canal. Branches to the the notochord. The cervical vertebrae were not present, but the mandible canine premolars are located above the branches to the incisors, and was present. The mandible was small at this early stage of development but lastly, branches to the molars are located cranially in the inferior the morphology was apparently normal. Source: T Söderqvist, Medicinsk alveolar nerve bundle (see Figure 3.21). The figure also shows the Museion, Copenhagen, Denmark. Reproduced with permission of T ectomesenchymal tissue in the alveolar bone within the fields. Söderqvist. Clinical relevance In the mandible, it is also important to consider whether a deviation in dentition occurs within a field or whether it crosses the field borders. It is also important to trace the deviation back to its origin. As a conclusion, there is an association between the dental fields registered in the alveolar process and the craniofacial fields

Developmental fields in the cranium and alveolar process 45 observed and described in this chapter. The connection between Further reading the PNS, the CNS, and the jaw formation is obvious. It is important to consider that the dental arch is composed of Axelson S. Longitudinal cephalometric standards for the neurocranium segments with different origins. The interrelationship is illus­ in Norwegians from 6 to 21 years of age. Eur J Orthod 2003;25: trated in the diagrams provided. 185–198. Highlights and clinical relevance Kjær I. Orthodontics and foetal pathology: a personal view on cranio­ facial patterning. Eur J Orthod 2010;32:140–147. • This chapter demonstrates how the different segments of the jaws are developmentally related to segments in the alveolar process. Kjær I. Review article: dental approach to craniofacial syndromes: how This means that there is an interrelationship between segments of can developmental fields show us a new way to understand patho­ the jaws and specific teeth due to similar neural crest origin. genesis? Hindawi 2010; Article ID 145749. Available at: http://dx.doi .org/10.1155/2012/145749. • The dental arch should no longer be considered a single, unbroken structure but should be regarded as at least six Kjær I, Keeling JW, Hansen BF. The prenatal human cranium, normal different fields with different innervations and different ecto­ and pathologic development. Munksgaard, Copenhagen, 1999. mesenchymal tissues having separate origins from the neural crest. This is the foundation for understanding etiology-based Lauridsen H, Hansen BF, Reintoft I, Keeling JW, Kjær I. Histological diagnostics of the dentition. investigation of the palatine bone in prenatal Trisomy 21. Cleft Palate- Craniofac J 2001;38:492–497. • Congenital and acquired conditions in the jaws and dental arches can be located within one field or within several fields. Le Douarin NM. The neural crest in the neck and other parts of the body. They can also appear at the borderlines between two fields, Birth Defects 1975;11:19–50. such as cleft lip. Le Douarin NM, Ziller C, Couly GF. Patterning of neural crest deriv­ • Cleft lip is a cleft between the frontonasal field and the atives in the avian embryo: in vivo and in vitro studies. Dev Biol maxillary field (see Chapter 13). 1993;159:24–49. • In diagnostics, it is important to remember the fields of Lomholt JF, Keeling JW, Hansen BF, Ono T, Stoltze K, Kjær I. The pre­ innervation and to evaluate whether the condition at hand natal development of the human cerebellar field in Downs syndrome. affects all teeth, only teeth within one specific field, or teeth Orthod Craniofacial Res 2003;6:220–226. within several fields but not all fields. Lomholt JF, Nolting D, Hansen BF, Stolze K, Kjær I. The pre-natal • If the defect is in one or two fields, the clinician should attempt development and osseous growth of the human cerebellar field. to evaluate the etiology behind the condition, for example by Orthod Craniofacial Res 2003;6:143–154. anamnesis. Nielsen BW, Mølsted K, Skovgaard LT, Kjær I. Cross-sectional sdy of the length of the nasal bone in cleft lip and cleft palate. Cleft-Palate Craniofac J 2005;42:417–422. Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen’s human embryology, 4th edn. Churchill Livingstone, Philadelphia, 2009.

CHAPTER 4 Tooth development and tooth maturation from early prenatal to postnatal life Dental development and maturation can be evaluated histologi­ different roles in tooth malformation, tooth eruption, and tooth cally, radiographically, and clinically. Possible methods for resorption. The different tissues can be congenitally abnormal and studying the onset and development of the primary dentition they can be disturbed by external factors. are through histology and, in certain restricted periods, radiog­ raphy. The onset of the permanent dentition is rarely studied Inner enamel epithelium and hard tissue histologically but often by radiographic analysis. Ongoing devel­ formation opment/maturation is assessed mainly by analysis of the primary The epithelial tooth bud is organized early on into an inner and and/or permanent dentition after birth. In the first 3–4 years of an outer enamel epithelium. The tissues involved in early tooth postnatal life, radiography is not a standard procedure. Different formation are marked with specific tissue markers for ectoderm, methods used in different periods of life make it impossible to innervation, and ectomesenchyme. The inner enamel epithelium give a continuous and complete longitudinal presentation of reacts positively with the same epithelial marker, p63, as the skin, tooth development from early pre-natal life to late post-natal life. hair follicles, oral mucosa and salivary gland tissue (Figure 4.3). The inner enamel epithelium also reacts positively in the early Histological evaluation of early tooth stages (before hard tissue formation) with the neuronal marker development nerve growth factor receptor (NGFR) (Figure 4.4) until hard dental tissue formation starts. The apical membrane (later root Tissues involved in dental bud formation membrane) reacts with NGFR which suggests that it is rich in The morphology of early tooth development is well known. A innervation (Figure 4.5). When dentin and the enamel tissues are tooth bud from the oral mucosa gradually changes morphology laid down, supported by the inner enamel epithelium, the during development. Genetic interactions in this phenotypic positive neuronal marking disappears from the inner enamel change during tooth development have been described in detail epithelium but is still present in the apical membrane. In the and further studies are in progress internationally. The oral initial stages, NGFR positivity can also be seen in the outer mucosa forming the dental lamina for the primary tooth is the enamel epithelium. Later, the innervation reaction is concen­ same mucosa that forms the permanent tooth (Figure 4.1). In later trated in the developing root membrane area. Special attention chapters, this is important to remember because similarities should be given to the tissue types that compose the outer follicle between the two dentitions can be due to a common origin (crown follicle) arising from the outer enamel epithelium. Atten­ from the mucosal ectoderm. tion is also given to the root membrane during development. In this chapter, we focus on the tissue types that surround the Outer enamel epithelium and crown follicle mucosal tooth bud. The tissue types forming the tooth are the The crown follicle appears early in tooth development. The mucosa, the ectomesenchyme stemming from the neural crest, follicle has an outer layer of ectomesenchymal tissue fibers and the innervation. The pathway that the nerve follows out to the and an inner layer of mucosa which originates from the outer target (the tooth bud) has been traced genetically. In Figure 4.2, enamel epithelium. By neuronal staining (NGFR), it can be seen the tissues involved in early tooth formation are illustrated. that a difference arises between the coronal part of the follicle, which appears NGFR negative, and the more caudal part which Clinical relevance appears positive (see Figure 4.5). This difference is present from The three main tissue components must be evaluated when abnor­ the start of hard dental tissue formation and throughout the mal tooth development is observed. It is important to consider prenatal period investigated. whether the deviation is caused by the ectoderm (mucosa), by the ectomesenchyme or by the innervation. Examples will be given Several studies have demonstrated how the follicle in its throughout the rest of the book. These different tissue types play coronal aspects initiates the resorption of the overlying hard tissue while the apical part of the crown follicle initiates bone Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 46

Tooth development and tooth maturation from early prenatal to postnatal life 47 Figure 4.1 Early formation of the primary and permanent tooth. (Left) This figure demonstrates the early tooth bud from a primary incisor with a green ring marking the inner enamel epithelium where the hard tissue formation starts. To the right in this figure is the mucosa offshoot (P) from where the permanent incisor later forms. It is important to note that the epithelial mucosa of the primary and of the permanent tooth originates from the same area in the dental lamina. This can partly explain the similarities in the two dentitions. (Right) A schematic drawing demonstrating three steps in primary tooth formation and two steps in the early formation of the permanent tooth. These two steps are each marked with a circle. The middle figure of the three is a schematic portrayal of the histological image to the left. formation. These charateristics of the coronal follicle of the developing tooth are important for understanding tooth erup­ tion and alveolar bone formation (see Chapter 10). Fetal pathology Abnormality in the early tooth formation has been observed in syndromes such as trisomy 18, chondrodystrophy, anhidrotic ectodermal dysplasia and in cases from maternal virus attack and spontaneous abortions. Ectodermal dysplasia can be diagnosed prenatally and post­ natally. By immunohistochemical marking of tissues, it can be proven in ectodermal dysplasia that the tooth bud formation Figure 4.2 A schematic drawing illustrating the three tissue types of Figure 4.3 P63 gene marker (brown coloring) in the mucosa. (a) The importance for tooth formation. The dark grey illustrates the mucosa. The enamel epithelium reacts positively with the epithelial marker p63. (b) The white circle illustrates the ectomesenchyme from which the bone tissue oral mucosa in its early stages shows positive reactivity with epithelial (red moon) develops. The black fork to the left illustrates the innervation. marker p63. (c) The brown coloring demonstrates the reaction of p63 in tissues involved in early hair formation. (d) The p63 marking of the basal cell layer in glandular tissue. This figure explains why deviations in p63 can affect teeth, hair, skin, and glandular function.

48 Chapter 4 Figure 4.5 NGFR reaction is illustrated with red markings in this histological section. The red coloring can be seen clearly in the lower part of the crown follicle (C), in the entire root membrane (R) and in the inner enamel epithelium (E) where dentin and enamel have not yet appeared. (Inset) A schematic drawing demonstrating the tooth bud with a positive NGFR reaction marked in red. Figure 4.4 Nerve growth factor receptor (NGFR) reaction marked with red in the inner enamel epithelium in the early stages before dentin and enamel production. The tooth bud is also surrounded by a positive NGFR reaction. (Inset) A schematic drawing in which the red color indicates a positive NGFR reaction in this early stage of tooth formation. starts normally but is interrupted at a certain stage. Ectodermal dysplasia has in the case provided (Figure 4.6) been marked by p63 with negative results. It appears that the mucosa formation of the tooth bud has started but arrests before hard tissue formation commences (see Figure 4.6). Root membrane and root development Figure 4.6 This figure demonstrates a tooth bud from a human fetus with The early root membrane is composed of a layer of ectomesen­ ectodermal dysplasia. The tissue section has been treated with p63 but has chymal tissue fibers covered by a layer of innervation (see reacted negatively (no reaction). The normal reaction is seen in the Figure 4.5). This innervation layer can be seen when marked inserted figure of a tooth bud from a nondysplastic fetus. specifically with silver impregnation (Figure 4.7). It is supposed that this root membrane functions in the same way as an outer surface membrane of a glandular cell (acini) with calcium release during function. Silver impregnation demonstrates how the release of positive calcium ions reacts with positive silver ions as seen in Figure 4.7. During the formation of the hard dental tissue, it is suggested that the developing root membrane creates

Tooth development and tooth maturation from early prenatal to postnatal life 49 Figure 4.7 A horizontal section of a mandible from a human fetus Figure 4.9 Histological sections of tooth buds in the maxilla and mandible. approximately GA 12 weeks. The section was silver impregnated before (a) A horizontal section of a human maxilla GA 15 weeks illustrating the staining with toluidine blue. The silver impregnation appears in black. The midpalatine suture (M), the incisal fissure (F), and the tooth buds of the silver (Ag+) changes places with the calcium (Ca++) ions and causes the primary incisors, canines and first molars. (b) A horizontal section of a alveolar bone tissue to appear black as expected (B). Unexpectedly, the human maxilla GA 20 weeks demonstrating the primary incisor, primary root membrane (two arrows) also reacted positively. This might indicate lateral, and primary canine. (c) A horizontal section of a human mandible that the root membrane functions in the same way as an outer surface GA 15 weeks demonstrating the symphysis menti (S), the primary central membrane of a glandular cell (acini) with calcium release during function. incisors, primary lateral incisors, and primary canines. D marks the bilateral dental buds. Note that the right bud has a thicker internal enamel epithelium when compared to the dental bud to the left. (Figure 4.8). On histological sections, it appears as if a virus attack This indicates that the right dental bud is more mature and the black (or another external agent) relieves the inner pressure of the tooth staining bordering this bud shows that it has begun to function with organ which then collapses. This applies to the development of the calcium release. SM marks the symphysis menti region and C, the bilateral hard tissue, the crown follicle, and the root membrane. Meckel’s cartilage. Note also the black ossifications within the cartilage which illustrate the cartilaginous origin of the anterior mandible. T marks Sequences in prenatal tooth formation the tongue and A indicates an artifact from the preparation. The prenatal maturity of the teeth can only be observed histo­ logically in the initial stages of hard tissue formation (Figure 4.9). pressure between the tooth and the root membrane, which then Because the dental germs are located in different levels, it is swells up like a balloon. The root membrane and root formation difficult to make a histological section in which all teeth in the cannot be studied later in fetal life due to autopsy laws. jaws can be seen. This makes prenatal maturity studies problem­ atic. The primary canine is the first tooth to form hard tissue both Fetal pathology in the mandible and in the maxilla. The mandibular canines are The outer enamel epithelium/crown follicle, the inner enamel formed in the area of the mental foramen and the maxillary epithelium, and the root membrane can be destroyed prenatally canines in the area of the infraorbital foramen. These are the areas where jaw bone is first formed. A histological section illustrating primary incisors in the maxilla demonstrates that the central incisor is slightly ahead of the lateral incisor in maturation at GA 20 weeks (Figure 4.10). Figure 4.8 A histological section of a human, prenatal tooth bud which Radiographic evaluation of normal dental has been disturbed interuterinely. The follicle has collapsed and the tooth maturation bud is angulated due to this collapse. The etiology behind this case might be a virus attack (or another external agent). Histological development of the teeth cannot be studied longi­ tudinally from prenatal to postnatal life. Radiography is therefore the only possible method.

50 Chapter 4 Figure 4.10 A vertical, histological section (from serial sections) from a does not play a defining role in dental maturation. When human fetus GA 20 weeks depicting a primary central incisor (left) and a analyzing an orthopantomogram, it is important to evaluate primary lateral incisor (right). The stages of maturity are slightly different, dental maturity which is age and gender dependent. the central incisor being slightly ahead of the lateral incisor. The etiology behind the ongoing process of dental maturity is not known. The maturity of the dentition is a process which involves morphological steps in crown formation and root formation. These steps are all analyzed radiographically and can be used to calculate the dental age of an individual. The problem with these dental calculations is that the final root lengths, which are used in the calculation, are not known. The final root length is difficult to predict. Some steps in the normal postnatal development of the primary and permanent dentitions appear in Figures 4.12, 4.13, 4.14, 4.15, and 4.16. The radiographs of the very young children (under four years) have been taken by medical teams for craniofacial diagnostics of various diseases. The quality of these exposures is therefore not optimal for dental maturity assessment but they can provide an indication of the early maturation process specifi­ cally in the primary dentition. Radiographic appearance of prenatal crowns Root morphology and root length before GA 22 weeks In the primary dentition, shedding of the roots is a normal, Radiographs taken by a Faxitron x-ray machine of a spontane­ physiological process occurring in close relation to the eruption ously aborted fetus GA 21 weeks demonstrate the early radio­ of the succeeding permanent tooth (Figure 4.17). Shedding is a graphic stages of maturity of the primary crown formation normal maturation process which can also occur without suc­ (Figure 4.11). At this early stage, all primary teeth except for ceeding permanent teeth. The shedding process is a root resorp­ the second molar have formed dental hard tissue. tion process which can become pathological. It will therefore be dicussed in further detail in Chapter 11. Radiographic appearance of postnatal dental maturation In the permanent dentition, some roots, especially in the The radiographic evaluation of postnatal dental maturity focuses second premolars in the lower jaw, appear short. This is sug­ especially on root development while the clinical evaluation of gested to be an arrest in root development but why this arrest dental maturity focuses mainly on tooth eruption. The ongoing occurs has not been explained. Extreme cases of short roots are maturation process which expresses the gain in size of the not considered normal variations. Other extremes such as very developing tooth is seemingly independent of jaw fields and long roots can also be seen without a clear explanation, but can so innervation. It can therefore be presumed that the innervation far be considered a normal variation (Figure 4.18). Nevertheless, long roots can also be a symptom of pathology (see Chapter 8). Figure 4.11 Three Faxitron radiographs of the cranial region in spontaneously aborted fetuses. (Left) Midsagittal segment. Contours of the incisal part of the maxillary primary central incisor are marked with an arrow, GA 20 weeks. Incisal fissure (F), palate (P), transpalatal suture (T). (Center) Midsagittal segment. Contours of the incisal part of the primary incisors are marked in the maxilla, GA 21 weeks. (Right) Parasagittal segment. Contours of the primary canines and first primary molars are marked in the maxilla, GA 21 weeks (from same fetus as center).

Tooth development and tooth maturation from early prenatal to postnatal life 51 Figure 4.12 Profile radiographs (slightly skewed) demonstrating maturation stages at age five months (left) and 17 months (right) from two children with hydrocephalus. The radiographs were taken for cranial analysis while the anesthetized child lay on a table. (Left) The stars mark the second primary molars in the left and right side. (Right) The stars mark the second primary molars in the left and right side and the arrows indicate the first permanent molars. Figure 4.13 Orthopantomogram (OP) from a child age four years and nine months illustrating the fully mature primary dentition. The resorption process of the incisors indicates that the shedding process has begun and that the permanent incisors have begun to erupt. This OP was taken because of an erupted mesiodens (extra tooth) in the midaxial maxillary region. Notice the late maturity stage of the mandibular second premolars. The short root anomaly is a malformation condition which can Figure 4.15 Photograph of a boy 6½ years of age at the clinical stage of be seen in the maxillary incisor fields and can be explained by maturity where the primary incisors are shedding and the permanent genetic deviations in these fields. The condition is inheritable. central incisors in the mandible have erupted. Short or seemingly abrupt root formation occurs often in the second premolars. The cause is not known. Taurodontia occurs in the molar roots and is classified accord­ ing to the degree of apical displacement of the pulp chamber floor The long root anomaly is difficult to diagnose because the in hypo-, meso-, and hypertaurodontia. Evaluation of the pulp difference in length of a long root compared to a normal root is cavity, which can change morphology with age due to calcifica­ not clearly defined. Conditions such as cystic fibrosis are char­ tion, is an important part of dental maturity assessment. How­ acterized by the long root anomaly but there are also cases of ever, the borderline between normal and abnormal pulp cavity extremely long roots without a known etiology. morphology is not clearly defined (see Chapter 8). Figure 4.14 Orthopantomogram (OP) from a boy five years of age. This Early and late maturation OP was taken because of the infraposition of the left, maxillary, second Early and late maturation are only noticeable in the most extreme primary molar. Note the maturity of the premolars and first permanent cases. There is often no explanation for either condition. The molars. etiology might be linked to a disease or to a certain type of medical treatment. Interestingly, some patients have delayed maturity of the first molars. Bimaxillary discrepancies in the maturation stages of identical teeth can also occur. In Proteus syndrome, the discrepancy in maturation is due to unilateral overgrowth of jaw tissue.

52 Chapter 4 asymmetries are considered to be pathological and will therefore be discussed further in Chapter 10. The evaluation of dental maturity is important in diagnostics and treatment planning. The ectomesenchymal tissue within the fields seems to be a factor in the regulation of crown maturity while innervation seems to influence the root maturity. Clinical evaluation of dental maturity Figure 4.16 Orthopantomograms from two individuals demonstrating Tooth maturity can be clinically assessed by the time of eruption. maturity stages from the periods before and after puberty. (Upper) Before/ Eruption times for both the primary and permanent dentition are during early puberty, the premolars and second molars have started available in several publications and textbooks. A tooth erupts eruption and the root lengths are between half and two-thirds of the final when the root has a length that is approximately one-half to two- length. (Lower) After puberty (approximately 18 years of age), the thirds of its final length. There is a difference between the dentition has fully developed except for the third molars. amounts of time required for a given tooth to form from the initial stages to the final root length. This is exemplified in Clinical relevance Figure 4.19. It is often difficult to distinguish when a development stage is normal and when it is pathological. It is important to consider the The sequence in which the primary teeth erupt will be further development of both the primary and the permanent dentition discussed in the chapter on eruption. Eruption of permanent within an actual field as well as between fields. There can also be teeth is also highlighted there. A six-year-old boy who has just bilateral differences in development. Severe bilateral entered the eruption process of the permanent teeth is displayed in Figure 4.15. Bilateral agreement in tooth maturation Generally, there is a bilateral agreement between the formation stages of corresponding teeth in the left and right sides of the jaws. However, it is well known that the second premolar can be late in development and that there can be asymmetry in the developmental stages in the two sides. The cause of this asym­ metry is not known. Asymmetry can also occur in the molars. Asymmetry may arise between the maxillary first molars and/or between the mandibular first molars. Clinical relevance In the clinical evaluation of tooth maturation, it is important to be aware of the spectrum of normal variations for both females and males. The broad variation spectrum can make it difficult to determine a pathological condition. Be aware also of bilateral differences in maturity. If a case is assessed as pathological, the next step is to determine a possible etiology (see Chapter 10). Tooth formation from the initial stages to the eruption stages: relation to fields, gender, age, and skeletal maturity Figure 4.17 A schematic drawing demonstrating how a primary molar • Initial, prenatal development of the primary dentition. from its full root length (left) undergoes normal, physiological resorption  The primary canines are the first teeth to develop followed by so that only the crown is left (right). Different maturity steps in the the central incisors in the upper jaw and the lateral incisors succeeding permanent tooth are illustrated. The yellow color marks the crown follicle of the permanent tooth. Green marks the pulp and the gray in the lower jaw. Both the maxillary and mandibular incisors shades the enamel (dark) and dentin (light). develop initially from a common alveolus.

Tooth development and tooth maturation from early prenatal to postnatal life 53 Figure 4.18 This figure demonstrates the possible differences in root length. (Left) Long and slender roots. (Right) Short and plump roots.  The first primary molars develop initially before the second Clinically, eruption times depend not only on tooth matura­ molar. tion stages but also on the space in the jaws and the innervation in the given field.  Gender differences and age differences prenatally are not clear. The number, size, and morphology of the teeth in the two dentitions are different and the enamel layer is thinner in the • Ongoing development/maturation. primary dentition when compared to the permanent dentition  The ongoing development before eruption is seemingly a (Figure 4.20). developmental process which is not specifically dependent on innervation but is more likely dependent on the Clinical relevance ectomesenchyme. There are normal variations in tooth morphology. This can concern size, shape, narrowness or broadness of crowns, and • Eruption. also the cusp pattern can differ. The molars of the primary and  Eruption is closely dependent on fields and innervation (see permanent dentitions can also be strikingly similar. Chapter 6).  Eruption is also age and gender dependent. The enamel is significantly thinner in primary teeth than in  There is a connection between the skeletal maturity in the permanent teeth. There are more enamel defects in permanent body and the dental maturity of the mandibular canines. teeth when compared to primary teeth. Whether this is caused by the maturity stage of the mucosa when enamel is formed is not • Bilaterality. known.  Normal tooth development occurs with great bilateral congruence. The mucosa, the ectomesenchyme, and the innervation are decisive for early tooth formation. For the ongoing formation of Similarities and differences in primary and the root, the innervation plays a lesser role. permanent dental development It can be difficult to distinguish between normal and patho­ In conclusion, the dental mucosa and the ectomesenchyme are logical development with regard to tooth morphology, eruption, local factors that play a determining role in the formation of the and resorption of the primary teeth. hard dental tissue in the primary as well as the permanent dentition. However, the location of the innervation is different Highlights and clinical relevance in the dentitions. This is due to jaw growth. The distance between the peripheral nerve ending and the developing tooth bud is • The peripheral nervous system plays a significant role in tooth different in the two dentitions. If the nerve does not quite reach development. the permanent tooth bud, tooth development can be delayed or absent. • The character of the oral epithelium decides the early tooth formation for both dentitions.

54 Chapter 4 Figure 4.19 A schematic overview of the entire maturation of the permanent maxillary canines and of the permanent mandibular canines in males. For each tooth, the maturity stage of the tooth root was evaluated. Crc, crown is complete; Ri, initiated root formation; R1/4, quarter root length; R1/2, half root length, R3/4, three-quarters root formation; Rc, root formation is complete. Ac, the apex is closed. Note that there is a difference between the amounts of time required for different teeth in the dentition to form from the initial stages to the final root length. Source: Svanholt and Kjær (2008). Reproduced with permission of Taylor and Francis Publishing Group.

Tooth development and tooth maturation from early prenatal to postnatal life 55 Figure 4.20 Similarities and differences in primary and permanent teeth. Chertkow S, Fatti P. The relationship between tooth mineralization and (Upper) The enamel is thicker in the permanent teeth when compared to early radiographic evidence of the ulnar sesamoid. Angle Orthod the primary teeth. (Lower left) The morphologies of the second primary 1979;4:282–288. molar and the first permanent molar are similar. (Lower right) Anthropological adult cranium demonstrating a fully erupted dentition (32 Christensen LR, Janas MS, Møllgård K, Kjær I. An immunocytochemical teeth) in the mandible and maxilla. There are only 20 teeth in the primary study of the innervation of developing human fetal teeth using protein dentition. gene product 9.5 (PGP 9.5). Arch Oral Biol 1993;38:1113–1120. • Dental maturity is seemingly primarily dependent on the Christensen LR, Kjær I, Græm N. Comparison of human dental and ectomesenchyme and to a lesser extent on innervation while craniofacial maturation on prenatal profile radiographs. Eur J Orthod the innervation plays a significant role from the stage where 1993;15:149–154. dentin and enamel begin to form. Christensen LR, Møllgård K, Kjær I, Janas MS. Immunocytochemical • The root lengths cannot be predicted accurately which is demonstration of nerve growth factor receptor (NGF-R) in develop­ problematic for the calculation of dental maturity. ing human fetal teeth. Anat Embryol 1993;188:247–255. Further reading Coutinho S, Buschang PH, Miranda F. Relationships between mandib­ ular canine calcification stages and skeletal maturity. Am J Dentofacial Andersen E, Skovgaard LT, Poulsen S, Kjær I. The influence of jaw Orthop 1993;3:262–268. innervation on the dental maturation pattern in the mandible. Orthod Craniofacial Res 2004;7:211–215. Daugaard S, Christensen IJ, Kjær I. Delayed dental maturity in dentitions with agenesis of manidbular second premolars. Orthod Craniofac Res Bath-Balogh M, Fehrenbach MJ. Illustrated dental embryology, histology, 2010;13:191–196. and anatomy, 2nd edn. Elsevier Saunders, Philadelphia, 2006. Haavikko K. The formation and the alveolar and clinical eruption of the Becktor K, Becktor JP, Karnes PS, Keller E. Craniofacial and dental permanent teeth. Suom Hammasläk Toim 1970;66:103–170. manifestations of Proteus syndrome: a case report. Cleft Palate Craniofac J 2002;39 (2):233–245. Haavikko K. Tooth formation age estimated on a few selected teeth. A simple method for clinical use. Proc Finn Dent Soc 1974;70:15–29. Becktor KB, Hansen BF, Nolting D, Kjær I. Spatiotemporal expression of NGFR during pre-natal human tooth development. Orthod Cranio­ Helm S, Seidler B. Timing of permanent tooth emergence in Danish facial Res 2002;5:85–89. children. Community Dent Oral Epidemiol 1974;2:122–129. Chertkow S. Tooth mineralization as an indicator of the pubertal growth Kjær I. Development of deciduous mandibular incisors related to spurt. Am J Orthod 1980;1:79–91. developmental stages in the mandible. Acta Odontol Scand 1980;38:257–262. Kjær I, Bagheri A. Prenatal development of the alveolar bone of human deciduous incisors and canines. J Dent Res 1994;78:667–72. Kock M, Nolting D, Kjær KW, Hansen BF, Kjær I. Immuno­ histochemical expression of p63 in human prenatal tooth primordia. Acta Odont Scand 2005;63:253–257. Larson EK, Cahill DR, Gorski JP, Marks SC Jr. The effect of removing the true dental follicle on premolar eruption in the dog. Arch Oral Biol 1994;39(4):271–275. Luukko K, Kvinnsland IH, Kettunen P. Tissue interactions in the regulation of axon pathfinding during tooth morphogenesis. Dev Dyn 2005;234:482–488. Lysell L, Magnusson B, Thilander B. Time and order of eruption of the primary teeth. A longitudinal study. Odont Rev 1962;13:217–234. Nordgarden H, Reintoft IM, Nolting D, Hansen BF, Kjær I. Craniofacial tissues including tooth buds in fetal hypohidrotic ectodermal dyspla­ sia. Oral Dis 2001;7:163–170. Sijona A, Luukko K, Kvinnsland IH, Kettunen P. Expression patterns of Sema3F, PlexinA4, -A3, Neuropilin1 and -2 in the postnatal mouse molar suggest roles in tooth innervation and organogenesis. Acta Odontol Scand 2012;70:140–148. Svanholt M, Kjær I. Developmental stages of permanent cannes, pre­ molars, and 2nd molars in 244 Danish children. Acta Odontol Scand 2008;66:342–350. Thesleff J. The genetic basis of tooth development and dental defects. Am J Med Genet 2006;140:2530–5. Uysal T, Sari Z, Ramoglu SI, Basciftci FA. Relationships between dental and skeletal maturity in Turkish subjects. Angle Orthod 2004;4:657–664. Wise GE, Yao S, Odgren PR, Pan F. CSF-1 regulation of osteoclasto­ genesis for tooth eruption. J Dent Res 2005;84(9):837–841.

CHAPTER 5 Periodontal membrane and peri-root sheet New studies have shown that there are great similarities between appear specifically in the outer later. These three tissue layers the periodontal membranes in the primary dentition and in the compose a structure called the peri-root sheet (Figure 5.3). permanent dentition but also that there are significant differ­ ences. In this chapter, we will look at the differences that set the Composition and function dentitions apart. Figure 5.1 is a histological section of a peri­ The peri-root sheet protects the root surface from root resorption odontal ligament. and is responsible for the reorganization of the periodontal membrane which is necessary when the eruptive motion of Periodontal membrane the tooth gradually guides the tooth out of the alveolar bone. Finally, it is presumed that these tissue layers initiate the osseous Characteristic for the primary dentition is that the roots resorb apposition which occurs during growth of the alveolar process. during development (Figure 5.2). This resorption can seemingly Hypothetically, it can be suggested that the peri-root sheet layer be provoked by eruption of an underlying permanent tooth or it provides attachment and stability of the Sharpey’s fibers, crossing can occur idiopathically (without known cause). What causes the periodontal membrane from the alveolar bone to the root of resorption to occur as a natural, developmental process in a the tooth. primary tooth is not known. The influence that the periodontal membrane has on root resorption is also not known. Other Some dentitions are more susceptible to resorption than questions not answered so far are when and how the membrane others, meaning that the three cell layers possibly can be affected forms. Question recently posed are “is there a difference in the in different ways by different diseases. An ectodermal disease periodontal membrane of the primary and permanent denti­ may change the morphology or composition of the Malassez’ tion?” and “could such a difference be the reason for the natural epithelium and also the mesodermal layer and the innervation resorption process of the primary dentition while the same layer may become deviated through different diseases. process is pathological in the permanent dentition?” To gain knowledge in this area, the periodontal membrane was studied Furthermore, it has been hypothesized that Malassez’ epithe­ on primary teeth and compared to that of permanent teeth. lial cell layer plays a role in periodontal regeneration. In the initial phase of human tooth formation, three different The peri-root sheet in the primary and tissues are essential for forming the tooth: ectodermal mucosa, permanent dentition ectomesenchyme, and innervation. It is suggested that these three tissue layers persist throughout the root formation both The goal of studying the periodontal membrane in primary teeth pre- and postnatally. was to analyze whether there is a peri-root sheet in the primary dentition and if so, whether it is comparable to the peri-root sheet Histological studies of the periodontal membrane reveal that of the permanent dentition. If there is a difference between the the tissue layers closest to the root are respectively composed of peri-root sheets, this may possibly answer the questions regard­ these cell layers: ectodermal (Malassez’ epithelium), ectomesen­ ing the difference between the two dentitions. The periodontal chyme (fibers), and innervation (see Figure 5.3). membrane in the primary teeth has received very little attention in the scientific literature. In recent studies by Bille et al., it has Peri-root sheet been shown that there is a peri-root sheet close to the primary root as well. Bille et al. demonstrated that there are three tissue Definition layers covering the primary tooth root in the same way as in the Closest to the permanent root is the innervation layer covered by permament tooth root but that there is a noteworthy difference a median layer of ectomesenchymal fibers, which in turn is especially in the outermost epithelial layer (Malassez’ tissue covered by a mucosal layer named Malassez’ tissue layer. Vessels layer) as this tissue layer appears to disintegrate in childhood (Figures 5.4 and 5.5). It could be suggested that it is the outermost Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 56

Periodontal membrane and peri-root sheet 57 Figure 5.1 Histological section of the human periodontal membrane. The tooth root can be seen to the left and the ossified alveolar process to the right. Alveolar crest fibers (A), horizontal fibers (H), oblique fibers (O). C, cementum; D, dentin; dcj, dentinocemental junction; B, bone (alveolar); V, vascular canals of bone. Source: Melfi and Alley (2000). Reproduced with permission of Lippincott Williams and Wilkins, a Wolters Kluwer company. layer that protects the tooth from resorption during the normal Figure 5.2 Radiograph of a mandibular, deciduous second molar where maturity process but this has not been proven. resorption of the roots occurs as a natural, developmental process. The permanent second premolar can be seen under the primary tooth. The The comparison between the two roots, the primary and the white arrow marks the periodontal membrane in the permanent premolar. permanent root (Figure 5.6), demonstrates that the structure and How and when this membrane arises is not known. The interrelationship composition of the tissue layers covering the roots are similar but between the periodontal membrane and the crown follicle marked by a that there is a main difference especially in the Malassez’ black arrow is another interesting subject area which has not been fully epithelium. This epithelium is nearly continuous in very young elucidated. children. In older children, the layer is made up of smaller structural units in the primary tooth. In the permanent dentition, be the cause of root changes. Similarly, it can be suggested that this epithelial layer has more prominent cell groups that form in mesodermal diseases as well as disease in the peripheral nervous rows in the permanent tooth. It is suggested that this epithelium system can cause pathological conditions in the membrane. This is important for protecting the root against resorption. It can is schematically illustrated in Figure 5.7. furthermore be suggested that the tissue covering the root is sparse in the primary dentition which could be an additional Clinical relevance reason for the natural process of primary tooth resorption. In the severe, dermatological condition called Papillon–Lefèvre, there is hyperkeratinization of skin on the palms of the Under pathological conditions, it can be hypothesized that a disease that affects the ectoderm generally throughout the body also affects the ectoderm in the peri-root sheet and that this can

58 Chapter 5 Figure 5.3 The peri-root sheet demonstrated histologically and schematically. Four histological sections (a–d) demonstrating the periodontal membrane close to the root (peri-root sheet). These sections are consecutive cuts from the same tissue block from an adolescent 16 years of age. The tooth embedded in the block was extracted due to orthodontic treatment. In each section, the root surface is to the right and the periodontal tissue to the left. (a) Alcian blue/van Gieson survey staining. It is not possible to distinguish either the structure or the location of the fibers, peripheral nerves, or the nature of the epithelial layer of Malassez which is demonstrated as a grayish line of cells parallel to the root surface and located in the center of the figure. (b) Immunohistochemical staining with antibody cytokeratin (wide spectrum screening) indicating the epithelial layer of Malassez as brown colored, not completely continuous, and parallel to the root surface. There are a few holes in the layer located in the center of the figure. (c) Immunohistochemical staining with antibody anti-vimentin showing a distinct difference in the amount as well as the orientation of the fibers in relation to the root surface and to the epithelial layer of Malassez. Between the epithelial layer of Malassez and the root surface there is a zone rich in brown fibers that are tightly packed with no specific orientation. On the other side of this epithelial layer of Malassez (to the left in the figure), there are fewer brown fibers oriented parallel to the root surface. (d) Immunohistochemical staining with antineuronal nuclei (NeuN) showing that the innervation (brown color) is located close to the root surface. Inserted over the histological sections is an illustration of the noncontinuous ectodermal tissue layer in the peri-root sheet. Source: Rincon et al. (2006). Reproduced with permission of John Wiley & Sons. (Right) A schematic drawing illustrating tissue sections in the peri-root sheet. The nerve tissue (yellow) closest to the root is followed by an ectomesenchymal tissue layer (green fibers) and then an outermost layer, the Malassez epithelium (red ovals). The pink lines indicate vessels close to the Malassez’ epithelium and in the ectomesenchymal layer. Innervation also appears sporadically in the Malassez’ epithelium. Figure 5.4 Two histological sections from a young child approximately hands. Furthermore, the teeth become exfoliated from the jaws three years of age demonstrating epithelial tissue in the peri-root sheet of a (Figure 5.8). This connection has never been understood but it is primary tooth. (a) The brown color demonstrates the epithelial tissue in believed that the ectoderm in the Malassez’ epithelium in the the oral mucosa (red arrow) and in the outer tissue layer of the peri-root peri-root sheet to which the root is attached is defective in sheet (black arrow). There is an artificial gap between the root to the right the same way as the skin on the palms of hands. This might and the soft tissue to the left. This gap illustrates how the extraction be the reason why the peri-root sheet is unable to retain the teeth. procedure can damage tissue and can make studies of the peri-root sheet difficult. (b) An enlargement of the section demonstrated in (a). The gap Other examples from everyday practice are highlighted in between the tooth (right) and the soft tissue (left) is marked by two stars. If Chapters 10 and 11. Here, it is demonstrated how the three layers the soft tissue is moved to the right so that the two stars cover each other, of the peri-root sheet affect eruption and resorption in different a complete peri-root sheet is formed. Note that the brown epithelial layer ways. (black arrow) in this young child has a nearly continuous appearance. This continuity lessens with age. Source: Bille et al. (2009). Reproduced with Highlights and clinical relevance permission of Taylor & Francis Publishing Group. • There are differences in the cell layers of the periodontal membrane close to the root surface in the primary and permanent dentition. It may be this difference that can par- tially explain the varying resorption susceptibility in the two dentitions. • The different cell layers in the peri-root sheet also explain different etiologies behind eruption deviations.

Periodontal membrane and peri-root sheet 59 Figure 5.5 Three consecutive histological sections from the same tissue block with a primary molar from a seven-year-old child. In each section, the root is to the right and the soft tissue to the left. The peri-root sheet appears close to the root surface. (a) Epithelial layer/Malassez’ epithelium. At this young age, only small islands of epithelial tissue remain (black arrows). (b) The brown color indicates the ectomesenchymal fiber layer located centrally in the peri-root sheet. (c) The brown color indicates the innervation layer covering the root. Source: Bille et al. (2009). Reproduced with permission of Taylor & Francis Publishing Group. Figure 5.6 Comparison of the peri-root sheet in the primary (left) and permanent (right) dentition. The figure illustrates the cellular components of the peri-root sheet. D, dentin; C, cement; yellow dots, innervation; green crosses, ectomesenchymal fibers; oblong red ovals, Malassez’ epithelium; pink, vessels. (Inset) A schematic drawing of a tooth to indicate the location of the peri-root sheet. Source: Bille et al. (2009). Reproduced with permission of Taylor & Francis Publishing Group.

60 Chapter 5 Figure 5.7 A schematic drawing of the peri-root sheet to the left. The three drawings to the right illustrate how different tissue layers in the peri-root sheet can be affected by disease/underdevelopment. Ecto – the Malassez’ epithelium is affected and reduced; meso – the mesoderm (ectomesenchyme) is affected and reduced; neuro – illustrates how the innermost innervation layer can be sparse when affected. Source: Kjær (2014). Reproduced with permission of Lippincott Williams and Wilkins, a Wolters Kluwer company. Figure 5.8 Orthopantomogram (OP) from a child eight years of age with Bille MLB, Notling D, Kjær I. Immunohistochemical studies of the Papillon–Lefèvre condition characterized by periodontitis and excessive periodontal membrane in primary teeth. Acta Odontol Scand keratin production in the palms and feet. The condition results in early 2009;67:382–387. loss of primary teeth and later, the loss of permanent teeth as seen on the OP. The condition can be inherited and is caused by the cathepsin C gene Bille MLB, Thomsen B, Kjær I. Apoptosis in the human periodontal in chromosome 11. membrane evaluated in primary and permanent teeth. Acta Odontol Scand 2011;69:385–388. • Deviations in the resorption of primary teeth may be inter­ related with abnormal resorption in the permanent dentition Bille MLB, Thomsen B, Kjær I. The inter-relation between epithelial cells because of the similarities in the peri-root sheets. of Malassez and vesels studied immunohistochemically in the peri­ odontal membrane of human primary and permanent teeth. Acta Further reading Odontol Scand 2012;70:109–113. Becktor KB, Nolting D, Becktor JP, Kjær I. Immunohistochemical Kjær I. Root resorption – focus on signs and symptoms of importance for localization of epithelial rests of Malassez in human periodontal avoiding root resorption during orthodontic treatment. Dental membrane. Eur J Orthod 2007;29:350–353. Hypotheses 2014;5 (2):47–52. Kjær I, Nolting D. The human periodontal membrane – focusing on the spatial interrelation between the epithelial layer of Malassez, fibers, and innervation. Acta Odontol Scand 2009;67:134–138. Lambrichts I, Creemers J, van Steenberghe D. Periodontal neural end­ ings intimately relate to epithelial rests of Malassez in humans. A light and electron microscope study. J Anat 1993;182:153–162. Melfi RC, Alley KE. Permar’s oral embryology and microscopic anatomy, 10th edn. Lippincott Williams & Wilkins, Philadelphia, 2000. Rincon JC, Young WG, Bartold PM. The epithelial cell rests of Malassez – a role in periodontal regeneration? J Periodontal Res 2006;41:245–252. Spouge JD. A new look at the rests of Malassez. A review of their embryological origin, anatomy, and possible role in periodontal health and disease. J Periodontol 1980;51:437–444.

CHAPTER 6 Normal tooth eruption and alveolar bone formation Tooth eruption mechanism and alveolar result of the crown follicle’s function and ability to create a bone formation pathway for eruption. It has been demonstrated experimentally that there is a difference between the upper part of the crown Normal tooth eruption in the primary and permanent teeth follicle and the lower, part of the follicle close to the root. The has two eruption phases: the preemergence phase and the upper part seems to be perforated and appears to be responsible postemergence phase. There are many different eruption for the osteoclastic and dentinoclastic breakdown of the over­ deviations that can occur in these phases. The eruption lying bone and, eventually, primary teeth. This is schematically problems can be understood from the development of the demonstrated in Figure 6.3 and histologically in Figure 6.4. The three tissue types that compose and guide the early tooth crown follicle’s ability to create the eruption pathway is shown in formation: the mucosa, the ectomesenchyme, and the inner­ Figure 6.5. The figure illustrates how the eruption path is created vation. These are the same tissue layers that later compose the even if there is not enough space for the succeeding tooth in peri-root sheet (Figure 6.1). the dental arch. Figures 6.2, 6.3, and 6.4 demonstrate that the lowermost apical part of the follicle has a location close to Preemergence phase the tooth germ. It has also been shown that this part of the The eruption starts when the crown has been formed and when follicle reacts positively with immunohistochemical staining for root formation begins. The eruption process is dependent on four innervation (see Figure 6.2). Thus the lower, more apical part of factors. the crown follicle is presumed to be active in the formation of the • Root membrane: a driving force from the apical area. alveolar bone during eruption. • Crown follicle: space for the eruption process created locally by Periodontal membrane the crown follicle. In the early stages of tooth formation, there is no periodontal • Periodontal membrane: the ability of the periodontal mem­ membrane. This membrane develops successively and is appar­ ently fully developed at the time of emergence. A detailed insight brane to reorganize in order to accommodate the tooth into the development and function of the periodontal membrane movement and to form the alveolar bone. during eruption has not yet been achieved. Immuno­ • Apical bone formation: a gradual, osseous filling of the cavity histochemical markings of apoptosis reveal a positive reaction left by the erupting tooth apically. in the periodontal layer close to the root in both the primary and permanent dentition in children with normally erupting teeth Root membrane (Figure 6.6). This reaction is the foundation for the theory of It is presumed that the force that pushes the tooth out of the continual reorganization of the periodontal membrane during alveolar bone arises from the root membrane which is highly eruption. Figure 6.7 shows a radiograph of a mandibular second innervated. It is presumed that this membrane acts like an premolar undergoing eruption. The crown follicle is marked “1,” exocrine acinus (Figure 6.2; see also Figure 4.5). In the endpiece the root membrane “2,” and the periodontal membrane “3.” The of an exocrine gland, a calcium (Ca++)-dependent potassium crown follicle initiates resorption of the second primary molar. (K+) transport protein is in place and plays a key role in secretion The permanent first molar has erupted. production. In the root membrane, there is a significant calcium accumulation which is demonstrated in Figure 4.7. This calcium Preemergence phase accumulation is the foundation for the root membrane Arrest in the preemergence eruption process may occur. Primary hypothesis. arrested eruption occurs before emergence when, for example, the crown follicle is unable to break down the overlying hard Crown follicle tissue. Arrested eruption can also occur due to deviations in the Destruction of the overlying hard tissue (bone and/or primary teeth) during eruption, making space for the erupting tooth, is a Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 61

62 Chapter 6 Figure 6.1 Schematic drawing of tooth formation and eruption from the early, prenatal period to the postnatal period. Red indicates the mucosa (surface ectoderm), green the ectomesenchyme, and yellow the innervation (neuroectoderm). Eruption before emergence of the oral mucosa is shown in the first three drawings from the left. In this preemergence period, the eruption process depends on the crown follicle (surface ectoderm), root membrane (innervation), and periodontal membrane (composed of all three tissue types and indicated by the fenestrated surface ectoderm – Malassez’ epithelium). The postemergence eruption process depends on the root membrane and the periodontal membrane and continues as long as there is growth in the jaw. Source: Kjær (2012). Reproduced with permission of Elsevier. ectomesenchyme such as brittle bone in the eruption path and due to innervation disturbances, for example by virus attack (for more information see Chapter 10). Postemergence phase In the postemergence phase, the crown follicle no longer has any influence. Thus, only three factors play a role in the continuous eruption that occurs through childhood. Figure 6.2 Histological section of a human tooth bud (GA 20 weeks) Figure 6.3 Schematic drawing indicating the perforated upper part of the immunohistochemically stained red with nerve growth factor receptor crown follicle (U), the lower part of the crown follicle (L), the developing (NGFR). The positive reactivity of the innervation appears in the root periodontal membrane (P), and the immature root membrane (R). The membrane (R) and in the lower part of the crown follicle (C). It also figure illustrates that the upper part of the crown follicle destroys the appears in the inner enamel epithelium (E) where hard, dental tissue has overlying bone by resorption (vertical arrows). not yet formed. A vertical, diagonal scratch from the microtome knife is visible through the tooth bud.

Normal tooth eruption and alveolar bone formation 63 Figure 6.4 Histological section from a human fetus GA 20 weeks. The section is stained with toluidine blue and demonstrates the upper, perforated part of the crown follicle (U), the lower part of the crown follicle (L), which closes in on the tooth germ apically, and the developing root membrane (R). • Root membrane: the driving force from the apical part of the Figure 6.6 The periodontal membrane (PDM) demonstrating an apoptotic tooth. reaction in the cell layer close to the root. C, cementum; D, dentin. (Upper) A histological section from an erupting human tooth • Periodontal membrane: the rebuilding of the periodontal immunohistochemically marked for apoptosis which appears brown (black membrane and ability to form alveolar bone. arrow). An island of Malassez’ epithelium is marked by a red arrow. (Lower) A schematic drawing of the apoptotic reaction (light brown dots) • Apical bone formation: the bone apically filling up the cavity close to the root in both the primary and permanent dentition. Note the left by the erupting tooth (Figure 6.8). outer markings of the Malassez’ epithelium (red). Source: Bille et al. (2011). Reproduced with permission of Taylor & Francis Publishing Group. The postemergence phase is recognized as the phase of clinical eruption until the tooth has reached occlusion. After this stage in development, continued eruption occurs until the jaw growth and appositional alveolar bone growth cease. In cases where an antagonist is lacking, the eruption process can continue in the postemergence phase. Figure 6.5 Dental radiograph from a child 12 years of age demonstrating a Apical bone formation nonerupted, ectopically located, mandibular second premolar. Regardless Apical bone formation occurs at the same time as the eruptive of the lack of space in the dental arch, the crown follicle of the second motion of the tooth (see Figure 6.8). It can be assumed that the premolar has created an eruption path (E). filling up of the alveolar bone with new bone tissue is also associated with the root membrane.

64 Chapter 6 Figure 6.7 Radiograph from a child 11 years of age demonstrating the preemergence stage of eruption of the mandibular premolars. In the second premolar, the crown follicle is marked “1,” the root membrane “2,” and the periodontal membrane “3.” The first permanent molar to the right has fully erupted. Alveolar bone formation Figure 6.8 Schematic drawing illustrating the postemergence stage of In growing children, there is a significant growth in the jaws and eruption of the permanent, left, mandibular first molar. (Upper) Drawings on the alveolar process which is closely coordinated with a from two superimposed cephalometric profile radiographs demonstrating continued eruption after emergence. two developmental stages of the first mandibular molar after emergence. Seven years of age is indicated by the red line and 15 years by the black These eruption patterns have been analyzed by Björk in his line. This figure demonstrates the significant eruption that occurs after the implant metal marker studies. Jaw drawings with erupting teeth tooth has reached occlusion with the upper molar at the age of seven. are demonstrated in Figure 6.9. In this postemergence stage, the (Lower) Schematic drawing illustrating the significant magnitude of the follicle has disappeared and is nonfunctional while the apical eruption that occurs after occlusion and until arrested growth. The membrane is the driving force for the eruption process as it is in drawing to the right is a hypothetical idea of what might happen if the jaw the preemergence phase. During this emergence phase, the bone did not grow by apposition along with the eruption process and if no periodontal membrane is constantly remodeled. Apoptotic new bone tissue was laid down in the empty alveolus. The drawing reactions along the root surface have been demonstrated in illustrates the magnitude of the movement and the changes that occur in the primary dentition as well as in the permanent dentition the jaw between seven and 15 years of age. during eruption in the postemergence period (see Figure 6.6). Again, there is a lack of knowledge concerning the reorganization completely. The periodical growth variations expressed by of the periodontal membrane during eruption. How the alveolar greater or lesser apposition are strikingly similar to the variations bone growth by apposition is coordinated with the eruption in eruption activity and to variation in body growth activity process has long been unknown, but the following can be (height). Postemergence eruption is not constant over the years, hypothesized from Figure 6.10. but follows closely the standard growth curve for body height. Figure 6.10 illustrates a plausible association between the erup­ Figure 6.10 demonstrates clearly the periodical apposition of tion intensity and the growth pattern of the alveolar ridge and bone tissue on the alveolar ridge. The amount of apposition body growth. varies and there appear to be “resting lines” where the growth by apposition is less. The histological section appears to be from a growth period in which the alveolar bone has not yet formed

Normal tooth eruption and alveolar bone formation 65 Figure 6.9 A cephalometric analysis of three stages of jaw growth and The biological explanation for the induction of alveolar eruption of the central incisor and first molar in the maxilla in the same bone growth during tooth eruption is not clear, but it has individual from age 11 years 10 months to 17 years 10 months. The been proposed that the lower, apical part of the crown follicle drawing illustrates the downward growth of the maxilla, the resorption of influencing the cervical periodontium has a special bone- the base of the nasal cavity, and the significant postemergence eruption building ability. It is well known that the lower part of the that occurs in adolescence. The growth and eruption in the first three-year follicle may persist in the cervical region and participate in the period (11 years 10 months to 14 years 11 months) is much greater than formation of the cervical part of the periodontal membrane. the changes seen in the second three-year period. This indicates the This theory is supported by the observations in Figure 6.10 interrelationship between growth intensity and eruption intensity. where the direction of the collagen fibers changes in the Source: Björk and Skieller (1972). Reproduced with permission of Elsevier. cervical part of the periodontal membrane. The directional change could indicate a close relationship between the cervical periodontal membrane and the alveolar process. The forma­ tion of the alveolar bone is closely connected to tooth eruption. It could be assumed that the upward movement of the tooth stretches the Sharpey’s fibers in the collum region. The stretched fibers connected to the periosteum of the bone may provoke bone apposition at the alveolar ridge. It is clear that the alveolar processes begin formation around the early tooth germs and that the processes grow with the development of the teeth and eruption (Figure 6.11). Patients with multiple agenesis (congenital missing teeth) do not have Figure 6.10 The interrelationship between the growth increment in body height (from Björk’s growth studies) and the growth increment on the alveolar process. (Left) Two male growth curves illustrating the total growth (upper) and the yearly incremental growth (lower) during puberty. Inserted between the two growth curves is a first molar with black horizontal lines in the alveolar process indicating the different magnitudes of growth of alveolar bone during puberty. (Right) Histological section of the human periodontal membrane. The tooth root can be seen to the left and the ossified alveolar process to the right. Source: Melfi and Alley (2000). Reproduced with permission of Lippincott Williams and Wilkins, a Wolters Kluwer company. Alveolar crest fibers (A), horizontal fibers (H), and oblique fibers (O). C, cementum; D, dentin; dcj, dentinocemental junction; B, bone (alveolar); V, vascular canals of bone. The blue arrow inserted on this figure indicates one of the several “resting lines” indicating the different increments in growth of the alveolar bone due to apposition during puberty.

66 Chapter 6 root sheet layers in the periodontal membrane function (see Chapter 5) is not known. The root membrane apparently functions as a glandular endpiece that creates pressure on the inside of the membrane, and thus helps to push the tooth up and out during the eruption process. A problem that is not understood is how the periodontal membrane accommodates during eruption and after emergence. It has been shown that apoptosis occurs close to the root surface during this continual reorganization process. What is not known is when the Sharpey’s fibers are formed and how they are organized/reorganized during the eruption process. Tooth eruption and jaw growth Figure 6.11 Frontal view of the cranium of a normally developing child The jaws have different morphologies and different skeletal between 0 and six months of age. Note the absence of the alveolar growth patterns. These patterns are normally analyzed ceph­ processes, the diminutive apertura periformis and the symphysis menti alometrically. The general jaw growth directions are down­ axially in the mandible. The dimensions of the cranium at this young age ward and forward. If these patterns differ significantly, then seem to be disproportional due to the underdevelopment of the jaws and the position of the teeth and the occlusion is influenced by the the alveolar bone. jaw growth. an alveolar process in the regions where teeth are missing The postemergence eruption of the dentition influences the (Figure 6.12). growth of the alveolar bone. From cephalometric studies, it is well known that the alveolar bone and the inclination of the teeth can The root membrane closes gradually in accordance with the compensate for abnormal skeletal jaw growth. It has been closure of the apex of the root. This might influence the eruption hypothesized that this compensatory and sometimes dysplastic ability in the later stages of dental maturation. growth of the alveolar process is regulated by innervation (Figure 6.13). Summary of eruption theory and alveolar bone Jaw size and space formation Jaw size and space are also factors of importance for tooth Thus the different parts of the tooth have different functions. In eruption. In the prenatal period, the teeth are very small and short, the crown follicle’s function is to create a pathway for the the developing jaw must be able to create enough space for the tooth during eruption and to protect the tooth during enamel growing primary teeth. This space is made in the mandible by and dentin formation. Furthermore, the apical part (root mem­ growth of the symphysis menti and by resorption anteriorly on brane) has a driving force function and a bone-building function the mandibular ramus. At the same time, there is apposition on for filling the cavity left by the erupting tooth. How the three peri­ the posterior edge of the mandibular ramus (Figure 6.14). Figure 6.12 Orthopantomogram (OP) and profile radiograph from a child eight years of age with multiple agenesis and ectodermal dysplasia. The radiographs display the absence of the alveolar bone in the regions without tooth germs (stars).

Normal tooth eruption and alveolar bone formation 67 Figure 6.13 Illustration of the peripheral nerves to the maxilla and mandible. The innervation influences the eruption of the teeth in the different innervation fields but might also influence the alveolar bone growth in these regions. (Left) The innervation paths from the trigeminal ganglion to the maxilla and mandible. (Right) Schematic drawing of an orthopantomogram illustrating the innervation of the different tooth groups. Incisors are marked I (red), canine premolars C/P (green), and molars M (blue). Source: Kjær (1998). Reproduced with permission of Taylor & Francis Publishing Group. It is assumed that the incisors, in accordance with the growing in development (see Figures 1.29 and 8.4). This might be a sign of size of the teeth, migrate medially towards the symphysis menti transverse tooth migration. Also the first primary molar might while the molars migrate posteriorly (see Figure 6.14). The migrate transversely during jaw growth. canines remain stationary and increase in size by outgrowth in a transverse, buccal direction. It has been shown that the In the maxilla, space is made for the growing incisors by canine does not have an alveolar wall laterally at this early stage growth of the intermaxillary suture and by remodeling of the Figure 6.14 (Left) Anthropological, human mandible (left side) in the late, Figure 6.15 Anthropological, normal, human cranium illustrating stable prenatal period demonstrating the alveoli for the primary teeth and the areas in the jaw (squares). The size of the teeth within these regions is first permanent molars in their initial stages. (Right) Drawing of a human approximately the same in both the primary and permanent dentition. The hemimandible (left side). Black dots are present in the white alveoli teeth anterior to this region migrate anteriorly to create space while the indicating the approximate starting point of tooth formation. The arrows teeth posteriorly located are dependent on growth in the jaws for space. mark the direction of tooth migration during maturation. The incisors migrate anteriorly (lower arrow) and gain space synchronously with the growth of the symphysis menti. The primary molars migrate posteriorly (two upper arrows). The canine, indicated by a second white ring, has a stable position in the jaw. During maturation, the tooth bud becomes larger and migrates slightly outward buccally.

68 Chapter 6 Figure 6.17 The dentition of a six-year-old female demonstrating spreading between the primary incisors which indicates that the shedding time for the primary teeth is approaching. The migration of the broader, permanent incisors and axial jaw growth have created this extra space. Figure 6.16 Anthropological, normal, human cranium demonstrating the by the lateral mandibular incisors and the maxillary incisors. The stable areas also seen in Figure 6.15. The axial midline of the maxilla and first primary molars and canines in both jaws appear in the mandible is marked with a yellow line. Space for the molars in the following eruption period, and finally the second primary molars mandible depends on the resorption of the ramus mandibulae and space appear at approximately age 2½ years (Figure 6.18). for the molars in the maxilla depends on growth in the transpalatine suture (see inset from figure 1.25 and Chapter 1). Space for the incisors in There are many reports on eruption times in the permanent the mandible depends on growth in the symphysis menti and in the dentition. There are great individual and gender differences in maxilla it depends on growth in the interincisal suture and reorganization eruption time and the duration of tooth maturation (see activity in the incisive fissure. Figure 4.19) and eruption also varies between the teeth in any given individual. In this book, we focus on the sequence of incisal fissure. The incisors migrate medially. Through growth in eruption. the transpalatine suture, followed by apposition on the tuber maxillae, space is created for the molars. The growing molars The eruption of the permanent dentition begins with the migrate posteriorly (Figures 6.15 and 6.16). mandibular central incisors (Figure 6.19) followed by the mandibular lateral incisors. This pattern is comparable to After birth, the growth pattern in the jaws remains the same the eruption sequence in the primary dentition and may be until early childhood when the width of the incisors reaches a caused by the close relationship to the symphysis menti which maximum. At approximately 1–2 years of age, the symphysis is richly vascularized, and the available space due to bone menti closes. The incisal fissure closes or stops functioning some growth. years later. The intermaxillary suture continues to grow until the permanent maxillary central incisors have erupted. At this time, The next permanent teeth to erupt are the maxillary central there occurs a spreading of the primary dentition which indicates incisors and maxillary lateral incisors, which again is comparable that the shedding time for the primary incisors is approaching to the eruption sequence of the primary dentition. The bone (Figure 6.17). formation and vascularization in the incisal fissure seems to create space for the incisors and thereby influences this eruption In conclusion, eruption is not only dependent on the local, pattern. The canines and the premolars erupt after the incisors biological process around the teeth, but also on the skeletal size and first molars (Figure 6.20). and growth of the jaws, the ability of the developing teeth to migrate, the growth of the alveolar process, and also on the Eruption of the first molars occurs in concurrence with but general body growth (height). independently of the incisors (Figure 6.21). In a large study on the eruption times of 24.000 children, it was demonstrated that the Eruption sequences in the primary and eruption times of the incisors were mutually interrelated, but permanent dentition were not interrelated to the eruption times of the molars (see Figure 6.21). This was true for both jaws. The first primary teeth to erupt are the mandibular central incisors at the age of 6–12 months. These incisors are followed To understand the sequences in tooth eruption, it is important to recall the innervation diagram shown in Figure 6.13 from which it appears that different tooth groups in the different fields are innervated by different nerve branches. As the innervation seems to be responsible for the driving force behind eruption, it is logical that teeth within the same innervation field are mutually coordinated while eruption of teeth in different fields is not

Normal tooth eruption and alveolar bone formation 69 Figure 6.19 Sequence of eruption of the permanent incisors. (Upper) As in the primary dentition, the mandibular incisors are the first teeth to erupt in the permanent dentition. They often appear orally to the primary incisors. (Lower) In this six-year-old child, the permanent, mandibular, central incisors have erupted and the permanent, maxillary, right, central incisor has just emerged. molars also erupt. The space for the second molars in the mandible is created by resorption of the anterior edge of the mandibular ramus while the space for the second molars in the maxilla is created by growth in the transverse palatine suture following by apposition at the tuber maxillae (see Figure 6.16). Figure 6.18 Eruption of the primary dentition. (Upper) The mandibular central incisors are the first teeth to erupt at approximately 6–9 months of age. (Center) The mandibular central incisors are followed by the maxillary central incisors and laterals. (Lower) A fully erupted primary maxillary dentition in the occlusal view at age 2½ years. coordinated. The eruption times of the permanent canines and Figure 6.20 Section from an orthopantomogram (OP) demonstrating premolars are interrelated (Figure 6.22) but occur several years tooth development and eruption of the permanent teeth near puberty. The after the incisors and first molars. The space for the erupting first permanent molar and the canine have erupted, the first premolar has permanent canines and premolars is nearly the same space that is nearly reached the occlusal level and the second premolar has begun available for the primary canines and molars (see Figure 6.15). In resorption of the overlying second primary molar. The second permanent the period when the canines and premolars erupt, the second molar has reached a stage of root development indicating that the tooth will soon be ready to emerge.

70 Chapter 6 Figure 6.21 The correlation between tooth eruption in the right and left sides of the mandible and the maxilla in boys and girls. There appears to be a close, bilateral correlation between eruption times of individual teeth. Furthermore, the graphs illustrate a correlation between eruption times of teeth within fields but not between fields. Source: Parner et al. (2002). Reproduced with permission of Sage Publications. In conclusion, the sequence in which the teeth erupt is closely just a single tooth, an entire tooth group (craniofacial fields) or an correlated with jaw growth and is influenced by the innervation entire dentition seemingly without boundaries. of the jaw fields. • Eruption retardation of a single tooth may be due to trauma, an Bilaterality obstruction in the eruption path (e.g. supernumerary tooth) or There is general congruency between the eruption patterns in the a malpositioning of the tooth (Figure 6.23). right and left sides of the jaws (Figure 6.21). Meanwhile, differ­ • Eruption retardation of a tooth group (field) may be seen in ences may arise often related to disruptions in the eruption association with arrested eruption due to innervation devia­ process of single teeth or several teeth in a developmental field. tions within specific craniofacial fields or with local dysplasia of Such cases will be discussed in Chapter 10. the ectomesenchyme (Figure 6.24) (see Chapter 10 for more information). Early and late eruption • General eruption retardation is seen mostly in association with In a pedodontic practice, it is important to be aware of possible syndromes affecting the ectomesenchyme but also sometimes early and late eruption patterns. An eruption problem can affect in seemingly normally developing children (Figure 6.25). There is no clear explanation of this at present.

Normal tooth eruption and alveolar bone formation 71 Figure 6.22 A profile radiograph colored according to different craniofacial fields with different embryological origins. The interrelationship between the teeth and jaw bone is demonstrated in the maxillary field (red) where the canine and two premolars are drawn. In the maxillary field, there is an association between the dentition and the jaw bone as well as between the individual teeth. Source: Caspersen et al. (2010). Reproduced with permission of Dental Anthropology. Figure 6.23 A dental film illustrating an ectopic, maxillary, second Figure 6.25 Three orthopantomograms from children with general late premolar with the crown pointing cranially. This is an example of an eruption of the permanent dentition. (Upper) Ten-year-old male. The first eruption problem regarding just a single tooth in the dentition. permanent molars in the right side have not penetrated the mucosa and also the incisors are late. This case is believed to be severely late but still within normal range. (Center) Ten-year-old male. The incisors have not erupted. The radiograph is very opaque which might indicate a possible bone dysplasia condition. The patient was referred to a specialist in endocrinology but no diagnosis was made. (Lower) Fifteen-year-old male. This radiograph demonstrates late shedding of the primary canines and molars and late eruption of the second permanent molars. This case has a phenotype similar to the one seen in IgE (immunoglobulin E) syndrome patients, but this patient did not test positive for the syndrome. Treatment involves extraction of all primary teeth (see Chapter 10). Highlights and clinical relevance Figure 6.24 Orthopantomogram of a nine-year-old boy where three • Preemergence eruption depends on the function of crown permanent first molars have erupted. The nonerupted first molar is in the follicle and the root membrane. maxillary right side. The molar is late in development and might be arrested in eruption. The second molar is not present. This is a pathological • Postemergence eruption depends on the function of the peri­ condition localized to the molar field in the dentition (see Chapter 10). odontal membrane and the root membrane. • The sequence in which the teeth erupt is closely correlated with the growth of the jaws and with the innervation of jaw fields. • The developmental fields in both the maxilla and the mandible function independently of one another regarding tooth eruption.

72 Chapter 6 • When the first permanent molar does not erupt at the same Haavikko K. The formation and the alveolar and clinical eruption of time as the incisors, this is not an error despite the common permanent teeth. Suomen Hammaslääkäriseuran Toimituksia belief that these teeth erupt simultaneously. The difference in 1970;66 (3):103–170. eruption is caused by the different innervations. Helm S, Seidler B. Timing of permanent tooth emergence in Danish • Eruption is closely interrelated with jaw growth and body children. Community Dent Oral Epidemiol 1974;2 (3):122–129. growth. Kjær I. Prenatal traces of aberrant neurofacial growth. Acta Odontol Further reading Scand 1998;56:326–330. Bille MLB, Thomsen B, Kjær I. Apoptosis in the human periodontal Kjær I. New diagnostics of the dentition on panoramic radiographs – membrane evaluated in primary and permanent teeth. Acta Odontol focusing on the peripheral nervous system as an important etiological Scand 2011;69:385–388. factor behind dental anomalies. Orthodont Waves 2012;71:1–16. Björk A, Skieller V. Facial development and tooth eruption: an implant Kjær I. Mechanism of human tooth eruption: Review article including a study at the age of puberty. Am J Orthod 1972;62:339–383. new theory for future studies on the eruption process. Scientifica 2014; ID 341905. Björk A, Skieller V. Growth of the maxilla in three dimensions as revealed radiographically by the implant method. Br J Orthod Lysell L, Magnusson B, Thilander B. Time and order of eruption of the 1977;4:53–64. primary teeth. A longitudinal study. Odontologisk Revy 1962;13:217–234. Björk A, Skieller V. Normal and abnormal growth of the mandible. A synthesis of longitudinal cephalometric implant studies over a period Marks Jr. SC, Schroeder HE. Tooth eruption: theories and facts. Anat Rec of 25 years. Eur J Orthod 1983;5 (1):1–46. 1996;245 (2):374–393. Caspersen L, Christensen IJ, Kjær I. Maxillary canine ectopia and Melfi RC, Alley KE, Permar’s oral embryology and microscopic anatomy, maxillary canine-premolar transposition are associated with devia­ 10th edn. Lippincott Williams & Wilkins, Philadelphia, 2000. tions in the maxilla. Dental Anthropol 2010;23:37–41. Parner ET, Heidmann JM, Kjær I, Væth M, Poulsen S. Biological interpretation of the correlation of emergence times of permanent teeth. J Dent Res 2002;81:451–454. Wise GE, King GJ. Mechanisms of tooth eruption and orthodontic tooth movement. J Dent Res 2008;87 (5):414–434.

CHAPTER 7 Etiology-based diagnostics: methods and classification of abnormal development Why use etiology-based diagnostics? deviation must be assessed. It is important to consider heredity and genetics if possible. This chapter will focus on the classifica­ Why are etiology-based diagnostic methods important for the tions of disorders leading to abnormal form and/or structure of evaluation of dentitions and crania? This question, which is the an organism or its parts. foundational concept for the book, requires knowledge of normal tissue relationships – much of which has been discussed in According to Spranger et al.’s classification (1982), a deviation Chapters 1–6. Chapter 7 is a borderline chapter between the in form/shape can be classified and defined as a malformation, normal development presented in previous chapters and the disruption, deformation or dysplasia. This is schematically pathological development of the following chapters. depicted in Figure 7.10 and explained in the following text. Insight into normal development is a prerequisite for creating Malformation an etiological understanding of where, when, and how a patho­ A malformation is a morphological defect of an organ, part of an logical condition can arise. Different etiologies also play a organ, or larger region of the body resulting from an intrinsically significant role in treatment planning. abnormal developmental process. Some dental and craniofacial conditions appear to be similar Intrinsic means that the developmental potential of the organ but have different etiologies and separate treatment approaches is abnormal. This suggests that from fertilization, the organ never must therefore be considered. Figures 7.1, 7.2, 7.3, 7.4, and 7.5 had a chance to develop normally. demonstrate various aspects of deviant dental development and exemplify the necessity of etiology-based diagnostics. The left Malformation is illustrated schematically in Figure 7.10. The mandibular tooth segments have been chosen to demonstrate early formation of the organ is deviant (red triangle) and it stays different conditions with varying etiologies and therefore varying malformed throughout prenatal and postnatal life. When regis­ treatment options. This is an overview of some aspects in deviant tered in the clinic, a red triangle indicates the malformation. dental development in just one part of the dentition. In the Malformation of the dentition is exemplified by a macrodontic, craniofacial region, the sella turcica serves as a key structure for permanent, maxillary incisor and a cleft palate in the cranium demonstrating the importance of etiology-based diagnostics in shown in Figure 7.11. the cranium (Figures 7.6, 7.7, 7.8, and 7.9). The etiology behind these examples of seemingly abnormal development will be Malformations can also be field defects. See Chapter 3 for a explained in later chapters as indicated. definition of developmental fields. Malformation of a single structure can also occur. Definitions of key words Disruption Etiology Disruption is a morphological defect of an organ, part of an Etiology means “the study of causes.” The term refers to “the organ, or a larger region of the body resulting from the extrinsic cause of abnormal structure, form or function” while “patho­ breakdown of or an interference with an originally normal genesis refers to the mechanism leading to the abnormal struc­ process. ture, form or function” (Spranger et al. 1982). Disruption is illustrated schematically in Figure 7.10. The early Deviations in the dentition and cranium are traditionally formation of the organ is normal (green square) but the normal diagnosed based on anamnestic reports, clinical observations developmental process is interrupted either prenatally or post­ of the face and body, as well as clinical and radiographic studies in natally, resulting in an abnormal organ postnatally (red triangle). the cranial region. In etiology-based diagnostics, the cause of Disruption of the dentition is exemplified in Figure 7.12 dem­ onstrating a dentition with short and narrow roots caused by chemotherapy. Trauma of the mandible is an example of a disruption affecting the cranium (Figure 7.12). Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 73

74 Chapter 7 Figure 7.1 Radiograph of a first, permanent, mandibular molar (within the Figure 7.4 Radiograph from the left side of the mandible demonstrating a red ring) which appears taurodontic. The etiology is a dysfunctional first permanent molar without a distal root. The etiology behind this epithelial sheet of Hertvig. abnormal development is disturbance by chemotherapy at a very young age. Figure 7.2 Radiograph of a first, permanent, mandibular molar (within the Deformation red ring). This molar has formerly been at the normal occlusal level but A deformation is an abnormal form, shape or position of a part of now appears significantly below this level. The etiology is believed to be a a body caused by mechanical forces. defect in the periodontal membrane resulting in ankylosis. Deformation is schematically illustrated in Figure 7.10. The early formation of the organ is normal (green square) but during prenatal or postnatal development, the organ is exposed to unusual mechanical forces resulting in an abnormal form or shape (red triangle). Deformations in dental and craniofacial diagnostics are few. A supernumerary tooth can deform a neighboring tooth (Figure 7.13). Deformation in the dentition is extremely rare but can be seen when an ectopic canine exerts a force on an incisor root that is still under development. Deformation in the cranium is often a result of a narrow birth canal, reduction of interuterine space, and/or the position of the fetus. Another example is the sleeping position of the newborn, which can influence the shape of the cranium. Some cultures practice artificial deformation and this is demonstrated in Figure 7.13. Figure 7.3 Radiograph demonstrating how a cyst can displace a second, Figure 7.5 Radiograph of molars and premolars in the left side of the mandibular molar tooth bud (red ring). The cyst deforms the dentition. mandible demonstrating abnormal root morphology. The first permanent molar is seen within the red ring. The etiology is dentinogenesis imperfecta.

Etiology-based diagnostics 75 Figure 7.6 Sections from profile radiographs demonstrating malformations of the sella turcica. (Left) A malformed sella turcica with a broad and bulging posterior wall. Anamnesis revealed that the patient was deaf which could indicate a congenital malformation. (Right) The anterior wall of the sella is slanted forward. Anamnesis revealed that the patient had a congenital urinary bladder malformation. Congenital malformations of the bladder and kidneys are sometimes associated with this particular malformation of the sella. Dysplasia How to use this nomenclature A dysplasia is an abnormal organization of cells into tissue(s) and When observing a patient with a structure that is abnormal in its morphological result(s). In other words, a dysplasia is the form and shape, the patient is regarded as a red triangle (see process and consequence of dyshistogenesis. Figure 7.10) which can have four different etiologies. The different etiologies mean that there are several different treat­ This means, for instance, that osteogenesis imperfecta belongs ment possibilities as well as different guidance for the patient and in the dysplasia classification because the abnormality is caused family regarding recurrence. by a defect in the histological bone formation process. Dysplastic processes are frequently not confined to single organs. The previous six chapters concern normal development sup­ ported by examples of pathological cases. The following chapters Dysplasia is illustrated schematically in Figure 7.10. The early concern abnormal development. The classification of disorders formation of the organ is dysplastic (red circle) and during presented in this chapter will be used for the etiology-based development the dyshistogenesis continues (small red circles), diagnostics that will be presented throughout the rest of the book. resulting in an abnormal organ/tissue (red triangle). Dysplasia of the dentition is illustrated in Figure 7.14, displaying permanent teeth in a case with dentin dysplasia. Dysplasia in cranial development is seen in osteogenesis imperfecta (see Figure 7.14). Figure 7.7 Section from a profile radiograph demonstrating a malformed Figure 7.8 Section from a profile radiograph demonstrating a malformed sella turcica. The sella is larger and has a more circular formation than sella turcica. The patient was referred to a neruologist who suggested a normal. Neuroradiographic scans diagnosed a partially “empty sella.” neuroradiographic scanning. The results were inconclusive.

76 Chapter 7 Figure 7.9 Section from a profile radiograph demonstrating a malformed sella turcica with an overlying bridge of bone tissue. The patient is retarded in growth and in dental maturity. There might be an association between the delayed growth and the malformation of the sella. Figure 7.11 Examples of congenital malformations in the dentition and in the craniofacial skeleton. (Upper) A clinical photograph and a radiograph of the same patient demonstrating a broad crown and a broad, malformed root. (Lower) A dental cast displaying bilateral, complete cleft lip and palate malformation from the occlusal view in a newborn. Figure 7.10 A schematic drawing illustrating the classification of In this book, focus is specifically placed on malformations, abnormality in development. Green square, normal development disruptions, and dysplasia. One aim is to describe (in cases where prenatally; green triangle, normal development postnatally; red triangle, possible) the different conditions from a prenatal stage and to abnormality in morphology pre- and postnatally; red circle, dysplastic continue with the diagnostics postnatally. Accordingly, the tooth/cell formation which continues from pre- to postnatal life; black observations in this book are based on embryological and lightning bolts, moment of disruptive disturbance pre- and postnatally; fetal-pathological results. Both malformations and disruptions black crescent, moment of deformation disturbance pre- and postnatally. will be related to developmental fields. The terms “disorder,” Source: Spranger et al. (1982). Reproduced with permission of Elsevier. “deviation,” and “anomaly” all describe an abnormal form and shape. Every time a deviation in the dentition is analyzed, it should be determined (if possible) whether it is a normal varia­ tion, a malformation, a disruption or a dysplastic condition. Furthermore, it should be questioned whether it is the ectoderm, the mesoderm or possibly the innervation that can explain the condition. Other key words Hypoplasia and hyperplasia Hypoplasia and hyperplasia “refer to the underdevelopment and overdevelopment of an organism, organ or tissue resulting respectively from a decreased or increased number of cells” (Spranger et al. 1982).

Etiology-based diagnostics 77 to the absence of a part of the body resulting from the failure of a present anlage to develop” (Spranger et al. 1982). Polytopic field defect This field defect is a pattern of anomalies derived from the disturbance of a single developmental field. An example is holoprosencephaly (discussed in Chapter 13). Sequence A sequence is a pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor. An example is myelomeningoceles (discussed in Chapter 13). Syndrome A syndrome is a pattern of multiple anomalies thought to be pathogenetically related and not known to represent a single sequence or a polytopic field defect. An example is Down’s syndrome (discussed in Chapter 13). Analyzing the dentition, oral cavity, and cranium: practical guide Anamnestic record In an anamnestic record, focus is placed on the general health and body development of an individual, as well as the specific disease or abnormality from which the patient suffers. Treatment and medical care are also important to note. General health and body development In the analysis of abnormal development in the dentition and/or cranium, it is important to produce thorough anamnestic records including former diseases, virus attacks, and general health status. Of importance are also remarks about body height, body proportions, endocrine development, skin and nail appear­ ance, lung function, glandular functions, and possible allergies. Furthermore, treatment of general diseases and types and periods of medicinal intake should be evaluated and noted. Figure 7.12 Examples of disruption seen in the dentition and in the Analysis of the face and head/cranium craniofacial skeleton. (Upper) Disruption in root formation of the Special attention is given to the following. mandibular premolars and second molar caused by chemotherapy. • Eyes and interocular distance. Vision is important to mea­ (Lower) Frontal radiograph illustrating mandibular asymmetry due to a disruptive fracture in the right side of the mandible at the age of seven sure. Patients with craniofacial disorders often have impaired years. Attempted treatments were not successful in correcting the midline. vision. Regardless of whether the interocular distance is too narrow (hypotelorism), as in single median maxillary central Hypotrophy and hypertrophy incisor (SMMCI), or too wide (hypertelorism) (Figure 7.15), Hypotrophy and hypertrophy “refer respectively to a decrease this is an indication of a deviation in the frontonasal segment and increase in size of cells, tissues or organs” (Spranger et al. and possibly the frontal part of the brain. 1982). • Nose and sense of smell. A tubular nose and a short ala nasi are examples of a frontonasal change which can be observed in Agenesis and aplasia SMMCI syndrome and Down’s syndrome. Diminished or “The term agenesis connotes the absence of a part of the body absent sense of smell as seen in Kallmann’s syndrome (see caused by an absent anlage (primordium) whereas aplasia refers Chapter 2) is associated with abnormal development in the nasal cavity.

78 Chapter 7 Figure 7.13 Examples of deformation in the dentition and cranium. (Left) A section from an orthopantomogram illustrating the permanent maxillary incisors. The left central incisor has a curved root which has been deformed due to a supernumerary tooth located in the root region. The extra tooth bud has been removed. (Right) An anthropological, deformed theca cranii due to binding of the head in childhood. Such deformations are performed by cultures for aesthetic reasons. (Inset) A drawing of how this binding can be accomplished. • Ears and hearing ability. Hearing loss and reduced hearing ability can occur in patients with craniofacial deviations. Ear morphology, placement, and orientation vary in different syndromes. A summary of this is given by Carey (2009). • Extraoral appearance, including lips. The philtrum and the lip contour differ among other features in cases with SMMCI, phenylketoneuria, and fetal alcohol syndrome (see Chapters 13 and 14). • Neck. Broad neck has been observed in chromosomal devia­ tions such as Turner’s syndrome and Down’s syndrome. • Hair, nails, eyebrows, skin pigmentation, and glands. Devi­ ations such as thin, absent or very light hair indicate an ectodermal etiology for some dental deviations. The ectoder­ mal origin of the hair and glands can be documented through histology (see Figure 4.3). The skin and its pigmentation are Figure 7.14 Examples of dysplasia in the dentition and in the craniofacial Figure 7.15 Sections from frontal radiographs demonstrating interocular skeleton. (Upper) An orthopantomogram from an adult with distances. The interocular distance indicates the development of the dentinogenesis imperfecta. Note the absence of pulp chambers in the teeth. frontonasal field. (Upper) Close-set eyes or hypotelorism observed in the (Lower) A profile radiograph from a child with bone dysplasia. The sutural SMMCI condition in which the frontonasal craniofacial field is reduced. bone growth is abnormal. (Lower) Increased interocular distance or hypertelorism in frontonasal dysplasia with a cleft in the nose.

Etiology-based diagnostics 79 Figure 7.16 Orthopantomogram from a child, with red markings Figure 7.17 Orthopantomogram with a drawn-in innervation diagram. indicating the areas in which the ectodermal tissue plays a role in tooth Each jaw field has a separate innervation. The fields are not only marked development. These areas are the inner enamel epithelium within the with innervation but also with the ectomesenchyme from the neural crest. crown, the peri-root sheet along the root, and the crown follicle in In each jaw, three bilateral fields are observed. In the maxilla, these fields nonerupted teeth. An ectodermal deviation can be the cause of a are the palatine fields (blue, molar field), the maxillary fields (green, malformed crown and/or root. Furthermore, the crown follicle may not be canine/premolar field), and the incisal fields (red, incisor field) which able to perform resorption of overlying bone and primary tooth during the appear as one field with bilateral innervation. In the mandible, the fields eruption phase due to the epithelial deficit. Abnormal development of the are still not named as in the maxilla but are indicated by the different epithelial lining in the root (Malassez’ epithelial islands) can affect the nerve branches in the mandibular channel (see Chapter 2). These are ability of the periodontal membrane to reorganize during tooth eruption. innervations to the molars, canine/premolars, and incisors. This diagram is Whether this epithelial lining also affects orthodontic tooth movement is used to determine the etiology behind various dental abnormalities in the still unknown. Meanwhile, it is known that the epithelium plays a role in clinic. The questions to ask are: Is the deviation restricted to a field? If yes, the protection of the root against root resorption. Dentitions with is the etiology abnormal innervation or abnormal ectomesenchyme? If not malformed teeth with epithelial etiology such as taurodontism and restricted to a field, the deviation might still be restricted to two invaginations are more susceptible to root resorption during orthodontic neighboring fields. These are aspects that will be elucidated in the treatment than dentitions without these deviations. Source: Kjær (2012). following chapters and visualized in Figure 7.18. Source: Kjær (2012). Reproduced with permission of Elsevier. Reproduced with permission of Elsevier. also indicators of ectodermal etiology, as well as the nails (see epithelium). The origin and the importance of the cementum are Figure 6.7). still being discussed. • Head/cranium. If cranial malformation is suspected, a profile radiograph and/or a frontal radiograph and/or a 3D exposure In the same way, an orthopantomogram can be used to analyze of the cranium are recommended. When these images are whether the etiological explanation behind the abnormal tooth analyzed, a schematic overview of the cranial fields, as shown in development is an innervation deviation or an ectomesenchymal Chapter 3, should be taken into account. deviation. This could be highlighted in tooth formation, tooth eruption or tooth resorption. This is illustrated in Figure 7.17 in Analysis of the oral cavity and teeth which the innervation pathways and ectomesenchyme mark the Former treatment and medication for oral diseases must be fields in the dental arch and in the jaw bones. recorded. Glands and saliva should be evaluated and the condi­ tion of caries and periodontal status should be noted. Possible Severe dental deviations are often limited to a field. The infection should also be recorded. Structurally, it is important to etiology could be a virus attack disturbing the innervation or be aware of the tongue’s volume and position, the incisive a localized defect in the ectomesenchyme. An example is dem­ papillae, the palatal mucosa and the superior labial frenulum onstrated in Figure 7.18. and other labial frenulae in the oral vestibulum. Figure 7.18 Orthopantomogram demonstrating abnormal development In the teeth, color and structure are important to notice localized to the right, maxillary, canine/premolar field. In this field, late clinically. Radiographically, it is recommended to take a dental development and pathological development of the teeth occur. The etiology is film or an orthopantomogram or a 3D exposure. These radio­ abnormal ectomesenchyme caused by segmental odontomaxillary dysplasia. graphs can be analyzed regarding dental maturity and also regarding development of dental and jaw deviations. If there are developmental deviations, the images are evaluated accord­ ing to the diagram of jaw innervation and jaw fields (see Figure 3.21). These fields are assessed for relationship to the structures with ectodermal origin which are schematically depicted in Figure 7.16. These structures are the shape of the crown follicle (outer enamel epithelium), the shape of the crown (inner enamel epithelium), and the shape of the root (Malassez’

80 Chapter 7 Diagrams for diagnostics • This chapter also concerns the nomenclature of developmental deviations and creates a transition from the normal develop­ Evaluation of tissue types affected in different dental conditions ment processes discussed in Chapters 1–6 to following chap­ and evaluation of the craniofacial fields involved are important to ters which discuss etiology-based diagnostics of pathological consider in every case. Use the diagrams provided in the chapters development processes. describing normality and in this chapter on classification. • Dental conditions: first and second diagrams. • For the use of etiology-based diagnostics in the dentition and cranium, schematic diagrams are provided.  These tooth diagrams can be used to demonstrate whether the developmental deviation is due to the ectoderm (general devia­ Further reading tion in tooth formation and follicles) (Figure 7.18) or whether the disturbance is localized to the ectomesenchyme or to the Axelsson S, Kjær I, Bjørnland T, Storhaug K. Longitudinal cephalometric neuroectoderm (field specific deviations) (see Figure 3.21). standards for the neurocranium in Norwegians from 6 to 21 years of age. Eur J Orthod 2003;25:185–198. • Craniofacial conditions: third diagram (see Figure 3.1).  This diagram shows fields in the cranium which can provide Axelsson S, Storhaug K, Kjær I. Post-natal size and morphology of information on whether the deviation is isolated to a single the sella turcica. Longitudinal cephalometric standards for Nor­ field or whether multiple fields are involved. It can also wegians between 6 and 21 years of age. Eur J Orthod 2004;26: provide a first-hand overview of whether the condition could 597–604. be a malformation, a disruption or a dysplasia. An overiew of the craniofacial fields is important in etiology- Carey JC, ed. Elements of morphology: standard terminology. Am J Med Genet Part A 2009;149(Special Issue):1–127. based diagnostics of the cranium. Note that several fields have a direct relationship to the sella turcica. Kjær I. Orthodontics and foetal pathology: a personal view on cranio­ facial patterning. Eur J Orthod 2010; 32140–147. In the following chapters, the practical application of these illustrations will be demonstrated. Kjær I. New diagnostics of the dentition on panoramic radiographs – focusing on the peripheral nervous system as an important aetiolog­ Highlights and clinical relevance ical factor behind dental anomalies. Orthodont Waves 2012;71:1–16. • This chapter concerns the background for etiology-based Kjær I. Review: Dental approach to craniofacial syndromes: how can diagnostics and illustrates the importance of asking “why is developmental fields show us a new way to understand pathogenesis? it so?” when observing an abnormal condition. It is important Int J Dent 2012; Article ID 145749. to describe the condition but a description alone may not provide sufficient information for treatment. Kjær I, Reintoft I, Poulsen H, et al. A new craniofacial disorder involving hypertelorism and malformations of external nose, palate and pitui­ tary gland. J Craniofac Genet Dev Biol 1997;17:23–34. Spranger J, Benirschke K, Hall JG, et al. Errors of morphogenesis: concepts and terms. Recommendations of an international working group. J Pediatrics 1982;100:160–165.

CHAPTER 8 Deviation in tooth morphology and color: normal and pathological variations including syndromes The analysis of tooth morphology involves assessment of the Among other malformations in the primary dentition, the crown (morphology, structure, and color), the root, and the pulp. more common findings are small, narrow incisors and can­ ines. These can appear as normal, morphological variations Primary dentition: crown, root, and pulp (Figure 8.6) but can also appear in cases where a genotypic deviation might be expected (Figure 8.7). In well-known Malformation of incisors, canines, and molars syndromes such as Down’s syndrome, the primary dentition Malformation of primary teeth is seldom seen. The percentage is also affected, with characteristically small teeth. occurrence of different types of primary tooth malformations is not given in this book but examples are provided. Changes in color Changes in crown color and crown shapes occur in young Fused teeth children, sometimes unexpectedly (Figure 8.8). Color changes One of the most common primary tooth malformations is fused have also been observed with renal diseases (Figure 8.9). Changes teeth seen between the central and lateral incisors in both jaws in molar morphology can be exemplified by Nance–Horan (Figure 8.1). Fusion can also occur between the mandibular syndrome. incisor and the canine (Figure 8.2). This type of fusion can occur in the primary dentition as well as in the permanent dentition. Root morphology Fusion between a lateral incisor and a canine does not occur in Taurodontic primary molars with abnormal pulp cavities occur the maxilla. The different nerve paths in the maxillary and in Klinefelter’s syndrome (Figure 8.10) but they can also occur in mandibular regions might explain this malformation pattern nonsyndromal cases. (Figure 8.3). In a national study of 215 patients with agenesis, 11 individuals had fusion between the lateral incisor and the canine Summary in the mandible. From an etiological point of view, there are single, unexplained findings in the primary dentition. There are also single findings In the maxilla, fusion can apparently only occur between the that are classified as malformations that are part of a syndrome incisors (see Figure 8.1). (SMMCI, Down’s, Klinefelter’s, Nance–Horan). In the early stages of tooth formation, the incisors in the Disruption in the primary dentition maxilla and the mandible share the same alveolus in their Trauma respective jaw bones (Figure 8.4). The fact that the tooth buds Trauma occurs quite often in the primary incisors and may result are so closely related might indicate that the incisors can fuse from minor, insignificant tooth injuries. Ankylosis of primary during this period. incisors can occur after a trauma and can influence normal development of the succeeding permanent incisor. In more Other malformations severe cases, a primary incisor might be forced into the jaw A very infrequently observed malformation in the primary bone. This condition and other severe traumas also cause dentition is a broad, single, central incisor which is part of the secondary injuries to the permanent dentition. Severe cases single median maxillary central incisor (SMMCI)/holoprosen­ are demonstrated in Figure 8.11. cephaly spectrum (Figure 8.5). This malformation has a compli­ cated etiology which also appears in the permanent dentition (see Virus p. 89). This condition also indicates the presence of one central Virus attack during pregnancy can spread to the fetus. The incisor in the permanent dentition. The broad central incisor can consequences for dental development of the fetus are have one root or a root which appears to be split apically. Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 81

82 Chapter 8 Figure 8.1 Two radiographic and one intraoral image of fused, primary, maxillary central, and lateral incisors. (Left) Radiograph of a filling that has been inserted between the fused maxillary primary incisors which in the permanent dentition are succeeded by one, permanent maxillary central incisor. (Center) Fusion of the maxillary primary incisors has occurred bilaterally. (Right) Radiograph of bilateral fused primary maxillary incisors. The fusion occurs between a central incisor and a supernumerary lateral incisor. A primary lateral incisor has erupted. The primary incisors are succeeded by a permanent central incisor and a permanent lateral incisor. Figure 8.2 Three radiographs demonstrating fusion of the mandibular incisors. (Left) Fusion between the central and lateral mandibular incisors. The fused teeth are succeeded in the permanent dentition by one permanent incisor. (Center) Fusion between a mandibular primary lateral incisor and a primary canine. The fused teeth are succeeded by a permanent incisor and a permanent canine. (Right) Fusion between the mandibular primary lateral incisor and a primary canine. The fused teeth are succeeded by a permanent canine. Figure 8.3 The types of fusions of primary incisors and canines that can occur in the maxilla and mandible. In the maxilla, fusion is never seen between the primary lateral incisor and the primary canine. However, this fusion may occur in the mandible. (Left) This figure demonstrates the lower face with primary teeth. The frontonasal field is represented in yellow and the anterior part of the left mandible in blue. The black rings indicate where fusion may occur. (Right) Histological sections of primary incisors and canines from human fetuses GA 12–15 weeks. The upper figure is of the maxilla, the lower is the mandible. The black rings indicate where fusion may occur.

Deviation in tooth morphology and color 83 Figure 8.4 Demonstration of how the primary incisors in the initial stages of development have a common alveolus. (Upper) An anthropological, right hemimaxilla (left) from a human fetus approximately GA 20 weeks. The photo demonstrates the alveolus of the primary incisor and canine. Posterior to the alveoli is the incisive fissure marked by an arrow. A schematic drawing (right) illustrates this. IC and IL indicate the location of the central and lateral incisors; C indicates the alveolus of the canine. Note that the canine has a separate alveolus which is not closed labially. IF marks the incisive fissure; IM marks the figurative location of the intermaxillary suture. (Lower) An anthropological, right hemimandible (right) from a human fetus approximately GA 18 weeks. The photo demonstrates the common alveolus for the primary incisors and a separate alveolus for the canine. Notice the deep furrow in the bottom of the common incisive alveolus marked by an arrow. This furrow is presumed to be the nerve canal to the incisors, indicating that there is a very short distance from the nerve innervating these anterior teeth to the tooth germs. A schematic drawing (left) illustrates a common alveolus for the primary incisors in the mandible. IC and IL indicate the location of the central and lateral incisors; C indicates the alveolus of the canine. Note that the canine in the mandible also has a separate alveolus which is not closed labially. SM indicates the figurative location of the symphysis menti. Source: Kjær and Bagheri (1999). Reproduced with permission of Sage Publications. Figure 8.5 Three radiographs and an intraoral photograph demonstrating single median maxillary central incisor (SMMCI) in the primary dentition. (Left) Radiograph from a child approximately 3½ years of age in which one single broad central incisor bordered by two primary lateral incisors is seen in the primary dentition. The primary central incisor is succeeded by one permanent central incisor in the midaxial plane. (Inset) An intraoral photograph of the same child. (Center) Radiograph from a child approximately six years of age. In the primary dentition, two narrow, individual crowns are present. In the permanent dentition, one broad midaxial central incisor succeeds them. Primary lateral incisors can also be observed as well as their permanent lateral incisor successors. (Right) Radiograph from a child approximately four years of age. In the primary dentition, one single, central maxillary incisor can be observed. A factor common to the cases demonstrated is that the morphology of the central incisor in both the permanent and the primary dentition is symmetrical. This may indicate that the shape of the tooth can be understood as the joined, lateral halves of two central incisors.

84 Chapter 8 Figure 8.6 Narrow primary incisors and spacing in the mandible of a normally developed child four years of age. Figure 8.7 An intraoral photograph from a child approximately six years Figure 8.8 Intraoral photographs of a child 11 years of age without known of age demonstrating narrow incisors, tooth agenesis, and tooth childhood anamnesis or known family medical history. The primary and malformations in the primary dentition. This is a very rare finding and permanent teeth show severe but inexplicable discoloration which must might indicate a syndrome. have occurred either in the fetal period or in the first year after birth due to an external influence. External influences might include disease, demonstrated in Figure 8.12. The case presented is a dental medication or pollution. section from a fetus infected with severe maternal rubella. explained. The condition appears within fields. In Figure 8.16, Operations the condition is depicted in a five-year-old boy who has ghost Postnatal operation in the ear can disturb the innervation to teeth in the right primary molar field (the permanent canine/ the teeth which can provoke a disruption in tooth formation premolar field). The etiology may be a virus attack or a localized (Figure 8.13). The disruption of the nerve supply can be healed by ectomesenchymal deviation. outgrowth of Schwann cells, resulting in normal development of the teeth that follow. Arrest in root formation Early retention of primary molars might arrest the root forma­ Disruption by radiation or other cancer treatments (Fig­ tion of these molars because the roots often appear needle- ure 8.14), as well as inflammation in the dental arch early in shaped (see Chapter 10). life (Figure 8.15), can disrupt tooth formation in the primary and permanent dentition. Ghost teeth “Ghost teeth” is a condition in which radiographic images show a shadow-like contour of developing teeth that cannot be

Deviation in tooth morphology and color 85 Figure 8.9 Intraoral photographs of the primary dentition in a child with a Figure 8.10 Section from an orthopantomogram demonstrating congenital kidney disease. Note the abnormal morphology, the enamel taurodontia in the primary molars and in the permanent molars. This disturbances, and the color changes. It appears as though the enamel could be a case of Klinefelter’s syndrome. development was normal at the time of incisive enamel formation and that a deviation occurred shortly after. Figure 8.11 Radiographs demonstrating trauma in the maxillary primary central incisors. (Left) Trauma leading to breakdown of the roots of the incisors without obvious damage to the permanent central incisors. (Right) Trauma leading to intrusion of the maxillary primary central incisors. Time will show whether the permanent incisors have been damaged by the trauma.

86 Chapter 8 Figure 8.14 An orthopantomogram of a child who received chemotherapy at one year of age. It appears that the primary dentition has been affected as the second primary molars have diminutive roots. The primary maxillary canines also appear short. Figure 8.12 Two sagittal, histological sections of maxillary primary central Figure 8.15 Section from an orthopantomogram from a child nine years incisors from human fetuses about GA 20 weeks. (Upper) Normal of age with a perinatal inflammation. The child has received antibiotic appearance of a tooth germ with a balloon-like crown follicle. An artifact treatment over a long period. Note the shadow-like distal root of the first due to preparation of the section is marked with a star. (Lower) The fetus molar and the abnormal pulp chambers in the primary molars. has suffered from a maternal varicella infection which has disturbed the crown follicle in the primary dentition. The crown follicle normally looks like a balloon (see above) and contains an inner pressure. When the crown follicle collapses due to virus attack, the tooth bud also collapses. The collapse appears to have occurred between the mineralized part of the tooth bud and the unmineralized part (arrow). Figure 8.16 An orthopantomogram from a child six years and two months old. The radiograph was taken due to the absence of maxillary teeth in the right side. It revealed regional ghost teeth disturbances in the canine premolar field and molar field. It is believed that the ghost teeth condition is caused by damage of the innervation to the affected fields. Figure 8.13 Section from an orthopantomogram demonstrating how an Calcification ear operation in the right ear at the age of 2½ years has disrupted the Pulp calcification occurs in primary teeth without known cause. formation of the primary molars in the right side. It is assumed to be related to dentinogenesis imperfecta or dentin dysplasia (Figure 8.17).

Deviation in tooth morphology and color 87 Figure 8.17 Section from an orthopantomogram from a young adult Figure 8.19 Section from an orthopantomogram from the left side of a patient diagnosed with multiple agenesis. Note the obliteration of the pulp child eight years of age demonstrating nearly complete obliteration chambers in the left mandibular primary molar as well as in the first and (calcification) of the mandibular primary molars and canine. second permanent molars. Dysplasia in the primary dentition Ectodermal dysplasia The most common form of dysplasia in the primary dentition is ectodermal dysplasia (Figure 8.18). The morphological devia­ tions are characterized by pointed teeth, a narrowing of the tooth collum, and a narrow and short tooth root. Dentinogenesis imperfecta This condition also occurs in the primary dentition (Figure 8.19). Heavy attrition is seen in the crown and the pulp, associated with severe calcifications. Color changes may also be observed. Amelogenesis imperfecta Figure 8.20 Section from an orthopantomogram from the right side Amelogenesis imperfecta also causes a dysplastic change in demonstrating amelogenesis imperfecta in the primary and permanent crown and root morphology (Figure 8.20). The morphologies dentition. The second primary molar has been crowned and the first of the crown and root are characterized by uneven contours and primary molar and canine appear to be worn occlusally. calcified pulp chambers such as in dentinogenesis imperfecta. Figure 8.18 Three intraoral photographs from two different children. Both have been diagnosed with ectodermal dysplasia. (Left and center) Intraoral photographs from a child five years of age (also shown in Figure 6.12). The abnormal morphology of the incisors and the occurrence of agenesis are characteristics of anhidrotic ectodermal dysplasia. (Right) Intraoral photograph from a child four years of age who has agenesis of the primary maxillary incisors and the primary mandibular lateral incisors. The central incisors in the mandible appear narrow and the canines pointed. This child lacks altogether 13 permanent teeth. The specific type of ectodermal dysplasia was not diagnosed.