EtiologyBased Dental and Craniofacial Diagnostics

188 Chapter 13 Figure 13.23 Midsagittal, histological sections of the sella turcica/pituitary gland region in fetuses with myelomeningoceles and encephaloceles. (Left) Histological sections. Malformations appear as a cleft in either the anterior wall or the anterior floor (arrows). The pituitary gland in the left section demonstrates normal tissue structures while the pituitary gland to the right was distorted during the brain autopsy. (Right) A schematic drawing of the sella turcica and the pituitary gland in myelomeningoceles, spina bifida, and encephaloceles. The uppermost of the three drawings illustrates normal morphology. All have a deviation located more or less in the anterior wall. Severe deviations may also involve the floor of the sella and the adenopituitary gland tissue which can be located subpharyngeally. Adenopituitary gland tissue, red; neuropituitary gland tissue, yellow; cartilage, blue; white dots are bone formation. Source: Kjær (2015). normal. Hand malformations have been observed with abnormal From the limited material available for investigation, agree­ ossification sequences in the first finger. Histological studies ment has been observed in the prenatal and postnatal findings demonstrate an acid mucopolysaccharide malfunction during regarding the ossification of bones in the first finger. Further­ ossification as well as during resorption. The sella turcica may be more, investigations show that the underlying ossification pro­ malformed and the nasal bone is late in prenatal development cess in fragile X syndrome is apparently abnormal. (Figure 13.37). Postnatal Crouzon’s syndrome In postnatal fragile X syndrome, intellectual disability is a characteristic symptom. Craniofacial analysis shows normal Prenatal morphology of the nasal bone, a deviation in the anterior wall Radiographic analysis of the vertebral column in a single fetus of the sella, and sporadic deviations of the cervical vertebra. In the demonstrates a bone formation pattern which is different from hand, deviant locations of the epiphyseal cartilage disks appear the pattern seen in normal fetuses (see Chapter 1). The corpora of both distally and proximally from the diaphysis in the meta­ the vertebral column which normally ossifies in the caudal to carpals of the first and second finger. Abnormal carpal ossifica­ cranial direction is late in ossification (Figure 13.38). This means tion has also been observed. Skeletal maturity is delayed. that early abnormal development in Crouzon’s syndrome occurs Figure 13.24 Radiograph profile of twin fetuses and two figures illustrating the pituitary gland malformation in hydrocephalus. (Left) Twin fetuses at the approximately 16 weeks GA. The left fetus has a normal cranium and the right fetus has severe hydrocephalus. Note that there is no difference in skeletal maturity between the two. (Upper right) A histological section demonstrating a large amount of adenopituitary gland tissue (A) located subpharyngeally. The upper mucosa in the pharynx is marked P. The section is from a different fetus approximately 18 weeks GA also diagnosed with severe hydrocephalus. (Lower right) The drawing illustrates the common appearance of the sella turcica/pituitary gland region in prenatal hydrocephalus. Notice the malformation in the floor of the sella turcica where there is a large opening. In this opening, the adenopituitary gland tissue appears (red). The neuropituitary gland is often not present in prenatal hydrocephalus. Cartilage is marked blue and white dots indicate ossification. Source: Kjær (2015) (upper and lower right).

Craniofacial syndromes and malformations 189 in the vertebral column. Autopsy analysis of the cranium was not performed in this specific prenatal case. Figure 13.25 Hydrocephalus in two children aged four months (left) and Postnatal eight years (right). Shunts have been inserted and appear on the In this syndrome, the sutures in the craniofacial area do not grow radiographs. The sella turcica appears normal in both individuals. normally. This results in phenotypic characteristics such as protruding eyes and a retrognathic maxilla (Figure 13.39). Furthermore, abnormal morphology of several cervical vertebrae has been observed. The limited material available for investigation of Crouzon’s syndrome has not allowed a proper comparison to be conducted between pre- and postnatal findings. However, it is interesting that the well-known phenotypic picture of facial devations in Crouzon individuals is associated with early, prenatal changes in the ossification of the spinal column. Less surprising is that this change in ossification of the column is related to postnatal malformations of the cervical vertebrae. The body (corpora) of the vertebra is formed around the notochord, which at its rostral end terminates in the medial cranial fossa. There is therefore a developmental association between the axial skeleton and the cranium which is affected in Crouzon’s syndrome, and probably initiated by the notochord. DiGeorge’s / velocardiofacial syndrome Prenatal Only one fetus has been studied with DiGeorge’s syndrome and in this fetus, early fusion of the basilar part of the occipital bone and the corpus of the sphenoid bone was found (Figure 13.40). This was an observation of a pathological ossification pattern. Figure 13.26 Illustration of sella turcicae in prenatal and postnatal Postnatal hydrocephalus as well as a histological section immunohistochemically In velocardiofacial syndrome, malformation or abnormal devel­ marked for Pax9 and exemplifying the genetic relationship between the opment occurs within a field that stretches from the brain to the body axis and the sella turcica region. (Upper) Two histological sections palate and further on to the septum of the heart (see from two different human fetuses with hydrocephalus. Notice the enlarged Figure 13.40). The osseous malformations can be observed in sella and the abnormal floor in the left section, and the abnormal anterior a lateral radiograph. In particular, the posterior wall of the sella wall in the right section. The pituitary gland appears normal in both turcica is malformed and the cranial base angle is increased (see sections. (Lower left) Section of a profile radiograph from a child seven Figure 13.40). These findings are combined with information in years of age with hydrocephalus demonstrating the slanting anterior sella the literature on the main defects in velocardiofacial syndrome: wall (white arrow) and the open basilar synchondrosis (blue arrow). palatal abnormalities, cardiac anomalies, thymic hypoplasia and (Lower right) Immuno-marking for Pax9 gene in a midsagittal section of a thymic aplasia, hypothyroidism, and posterior brain abnormal­ rat (GA 14 days). The black stars indicate positive reactivity with Pax9 and ity. By combining these areas of abnormality, the specific neural demonstrate that the same gene product is present in the vertebral bodies crest field could be defined (see Figure 13.40). This is a field (midaxial plane) as well as in the jaw region. This example illustrates a representing cell migrations from the brainstem to the septum of genotypic interrelationship between the lower body axis and the sella the heart. It is well known that the neural crest cells form the turcica and jaw regions. Source: Sonnesen et al. (2008). Reproduced with septum of the heart. This velocardiofacial syndrome field can be permission of Wolters Kluwer. considered an extension of the palatine field. The prenatal findings of an osseous malformation in the region posterior to the sella turcica are in agreement with the postnatal observations in the same region.

190 Chapter 13 Figure 13.27 Anthropological crania demonstrating grotesque hydrocephalus before shunt treatment was possible as a treatment of these severe malformations. (Left) A cranium from a child approximately five years of age demonstrating open sutures and fontanelles. Source: Medical Museion in Copenhagen, reproduced with permission. (Center and right) Hydrocephalus in an adult cranium. The size and morphology of this cranium are compared with a normal cranium in the radiograph to the right. Cleft lip and palate Cleft lip: pre- and postnatal findings The cleft lip is located between the frontonasal field and the maxillary Cleft lip and palate malformations can be part of a phenotypic field. It is presumed that the etiology behind the cleft is either a spectrum for several different syndromes. They can also be reduced quantity/quality of neural crest cells in the frontonasal field nonsyndromic. In the following discussion, the three cleft mal­ or a change in the normal timing of the development of the formations will be described as nonsyndromic (despite the fact frontonasal field. This suggestion is based on the late prenatal that these facial malformations could be symptoms of a syn­ developement of the nasal bone and the finding of a short nasal drome that was not diagnosable in early, prenatal life). bone postnatally. The nasal bone is located within the frontonasal field. Deviations in the nasal septum developed from the frontonasal Spontaneously aborted fetuses with clefts often also have other field have also been observed. Only rarely are malformations seen in malformations (Figure 13.41). Therefore, no specific prenatal the anterior wall of the sella turcica. The dentition in cleft lip cases is cranial studies have been conducted in nonsyndromic cases of characterized by supernumerary teeth in the clefted incisor region. cleft lip, isolated cleft palate or combined cleft lip and palate. The cleft cases demonstrated in this section might be syndromic or Isolated cleft palate: pre- and postnatal nonsyndromic. findings The isolated cleft palate is formed due to a cleft between the bilateral The etiologies behind cleft lip, isolated cleft palate, and maxillary and palatal parts of the palate. These parts are developed combined cleft lip and palate are different. This can be under­ from the neural crest regions located further behind the neural crest stood when we recall the developmental fields in the maxillary region from where the frontonasal skeleton develops. The isolated alveolar process and palate. These fields have different etiological cleft palate is the result of an embryological development that starts backgrounds and the fields are involved in different ways in the three types of clefts (Figure 13.42). Figure 13.28 Down’s syndrome (trisomy 21). (Far left) Clinical appearance of a Down’s syndrome fetus at GA 17 weeks. (Center left) Radiograph of a midsagittal segment of a human fetus seven weeks GA with Down’s syndrome. Note the absence of the nasal bone (white arrow). The basilar part of the occipital bone is short (blue arrow). The nasal bones in prenatal Down’s syndrome are either absent or short. (Center right) A histological section of the sella turcica and pituitary gland in a fetus 16 weeks GA with Down’s syndrome. The rostral end of the notochord often appears curved (arrow). (Far right) Schematic drawings indicating various morphologies of the sella turcica and various placements of the adenopituitary gland tissue (red) in Down’s syndrome. The neuropituitary gland (yellow) appears normal. Cartilage, blue; ossification, white dots. Source: Kjær et al. (1998). Reproduced with permission of John Wiley & Sons.

Craniofacial syndromes and malformations 191 Figure 13.29 Radiograph of the vertebral column in a human fetus 18 when the musculus genioglossus contracts and pulls the tongue week GA with Down’s syndrome. The anterior face points to the left. Note away from its position between the vertically positioned palatine the severe malformation of the vertebral bodies which are partially clefted shelves (Figure 13.43). This motion, possibly associated with the (white arrow) and sometimes completely clefted (blue arrow). natural elevation of the head, gives the palatal processes the chance Malformations in the vertebral bodies can serve as indicators for the to move to a horizontal position in the mouth. By this movement, degree of severity of the syndrome. The less severe cases often have only the oral cavity becomes separate from the nasal cavity. It is supposed minor malformations in the cervical column. that retraction of the tongue musculature is followed by forward movement of the mandible which is possible after palatal closure. Later, the mandible retracts to its more posterior position and becomes stable, whereupon the mandibular condylar process can begin its development (see Chapter 1). During palate formation, the mandible moves in the sagittal, vertical, transverse direction provoked by the tongue. These movements are only possible because the condylar tissue is not yet formed at 12–13 weeks GA, nor has the joint between the mandible and the cranial base been formed. Cephalometric studies on newborns and adults with isolated cleft palate have documented that the maxillary bone is short and malformed and the mandible is retrognathic. The dentition characteristics for isolated cleft palate are the presence of teeth with short and sometimes malformed premolars (Figure 13.44). Premolar agenesis is also a frequent finding. This corresponds to the developmental background for these teeth formed in the maxillary and palatine fields which are involved in the isolated cleft palate condition. An overview of the mal­ formation sites in the three cleft types appears in Figure 13.44. Figure 13.30 Profile radiographs from three children with Down’s syndrome demonstrating various phenotypes in this condition. (Left) The child is about three years of age. Note the deviant anterior wall in the sella turcica (white arrow) and the malformations in the cervical column (blue arrow). (Center) The child is about eight years of age. Note the retrognathia of the maxilla and the increased thickness of the theca cranii. Note also the deviation of the anterior wall in the sella turcica (arrow) and the severe malformations in the cervical column (blue arrows). (Right) The child is about nine years of age. The sella turcica appears normal. The cervical column is difficult to diagnose exactly due to the backward tilt of the head. The lower part of the occipital bone belonging to the occipital field has a “drop” which is characteristic for Down’s syndrome patients. Figure 13.31 Sections of radiographs demonstrating the morphology of the sella turcica in three different newborn children with Down’s syndrome. The anterior face is to the right. These postnatal appearances of the sella are in agreement with what can be observed histologically, prenatally (see also Figure 13.28 for schematic overview). (Left) The anterior and posterior walls of the sella turcica converge. The anterior wall is especially slanted. (Center) There is a large invagination in the upper part of the anterior wall (arrow). (Right) There is a gap in the anterior floor of the sella (arrow).

192 Chapter 13 Figure 13.32 Percentage of agenesis of the second premolars and the Figure 13.34 Prenatal Turner’s syndrome. (Left) Photograph of a Turner’s incisors in individuals with Down’s syndrome. The upper diagram syndrome fetus with a fluid-filled “sack” extending from the back of the expresses the frequency in the maxilla and the lower diagram expresses the cranium to the seventh cervical vertebra where there is a sharp borderline frequency in the mandible. It is obvious that agenesis occurs more between the sack and the rest of the body. Prenatal Turner’s syndrome can frequently in Down’s syndrome individuals than in nonsyndromic also be characterized by a broad neck without this sack. The hands and individuals. The percentage agenesis of the mandibular central incisor feet appear short. Source: Kjær et al. (1999). Reproduced with permission (24%) is especially significant. of John Wiley & Sons. (Right) A radiograph of the cervical vertebrae illustrating remnants of extra, bilateral ribs at the seventh cervical vertebra Figure 13.33 Two different dentitions in Down’s syndrome. (Upper) An (arrows) which is a frequent finding in Turner’s syndrome fetuses. intraoral photograph demonstrating the occurrence of agenesis in the mandibular front as well as in the maxilla, where agenesis occurs of one or Combined cleft lip and palate: pre- and two permanent lateral incisors and the right maxillary permanent second postnatal findings premolar. (Lower) Sections from the same orthopantomogram In the combined cleft lip and palate, not just the alveolar bone demonstrating eruption deviations in the premolars and small permanent and lip are clefted but also the entire palate. Skeletally, it has second molars. Apical infections might be present in the permanent been shown that the nasal bone in the frontonasal field is mandibular second molars. Deviation in size and morphology of the normal in this cleft type (Figure 13.45). It is supposed that the dentition is a regular finding in Down’s syndrome. combined cleft lip and palate malformation arises from an abnormal function of the cranial part of the notochord, and that this malformation develops very early. Hypothetically, this condition can be considered a nonclosure of the ante- notochordal region. In many ways, this malformation can be compared to a spina bifida malformation with nonclosure of the neural tube. Newborn children with complete clefts have a broader sphenooccipital synchondrosis compared to children with a minor, incomplete cleft lip (Figure 13.46). Also the distance from the superior part of the synchondrosis to the sella point (center point in the sella turcica) is shorter in children with complete cleft. These findings can be related to a defect or a delay in maturity in the early development of the cartilaginous cranial base in children with complete clefts. The width of the cranial base and the bilateral angulation of the sphenoid bone are increased in complete cleft individuals, and increased maxillary width was found in complete cleft lip and palate patients. Furthermore, a depressed lower part (cartila­ ginously formed) of the occipital squama has been described cephalometrically both prenatally and postnatally. These findings all confirm that the complete cleft cases are not isolated malformations localized to the jaw, but that this also involves the cartilaginous cranial base and the entire occipital field. Malformed vertebrae have been reported in combined cleft lip and palate cases. The dentition in the combined cleft lip and palate is charac­ terized by agenesis of teeth in the incisor region and different types of malformations in the premolar and molar teeth.

Craniofacial syndromes and malformations 193 Figure 13.36 An orthopantomogram from a girl with Turner syndrome. Figure 13.35 Profile radiographs of three Note the roots are generally short throughout the dentition. The second female patients with Turner’s syndrome. molars appear diminutive. (Left) Note the normal sella turcica and the very short first vertebra (atlas) (arrow). The nasal bone is not visible in this radiograph. (Center) Note the normal sella turcica and low arch of the atlas. A magnification of the nasal bone is inset. The nasal bone appears narrow (needle-shaped) and short. (Right) The sella turcica appears slightly smaller than normal in the radiograph and the atlas is both short and low. A magnification of the nasal bone is inset. The nasal bone appears narrow (needle-shaped) and short. Cleft lip and palate etiologies Fogh-Andersen suggested, in his famous study from 1942 on the cleft lip and palate conditions, that the three cleft types might have different origins. The skeletal malformations and dental deviations observed in the three types of clefts support this viewpoint. The concept can be understood from cell migration from different regions on the neural crest (see Chapter 3). Visually, the different dentition phenotypes in the different cleft types illustrate that there are three etiological backgrounds for the three cleft types (Figures 13.47 and 13.48). Study of prenatal material has allowed comparison of the deviations observed in the nasal bone, the morphology of the cervical column and the morphology of the occipital squama with their postnatal counterparts. In these regions, there was high agree­ ment between the prenatal and postnatal deviations observed in the different cleft types. Figure 13.37 Images from prenatal and postnatal fragile X syndrome Figure 13.38 Schematic drawings demonstrating the anterior view of the individuals. (Upper left) Histological section of the maxillary complex, the vertebral column in a Crouzon’s syndrome (CS) fetus at 13 weeks GA cranial base, and the lower part of the frontal bone. The anterior face compared to anterior view of normally developed vertebral columns (N) points to the left. It is characteristic that the nasal bone which is supported age 12 weeks GA and 14 weeks GA. Marked in the vertebral column are by underlying cartilage (purple) is extremely short and underdeveloped. the vertebral bodies and the bilateral vertebral arches. By comparison of The nasal bone, which is difficult to observe, is marked by a black arrow. the sequence and pattern in development, it appears that the vertebral The sella turcica has a deep invagination in the anterior wall (blue arrow). bodies, which are formed first in the lumbar region and rostrally A remnant of the notochord appears malpositioned (yellow star). (Upper thereafter, are delayed in maturity in CS compared to the normal cases. In right) Section from a profile radiograph of a child with fragile X syndrome. contrast, the arches which develop in the opposite direction mature earlier Note the anterior wall of the sella turcica (arrow) and a sella bridge compared to the normal cases. Source: Kjær et al. (2000). (directly below arrow) which connects the anterior and posterior walls. (Lower) An orthopantomogram from a child with fragile X syndrome. Note several intracoronal black spaces (for example, in the right mandibular molar and second premolar). The etiology behind this condition might be connected to the deviant, acidic mucopolysaccharides which are characteristic for this syndrome, but this has not been proven.

194 Chapter 13 for determining an etiological background in diagnostics. In prenatal specimens, it is possible to localize the areas in which the malformations first arose. How these developmental deviations affect later development can also be analyzed. Prenatal material is valuable also for determining fields of development, for example in holoprosencephaly and in cleft lip and palate cases. The prenatal material is also advantageous because histologi­ cal studies can supplement radiographic analysis and support the existence of fields by marking borderlines between malformed and nonmalformed areas. Restrictions One restriction of comparative pre- and postnatal analysis is that the material available for study is limited at any given stage. This is applicable to many postnatal syndromes where the prenatal material is not accessible. One example is provided. Figure 13.39 A profile radiograph from a child with Crouzon’s syndrome. Treacher Collins syndrome Note the very small sella turcica and the retrognathia of the maxilla. The In this syndrome, bone malformation was not described in a nasal bone is difficult to recognize and an enlargement of the nasal bone prenatal specimen. Postnatally, a common finding is a regional area is inset. lack of bone tissue on the zygomatic arch and abnormal devel­ opment of the condylar process (Figure 13.49). The close con­ nection between these bone abnormalities suggests a common field, but this cannot be proven. Comparison between pre- and postnatal Malformations: nonsyndromic examples findings: results and restrictions Results Malformations can exist without a syndromal diagnosis, as in There is a convincing association between symptoms observed in SMMCI and cleft lip and palate conditions. Five examples of such prenatal syndromes presented in this chapter and postnatal malformations in the jaws and cranium are briefly detailed symptoms. This means that the prenatal material is valuable below. Figure 13.40 Prenatal and postnatal images of DiGeorge’s syndrome (also called velocardiofacial syndrome). (Left) Radiographs of the prenatal maxillary complex, the cranial base, and the frontal bone in a normal fetus and in a DiGeorge’s syndrome fetus (approximately 20 weeks GA). Notice how the anterior and posterior parts of the sphenoid bone appear to be united (arrow). This indicates an early malformation in the sella turcica region. (Center) The sella turcica appears with a deviant, anteriorly located planum sphenoidale (black arrow). The posterior wall also has a deviant, backward-tilted morphology (white arrow). (Right) A schematic drawing illustrating how the symptoms of DiGeorge’s syndrome can be explained as occurring within the same neural crest field. The symptoms are observed in the brain (corpus callosum, C), in the sella turcica (pituitary gland, P), in the posterior part of the palate, in the thyroid gland and thymus gland as well as in the heart septum. These symptoms are indicated by the green area in the right drawing which can be understood from the migration pattern of the neural crest cells demonstrated in the left drawing as green dots from the neural crest to the heart septum. The red line indicates the notochord in both drawings. Inset is a legend of the various affected structures. Source: Mølsted et al. (2010). Reproduced with permission of John Wiley & Sons.

Craniofacial syndromes and malformations 195 Figure 13.41 Cleft palate and cleft lip illustrated in human fetuses which are deviscerated due to intrauterine death. (Left) A cleft palate not involving the frontonasal field observed in the occlusal view. (Upper right) Frontal view of a unilateral cleft lip in the left side. (Lower right) Frontal view of a bilateral cleft lip. Figure 13.42 An illustration of the face and the palate demonstrating that the etiologies behind cleft lip, isolated cleft palate, and combined cleft lip and palate are different. (Upper) This photograph of a child with a cleft lip depicts the craniofacial fields described in Chapter 3. The cleft lip is located between the frontonasal field (blue) and the maxillary field (light purple). The nasal bones arae located within the frontonasal field (marked by two purple shapes). In isolated cleft lip, the nasal bones appear short. It is presumed that the etiology behind the cleft is either a reduced quantity/quality of neural crest cells in the frontonasal field or a change in the normal timing of the development of the frontonasal field. Both hypotheses include involvement of the nasal bones. The dark purple contours represent the palatine fields. The green areas mark the bilateral mandibular fields. The arrows indicate the direction of cell migration from the neural crest. (Lower) Four schematic drawings of the palate observed in the occlusal view with colors marking the various fields involved in different cleft lip and palate conditions. (Far left) Drawing of the various bilateral fields with field names inserted. (Center left) The black lines indicate the location of the bilateral isolated clefts in the lip and in the alveolar bone. (Center right) The black line indicates the location of the isolated cleft in the palate. The extension (and location) of the palate cleft differs in different individuals. (Far right) The black line indicates a combined cleft lip and palate. This is a cleft which is between the bilateral palatine fields, the bilateral maxillary fields and, in one side, between a frontonasal field and a maxillary field. This type of cleft can also be bilateral.

196 Chapter 13 Figure 13.43 This image marks the contour of the tongue (T) and the mandible (M) seen in the lateral view. The red bars indicate the direction in which the muscles pull the tongue and mandible backward and downward. This movement allows the vertically positioned maxillary palatal shelves to move into a horizontal position, forming the early palate. The upper red bar represents the genioglossal muscle and the lower bar represents the geniohyoid muscle. Source: adapted from Ono et al. (2003). Figure 13.44 Three schematic drawings over the same profile radiograph. The black dots indicate where the malformations occur in three different cleft types. (Left) In cleft lip, the anterior wall of the sella turcica can have a deviant morphology. The nasal bone is short and the cleft often results in supernumerary lateral incisors. These three regions are marked with black dots. (Center) In isolated cleft palate, the anterior wall and the floor of the sella turcica can have a deviant morphology. The premolars and molars are affected by agenesis and malformation occurrences and the mandible has a retrognathic position. The areas of occurrence of phenotypic traits are marked by black dots. (Right) In combined cleft lip and palate, the sella turcica is often malformed, including the posterior wall. At birth, there is a very broad sphenobasilar synchondrosis. The cranial base angle is larger than normal and the occipital bone squama has a “drop.” Agenesis often occurs in the incisor region. The premolars and molars are also affected by agenesis as well as malformation occurrences. The maxilla and the mandible have a retrognathic position. Furthermore, there are several malformations in the vertebral column. All these phenotypic traits are marked by black dots. In summary, the defect in the cleft lip is localized to the frontonasal field; the defect in the cleft palate is localized to the maxillary and palatine fields, and to the mandible, while the combined cleft lip and palate is localized to the maxillary and palatine fields, to the mandible and to the occipital field (which is only affected in this type of cleft). Figure 13.45 Demonstration of combined cleft lip and palate and the fields involved in this condition. (Left) Cranium from an adult in the frontal view showing the clefted alveolar process in the right side and agenesis of a lateral incisor in the same side. (Center) The palatal view of the cleft demonstrated in the image photograph to the left. This a complete cleft which extends to the pharynx. (Upper right) Schematic drawing on a frontal radiograph demonstrating the frontonasal field (yellow) and the maxillary and palatine fields (red). (Lower right) A 3D scanning of a patient with combined cleft lip and palate demonstrating the reversed overjet which is often observed in this condition.

Craniofacial syndromes and malformations 197 Figure 13.46 Three sections from three different profile radiographs from three different children with combined cleft lip and palate. The stars mark the contour of the sella turcica, while the arrows indicate the sphenobasilar synchondrosis which is significantly wider in children with combined cleft lip and palate in comparison to children with only cleft lip. The left figure is from a child approximately 12 years of age while the center and right radiographs are from newborns. The sella turcica in the right figure has a pathological appearance with divergent walls and a shallow depth, and notice also the very wide synchondrosis. Figure 13.47 Diagram demonstrating dental deviation in 30 children with cleft palate. A legend over the various deviations is provided to the right. The y-axis indicates the number of children in which each specific deviation was observed. The red column in the lateral incisor region indicates a high frequency of supernumerary lateral incisors in this cleft type. Inset is a dental film demonstrating a clefted alveolar bone in a patient with cleft lip. Supernumerary lateral incisors appear in the left region. Source: Riis et al. (2014). Reproduced with permission of Taylor & Francis. Figure 13.48 Two graphs demonstrating the dentition in isolated cleft palate (30 individuals) and in unilateral combined cleft lip and palate (30 individuals). The different malformations are explained in the legends to the right of each graph. The y-axis indicates the number of cases in which each specific deviation was observed. (Left) In isolated cleft palate, agenesis and malformed roots occur in the molar and premolar regions. These teeth originate from the palatal shelves which form the maxillary and palatine fields in the palate. This indicates that the dentition formed in these shelves can be abnormal. (Right) In unilateral combined cleft lip and palate, the dentition can have several malformations throughout, mostly in the incisor and molar regions. In the incisor region, malformation and agenesis of lateral incisors occur frequently. This pattern differs from that seen in the cleft lip condition (see Figure 13.47). Source: Riis et al. (2014). Reproduced with permission of Taylor & Francis.

198 Chapter 13 Figure 13.49 An anthropological case and a profile radiograph of a patient demonstrating the appearance of Treacher Collins syndrome. (Far left) This view of the occluding jaws displays a mandible with a notch anteriorly to the mandibular angle (arrow) and a short ramus with a malformed condyle as well as the absence of the zygomatic arch. (Center left) The mandible appears with a malformation in the basis mandibulae (arrow) and with an underdeveloped mandibular condyle. (Center right) This view of the external cranial base reveals a total absence of the bilateral zygomatic arches (arrows) and the seemingly normal structures in the palate and the cranial base. (Far right) Profile radiograph illustrating retrognathia of the mandible, the antegonial notch of the mandible, and a diminutive atlas. The area where the zygomatic arch should appear cannot be analyzed on a profile radiograph. • The first example is a mandible without a condylar process influence the intracranial pressure and therefore the formation (Figure 13.50). It is either congenital or acquired. The cause of of impressiones digitatae, but this is still speculative (Figure this deviation is unknown. As the mandible in Figure 13.50 is 13.53). an anthropological finding, no anamnestic records exist and • Sella turcica malformations are a fourth example. These appear the precise etiology of the condition cannot be determined. in profile radiographs which have been taken for orthodontic treatment planning. The malformations in the sella occur in • The second example with unknown etiology is abnormal connection with severe skeletal jaw and dental deviations but maxillary development. Figure 13.51 demonstrates an asym­ the interrelationship between the jaw/tooth development and metrical maxilla also involving the nasal septum. Whether this the sella turcica is still awaiting clarification (Figure 13.54). is an intrauterine deformation or a disruption cannot be • The fifth example is occipitalization where there is a fusion clarified by radiographs. The anamnesis provided no indica­ between the upper vertebra, atlas, and cranial base (Figure tors for a possible etiology. Figure 13.52 demonstrates a 13.55). In individuals with occipitalization, the occipital field is diminutive frontonasal field in the palate. The etiology behind malformed but the etiology behind this abnormality cannot be this condition is not known. • Synostosis is a third example. Early closure can occur in a single suture or in several sutures. Genotypic mapping has been conducted but when and why this occurs is not known. It could be a dysplastic change in the soft tissue of the suture, but no studies have been conducted to support this viewpoint. Examples are scaphocephaly and oxycephaly. Dysostosis may Figure 13.50 Anthropological mandible and cranium illustrating a Figure 13.51 Frontal radiograph of the cranium of a child with an seemingly congenital malformation in the mandibular condyle. No asymmetrical nasal cavity and maxilla. The occlusal plane is slanted. The anamnestic information exists. (Left) The mandibular condyle is absent etiology behind this left-side malformation in the maxillary-nasal complex and the coronoid process appears enlarged. When this defect arose is not is not known. known but the extended coronoid process might indicate overactivity of the temporal muscle during mastication. (Right) A cranium with the mandible seen from below. This mandible is not the same as that seen to the left. The defect in the left side arose earlier than the defect observed in the left figure. In this cranium, the mandible is severely underdeveloped in the left side, resulting in severe asymmetry of the jaws.

Craniofacial syndromes and malformations 199 Figure 13.53 Two anthropological crania illustrating synostosis and abnormal suture configurations in the theca cranii. (Left) Frontal view of a cranium with synostosis of the interparietal suture, meaning that the theca does not have a normal width. The width in the jaw region is normal. (Right) The view from above of the theca where the suture configuration is abnormal. In this case, a brain scan could have helped to understand the etiology. Figure 13.52 Section from the anterior part of the palate from an • Prenatal findings in syndromes are based on histology and anthropological cranium. In this case, the premaxilla is underdeveloped. compared to postnatal findings on radiographs of the same Note the small incisive foramen (blue arrow) and the traces of the bilateral syndromes. This “bridging” between the pre- and postnatal incisive fissures (blacks arrows). The agenesis of the incisors in this case is observations provides an opportunity for improving etiology- due to congenital maldevelopment of the bilateral frontonasal field. This is based diagnostics. not a holoprosencephalic case because the midpalatine suture can be seen anteriorly. • The dentition in cleft lip and palate syndromes supports the viewpoint of separate etiologies/genotypes behind different explained. It is not known when or why occipitalization occurs cleft types. or whether it is related to other deviations in the body. • In syndromes, osseous deviations can occur within specific Highlights and clinical relevance fields or in the entire body. A condition called SMMCI with one single central incisor is the first sign of a localized field • In this chapter, osseous malformations are explained through involving the lower brain hemispheres, the area between the their relationship to specific developmental fields. eyes, nasal septum, and incisors. Intellectual disability can occur as part of this syndrome. The dentist is often the first • Explanations for cranial syndromes sometimes involve the professional to recognize and diagnose this condition. For vertebral column. One example is Crouzon’s syndrome; diagnostic purposes, it is important to notice the lip contour. another is combined cleft lip and palate. Patients with SMMCI often have a vaguely prominent phil­ trum, without the Cupid’s bow of the central upper lip contour. • Prediction of development and treatment options can be improved when the diagnosis is based on an etiological back­ ground supported by prenatal and postnatal findings. Figure 13.54 Four sections from profile radiographs of four different individuals with craniofacial malformations. The sections demonstrate sella turcicae. (Far left) The sella turcica has an overlying bridge in this individual with severe mandibular prognathia. (Center left) The sella turcica has an overlying bridge demonstrated in the inset drawing. This patient has a cranial base malformation and malformations of the vertebral column. Note the persistence of the sphenooccipital synchondrosis (arrow). Inset source: Becktor et al. (2000). Reproduced with permission from Oxford University Press. (Center right) This is a very narrow sella in a case with a congenital brain malformation. Surgical staples are seen in the cranium. (Far right) A wide open sella turcica without a distinct posterior wall observed in an individual with hydrocephalus who has been treated with a shunt.

200 Chapter 13 Figure 13.55 View of the external cranial base in the area of the foramen Keeling J.W. (ed.) Fetal and neonatal pathology, 2nd edn. Springer magnum (M). Note that the uppermost cervical vertebra (atlas) is united Verlag, London, 1993. with the cranial base and that the arch is not fully closed posteriorly (broken line). The uniting of the atlas to the cranial base is called Keeling JW. Fetal pathology. Churchill Livingstone, Hong Kong, 1994. “occipitalization” and gives the foramen magnum an abnormal shape. Keeling JW, Hansen BF, Kjær I. Pattern of malformations in the axial How this influences the central nervous system is not known. The etiology is also unclear but it is thought to be a malformation that arises before skeleton in human trisomy 21 fetuses. Am J Med Genet birth. 1997;68:466–471. Kjær I. Sella turcica morphology and the pituitary gland – a new Further reading contribution to craniofacial diagnostics based on histology and neuroradiology. Eur J Orthod 2015;37:28–36. Andersen E, Sonnesen L, Kjær MS, Hansen BF, Kjær I. The prenatal Kjær I, Balslev-Olesen M. The primary maxillary central incisor in the cranial base complex and hand in Turner syndrome. Eur J Orthod Solitary Median Maxillary Central Incisor Syndrome. Eur J Paed Dent 2000;22:185–194. 2012;13;73–75. Kjær I, Hansen BF. Human fetal pituitary gland in holoprosencephaly Arntsen T, Kjær I, Sonnesen L, Mølsted K. Skull thickness in patients and anencephaly. J Craniofac Genet Dev Biol 1995;15:222–229. with clefts. Orthod Craniofac Res 2010;13:75–81. Kjær I, Hansen BF. Cervical ribs in fetuses with Ullrich-Turner syn­ drome. Am J Med Genet 1997;71:219–221. Becktor JP, Einersen S, Kjær I. A sella turcica bridge in subjects with Kjær I, Hansen BF. The prenatal pituitary gland – hidden and forgotten. severe craniofacial deviations. Eur J Orthod 2000;22:69–74. Pediatr Neurol 2000;22:155–156. Kjær I, Niebuhr E. Studies of the cranial base in 23 patients with Cri-du- Buyse M.L. (ed.) Birth defects encyclopedia. Blackwell Scientific Publica­ Chat syndrome suggest a developmental field involved in the condi­ tions, Oxford, 1990. tion. Am J Med Genet 1999;82:6–14. Kjær I, Becktor KB, Lisson J, Gormsen C, Russell BG. Face, palate and Drews U. Color atlas of embryology. Thieme, New York, 1995. craniofacial morphology in patients with a solitary median maxillary Fogh-Andersen P. Inheritance of harelip and cleft palate. Thesis, Uni­ central incisor. Eur J Orthod 2001;23:63–73. Kjær I, Hansen BF, Keeling JW. Axial skeleton and pituitary gland in versity of Copenhagen, Nyt Nordisk Forlag, 1942. human fetuses with spina bifida and cranial encephalocele. Pediatr Gilbert-Barness E, Debich-Spicer D. Embryo and fetal pathology. Cam­ Pathol 1996;16:909–926. Kjær I, Hansen BF, Kjær KW, Skovby F. Abnormal timing in the prenatal bridge University Press, Cambridge, 2004. ossification of vertebral column and hand in Crouzon syndrome. Am J Gorlin RJ, Cohen MM, Levin L.S. (eds) Syndromes of the head and neck, Med Genet 2000;90:386–389. Kjær I, Hansen BF, Reintoft I, Keeling JW. Pituitary gland and axial 3rd edn. Oxford University Press, New York, 1990. skeleton malformations in human fetuses with spina bifida. Eur J Hansen L, Nolting D, Holm G, Hansen BF, Kjær I. Abnormal vomer Pediatr Surg 1999;9:354–358. Kjær I, Hjalgrim H, Russell BG. Cranial and hand skeleton in Fragile X development in human fetuses with isolated cleft palate. Cleft Palate- Syndrome. Am J Med Genet 2001;100:156–161. Craniofac J 2004;41:470–473. Kjær I, Keeling JW, Græm N. The midline craniofacial skeleton in Hansen L, Skovgaard LT, Nolting D, Hansen BF, Kjær I. Human prenatal holoprosencephalic fetuses. J Med Genet 1991;28:846–855. nasal bone lengths: normal standards and length values in fetuses with Kjær I, Keeling JW, Græm N. Cranial base and vertebral column in human cleft lip and cleft palate. Cleft Palate-Craniofac J 2005;42:165–170. anencephalic fetuses. J Craniofac Genet Dev Biol 1994;14:235–244. Hjalgrim H, Hahnemann JM, Kjær I, Brøndum-Nielsen K. Absence of Kjær I, Keeling JW, Græm N. Midline maxillofacial skeleton in human nasal bone and detection of trisomy 21. Lancet 2002;359:1343–1344. anencephalic fetuses. Cleft Palate-Craniofac J 1994;31:250–256. Hjalgrim H, Hansen BF, Brøndum-Nielsen K, Nolting D, Kjær I. Aspects Kjær I, Keeling JW, Hansen BF. The prenatal human cranium: normal of skeletal development in Fragile X syndrome fetuses. Am J Med and pathologic development. Wiley, Chichester, 1999. Genet 2000;95:123–129. Kjær I, Keeling JW, Hansen BF, Becktor KB. Midline skeletodental morphology in holoprosencephaly. Cleft Palate-Craniofacial J 2002;39:357–363. Kjær I, Keeling JW, Reintoft I, Nolting D, Hansen BF. Pituitary gland and sella turcica in human trisomy 21 fetuses related to axial skeletal development. Am J Med Genet 1998;80:494–500. Kjær I, Keeling J, Russell B, Daugaard-Jensen J, Hansen BF. Palate structure in human holoprosencephaly correlates with the facial malformation and demonstrates a new palatal developmental field. Am J Med Genet 1997;73:387–392. Kjær I, Wagner A, Madsen P, Blichfeldt S, Rasmussen K, Russell B. The sella turcica in children with lumbosacral myelomeningocele. Eur J Orthod 1998;20:443–448. Kjær I, Wagner A, Thomsen LL, Holm K. Brain malformation in single median maxillary central incisor. Neuropediatrics 2010;40:280–23.

Craniofacial syndromes and malformations 201 Lauridsen H, Hansen BF, Reintoft I, Keeling JW, Kjær I. Histological understanding of cleft aetiology. J Plast Surg Hand Surg investigation of the palatine bone in prenatal trisomy 21. Cleft Palate- 2014;48:126–131. Craniofacial J 2001;38:492–497. Russell BG, Kjær I. Tooth agenesis in Down syndrome. Am J Med Genet 1995;55:466–471. Lauridsen H, Hansen BF, Reintoft I, Keeling JW, Skovgaard LT, Kjær I. Russell BG, Kjær I. Postnatal structure of the sella turcica in Down Short hard palate in prenatal trisomy 21. Orthod Craniofacial Res syndrome. Am J Med Genet 1999;87:183–188. 2005;8:91–95. Saraga-Babic M, Saraga M. Role of the notochord in the development of cephalic structures in normal and anencephalic human fetuses. Lomholt JF, Hansen BF, Keeling JW, Reintoft I, Kjær I. Subclassification Virchows Arch A Pathol Anat Histopathol 1993;422:161–168. of anencephalic human fetuses according to morphology of the Schumacher R, Saever LH, Spranger J. Fetal radiology. A diagnostic atlas. posterior cranial fossa. Pediatr Dev Pathol 2004;7:601–606. Springer Verlag, Berlin, 2004. Siebert JR, Cohen Jr. MM, Sulik KK, Shaw C-M, Lemire RJ. Holopro­ Mølsted K, Boers M, Kjær I. The morphology of the sella turcica in sencephaly. An overview and atlas of cases. Wiley-Liss, New York, velocardiofacial syndrome suggests involvement of a neural crest 1990. developmental field. Am J Med Genet 2010;152A:1450–1457. Sonnesen L, Nolting D, Kjær KW, Kjær I. Associations between the development of the body axis and the craniofacial skeleton studied by Mølsted K, Kjær I, Dahl E. Spheno-occipital synchondrosis in three­ immunohistochemmical analysis using Collagen II, Pax9, Pax1, and month-old children with clefts of the lip and palate: a radiographic Noggin antibodies. Spine 2008;33:1622–1626. study. Cleft Palate-Craniofac J 1993;30:569–573. Tabatabaie F, Sonnesen L, Kjær I. The neurocranial and craniofacial morphology in children with solitary median maxillary central incisor Mølsted K, Kjær I, Dahl E. Cranial base in newborns with complete cleft (SMMCI). Orthod Craniofac Res 2008;11:96–104. lip and palate: radiographic study. Cleft Palate-Craniofac J Taylor E. (ed.) Dorland’s illustrated medical dictionary, 27th edn. WB 1995;32:199–205. Saunders, Philadelphia, 1998. Temraz J, Rethoré MO, Lejeune J, et al. Brain morphometry using MRI in Nielsen BW, Mølsted K, Kjær I. Maxillary and sella turcica morphology cri-du-chat syndrome. Report of seven cases with review of the in newborns with cleft lip and palate. Cleft Palate-Craniofac J literature. Am Genet 1993;36:75–87. 2005;42:610–617. Tuxen A, Keeling JW, Reintoft I, Hansen BF, Nolting D, Kjær I. A histological and radiological investigation of the nasal bone in fetuses Nielsen BW, Mølsted K, Skovgaard LT, Kjær I. Cross-sectional study of with Down syndrome. Ultrasound Obstet Gynecol 2003;22:22–26. the length of the nasal bone in cleft lip and cleft palate. Cleft Palate- Craniofac J 2005;42417–422. Ono T, Hansen BF, Nolting D, Kjær I. Nerve growth factor receptor immunolocalization during human palate and tongue development. Cleft Palate-Craniofac J 2003;40:116–125. Riis LC, Kjær I, Mølsted K. Dental anomalies in different cleft groups related to neural crest developmental fields contributes to the

CHAPTER 14 Craniofacial disruptions: prenatal and postnatal observations Disruption is defined as a defect caused by an external distur­ deviations. However, similar deviations can also be seen in cases bance of a normal development process. without fetal alcohol syndrome. Prenatal disruptions The etiology behind these changes in the brain, face, and dentition is presumably that alcohol affects the fat deposits in the Amniotic band: sequence brain and the myelin sheaths of the peripheral nervous system. It The amniotic band disruption complex, or the early amnion is believed that the demyelinization of the peripheral nerves rupture sequence, is characterized by a variation of combinations provoked by alcohol or virus attack causes this dysmorphology of fetal disruptions often involving different body regions, which can clearly be identified in the head but not in other parts including the cephalic region. Insight into normal prenatal of the body. Dentists and pediatric doctors therefore have a developmental sequences and changes in bone morphology special obligation to recognize and diagnose fetal alcohol during development makes it possible to distinguish ruptures syndrome. from malformations. Disruption of the limbs or a part of a limb is not difficult to understand etiologically. Cases in which the Maternal illnesses or medicinal intake during pregnancy may brain and/or face are disrupted are more complicated matters also influence fetal development. This aspect is not included here. (Figure 14.1). The disrupted fetus could have been abnormal in development (e.g. anencephalic) or it could have been normal Postnatal disruptions before disruption. In fetal pathology, this distinction is important for genetic counseling. Newborns with amniotic band disruption Premature birth in the face and brain often have a short postnatal life span. Several craniofacial parameters differ significantly between chil­ dren born prematurely and those born at full term. The most Virus infection and maternal alcohol intake pronounced differences are that preterm children have a shorter In the early prenatal period, it is difficult to determine how virus anterior cranial base, a less convex skeletal profile, and a shorter infection or alcohol intake during pregnancy affects the fetal maxillary length. cranium. Varicella can affect the prenatal tooth formation. Also maternal rubella can affect the dentition. However, knowledge Trauma within this field is very limited. A common trauma in the cranium during childhood is a mandibular condyle fracture. This fracture can result in asym­ Severe alcohol abuse by a pregnant woman can result in a metry of the jaws and face. Treatment for this type of trauma can child with reduced theca size and facial dysmorphology. The be lifelong (see Figure 7.12). Other forms of craniofacial trauma severity of the child’s condition may depend on when, how can be observed in anthropological material. much, and which type of alcohol was consumed. The facial dysmorphologies common to fetal alcohol syndrome are Virus and bacterial attack reduced ocular distance, a depressed nasal ridge, thin upper An example of a virus attack which can involve abnormal cranial lip, a smooth philtrum, and backward-tilted ears (Figure 14.2). development is meningitis. In some cases, this virus attack can In the maxilla, voluminous alveolar processes are often observed be complicated by hydrocephalus. Also the dentition can be (Figure 14.3). Regarding tooth formation, all types of deviations involved; this may include arrested eruption and arrested tooth may occur – from minor to severe, including eruption formation (see Figure 8.5), as well as undesirable resorption (see Figure 11.6). Little is known about this field. Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 202

Craniofacial disruptions 203 Figure 14.1 A photograph of the face and brain of a human fetus Figure 14.3 Dental cast demonstrating the upper jaw from the occlusal approximately 21 weeks GA which has been disrupted by amniotic bands view from a child with fetal alcohol syndrome. Note the very broad in the uterus. This is not a genetic disturbance. Source: Kjær et al. (1999). alveolar processes and the narrow palate. Reproduced with permission of John Wiley & Sons. Radiation and chemotherapy are known to affect tooth for­ Leprosy is caused by a bacterial attack (Mycobacterium leprae) mation (see Chapter 8) but may also affect sutural and condylar which leads to nerve inflammation and affects the innervation in growth (Figure 14.8). the body as well as in the peri-root sheet. The condition affects the maxillary incisors (see Figure 8.54) and the development of Acromegaly the nasal cavity and the anterior part of the maxillary bone Acromegaly is a condition in which growth hormones are (Figure 14.6). Various infections that affect tooth development produced in adulthood after the epiphyseal growth plates have and development of the alveolar process but without known closed. This is due to a pituitary adenoma. It is characteristic for craniofacial influence are described in Chapter 8. Infection might the hands and feet of the patient to become large and for the also affect the condylar growth (Figures 14.6 and 14.7). mandible to grow in length. The jaw growth often results in a reverse overbite and bilateral open bite (Figure 14.9). The first Brain tumors and radiation/chemotherapy sign of acromegaly is often observed by the dentist who notices Brain tumors in children can disturb the hard tissue formation in the change in occlusion. On a profile radiograph, it can be different ways. Examples appear in Chapter 2. observed that the sella turcica is enlarged (Figure 14.9) and the theca thickness also can be increased. Treatment is generally surgical and/or endocrinologically based. Figure 14.2 Illustrations and photographs from a child with fetal alcohol syndrome. The maternal alcohol intake has disrupted the peripheral and central nervous system. Note the short interocular distance, the depressed and broad nasal bridge, the low-set ears, and the reduced height of the upper lip. Exact information about the maternal alcohol intake is not known.

204 Chapter 14 Highlights and clinical relevance Figure 14.4 Disruption due to mandibular trauma can severely affect • There are deviations in the cranium and dentition which condylar growth and result in frontal asymmetry of varying degrees, as described in Figures 14.5 and 14.6. This section from a profile radiograph appear to be malformations but which are disruptions. The shows how a unilateral mandibular trauma has caused reduced growth etiology is different and the diagnostic process is difficult but (black arrows) in the trauma side when compared to the normally developed contralateral side (white arrows). There is a skeletal retrognathia necessary. of the mandible and a dental, compensatory increase in the inclination of • For many disruptions, it is important that the dentist notices the mandibular incisors. signs in the early stages and refers the patient to treatment. This includes trauma, hydrocephalic changes in the cranium, brain tumors, endocrine deviations, and fetal alcohol disruptions, all of which can have first signs in the craniofacial area. • It is important to be aware that chemotherapy affects dentition differently at the various stages of maturity. • Fetal alcohol syndrome is difficult to diagnose. Characteristic symptoms are:  mental disabilities  eruption problems in the dentition (see Figure 13.16)  broader than normal alveolar process  thin upper lip  smooth philtrum. Figure 14.5 Cranial remnants from two individuals who suffered from leprosy. Both cases have resorption of bone anteriorly in the maxilla which is thought to be a disruption due to infection. (Left) A cranium showing that Mycobacterium leprae has disturbed the bone tissue in the anterior maxilla. The bacteria thrive in a moist environment and can live in the outer nasal mucosa and the nasal floor. From this position, the bacteria disturb the local bone tissue. Note that this anthropological case has already developed the incisive roots, meaning that the cranium is from an individual who is presumably older than nine years. (Right) An early attack by M. leprae (upper) causing exposure of the roots of the maxillary incisors. In this case, the incisors are not fully developed and the photograph below illustrates how a bacterial attack during tooth development can change the tooth morphology. The individual in these photographs must therefore be younger than the individual to the left. (Lower right) Incisor development which has been disturbed by an early bacterial attack shortly after the crown has formed. In this case, there are no cranial remnants. Source: Møller-Christensen (1978). Reproduced with permission from Odense University Press.

Craniofacial disruptions 205 Figure 14.6 Demonstration of a human cranium with a mandibular, condylar ankylosis in the right side. This is thought to be a disruption due to infection. (Left) Close view of the condylar area demonstrating abnormal bone tissue and ankylosis which inhibit normal jaw movements for mastication. (Right) An orthopantomogram of the same human cranium demonstrating the asymmetrical mandibular development and the ankylosis. The ramus in the right side is short and a gonial notch (arrow) appears antegonially. The teeth that are missing in the left side are thought to have been removed in order to enable food intake. The mandibular asymmetry is mild which indicates that the infection in the right jaw occurred late in development and did not have a serious impact on condylar growth. Figure 14.7 An anthropological cranium which demonstrates a left-side ankylosis of the mandibular condyle. What has caused this ankylosis is not known but it might be due to infection. (Left) A lateral view of the cranium demonstrates the abnormal morphology of the mandibular condyle, the short mandibular ramus, the prominent gonial region, and the deep antegonial notch. These are characteristics indicating that disruption of the mandibular condyle occurred during childhood and resulted in a significant reduction in mandibular prognathia. (Right) Frontal radiograph of the same cranium demonstrating the significant asymmetry of the mandible due to ankylosis of the condyle in the left side. This asymmetry supports the theory that this disruption occurred during childhood. Note that the upper jaw and the rest of the cranium are apparently not affected. Figure 14.8 Two radiographs from the same child demonstrating how chemotherapy can apparently disrupt both tooth development and jaw growth. (Left) Orthopantomogram demonstrating the influence of chemotherapy on bilateral root formations of premolars and permanent second molars. The root appears short due to disruption caused by chemotherapy. As the first molars have a normal length, it can be assumed that the chemotherapy started after these teeth were fully developed. It is suggested that the therapy could have started at the age of 9–10 years. (Right) A profile radiograph of the same child showing a significant retrognathia of the maxilla. It is suggested that pubertal growth in the many sutures that surround the maxilla has been disrupted by chemotherapy.

206 Chapter 14 Figure 14.9 Two profile radiographs from the same individual taken a few years apart. (Left) This radiograph was taken because of the patient’s incisor occlusion and lateral open bite. The patient missed several appointments and came back to the clinic a few years later. (Right) This radiograph was taken when the patient returned to the clinic. A reverse overjet has now developed and the lateral open bite is increased. The dentist noticed the enlarged sella turcica (arrow) and suspected acromegaly, a condition in which normal arrest of cranial growth is disrupted due to overproduction of growth hormone caused by a pituitary gland adenoma. The disruption causes the sella to become enlarged and the reactivation of condylar growth results in an enlarged and protruding mandible which is the etiology behind the reverse overjet. The patient was referred to a neurologist and was treated for acromegaly. Further reading Kjær I, Keeling JW, Hansen BF. The prenatal human cranium: normal and pathologic development. Munksgaard, Copenhagen, Buyse ML (ed). Birth defects encyclopedia, Blackwell Scientific Publica­ 1999. tions, Oxford, 1990. Møller-Christensen V. Leprosy changes of the skull. Odense University Gilbert-Barness E, Debich-Spicer D. Embryo and fetal pathology. Cam- Press, Odense, 1978. bridge University Press, Cambridge, 2004. Poulsson L. Premature birth. Studies on orthodontic treatment need, Keeling JW (ed). Fetal and neonatal pathology, 2nd edn. Springer Verlag, craniofacial morphology and function. Swedish Dent J 2009; London, 1993. 199 (suppl):7–110. Keeling JW, Kjær I. Diagnostic distinction between anencephaly and amnion rupture sequence based on skeletal analysis. J Med Genet 1994;31:823–829.

CHAPTER 15 Craniofacial dysplasia: prenatal and postnatal observations Endochondral and intramembranous bone craniofacial region: cartilage, bone, epithelium, connective tissue, dysplasia in the cranium enamel, and dentin. The cranium is composed of both cartilage-formed bones and Chondrodystrophy intermembranously formed bones (see Chapter 1). Bones which Chondrodystrophia involves a maldevelopment of the skeleton are partially formed by both processes also exist. Furthermore, due to abnormal cartilage formation. There are several variations there are some bones which appear to have arisen intermem­ and diagnoses for chondrodystrophia before birth. Prenatal branously but are supported by cartilaginous tissue during studies aim to highlight when and where ossification occurs formation. How this cartilage influences the bone formation is and to elucidate the condition histologically. Figure 15.2 depicts a not known. Dysplasia in bone formation is a congenital, meta­ radiograph of structures in the cranium from a thanotophoric bolic cell disturbance in osteoblasts (see Chapter 7). fetus (chondrodystrophia case) in which the early ossification process is highly irregular. From the histological section An overview of the cartilaginous and intermembranous ossi­ (Figure 15.3), it can be observed how the cartilage and the sella fication sites in the cranium appears in Figure 15.1, in which a turcica are deviated. schematic drawing of the human profile illustrates the various origins of bone tissue. An example of a bone that is purely Figure 15.4 depicts a postnatal frontal and profile radiograph endochondral is the ethmoid bone. A bone that is intramem­ of an individual with the tentative diagnosis of chondrodystro­ branous is the parietal bone. A bone that arises from a combina­ phia. It appears that the cranial base angle is reduced and the tion of these two ossification processes is the occipital bone which cartilaginous part of the occipital squama is thin and caudally is mostly formed by cartilage while the uppermost part of the positioned. occipital squama is intermembranously formed. Some other bones are formed intermembranously but are supported by Osteogenesis imperfecta cartilage during formation. These include the nasal bones, the This type of bone dysplasia is a genetic disease caused by a vomeral bone, and the central part of the mandible. In prenatal collagen defect which results in an elevated risk for bone frac­ life, it is easy to distinguish between the different etiologies of tures. There are various types as well as varying degrees of bone formation, but this is more difficult postnatally. Figure 1.30 severity. Cranial radiographs from patients with osteogenesis provides an example of a fetus with an ossification defect in the imperfecta are demonstrated in Figures 15.5 and 15.6. It appears mandible where only the intermembranously formed area sup­ that the cranial base angle is enlarged. ported by cartilage has not been formed. Only certain parts of the mandible have ossified when compared to a normally developing Osteosclerosis mandible (see Chapter 1). Osteosclerosis is an increase in the density of bone tissue. On radiographs, these areas appear as white shadows which In this chapter, different types of dysplastic conditions of the indicate hypermineralization of the bone tissue. This may cranium will be elucidated. There are many conditions that be a general characteristic of an individual’s skeleton or it involve dysplasic developmental processes in the craniofacial may be restricted to a specific region, provoked by a local region. factor such as an infection. In the everyday dental/orthodontic clinic, patients with osteosclerosis-like symptoms are observed A selection of dysplasias is listed below; this is not a complete often without a medical diagnosis (Figure 15.7). This is a field list but rather a sample of the cases most often seen clinically. in need of elucidation. The dysplasia conditions mentioned have been chosen because they exemplify dysplasia in the following tissue types in the Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 207

208 Chapter 15 Figure 15.1 A schematic drawing of the human skull indicating the bony origins from cartilage (green) and intramembranously (red). Bone with an intramembranous origin developing on a scaffold of cartilage is marked by diagonal lines (nasal bone, vomeral bone, and the anterior part of the mandible). If dysplasia occurs in the cartilaginous tissue, it may affect the cranial base, the ethmoid bone, and/or the occipital field including the cervical vertebrae. If dysplasia occurs in intermembranous tissue, it might affect the thickness of the theca cranii. Source: Gjørup et al. (2011). Reproduced with permission of John Wiley & Sons. Figure 15.2 Radiographs of the trunk, maxilla, and cranial base from a stillborn fetus with thanatophoric dysplasia (thanatophoric = Greek “death bearing”). This is a rare skeletal disorder characterized by short limbs, an enlarged head, and wide-set eyes. The etiology is a mutation in the FGFR3 gene which is involved in the development of the bone and brain tissue. (Left) A radiograph of the trunk demonstrating severe dysplasia of the vertebral bodies which are partly absent and of the vertebral arches which are completely absent. Other bones in the radiograph, including the ribs and clavicles, appear abnormal. (Right) Note the abnormal contours of all bones. One example is the basilar part of the occipital bone, the sphenoid bone complex, the nasal bone, the maxillary and palatine bone as well as the lower part of the frontal bone. This is a dysplasia condition involving cartilaginous bone tissue as well as intramembranous bone tissue.

Craniofacial dysplasia 209 Figure 15.3 Histological appearance of prenatal chondrodystrophia and a radiograph of the cranial base in a fetus with this condition. (Upper left) The sella turcica from a chondrodystrophic fetus. Note the wavy, uneven anterior wall which is cartilaginously formed. (Middle and lower left) Histological sections from chondrodystrophic fetuses illustrating the sporadic occurrence of mucopolysaccharides seen in Alcian green staining (middle) and toluidine blue (lower). All the cells appear as chondrocytes in morphology but the intercellular matrix appears abnormal. (Right) A radiograph of the cranial bases with the mandible attached from a fetus 21 weeks GA with chondrodystrophia. Anterior points upward. The most striking feature is the very small mandible (black arrows). The position of the symphisis menti is marked by a yellow star. At this time in development, the mandible should extend to the incisive foramen region (white arrow). The condylar dysplasia has resulted in reduced growth of the cartilaginous mandibular condyle. Another observation worth noting is the thick, ossified region surrounding the basilar part of the occipital bone (red arrows). Similar ossification patterns are observed in the phalangeal bones and long bones of the body. This pattern illustrates the abnormal ossification in this condition. Figure 15.4 Radiographs from an adult patient with a tentative diagnosis of chondrodystrophy which is a term for “cartilage maldevelopment” when a more precise diagnosis is not possible. It appears from the profile radiograph (left) that the cranial base is short, the cranial base angle is diminished, and that there is an occipital “drop.” The skull is thin in the occipital region which is cartilaginously preformed. The posterior wall of the sella turcica is delicately thin and the sinuses are large. On the frontal radiograph (center), the large frontal sinuses are also visible. A section from an orthopantomogram is provided to the right displaying taurodontic roots. The space for the periodontal membrane is not clearly visible.

210 Chapter 15 Figure 15.5 A series of profile radiographs from childhood (six years of age) to adulthood (28 years of age) from an individual with a tentative diagnosis of osteogenesis imperfecta (OI). The series illustrates the abnormal developmental relationship between the jaws which clearly becomes more severe with time. OI is a congenital, connective tissue condition which typically results from deficiency in collagen production. The exact type of OI and the genotype of the patient are not known. Cephalometric measurements revealed an increased cranial base angle. Figure 15.6 Profile radiograph from an adolescent male with osteogenesis imperfecta. Note the increased cranial base angle. Figure 15.7 Radiographs from a patient who approached an orthodontic clinic for treatment. The radiographs revealed general osteosclerosis in the cranium. The condition is characterized by an abnormal increase in skeletal density which sometimes compromises the bone marrow space. The condition is diagnosed by increased radiographic opacity suggesting an increase in mineral deposition. This might also create difficulties regarding orthodontic treatment. The child was referred to a medical hospital for special treatment.

Craniofacial dysplasia 211 Figure 15.8 Profile radiograph of a patient with hypophosphatemic rickets Figure 15.9 Profile radiograph from a child approximately eight years of which is a condition characterized by low serum phosphate levels. The age with dysostosis cleidocranialis. This condition is normally inherited condition is generally linked to vitamin D deficiency, as in the case but can also occur without a known etiology. Open skull sutures and large presented, but other etiologies also exist. Note the significantly increased fontanelles are characteristic in the cranium. Examples appear clearly in thickness of the skull. Source: Gjørup 2011. Reproduced with permission the radiograph where the theca bone structure “disappears” in the coronal of John Wiley & Sons. fontanelle region (white arrow) and appears to be very thin in the lamboidea region (blue arrow). The skull is thicker than normal in the occipital region. The teeth are late in eruption. Hypophosphatemic rickets Prenatal studies have so far not provided information on the The craniofacial deviations of this condition have recently been ossification process in this syndrome. intimately studied. Traditionally, rickets is defined as a disease caused by vitamin D deficiency, which results in abnormal Dysplasia in nonosseous tissue calcium and phosphorus metabolism and deficient mineraliza­ tion of bone with skeletal deformities. Though rickets are linked Ectodermal dysplasia to vitamin D metabolism, other etiological factors have been Ectodermal dysplasias are a group of conditions in which there described. A profile radiograph from an individual with this are abnormalities of several ectodermal structures. More than condition is shown in Figure 15.8; the patient has vitamin D- 150 different kinds of ectodermal dysplasia have been defined. deficient hypophosphatemic rickets. The most apparent signs are Some types involve severe cases of agenesis and deviations in the extremely thick theca bones which are endochondral as well as enamel formation which is ectodermally formed. Regarding the intermembranously formed. cranium, where ectodermal tissue is not involved, cranial radio­ graphs show normal development. Multiple agenesis and lack of Dysostosis cleidocranialis alveolar bone, which can occur in this condition, influence the This condition appears as a delayed ossification of the midline jaw morphology observed on profile radiographs (Figure 15.11). structures of the body. This can be observed through hypopla­ sia of the clavicle, open skull sutures, and large frontal fonta­ Localized scleroderma en coup de sabre nelles. The face is characterized by hypertelorism – widely set Localized scleroderma en coup de sabre is a localized, connective eyes. In the dentition, supernumerary teeth are observed (see tissue dysplasia condition. Local changes are observed in con­ Chapter 9). An open cranial fontanelle is demonstrated in nective tissue, skin, and dentin. The condition is described in Figures 15.9 and 15.10. It is characteristic for the theca to Chapter 10. A similar condition is called Perry Romberg disease. appear thin in the frontal and parietal areas. Also the intra­ membranous upper part of the occipital squama appears very thin. On a frontal radiograph, the open fontanelle can be clearly seen in the frontal-parietal region (see Figure 15.10).

212 Chapter 15 Figure 15.10 Demonstration of the cranium and the dentition in an individual with dysostosis cleidocranialis (DC). This condition is normally inherited but can also occur without a known etiology. Open skull sutures and large fontanelles are characteristic in the cranium. In the cranial radiographs, a large, open coronal fontanelle is indicated on the frontal radiograph by a dark area in the uppermost part of the frontal bone. The fontanelle is not visible in the profile. The interocular distance is greater than normal and the profile radiograph depicts a relatively thick skull in the occipital field as well as molars ectopically located in the angulus mandibulae. The orthopantomogram to the right displays several ectopically located teeth including permanent molars, premolars, incisors, and canines. It is well known that eruption problems and often supernumerary teeth are dental characteristics of DC. Figure 15.11 Demonstration of cranium and dentition in a patient eight years of age with ectodermal dysplasia (ED). ED is a genetic disorder with more than 150 variations in which the hair, teeth, nails, and sweat glands can be affected. Although bone tissue is not directly affected, the mandible and maxilla are strikingly “undeveloped.” This is due to the involvement of the dentition in ED. The orthopantomogram to the right reveals that 22 permanent teeth are absent due to agenesis (third molars are not included). Agenesis also occurs in the primary dentition. The presence of teeth and the eruption of teeth in the jaws are the foundation for the development of the alveolar processes. When teeth are absent, the alveolar processes do not develop and the anterior face height is diminished. There are two special dysplasias which are generally only have posterior, lateral open bite. The occurrence of open bite in associated with changes in the teeth: amelogenesis imperfecta all three patients might indicate that the etiology behind primary and dentinogenesis imperfecta. Profile radiographs of these two failure of eruption could be linked to a defect similar to the conditions are not normally of special concern but will be amelogenesis imperfecta condition. This seems to be an inter­ provided here. esting topic for further investigation. Amelogenesis imperfecta Dentinogenesis imperfecta and dentin Amelogenesis imperfecta is a severe enamel tissue dysplasia dysplasia which is discussed in Chapter 8. Eruption problems in this Dentinogenesis imperfecta is a severe dentin dysplasia which condition are included in Chapter 10. is discussed in Chapter 8. Profile radiographs of patients with dentinogenesis imperfecta are provided in Figures 15.13 Three patient cases with this condition are demonstrated in and 15.14. The osseous contour of the cranium appears Figure 15.12. The theca cranii appears slightly thicker than normal. normal, but there are no apparent changes in the osseous tissue. Possible variations are seemingly within the nonsyndromic There are forms of osteogenesis imperfecta in which dentino­ spectrum. Of special interest is that the patients all seem to genesis imperfecta is also present (both conditions involve

Craniofacial dysplasia 213 Figure 15.12 Radiographs from three different young adults diagnosed with amelogenesis imperfecta (AI). The two radiographs in the upper center and upper right are from the same patient. The two lower radiographs are from another patient. AI is a condition of enamel dysplasia. Over 10 different types of AI have been identified and described with different involvement of the dentition from very mild cases to very severe cases. The bone tissue does not appear to be directly affected in AI. Newer studies have revealed that the theca bone tends to be thicker in AI. Also noteworthy is that each patient has a posterior, lateral open bite. In the dentition demonstrated in the orthopantomogram (lower right), eruption problems can be identified in the molar fields. See Chapter 8 for further information. Figure 15.13 A profile radiograph from a patient 14 years of age with dentinogenesis imperfecta (DI). Primary failure is seen in dentin formation through discoloration of the teeth (see Chapter 8). Three types of DI have been described, of which type I occurs together with osteogenesis imperfecta. The profile radiograph presented has a seemingly normal appearance.

214 Chapter 15 Figure 15.14 Radiographs from a patient with dentinogenesis imperfecta. In this condition, primary failure is seen in dentin formation through discoloration of the teeth (see Chapter 8). Three types of DI have been described, of which type I occurs together with osteogenesis imperfecta.The profile radiograph (left) appears normal while the orthopantomogram (right) reveals abnormal molar morphology. The molars become narrow in the cervical region and the pulp chamber contours are not visible in several teeth. These are characteristic radiographic findings for DI. Figure 15.15 Radiographs from a patient with dentin dysplasia (DD). DD is a genetic disorder in which two subgroups have been classified. Type I affects primarily the tooth roots and pulp chambers (obliterated) while type II affects the crown and the pulp chambers (enlarged). The profile radiograph reveals possible irregularities in the cervical spine and a “drop” in the occipital region but otherwise normal features. The orthopantomogram reveals that this patient has a type II dentin dysplasia. a collagen defect). In a case where both are present, osteo­ Highlights and clinical relevance genesis imperfecta is maintained as the general diagnosis. In dentin dysplasia, the craniofacial profile appears with a “drop” in • Signs and symptoms registered prenatally can be rediscovered the cartilaginous formed occipital squama region but otherwise postnatally. less affected (Figure 15.15). • Prenatal pathology is a field that allows detailed tissue analysis Suture dysplasia which is essential for understanding early human develop­ Normal cranial development requires normal suture and fonta­ ment. One example is the association between sella turcica nelle development. It has been exemplified in cleidocranial morphology and the distribution of the pituitary gland tissue. dysostosis that a deviation in the fontanelle/sutures can create Fetal pathology can systematically illustrate the early tissue a squareish head and changes in the theca bone thickness. association that can improve postnatal diagnostics. Synostosis describes a condition in which sutures close prema­ turely. Whether this is a bone tissue dysplasia or a connective • Despite the ability to study dysplasia both pre- and postnatally, tissue dysplasia is not yet clear. Three patient cases in an etiological evaluation can be difficult. Cranial synostosis Figure 15.16 demonstrate the deviant cranium morphology could be a malformation (see Chapter 12) or a dysplasia. An despite a seemingly unaffected dentition. The abnormal skull example is given in Figure 15.17 of a presumed cloverleaf skull seen in Cloverleaf skull, which is a severe form of craniosynos­ from a newborn. It is difficult to determine whether it is the tosis and suture development, is demonstrated in Figure 15.17. endochondral or intermembranous tissue that is dysfunctional or whether it is a combination, but the condition is clearly a lethal dysplasia.

Craniofacial dysplasia 215 Figure 15.16 Radiographs demonstrating three different patients with cranial synostoses (presumably oxycephaly). The lower radiographs are from the same patient. The three cases have different cranial and cervical spine morphologies but in all three cases the skull morphology is pointed due to early closure of the coronal suture. Other sutures may be involved in this premature closure as well. Note the impressiones digitatae which are present on the internal skull following the shape of the brain surface. The orthopantomogram visualizes normal morphology of the dentition. Figure 15.17 An anthropological cranium from a newborn supposedly with a cloverleaf skull. Source: Reproduced with kind permission of T. Söderqvist.

216 Chapter 15 • Bone tissue is fragile in osteogenesis imperfecta and patients Gjørup H, Kjær I, Sonnesen L, et al. Craniofacial morphology in suffer from multiple fractures. From profile radiographs, it patients with hypophosphatemic rickets: a cephalometric study appears that the theca cranii can also be very thin. focusing on differences between bone of cartilagenous and intra­ membraneous origin. Am J Med Genet Part A 2011;155: • When observing dysostosis cleidocranialis, the theca bones 2654–2660. vary in thickness. In the jaws, increased bone thickness occurs and this may influence the severe eruption problems associated Gjørup H, Kjær I, Sonnesen L, et al. Morphological characteristics of with this condition. frontal sinus and nasal bone focusing on bone resorption and apposition in hypophosphatemic rickets. Orthod Craniofac Res Further reading 2013;16:246–255. Brons JTJ, van der Harten JJ. Skeletal dysplasias. Pre- and postnatal Kjær I, Matthiessen ME. Mitochondrial granules in human osteoblasts identifications. An ultrasonographic, radiologic and pathologic study. with a reference to one case of osteogenesis imperfecta. Calcif Tissue Thesis, University of Amsterdam, 1988. Res 1975;17:173–176. Buyse ML (ed). Birth defects encyclopedia. Blackwell Scientific Publica­ Kjær I, Matthiessen ME. Cytochemical and ultrastructural character­ tions, Oxford, 1990. istics of human osteoblasts in relation to general skeletal growth activity. Calcif Tissue Res 1976;21:102–107. Gjørup H. The morphology of the cranium and the cervical vertebral column in patients with hypophosphatemic rickets. PhD thesis, Nolting D, Hansen BF, Keeling JW, Kjær I. Histological examinations of Aarhus University, 2014. bone and cartilage in the axial skeleton of human triploidy fetuses. APMIS 2002;110:186–192. Rice DP (ed). Craniofacial sutures: development, diseases and treatment. Frontiers of Oral Biology vol. 12 Karger, Switzerland, 2008.

CHAPTER 16 Hard tissue as a diagnostic tool in medicine Introduction • The ectodermal cell layer has a determining influence on tooth morphology, eruption, and resorption. In this book, neuroosteological factors are central for etiology- based diagnostics. It is characteristic for neurologists and neuro­ • Cellular signaling between the ectoderm, ectomesenchyme, physiologists to consider only the central nervous system (CNS) and innervation can provide an etiology-based understanding and peripheral nervous system (PNS) development while den­ of deviations in the dentition. tists and doctors with specific bone tissue expertise focus pre­ dominantly on mineralized hard tissue. Neuroosteology bridges • Seemingly normal dentitions are phenotypically different. these disciplines. • Lastly, there is complete agreement between the deviations Furthermore, the contents of this book have highlighted observed in syndromes and dysplasia in prenatal and postnatal interrelationships between the development of hard tissues life. pre- and postnatally. However, there are still many associations The many associations presented have been explored and in cranial and body axis development that are not understood. explained as well as is currently possible. As a general conclusion, the etiology-based diagnostics presented in this book highlights The intentions of this book have been to demonstrate the that prenatal pathology predicts postnatal development. following. • There is an interrelationship between dental and craniofacial Perspectives for prenatal craniofacial pathology development. • There is an association between the maturation stages of In spontaneously aborted fetuses, it can be difficult to make a diagnosis. This can be due to the fact that the fetus is disinte­ different bones in the body. grated due to intrauterine death or that it was disrupted by the • There is a close association between development of the body amnionic bands, as demonstrated in Figure 14.1. In cases like these, analysis of the hard tissue which does not disintegrate is axis and the cranium. vital for pathological diagnostics. Examples include the registra­ • There is a close association between cranial development and tion of the nasal bone, which is short in several syndromes such as trisomy 21, trisomy 18, and cleft lip. Also, analysis of the vertebral development of the brain. column can provide information about pathological develop­ • There is an interrelationship between prenatal and postnatal ment. Fusion between the vertebral bodies can reveal triploidy, and regional vertebral body malformations such as twin bodies deviations in bone tissue. and malformed bodies can reveal trisomy 21, trisomy 18, and • There is a connection between the deviations in primary and trisomy 13 (Figure 16.1). The absence of a single or several vertebral bodies can indicate malfunction of the notochord permanent dentition. (Figure 16.2). • Developmental fields in the cranium and dental arches can be The basilar part of the occipital bone, as mentioned in used in etiology-based diagnostics. Chapter 2, can reveal CNS malformations. The sella turcica • Developmental fields in the cranium arise from various cell has not ossified completely during the first 21 weeks GA but malformation in the floor which arises first may occur. Malfor­ migrations from the neural crest. mations of the sella floor demonstrate various deviations which • Developmental fields in the alveolar bone subdivide the dental are different according to the genes involved (Figure 16.3). arches into segments which are innervated separately. • The periodontal membrane covering the root has three layers (peri-root sheet) which can contribute to the explanation of eruption and resorption. • There is an interrelationship between the deviations found in the various fields in the dentition and between the dentition and the fields in the cranium. Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 217

218 Chapter 16 In fetal pathology, other body parts useful for hard tissue diagnosis are the extremities, specifically the hands and feet. Absence of phalangeal bones or supernumerary phalangeal bones as well as morphological deviations of these are important in fetal pathological diagnostics. Also the developing dentition can reveal congenital disruption (Figure 16.4). Perspectives for perinatal and pediatric pathology Figure 16.1 Schematic drawing of four body axes from four fetuses with The prenatal deviations presented above can help to explain the different genotypes. From left: trisomy 18, trisomy 21, trisomy 13, and perinatal and postnatal conditions. It is therefore important to triploidy. Green indicates a normal appearance, red indicates a conduct a hard tissue analysis including the nasal bone, the pathological appearance, and yellow represents areas which are sometimes vertebral column, the hand, and the cranial base in newborns normal and sometimes pathological. N, nasal bone; S, sphenoid bone; O, where the phenotype does not provide clarity for diagnostics. basilar part of the occipital bone; C, cervical vertebrae; T, thoracic Although most bone tissue is formed early in the prenatal period, vertebrae; L, lumbosacral vertebrae. Note that the different parts of the there are bony structures that form later in prenatal life and even body axis express different development in different genotypes. This can in the beginning of postnatal life. Occipitalization is an example be compared to fields in cranial development. of a condition which can first be observed postnatally. Figure 16.2 Two radiographs of the upper part of the vertebral column from two spontaneously aborted fetuses both 12–14 weeks GA. Autopsy did not reveal any pathological anatomical diagnoses. (Left) A thoracic vertebral body is absent (arrow). (Right) Two cervical arches are missing bilaterally (arrows). These radiographs reveal an abnormality in the development of the vertebral column which signaled a congenital body axis malformation. Figure 16.3 Two histological sections of the sella turcica/pituitary gland region from two human fetuses. (Left) Trisomy 21 fetus GA 18 weeks. (Right) Trisomy 18 fetus GA 18 weeks. Anterior points to the left. Note that a channel appears in the floor of both sellae but that the ossification related to the channel differs in the two genotypes. In trisomy 21, ossification of the cartilage occurs posteriorly to the channel (star). In trisomy 18, ossification of the cartilage appears anteriorly to the channel (star). This supports the observation that the sella turcica is composed of posterior and anterior sections in development (see Chapter 1) and that these two sections have different deviations in different genotypes.

Hard tissue as a diagnostic tool in medicine 219 Also, the neuroosteological interrelationship between the brain malformation and the single median maxillary incisor has been highlighted in this book (see Chapter 13). Figure 16.4 A histological section of the sella turcica/pituitary gland Neurological aspect involving the CNS region from a spontaneously aborted human fetus approximately GA 19 The neuroosteological aspect has also been covered in relation to weeks in which a pathological anatomical autopsy did not reveal the Arnold–Chiari syndrome in Chapter 2, in velocardiofacial syn­ etiology behind the abortion. The section of the cranial base including the drome, mentioned in Chapter 3, and in cri du chat syndrome, maxillary incisor reveals a seemingly disruptive change in the tooth bud mentioned in Chapter 13. In myelomeningoceles and hydro­ and the crown follicle. In this case, an abnormally functioning placenta cephalus, this neuroosteological aspect has also been discussed was later registered as a possible etiological explanation for the disruption, (Chapter 13). One question which has not been elucidated is diagnosed in the dentition. whether the severity or the number of osseous deviations, which can be observed for example in Down’s syndrome, fragile X Perspectives for clinical and basic research syndrome, and fetal alcohol syndrome, are related to the mental status. In other words, is a Down’s syndrome fetus with severe body axis malformation, absence of finger bones, short nasal bone, and a severe craniofacial malformation more mentally affected than one with only a single deviation in a cervical vertebral body? Another question is whether the type of occipitalization that results in a narrow foramen magnum, difficult to diagnose, might be the cause of unexplainable neurophysiological conditions. This has seemingly never been answered. The prenatal cranium as a predictor for Neurological aspect involving the PNS postnatal development The peripheral nervous system has proven to be an important key Prenatal pathology provides a unique basis for understanding in etiology-based diagnostics of the dentition (see Chapters perinatal and postnatal pathology. This perspective has been 8–11). Virus and bacterial attacks can spread through innerva­ highlighted throughout the book. When a child is born, traces of tion pathways and destroy dental and cranial regions within their prenatal bone defects might no longer be apparent. In the early innervation fields. The fact that tooth development can be stages, the corpus of the occipital bone can reveal different affected by virus attack is relatively new knowledge. The use genetic conditions, as illustrated in Figure 16.5. Also early fusion of penicillin-like products means that there are few deviant and nonseparation of bony elements are keys that can be used to changes in the dentition due to bacterial attacks. The relationship evaluate when and where a defect arose. This is exemplified by between bacterial infection and dental formation is especially velocardiofacial syndrome See chapter 13. Defects and absence of clear anthropologically in cases like leprosy (see Chapter 14). Not osseous tissue formation can be observed in prenatal life, but at only virus attacks but also malformation of the peripheral nerves the time of birth these signs have often disappeared due to influence tooth and jaw development. This can be observed in apposition and overlapping of structures. Figures 2.34 and 10.19, which are cases that demonstrate how hard tissue embryology can reveal peripheral nerve malforma­ The cranium can also act as a predictor for brain abnormali­ tions which otherwise would not have been discovered. ties, especially regarding the pituitary gland and the sella turcica. Figure 16.5 Schematic drawing of five different morphologies of the basilar part of the occipital bone. The drawings are based on five different human fetuses GA 18 weeks with different diagnoses. From left to right: anencephaly without myelomeningocele, anencephaly with myelomeningocele, lumbosacral myelomeningocele, Mechel–Gruber syndrome, and trisomy 18 syndrome. The normal contour of the bone is illustrated by the broken line. The different conditions are characterized by different morphologies of this bone. To the right is a photograph of a deviscerated basilar part of the occipital bone from a human fetus with trisomy 18 GA 21 weeks. Note that the notch (arrow) in the bone appears unilaterally. Bilateral notches can also occur (as seen in the illustration). The notches always appear at the same level of the bone. Source: Kjær et al. (1999). Reproduced with permission of John Wiley & Sons.

220 Chapter 16 Dermatomes example is hypophosphatasia, where the dentist observes The paraxial mesoderm of the body axis undergoes segmentation missing or exfoliating teeth (see Figure 10.52). Other diseases and forms the epithelial somites. The somites differentiate into such as hyper-IgE are also often first recognized by a dentist sclerotomes, dermatomes, and myotomes. The dermatomes lie (see Chapter 10). underneath the surface ectoderm and contribute to the dermis of the skin. Each single dermatome is innervated by a single spinal Etiological evaluation nerve. The dermatomes in the cranium are poorly understood Many diseases manifest unchangeable markings in the teeth and and it is likely that the craniofacial fields described in Chapter 3 possibly also in the jaws. These markings can provide informa­ are dermatome fields on the surface and that these fields stretch tion on the etiology of the disease. An example is the three cleft lip deeper into the underlying tissue. It is well known from body and palate conditions, in which both the teeth and the jaw bones analysis that the dermatomes overlap slightly (meaning that they reveal that there are three different phenotypes, which in turn share peripheral innervation). It is probable that there are also indicates three separate etiological backgrounds for these seem­ overlaps in the dermatomes of the craniofacial region. These ingly similar conditions (see Chapter 13). Former studies in this overlaps could be a key in the etiology of transposition of teeth. field have suggested that the cleft lip, cleft palate, and combined This is currently a hypothetical concept which is difficult to cleft lip and palate are phenotypic variations which arose at prove. Following the same thought pattern, agenesis of the different times. canines (which are located on the border between two fields) could be due to a small gap (“underlap”) between dermatomes. The dentition reveals complications after infections and This is currently the only way in which agenesis of the canines in operations otherwise normally developed dentitions can be understood. The dentition can reveal the after-effects of a viral or bacterial infection in the body and also complications after operations in Endocrine perspective the head and neck region, as exemplified in Chapter 8. From an endocrine perspective, it is also important to study the osseous tissue. The pituitary gland and the bilateral vomeronasal The changes that occur in the dentition during leprosy can organs develop prenatally. These bilateral endocrine glands are appear similar to changes seen on radiographs during resorption crucial for producing luteinizing hormone releasing hormone of permanent teeth where the etiology is unknown. In this way, (LHRH) during early fetal life. If this hormone is lacking, then known diseases affecting the dentition can contribute to deeper skeletal development during puberty is abnormal. These are also insight into the mechanism behind abnormal developmental reasons for studying fetal pathology as a base for understanding patterns. postnatal development. The dentition reveals complications after medical As a conclusion, the results gained through fetal pathology are treatment valuable for postnatal diagnostics not only in dentistry but also in Examples of this type mentioned in the book are changes in the branches of pediatrics. dentition primarily due to chemotherapy. How different types of chemotherapy and different doses affect the dentition is not clear. The dentition as a diagnostic tool in medicine This is often due to lack of permission for dentists to analyze Onset of a disease medical cancer treatment protocols. The dentition can indicate by a mark in the enamel the onset and duration of a malformation or disease. Examples are given in There is a long list of other medical treatments that appear to several chapters. Furthermore, a condition called molar incisor influence the dentition. In Figure 16.6, a child who has received hypoplasia (MIH), which appears as brownish spots occlusally in treatment for epilepsy over several years displays deviant denti­ the permanent first molars and as brownish bands on the facial tion changes. However, despite the apparent connection, there is surface of the permanent incisors, is suggested to reveal a general no evidence for the influence of these treatments on the denti­ health state at the time of birth. MIH is restricted to the early tion. This is an important area for future elucidation. perinatal period, but the etiology is not known (see Figure 8.59). From an odontological perspective, this condition is sometimes Association between dental and craniofacial associated with pain in the teeth, which may, in severe cases, development result in tooth extraction. The information which comes from the neural crest of the brainstem to the cranium is the same information that is received Dentition as a first indicator of abnormal development by the teeth. There is therefore a clear association between The dentition can be the first indicator of a general disease or deviations in the teeth and in the cranium. For the dentist, a syndrome. The condition solitary median maxillary central this means that close observation and attention should not incisor (SMMCI) often first appears clearly at the time of only be paid to the teeth, but also to the alveolar process and tooth eruption and it is therefore often the dentist who first the cranium, interrelationships that are highlighted in this book. discovers the midline defect (see Chapters 8 and 13). Another For the syndromologist or pediatrician, it is therefore essential to be aware of the signs and symptoms in the dentition, and for the

Hard tissue as a diagnostic tool in medicine 221 Figure 16.6 Orthopantomogram from an individual 15 years of age with Figure 16.8 Anthropological remnant from a human sphenoid bone. The diabetes. Since the age of three years, the patient has been treated for anterior direction points upward. Note the hole in the floor of the sella epilepsy. Note the abnormal root contours. Whether these deviations are turcica (green arrow). This hole is a malformation which might indicate a provoked by the disease or by the medicine is not known but this is an genotypic deviation or the location of a transsphenoidal encephalocele. example of how a general health condition can also be traced to the dentition. dentist and orthodontist to follow ongoing research and clinical experience in neuropediatrics. Perspectives for anthropology difficult to assemble with other cranial remnants, exemplified in Figure 16.8. In such anthropological cases, an embryological Anthropological craniums can often be difficult to diagnose. This developmental deviation can help to identify the associated is exemplified in Figure 16.7. Cranium remnants can also be pieces. In contrast, anthropology can support embryological Figure 16.7 Severe cranial malformations in which the innervation holes reveal that the pathological condition arose in early prenatal life. An anthropological cranium demonstrating severe asymmetry (upper and lower left) and ankylosis of the mandibular joint in the right side (upper center and upper right). On the lingual side, a hole with an entrance to the mandibular incisors appears in the anterior region (arrow) (lower center). The mental foramen in the right side is absent (lower right). This case has the same pathological condition in the mandibular channel as the case presented in Figures 2.33 and 2.34 and also mandibular ankylosis. This is presumably a prenatal malformation which was later complicated by development of ankylosis. A lateral view of the same human specimen is illustrated in the center image. The mandibular morphology appears abnormal. Note the absence of both molars and premolars and how the alveolar bone is not present in this region. Inspections of the internal mandibular ramus surface show that there is no mandibular foramen or mandibular canal. Anteriorly on the inside of the mandible is a hole continuing into canals to the incisors. This case demonstrates that the malformation arose early in prenatal life and that the canals containing innervation are important for tooth development. When the mandibular ankylosis arose is difficult to pinpoint. It is presumably a postnatal occurrence.

222 Chapter 16 findings and ideas. An example of the latter is found in Chapter 3 which describes craniofacial fields. It is through anthropological findings that these fields have been proven. Conclusion Bone tissue is “living” tissue which undergoes functional changes and growth. Congenital deviations in bone tissue are not always visible but bone may contain traces of inherited malformations, and past diseases and treatments (Figure 16.9). Early traces of tooth development are like the growth rings of a tree, which do not disappear but persist (Figure 16.10), and these traces can be used in interdisciplinary collaboration between odontology, medical professions, and anthropology for improv­ ing prediction, diagnostics, and treatment of patients. Figure 16.9 Two profile radiographs, one from a human fetus GA 18 weeks (left) and one from a child eight years of age (right). The radiographs illustrate the growth changes which occur during childhood. Malformed bony structures during prenatal life persist into childhood and adulthood but abnormal growth and function make identification of the initial malformation site difficult. Figure 16.10 Demonstration of how tooth malformations and discolorations which arise during prenatal and postnatal tooth development remain stable and make determination of the etiology possible. The tooth presented in Figure 8.52 is inset on the surface of the trunk of a tree for a developmental comparison (left). A magnification appears to the right. The growth of a tree starts centrally and continues appositionally, resulting in visible rings. The incisor starts enamel formation at the incisive edge and continues apically. The growth rings of a tree do not disappear but persist and make tracing of soil conditions and climate possible. In the same way, malformations in the teeth can be used to trace diseases, treatment, heredity, and genotype deviations.

Hard tissue as a diagnostic tool in medicine 223 Further reading Kjær I, Keeling JW, Hansen BF. Pattern of malformations in the axial skeleton in human trisomy 13 fetuses. Am J Med Genet Arntsen T, Kjær I, Sonnesen L, Mølsted K. Skull thickness in patients 1997;70:421–426. with clefts. Orthod Craniofac Res 2010;13:75–81. Kjær I, Keeling JW, Hansen BF. The prenatal human cranium – normal Keeling JW, Kjær I. Diagnostic distinction between anencephaly and and pathologic development. Wiley, Chichester, 1999. amnion rupture sequence based on skeletal analysis. J Med Genet 1994;31:823–829. Kjær I, Keeling JW, Smith NM, Hansen BF. Pattern of malformations in the axial skeleton in human triploid fetuses. Am J Med Genet Kenrad A, Christensen IJ, Kjær I. Craniofacial morphology of the 1997;72:216–221. frontonasal segment in patients with one or two macrodontic maxil­ lary central incisors. Eur J Orthod 2013;35:329–334. Mentz RG, Engel U, Kjær I. Nasal bone length in trisomy 18, triploidy and Turner syndrome analyzed on postmortem radiographs. Ultra­ Kjær I. Review: Dental approach to craniofacial syndromes: how can sound Obstet Gynecol 2009;34:607–608. developmental fields show us a new way to understand pathogenesis? Int J Dent 2012; article ID 145749 Schoenwolf GC, Bleyl SB, Brauer PB, Francis-Weat PH. Larsen’s human embryology, 4th edn. Churchill Livingstone Elsevier, Oxford, 2009. Kjær I, Keeling JW, Hansen BF. Pattern of malformations in the axial skeleton in human trisomy 18 fetuses. Am J Med Genet Sejrsen B, Kjær I, Jakobsen J. The human incisal suture and premaxillary 1996;65:332–336. area studied on archeologic material. Acta Odontol Scand 1993;51:143–151.

CHAPTER 17 Clinical cases and unanswered questions Clinical cases discussions leading to dialogue and improvement of etiology- based craniofacial and dental diagnostics. It might also inspired In everyday clinical practice, the diagnosis of a condition is the future research projects. background for treatment. Treatment has two aspects: treatment type and treatment timing. On the background of earlier clinical experiences, six hypo­ thetical conditions involving etiology-based and nonetiology­ A diagnosis is the categorization of a condition within a group based diagnostics will be presented. of known diagnostic types. This is the most commonly used method for treatment planning. Etiology-based treatments of the Conditions in diagnostics, treatment dentition rely on knowledge of the cause of the condition and the planning, and outcome association of the condition in teeth with craniofacial and general health factors. The conditions can be categorized as follows. In etiology-based treatment of a given condition, ideally the Optimal treatment situation cause of the condition should be treated directly or removed. This The diagnosis is etiology based and the treatment is directed is of course not always possible. In this chapter, it will be towards the cause. The timing for the treatment and the treat­ demonstrated how the etiology behind a condition influences ment method are optimal. both the treatment type and its optimal timing. It will also be shown how a condition can be improved or worsened during an Observation of the condition observation period. Some of the demonstrated examples did not The diagnosis is not etiology based and the clinician decides on have a favorable outcome. They were all treated when the an observation period for the patient. This period can provide etiology of each condition demonstrated was unknown. The insight into the etiology which can be an advantageous or a purpose of showing these cases is to demonstrate how knowing disadvantageous choice, leading to either an optimal or a non- the etiology can improve the decision on treatment planning and optimal situation. thereby the outcome. It is therefore important not to focus on the outcome of these treatments, but rather on what happened in the Nonoptimal treatment situations individual cases during observation or treatment. • An etiology-based diagnosis is possible. The treatment is One way to improve our insight into diagnostics and treat­ performed at the correct time but with a nonoptimal treatment ment is to learn from our own experiences and those of other method. professionals. Sometimes etiology-based diagnostics is simply • The diagnosis is etiology based and the method for treatment is not possible. optimal but the timing of the treatment is not ideal. • The diagnosis is not etiology based. The treatment plan chosen In this chapter, both treatments that have gone well and those and the timing are optimal. The result is a desirable outcome that have not succeeded are demonstrated. Professionals who without insight into the root of the cause. willingly expose their own patient cases for the betterment of • The etiology is unknown and the diagnosis is not etiology medical knowledge should be thanked for their contributions in based. The treatment plan chosen and the timing of the this respect. treatment are both nonoptimal. The result is an undesirable outcome. Showing both successful and nonsuccessful cases demon­ This book has systematically described and provided diag­ strates how diagnosis can be challenging, sometimes despite nostics for a long list of deviations in the dentition and cranium. positive efforts. In some cases, the diagnosis must be accepted The etiology-based diagnostic methods are intended as a guide as uncertain or in special cases as undefinable. The most impor­ for maintenance and improvement of treatment of future tant part of the diagnostic process is to share insights with others. patients. The present chapter provides examples of how these This is the ultimate goal of describing nonsuccessful cases. The chapter ends with some cases in which the author is unable to perform an etiology-based diagnosis with our current knowledge. It is hoped that this chapter will provoke professional Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 224

Clinical cases and unanswered questions 225 diagnostic methods can be applied concerning eruption. A few Maxilla other examples will also be mentioned. Figure 17.6 is an example of a successful treatment in the maxilla. Figure 17.7 demonstrates an unsuccessful treatment. There are many questions within the realm of dental and craniofacial diagnostics that remain unanswered. Several such Problems in permanent molar eruption: later questions have been raised throughout the book. At the end of diagnosed as secondary retention this chapter, further examples of questions are given to encour­ Mandible age professionals to perform basic and clinical research in order Figure 17.8 depicts an unsuccessful treatment of a mandibular to expand our insight into dental and craniofacial diagnostics. first molar. Examples of diagnostics and treatment of Problems in permanent molar eruption: later eruption problems diagnosed as primary failure of eruption Two examples of unilateral primary failure of eruption treated Problems in permanent molar eruption: later long before the condition was understood are demonstrated in diagnosed as primary retention Figures 17.9 and 17.10. In both cases, the patient and the Mandible clinician experienced great frustration because the teeth One example of a successful treatment can be found in reacted differently to normal treatment. It is now known Chapter 10 (Figure 10.23). Other successful diagnostic and that a deviation in the periodontal membrane is the etiology treatment cases are demonstrated in Figures 17.1 and 17.2. behind primary failure of eruption and that the condition can Unsuccessful treatments are exemplified in Figures 17.3, 17.4, be inherited. It is therefore important to conduct a thorough and 17.5. anamnesis of the patient as soon as the teeth appear to react unexpectedly. Figure 17.1 (Upper) Orthopantomogram from a seven-year-old boy demonstrating primary retention of the mandibular first left molar. The etiology is a nonfunctioning crown follicle covering the crown of the first molar. The crown follicle is unable to break down the overlying bone to create a pathway for eruption. The optimal treatment is to surgically remove the crown follicle and the alveolar bone covering the first molar. This was the treatment that was performed. (Lower left) Section from an orthopantomogram of the same patient taken one year later (eight years old). The overlying bone has been removed. (Lower right) Section from an orthopantomogram of the same patient at age 13 years. The first molar appears to have erupted and has a correct position in the alveolar bone.

226 Chapter 17 Figure 17.3 (Upper) Section from an orthopantomogram from a nine­ year-old girl demonstrating primary retention of the left mandibular first molar. Despite this diagnosis, it is noteworthy that there is a resorptive change in the mesial side of the tooth collum. A surgical exposure, as was performed, would therefore likely not provoke eruption. This was in fact the case. (Lower) Section from an orthopantomogram of the same patient taken at age 12. The first molar has not erupted and the new treatment plan is surgical removal of the first molar. Figure 17.2 (Upper) Section from an orthopantomogram from a 10-year­ old boy demonstrating primary retention of the right mandibular first molar. The etiology is a nonfunctioning crown follicle covering the crown of the first molar. The crown follicle is unable to break down the overlying bone to create a pathway for eruption. The optimal treatment is to create eruption space by surgical removal of the crown follicle and the alveolar bone covering the first molar. This was the treatment that was performed. (Lower) Section from an orthopantomogram of the same patient taken four years later. The molar has erupted and is correctly positioned in the dental arch. Note the bent roots which have not affected the outcome of the eruption process. Problems in premolar eruption Figure 17.4 Two orthopantomograms from the same patient at age 13 years If the primary canines and molars do not shed at the time when (upper) and 16 years (lower) demonstrating an unsuccessful treatment. At 13 the succeeding teeth have the appropriate root length (still with years of age, primary retention of the right mandibular second molar was open apices), then eruption problems may arise for the perma­ diagnosed. The crown follicle and the overlying tissue were surgically removed nent teeth due to obstruction of the eruption path. This condition to enable eruption. It could be questioned whether there was enough space is discussed in Chapter 6. The correct treatment is to extract the available for the tooth to erupt at this time. Another concern is whether primary teeth while the succeeding permanent teeth still have collum resorption might have been present on the distal surface of the second open apices. In this chapter, an example of premolar noner­ molar at the time of the first radiograph. At the age of 16 years, eruption has uption is provided in a patient with delayed treatment beginning still not proceeded, the potential space problem has worsened, and severe at the age of 19 years (Figure 17.11). A patient case where the resorption is apparent. The molar must be extracted. treatment started even later (Figure 17.12) shows that the premolar did not have the ability to erupt at this late stage. The figures illustrate the importance of treatment timing.

Clinical cases and unanswered questions 227 Figure 17.5 Four sections from orthopantomograms from the same Figure 17.6 Two orthopantomograms from the same patient at age nine patient taken during a 3-years period. (Upper) arrested eruption of the years (upper) and 11 years (lower) demonstrating a successful treatment of permanent right first mandibular molar. (Upper center) orthodontic the left maxillary first molar. At nine years of age, the patient was appliance was inserted for supporting eruption of the first mandibular diagnosed with primary retention of the maxillary first molar. It was also molar. The treatment was unsuccessful. (Lower center) the first mandibular noted at that time that the second molar in the left side of the maxilla was molar was extracted. (Lower) the extraction of the first molar was followed late in formation compared to the contralateral molar. This could be a sign by a successful orthodontic treatment. This case demonstrates a secondary of temporary delay in development due to external factors, for example retained permanent first mandibular molar. The vertical alveolar bone virus attack. The first molars was surgically exposed and erupted to a contours surrounding the first molar in the upper figure indicate natural position in the dentition at 11 years of age. Note that the second secondary retention. See text for treatment of this condition. molar has regained a normal crown formation. Figure 17.7 Sections from two orthopantomograms from the same patient at age 11 years (left) and 19 years (right) demonstrating an unsuccessful treatment of the right permanent maxillary first molar. The diagnosis was uncertain and it was decided that the first molar should be extracted. In the following eight years, neither the second maxillary molar nor the third maxillary molar erupted. The etiology behind this molar field defect is not known.

228 Chapter 17 Figure 17.8 Sections from two orthopantomograms from the same patient at age 14 years (left) and 17 years (right) demonstrating an unsuccessful treatment of the right permanent mandibular first molar. The molar was secondarily retained and the correct treatment would have been to extract the first molar at the time of the first radiograph. However, distinction between primary and secondary retention was not clearly defined in dentistry at the time when the patient approached the clinic. Figure 17.9 Orthopantomograms from a patient originally without a diagnosis. The treatment outcome revealed that the patient had a case of primary failure of eruption. The patient could not provide any dental records from family members. (Upper) Radiograph taken at age 12. At this time, the vertical elastics in the right premolar/molar regions were inserted. (Center) Radiograph taken at age 15. The first molars were unable to erupt and were therefore extracted. (Lower left) Section from a radiograph taken at age 17. An orthodontic fixed appliance has been inserted. A coil has been used for correcting the medially tipped mandibular second molar. The treatment was not successful. (Lower right) Section from a radiograph taken at age 19. The treatment of the molars has been abandoned. A lateral open bite is apparent and an orthodontic appliance has been inserted for retention of the premolars.

Clinical cases and unanswered questions 229 Figure 17.10 Orthopantomograms demonstrating a molar eruption problem which turned out to be a severe, unilateral case of primary failure of eruption. (Upper left) Taken at eight years of age. A vertical draw appears between the permanent first molars in the left side. (Upper right) Section of a radiograph taken at 11 years showing that eruption of the first molar has not succeeded. The first molars have both been extracted. The new goal was that the second molar and the second premolar should erupt naturally. (Lower left) A section of a radiograph taken at age 13 years. The second premolar and the second molar in the mandible and maxilla did not erupt. It was decided that these teeth should be extracted. (Lower right) Section of a radiograph taken at age 14 years at which time provoking premolar and molar eruption in the left side was abandoned entirely. The treatment in this case was performed a decade prior to understanding that there were unilateral cases of primary failure of eruption. The possibility of heredity in a condition such as this had not been reported. Figure 17.11 Three orthopantomograms from a young female patient. (Upper) 19 years old. This orthopantomogram demonstrates nonclosure of apices in the premolars and three canines. The etiology is nonability of the crown follicle to resorb the overlying primary teeth. The optimal treatment plan is extraction of the remaining primary teeth, as was performed. (Center) 21 years old. Two years after extraction of the remaining primary teeth, the premolars have still not erupted. Most of the molars are now covered by alveolar bone (see inset figure of left second premolar). The teeth will persist in the jaw unless surgical removal of the overlying bone is undertaken and orthodontic treatment initiated. This was performed. (Lower) 22 years old. One year later, the teeth had the correct position in the alveolar bone. An acrylic cap was added to the occlusal surface of three permanent second molars to ensure the eruption path. The conclusion of this case was that the treatment time was nonoptimal – five years too late. Despite this being the optimal procedure, the teeth were unable to erupt. The permanent teeth had reached a stage at which eruption was arrested due to apices closure. Without orthodontic treatment, the teeth would have persisted in the jaws.

230 Chapter 17 Figure 17.12 Orthopantomogram from an adult 28 years of age who had waited several years for the premolars and permanent canines to erupt. Extraction of the primary molars was performed too late at the age of 24. At this time, it had only recently been determined that the primary molars should be extracted. The orthodontist hoped that the nonerupted premolars and canines would begin the eruption process despite the lack of knowledge in this particular field. The nonerupted premolars and canines, as seen on the radiograph, remained nonerupted in the following years. The etiology was never determined. Eruption problems can be a sign of reoperation. This type of situation is demonstrated in Figures susceptibility to root resorption 17.14 and 17.15. A single case is demonstrated in Figure 17.13 where arrested eruption of a molar was the first indication in the dentition of Unanswered questions later resorption during orthodontic treatment. Eruption problems caused by supernumerary “What is this?” teeth Figures 17.16, 17.17, 17.18 and 17.19 depict some of the many When removing supernumerary teeth to secure an eruption path, unanswered questions about various etiologies in the dentition. the surgeon may not be able to remove the entire crown follicle. The goal is to encourage professionals in various fields to discuss This is problematic because the crown follicle can regenerate a these questions in order to gain insight and develop new knowl­ tooth-like structure which might still obstruct the eruption path. edge in this area. This can complicate the surgical procedure and may result in Figure 17.13 Intraoral photograph from a child approximately 11½ years of age without a general diagnosis at the start of orthodontic treatment. The child has light, thin hair and thin, barely visible eyebrows. The initial treatment plan was extraction of the four premolars by gentle force and insertion of a fixed orthodontic appliance. The radiographs (not shown) revealed that all teeth were present but that a mandibular first molar was arrested in eruption and had a short distal root (upper right). During treatment, the right mandibular first molar had to be extracted because it was heavily resorbed. Before the end of treatment, aggressive resorption of the maxillary central incisors was also noticeable (lower right). This figure demonstrates how the appearance of the face and hair combined with an eruption deviation and root malformation can reveal an ectodermal dysplasia condition. In these cases, the orthodontic treatment plan must proceed with great care and might be subject to change. Source: Kjær (2014). Reproduced with permission of Wolters Kluwer.

Clinical cases and unanswered questions 231 Figure 17.14 Dental films demonstrating supernumerary tooth buds in the maxillary central incisor region blocking the eruption path for the permanent central incisors. The radiographs were taken when the patient was seven (left) and eight years of age (right). The supernumerary teeth were surgically removed but the surgeon was not able to remove the entire follicle without disturbing the overlying permanent teeth. The crown follicles regenerated tooth-like structures which continued to obstruct the eruption path and made reoperation necessary. Figure 17.15 Sections from three orthopantomograms from the same patient before, during, and after puberty (from left to right). Due to an eruption problem of the right mandibular second molar, a supernumerary tooth bud in the region (seen in the radiograph to the left) was surgically removed. The removal appears to have been a success, as indicated by the center radiograph, and the second molar has erupted. Meanwhile, a tooth-like structure was discovered in the same location as the previous supernumerary tooth, indicating that the follicle encircling the extra tooth bud was not completely removed. This might have been due to caution because of the close relationship to the permanent molar which is observed in the first radiograph. Source: Reproduced with kind permission of Eirik Torjuul Halvorsen. Figure 17.16 This radiograph is from a child eight years of age without Figure 17.17 An orthopantomogram from a nine-year-old girl known anamnestic information. What has happened in the second demonstrating very delayed maturity of the maxillary molars in the right premolar region? side. What is the explanation?

232 Chapter 17 Figure 17.18 Dental radiographs from two different patients. (Left and center) Dental radiographs from a female 18 years of age without roots at her right maxillary first molar. No prior treatment has been performed. Looking back into the patient record, it was obvious that there were root structures present when she was nine years old. What has happened? Why is only the first molar affected? (Right) Dental film from another patient with arrested root formation in the mandibular first molar. The radiograph was taken when the patient was nine years old. What has happened? Figure 17.19 Orthopantomogram from a 10-year-old boy where the maxillary first molars have not yet erupted. The root formation is very delayed. What is the explanation? Figure 17.20 In several chapters, special attention has been given to the mandibular first molar. The root is often short and it is this tooth root that is most susceptible to disruption. Why is it that the distal root of the mandibular first molar is especially susceptible to malformations and disruptions? In the upper radiograph, disruption of the distal first molar roots due to chemotherapy is visible. The lower orthopantomogram from a child seven years of age depicts a nearly complete absence of the roots in the permanent first molars. There is no anamnestic record for this patient. What has happened? Figure 17.21 Orthopantomogram from a child who has received large “Can medication influence tooth formation?” amounts of adrenocortical hormone as asthma treatment. Are the short The question of the influence of medicine on the morphology roots of the premolars in the radiograph a disruption due to this and eruption processes in the dentition is still completely treatment? unanswered. It is well known that chemotherapy (Figure 17.20) influences the dentition but the effect of oral medications is a subject which is seldom touched upon. A few cases are

Clinical cases and unanswered questions 233 Figure 17.22 Dental films from a young adult who has received hormonal treatment for incontinence over a long period. Do these short premolar roots have a connection to the medication? Figure 17.23 Orthopantomogram from a patient 17 years of age who has been treated for epilepsy since the age of three years. Do the root morphology and the lack of periodontal contour have an association to the medication? provided in Figures 17.21, 17.22, and 17.23 to illustrate possible Figure 17.24 Orthopantomogram from a young patient who has received links between dentition deviations and medicinal intake. hormonal treatment for a severe asthma condition. Do these short premolar roots have a connection to the medication? Further reading Hansen IV, Vedtofte H, Kjær I. Remember the periroot sheet in Kjær I. Root resorption – focus on signs and symptoms of importance for orthodontic treatment of ectodermal dysplasia patients. Dent Hypoth- avoiding root resorption during orthodontic treatment. Dent Hypoth­ eses 2014;5:164–167. eses 2014;5 (2):47–52.

Index A bilateral ectopia of canines, 132 abnormal dental development mandibular canine dental abnormalities, 107 bilateral ectopia, 131 fields and bilateralism, 107 tilted position, 131 regional dysplasia of teeth, 110 anthropological human mandible, 34, 133 abnormal eruption anthropology, 221 etiology, 145–147 aplasia, 41, 77, 130, 189 syndromes and dysplasia, 137–139 apoptosis, 66 Arnold–Chiari syndrome, 219 amelogenesis imperfecta, 137–139 arrested eruption ectodermal dysplasia, 139 permanent dentition, 144, 145 linear scleroderma en coup de sabre, 139 primary dentition, 144, 145 aborted human fetus atlas, 2, 27, 41, 187, 193, 198 frontolateral view, 25 axial nasal cartilage, 17 lateral view, 25 acrodermatoungual lacrimal tooth (ADULT) syndrome, 115 B acromegaly, 31–32, 203 basilar occipital bone, 4, 5, 8 profile radiographs, 32 bilateral palatal canine ectopia ADULT syndrome. See acrodermatoungual lacrimal tooth orthopantomogram, 128, 131 (ADULT) syndrome bimaxillary retrognathia, 173, 174 agenesis, 77, 111, 168. see also permanent dentition agenesis body axis mandible, 111 and cranium, interrelationship between, 2 maxilla, 111 development, 1 multiple, 114 in a human fetus, 4 permanent canines, 115 body ossification, of a human fetus, 4 permanent molars, 115 brain premolars, 115 clinical relevance, 23–24 primary incisors, 112 components, 22 single teeth, 114 cranium and components, midaxial plane, 22 aggressive resorption, 162, 164 inner neuroectodermal layer, develops from, 21 alveolar bone formation, 61 brainstem, 1, 3, 8, 21, 189 abnormal patterns including syndromes, 125–147 falx cerebri alveolar process, developmental fields in cranial fields interrelated with development of, 44 crista galli, attached to, 21 lower jaw and dentition fetal pathology, 23 foramen of Monro, 21 clinical relevance, 44, 45 midsagittal section of a human fetus upper jaw and dentition radiograph, 22 clinical relevance, 44–45 ossification patterns, 22–23 amelogenesis imperfecta, 211 tentorium cerebelli, 21 buccal ectopia, 172 orthopantomogram, 143 radiographs, 142 C canines, 111, 175 young adults diagnosed with, 213 anamnestic record, 77 arrested eruption, 139 ankylosis, 13, 15, 41, 74, 81, 103, 135, 142, 144, 174, 205, nonshedding, inheritable factor 216, 221 orthopantomogram, 142 anthropological craniums, 221 jaws with Etiology-Based Dental and Craniofacial Diagnostics, First Edition. Inger Kjær. © 2017 John Wiley & Sons, Ltd. Published 2017 by John Wiley & Sons, Ltd. 235

236 Index cartilage, 2, 6, 7, 12–19, 24, 114, 187, 188, 190, 193, 207, 208, 218 diagram demonstrating dental deviation in children with, 197 Meckel’s, 49 etiologies, 193, 195 septum, 17 graphs demonstrating dentition in isolated cleft palate, 197 illustrated in human fetuses, 195 caudal neuropore, 2 pre- and postnatal findings, 190–192 cell layers, 56 combined cleft lip and palate, 192 ectodermal, 56 image marking contour of tongue and mandible in lateral ectomesenchyme, 56 innervation, 56 view, 196 cellular signaling, 217 radiographs with combined cleft lip and palate, 197 central nervous system (CNS), 1 schematic drawings, 196 embryo gestational age (GA) 4 weeks, 2 germ disk with a caudal neuropore, 2 anterior wall of sella turcica, deviant morphology, 196 pre- and postnatal neurocranial development, in relation malformations occur in cleft types, 196 clinical cases, 224 to, 21–31 clinical research, 219 brain, 21 CNS. see central nervous system (CNS) brainstem, 21–23 collum resorption, 162 cerebellum, 23 conditions, in diagnostics, treatment planning, and outcome, 224 encephaloceles, 23 condylar ankylosis, 13, 14, 41, 205 hemisphere, 23 condylar cartilage, 13 pituitary gland and the sella turcica, 28–31 condylar disk, 13 spinal cord, 24–25 condylar fossa, 13 trigeminal ganglia, 26 congenital brain malformation vomeronasal organs, 26–28, 34 with sella turcica malformation, 27 cephalometric studies, 13, 66, 175, 191 cranial base, 4, 5, 6 cerebellar hypoplasia/cri-du-chat syndrome, 180 cranial neuropores, 2 postnatal, 182, 185–186 cranial remnants, suffered from leprosy, 204 prenatal, 180, 182 crania, with different synostoses, 17 radiographs craniofacial cephalometric growth analysis, 35 front maxillary complex and cranial base, 186 craniofacial development pre- and postnatally, 1, 4–18, 220 and a schematic drawing of structures involved in, 186 cranial base (excluding sella turcica), 4–6 cerebellum, 21–26, 28, 41, 182, 185, 186 clinical relevance, 6 Arnold–Chiari type 1, 26, 28 fetal pathology, 6 and basilar part of the occipital bone, interrelationship, 26 mandible, 12, 13 cerebral hemispheres, 1, 21, 24, 182, 185 clinical relevance, 13–15 cervical spine pre- and postnatally, 1 fetal pathology, 13 chemotherapy maxilla, 8, 9, 11–12 agenesis of mandibular second molar and, 117 clinical relevance, 10, 11 apparently disrupt tooth development and jaw growth, 203 fetal pathology, 10 brain tumors in children disturbing hard tissue formation, 203 nasal bones, 17 disruption in root formation of mandibular premolars and clinical relevance, 18 fetal pathology, 18 second molar due to, 77 sella turcica, 7 orthopantomogram of a child receiving, 86 clinical relevance, 7, 8 radiation treatment causing malformation, 105 fetal pathology, 7 cherubism, 137, 142 temporal bone, 18 orthopantomogram, 142 clinical relevance, 18 chondrodystrophy, 207 fetal pathology, 18 histological appearance of prenatal chondrodystrophia, 209 theca cranii, 15, 16 radiographs clinical relevance, 16 vomeral bone, 16, 17 from adult patient with a tentative diagnosis, 209 clinical relevance, 17 cranial base, 209 craniofacial fields, 220 trunk, maxilla, and cranial base from stillborn fetus with, 208 frontonasal field, 42 clefting, 7 human cranium from newborn, 42 midaxial, 42 maxillary and palatine neural crest fields, 43 verteberal, 42 mandibular field, 41, 43 cleft lip and palate, 118, 190, 192 maxillary and palatine field clinical relevance, 199 cranium from newborn with bilateral cleft lip, 44 demonstration of combined cleft lip and palate and fields involved in, 196

Index 237 human cranium lacking development of palatine neural crest with persistence of a primary molar in adulthood, 176 field, 43 with supernumerary teeth, 171 for tooth transplantation, 174 midline cleft, 42 with transpositions, 173 occipital field, 43 dermatomes, 24, 32, 220 theca field, 41, 43 developmental fields, in cranium craniofacial malformations, 16, 38, 199, 219 cerebellar field, 41 craniofacial morphology, and growth, 19 definition, 37 craniofacial skeleton frontonasal field, 37 congenital malformations, 76 disruption, 77 bilateral, 37 dysplasia, 77 clinical relevance, 37 cranium, 2, 6, 15, 220 congenital skin abnormalities, 38 with an occipital cleft, 9 different fetal pathological aspects, within frontonasal deformation, 78 developmental fields in (see developmental fields, in cranium) fields, 39 indicating bone structures, 34 fetal pathology, 37 with a mandibular, condylar ankylosis, 205 frontonasal field marked, on human crania, 39 crista galli, 177 normally developed infant, 39 Crouzon’s syndrome origins of, human palate from neural crest, 39 anterior view of vertebral column, 193 schematic drawing of, child with unilateral cleft lip, 39 clinical relevance, 199 mandibular field postnatal, 188, 189 agnathia, 40, 41 prenatal, 188 clinical relevance, 41 profile radiograph from a child with, 194 fetal pathology, 40–41 crown follicle, 46, 48, 49, 52, 57, 61, 65 maxillary field crown resorption, before emergence, 162, 163, 165 bony components of, palate seen in occlusal view, 40 clinical relevance, 40 D fetal pathology, 38–40 delayed maturity, of maxillary molars, 231 intraoral photographs, different prenatal palatal dental bud formation, 46 malformations, 40 tissues involved, 46 midaxial cranium, 37 dental development, 53, 220 normally developed infant, 39 occipital field, 41 permanent, 53 primary, 53 clinical relevance, 42 dental maturation, 49 fetal pathology, 42 clinical evaluation, 52 frontal view of, human fetus, with Turner’s syndrome, 42 radiographic evaluation, 49, 50 profile radiograph of human fetus GA 20 weeks, 42 root length, 50 palatine field root morphology, 50 bony components of, palate seen in occlusal view, 40 dental maturity, 55 clinical relevance, 40 dentin, 55, 63, 65, 66, 138, 152, 157, 163 fetal pathology, 38–40 dysplasia, 75, 211 intraoral photographs, different prenatal palatal dentinogenesis imperfecta, 211 profile radiograph, 213, 214 malformations, 40 dentition, 168 paraaxial cranium, 37 with agenesis of single teeth, 168 with arrested eruption cranial fields marked, on profile and frontal radiographs, 38 overview of, 38 of permanent teeth, 174 schematic illustration, in craniofacial region, 38 of primary molars, 174 theca field congenital malformations, 76 clinical relevance, 41 deformation, 78 fetal pathology, 41 development, first mandibular molars, secondary retention, 130 profile radiograph of human cranium, 41, 42 disruption, 77 diagnostics and treatment, of eruption problems, 225 dysplasia, 78 diagnostics diagrams, 80 with ectopic canines, 172 DiGeorge’s/velocardiofacial syndrome, 189–190 with idiopathic collum resorption, 176 postnatal, 189 with macrodontic maxillary central incisors, 171 prenatal, 189 with multiple tooth agenesis, 170 radiographs of prenatal maxillary complex, cranial base, and frontal bone, 194 symptoms, 194

238 Index disorders, classifications of, 73, 75–76 lumbar myelomeningocele, 25 deformation, 73 occipital, 185 disruption, 73 endochondral and intramembranous bone dysplasia in dysplasia, 75 how to use, 75–76 cranium, 207 malformation, 73 human skull indicating bony origins from cartilage, 208 endocrine perspective, 220 disruption, 73, 81, 98, 109, 114, 116, 122, 127, 136, 202, epithelial layer, 56, 58, 59 205, 219, 232 eruption, heredity, relation with, 139–142 eruption problems, caused by supernumerary teeth, 230 due to mandibular trauma, severely affecting condylar dental films demonstrating supernumerary tooth buds growth, 204 in maxillary central incisor region blocking eruption, 232 in permanent dentition, 98 orthopantomograms, 231 in primary dentition, 81 eruption problems, sign of susceptibility to root resorption, 230 Down’s syndrome, 42, 77, 78, 99, 115, 160, 186 intraoral, with orthodontic treatment, 230 agenesis of second premolars and incisors, percentage of, 192 ethmoid bone, 5, 8, 17, 23, 37, 177, 185, 208 basilar part of occipital bone, 190 etiological evaluation, 220 clinical appearance of a Down’s syndrome fetus at, 190 etiology-based diagnostics, 73, 219 demonstrating morphology of sella turcica, 191 classification of abnormal development, 73–80 dentitions in, 192 method, 73–80 intraoral photograph, 126 morphologies of the sella turcica and various placements of the F face and head/cranium adenopituitary gland tissue, 190 orthopantomogram, 193 analysis, 77–79 postnatal, 186, 187 ears and hearing ability, 78 prenatal, 186 extraoral appearance, 78 proile radiographs from children with, demonstrating eyes and interocular distance, 77 hair, nails, eyebrows, skin pigmentation, and gland, 78 phenotypes, 191 head/cranium, 79 vertebral column, radiograph of, 191 neck, 78 dyshistogenesis, 75 nose and sense of smell, 77 dysostosis cleidocranialis, 211 cranium and dentition in individual with, 212 faxitron radiographs, of cranial region in spontaneously aborted profile radiograph, 211 fetuses, 50 dysplasia, 117 condition, 71 fetal alcohol syndrome, 78 craniofacial, 207 fetal, anthropological mandibles, 32 ectodermal (see ectodermal dysplasia) fetal pathology, 1, 47 ectodermal tissue, 117 follicles, premature opening, radiograph, 145 ectomesenchymal tissue, 117 fontanelles, 17 nonosseous tissue, 211 foramen magnum, 219 prenatal ectodermal, 117 Fragile X syndrome, 187–188 regional (see regional dysplasia) suture (see suture dysplasia) histological section of the maxillary complex, cranial base, and lower part of frontal bone, 193 E ectodermal deviations, 109, 115, 137 postnatal, 187, 188 ectodermal disorder, 107 prenatal, 187 ectodermal dysplasia, 47, 87, 106, 111, 118, 139, 211, 212, 230 frontal bone, 5 demonstration of cranium and dentition, 212 G like symptoms, tooth film, 143 Gapo’s syndrome ectodermal tissue, 149, 150 ectomesenchyme, 1, 56, 61, 70 radiograph, 127 ectopic mandibular canines surgical removal of primary dentition orthopantomogram, 131 three-dimensional scanning, 132 orthopantomogram, 127 Ellis-van Creveld syndrome, 16, 114 germ disk, 1 enamel, 46, 48, 49, 53, 55, 79, 85, 94, 104, 107, 141, 163, 165, 211, gestational age, embryo, 2 Goldenhaar’s syndrome, 5 220 epithelium, 46 H encephaloceles, 23, 27, 185, 187, 188 hemimandible, 14 hemispheres anencephaly