Concepts of Growth and Development
A thorough background in craniofacial growth and development is necessary for every dentist. Even for those who never work with children, it is difficult to comprehend conditions observed in adults without understanding the developmental processes that produced these problems. For those who do interact professionally with children—and almost every dentist does so at least occasionally—it is important to distinguish normal variation from the effects of abnormal or pathologic processes. Since dentists and orthodontists are heavily involved in the development of not just the dentition but the entire dentofacial complex, a conscientious practitioner may be able to manipulate facial growth for the benefit of the patient. Obviously, it is not possible to do so without a thorough understanding of both the pattern of normal growth and the mechanisms that underlie it.
The very terms growth and development can cause difficulties in understanding. Growth and development, though closely related, are not synonymous. In conversational English, growth usually refers to an increase in size but tends to be linked more to change than anything else. Only if growth meant change, after all, could someone seriously speak of a period of economic recession as one of “negative economic growth.” Since some tissues grow rapidly and then shrink or disappear, a plot of physical growth versus time may include a negative phase. On the other hand, if growth is defined solely as a process of change, the term becomes almost meaningless. In this chapter, the term growth usually refers to an increase in size or number. Occasionally, however, the increase will be in neither size nor number, but in complexity.
As a general term, development connotes an increasing degree of organization, often with unfortunate consequences for the natural environment. With reference to growth, the term development is used almost always to refer to an increase in complexity, and it is used in that way in this chapter. Development carries an overtone of increasing specialization, so that one price of increased development is a loss of potential. Growth is largely an anatomic phenomenon, whereas development is physiologic and behavioral.
It should be kept in mind that although dentists work with the physical features of the teeth and face, a major reason for orthodontic treatment is its psychosocial effects. Furthermore, patient cooperation is necessary, and eliciting it in children of different ages requires a knowledge of social and behavioral development. Both physiologic and psychosocial development are important subjects for this chapter. For convenience, not because they are innately more important, physical growth concepts are presented first, and then developmental factors are reviewed.
In studies of growth and development, the concept of pattern is an important one. In a general sense, pattern (as in the pattern from which articles of clothing of different sizes are cut) reflects proportionality, usually of a complex set of proportions rather than just a single proportional relationship. Pattern in growth also represents proportionality, but in a still more complex way, because it refers not just to a set of proportional relationships at a point in time, but to the change in these proportional relationships over time. In other words, the physical arrangement of the body at any one time is a pattern of spatially proportioned parts. But there is a higher level pattern, the pattern of growth, which refers to the changes in these spatial proportions over time.
Figure 2-1 illustrates the change in overall body proportions that occurs during normal growth and development. In fetal life, at about the third month of intrauterine development, the head takes up almost 50% of the total body length. At this stage, the cranium is large relative to the face and represents more than half the total head. In contrast, the limbs are still rudimentary and the trunk is underdeveloped. By the time of birth, the trunk and limbs have grown faster than the head and face, so that the proportion of the entire body devoted to the head has decreased to about 30%. The overall pattern of growth thereafter follows this course, with a progressive reduction of the relative size of the head to about 12% of the adult. At birth, the legs represent about one third of the total body length, while in the adult, they represent about half. As Figure 2-1 illustrates, there is more growth of the lower limbs than the upper limbs during postnatal life. All of these changes, which are a part of the normal growth pattern, reflect the “cephalocaudal gradient of growth.” This simply means that there is an axis of increased growth extending from the head toward the feet.
FIGURE 2-1 Schematic representation of the changes in overall body proportions during normal growth and development. After the third month of fetal life, the proportion of total body size contributed by the head and face steadily declines. (Redrawn from Robbins WJ, et al. Growth. New Haven: Yale University Press; 1928.)
Another aspect of the normal growth pattern is that not all the tissue systems of the body grow at the same rate (Figure 2-2). Obviously, as the relative decrease of head size after birth shows, the muscular and skeletal elements grow faster than the brain and central nervous system. The overall pattern of growth is a reflection of the growth of the various tissues making up the whole organism. To put it differently, one reason for gradients of growth is that different tissue systems that grow at different rates are concentrated in various parts of the body.
FIGURE 2-2 Scammon’s curves for growth of the four major tissue systems of the body. As the graph indicates, growth of the neural tissues is nearly complete by 6 or 7 years of age. General body tissues, including muscle, bone, and viscera, show an S-shaped curve, with a definite slowing of the rate of growth during childhood and an acceleration at puberty. Lymphoid tissues proliferate far beyond the adult amount in late childhood and then undergo involution at the same time that growth of the genital tissues accelerates rapidly. (From Scammon RD. The measurement of the body in childhood. In: Harris JA, ed. The Measurement of Man. Minneapolis: University of Minnesota Press; 1930.)
Even within the head and face, the cephalocaudal growth gradient strongly affects proportions and leads to changes in proportion with growth (Figure 2-3). When the skull of a newborn infant is compared proportionally with that of an adult, it is easy to see that the infant has a relatively much larger cranium and a much smaller face. This change is an important aspect of the pattern of facial growth. Not only is there a cephalocaudal gradient of growth within the body, there also is one within the face. From that perspective, it is not surprising that the mandible, being farther away from the brain, tends to grow more and later than the maxilla, which is closer.
FIGURE 2-3 Changes in proportions of the head and face during growth. At birth, the face and jaws are relatively underdeveloped compared with their extent in the adult. As a result, there is much more growth of facial than cranial structures postnatally. (Redrawn from Lowery GH. Growth and Development of Children. 6th ed. Chicago: Year Book Medical Publishers; 1973.)
An important aspect of pattern is its predictability. Patterns repeat, whether in the organization of different-colored tiles in the design of a floor or in skeletal proportions changing over time. The proportional relationships within a pattern can be specified mathematically, and the only difference between a growth pattern and a geometric one is the addition of a time dimension. Thinking about pattern in this way allows one to be more precise in defining what constitutes a change in pattern. Change, clearly, would denote an alteration in the predictable pattern of mathematical relationships. A change in growth pattern would indicate some alteration in the expected changes in body proportions.
A second important concept in the study of growth and development is variability. Obviously, everyone is not alike in the way that they grow, as in everything else. It can be difficult but clinically very important to decide whether an individual is merely at the extreme of the normal variation or falls outside the normal range.
Rather than categorizing growth as normal or abnormal, it is more useful to think in terms of deviations from the usual pattern and to express variability quantitatively. One way to do this is to evaluate a given child relative to peers on a standard growth chart (Figure 2-4). Although charts of this type are commonly used for height and weight, the growth of any part of the body can be plotted in this way. The “normal variability,” as derived from large-scale studies of groups of children, is shown by the solid lines on the graphs. An individual who stood exactly at the midpoint of the normal distribution would fall along the 50% line of the graph. One who was larger than 90% of the population would plot above the 90% line; one who was smaller than 90% of the population would plot below the 10% line.
FIGURE 2-4 A, Growth of a normal girl plotted on the chart for females. Note that this girl remained at about the 75th percentile for height and weight over this entire period of observation. B, Growth of a boy who developed a medical problem that affected growth, plotted on the male chart. Note the change in pattern (crossover of lines on the chart) between ages 10 and 11. This reflects the impact of serious illness beginning at that time, with partial recovery after age 13 but a continuing effect on growth. (Data from Hamill PVV, et al. National Center for Health Statistics, 1979; charts developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion, published May 30, 2000, revised 11/21/00.) (Charts available from www.cdc.gov/growthcharts/.)
These charts can be used in two ways to determine whether growth is normal or abnormal. First, the location of an individual relative to the group can be established. A general guideline is that a child who falls outside the range of 97% of the population should receive special study before being accepted as just an extreme of the normal population. Second and perhaps more importantly, growth charts can be used to follow a child over time to evaluate whether there is an unexpected change in growth pattern. Pattern implies predictability. For the growth charts, this means that a child’s growth should plot along the same percentile line at all ages. If the percentile position of an individual relative to his or her peer group changes, especially if there is a marked change (see Figure 2-4, B), the clinician should suspect some growth abnormality and should investigate further. Inevitably, there is a gray area at the extremes of normal variations, at which it is difficult to determine if growth is normal.
A final major concept in physical growth and development is that of timing. Variability in growth arises in several ways: from normal variation, from influences outside the normal experience (e.g., serious illness), and from timing effects. Variation in timing arises because the same event happens for different individuals at different times—or, viewed differently, the biologic clocks of different individuals are set differently.
Variations in growth and development because of timing are particularly evident in human adolescence. Some children grow rapidly and mature early, completing their growth quickly and thereby appearing on the high side of developmental charts until their growth ceases and their contemporaries begin to catch up. Others grow and develop slowly and so appear to be behind, even though, given time, they will catch up with and even surpass children who once were larger. All children undergo a spurt of growth at adolescence, which can be seen more clearly by plotting change in height or weight (Figure 2-5), but the growth spurt occurs at different times in different individuals.
FIGURE 2-5 Growth can be plotted in either height or weight at any age (the black line here) or the amount of change in any given interval (the maroon line here, showing the same data as the black line). A curve like the black line is called a “distance curve,” whereas the maroon line is a “velocity curve.” Plotting velocity rather than distance makes it easier to see when accelerations and decelerations in the rate of growth occurred. These data are for the growth of one individual, the son of a French aristocrat in the late eighteenth century, whose growth followed the typical pattern. Note the acceleration of growth at adolescence, which occurred for this individual at about age 14. (Data from Scammon, 1927, Amer F Phys Anthrop.)
Growth effects because of timing variation can be seen particularly clearly in girls, in whom the onset of menstruation (menarche) gives an excellent indicator of the arrival of sexual maturity. Sexual maturation is accompanied by a spurt in growth. When the growth velocity curves for early-, average-, and late-maturing girls are compared in Figure 2-6, the marked differences in size between these girls during growth are apparent. At age 11, the early-maturing girl is already past the peak of her adolescent growth spurt, whereas the late-maturing girl has not even begun to grow rapidly. This sort of timing variation occurs in many aspects of both growth and development and can be an important contributor to variability.
FIGURE 2-6 Growth velocity curves for early-, average-, and late-maturing girls. It is interesting to note that the earlier the adolescent growth spurt occurs, the more intense it appears to be. Obviously, at age 11 or 12, an early maturing girl would be considerably larger than one who matured late. In each case, the onset of menstruation (menarche) (M1, M2, and M3) came after the peak of growth velocity.
Although age is usually measured chronologically as the amount of time since birth or conception, it is also possible to measure age biologically, in terms of progress toward various developmental markers or stages. Timing variability can be reduced by using developmental age rather than chronologic age as an expression of an individual’s growth status. For instance, if data for gain in height for girls are replotted, using menarche as a reference time point (Figure 2-7), it is apparent that girls who mature early, average, or late really follow a very similar growth pattern. This graph substitutes stage of sexual development for chronologic time to produce a biologic time scale and shows that the pattern is expressed at different times chronologically but not at different times physiologically. The effectiveness of biologic or developmental age in reducing timing variability makes this approach useful in evaluating a child’s growth status.
Before beginning the examination of growth data, it is important to have a reasonable idea of how the data were obtained. There are two basic approaches to studying physical growth. The first is based on techniques for measuring living animals (including humans), with the implication that the measurement itself does no harm and that the animal will be available for additional measurements at another time. The second approach uses experiments in which growth is manipulated in some way. This implies that the subject of the experiment will be available for study in some detail, and the detailed study may be destructive. For this reason, such experimental studies are largely restricted to nonhuman species.
Craniometry: The first of the measurement approaches for studying growth, with which the science of physical anthropology began, is craniometry, based on measurements of skulls found among human skeletal remains. Craniometry was originally used to study the Neanderthal and Cro-Magnon peoples whose skulls were found in European caves in the eighteenth and nineteenth centuries. From such skeletal material, it has been possible to piece together a great deal of knowledge about extinct populations and to get some idea of their pattern of growth by comparing one skull with another. Craniometry has the advantage that rather precise measurements can be made on dry skulls; it has the important disadvantage for growth studies that, by necessity, all these growth data must be cross-sectional. Cross-sectional means that although different ages are represented in the population, the same individual can be measured at only one point in time.
Anthropometry: It is also possible to measure skeletal dimensions on living individuals. In this technique, called anthropometry, various landmarks established in studies of dry skulls are measured in living individuals simply by using soft tissue points overlying these bony landmarks. For example, it is possible to measure the length of the cranium from a point at the bridge of the nose to a point at the greatest convexity of the rear of the skull. This measurement can be made on either a dried skull or a living individual, but results would be different because of the soft tissue thickness overlying both landmarks. Although the soft tissue introduces variation, anthropometry does make it possible to follow the growth of an individual directly, making the same measurements repeatedly at different times. This produces longitudinal data: repeated measures of the same individual. In recent years, Farkas’ anthropometric studies have provided valuable new data for human facial proportions and their changes over time.1
Cephalometric Radiology: The third measurement technique, cephalometric radiology, is of considerable importance not only in the study of growth but also in clinical evaluation of orthodontic patients. The technique depends on precisely orienting the head before making a radiograph, with equally precise control of magnification. This approach can combine the advantages of craniometry and anthropometry. It allows a direct measurement of bony skeletal dimensions, since the bone can be seen through the soft tissue covering in a radiograph, but it also allows the same individual to be followed over time. Growth studies are done by superimposing a tracing or digital model of a later cephalogram on an earlier one, so that the changes can be measured. Both the locations and amounts of growth can be observed in this way (Figure 2-8). Cephalometric superimposition techniques are described in detail in Chapter 6.
FIGURE 2-8 A, A cephalometric radiograph merits this name because of the use of a head positioning device to provide precise orientation of the head. This means that valid comparisons can be made between external and internal dimensions in members of the same population group or that the same individual can be measured at two points in time because the head orientation is reproducible. B, This radiograph was taken in natural head position (NHP) (see Chapter 6 for a description of this head-positioning technique).
The disadvantage of a standard cephalometric radiograph is that it produces a two-dimensional (2-D) representation of a three-dimensional (3-D) structure, and so, even with precise head positioning, not all measurements are possible. To some extent, this can be overcome by making more than one radiograph at different orientations and using triangulation to calculate oblique distances. The general pattern of craniofacial growth was known from craniometric and anthropometric studies before cephalometric radiography was invented, but much of the current picture of craniofacial growth is based on cephalometric studies.
Three-Dimensional Imaging: New information now is being obtained with the application of 3-D imaging techniques. Computed axial tomography (CAT or more commonly, CT) allows 3-D reconstructions of the cranium and face, and this method has been applied for several years to plan surgical treatment for patients with facial deformities (Figure 2-9). Recently, cone beam rather than axial CT has been applied to facial scans. This significantly reduces both the radiation dose and cost. Cone beam CT (CBCT) allows scans of patients with radiation exposure that is much closer to the dose from cephalograms. Superimposition of 3-D images is much more difficult than the superimpositions used with 2-D cephalometric radiographs, but methods developed recently are overcoming this difficulty (Figure 2-10).2 Magnetic resonance imaging (MRI) also provides 3-D images that can be useful in studies of growth, with the advantage that there is no radiation exposure with this technique. This method already has been applied to analysis of the growth changes produced by functional appliances.3 Three-dimensional photography now makes possible much more accurate measurements of facial soft tissue dimensions and changes (Figure 2-11).4 A more detailed examination of 3-D changes in growing patients almost surely will add to current knowledge of growth patterns in the near future.
FIGURE 2-9 Computed tomography (CT) scans are the best way to determine the details of skeletal deformities. These views of a 9-year-old girl (A) with severe hemifacial microsomia (and previous surgical treatment to build up the affected side of the mandible) illustrate that CT scans can show both skin contours and bony relationships from any aspect. Color can be added to different structures to make it easier to visualize them (B), and surface layers can be made transparent (as in C to F) to reveal the skeletal structures beneath. Views of this type greatly facilitate surgical treatment planning. (Courtesy Dr. L. Cevidanes.)
FIGURE 2-10 Superimposition of CT images is much more difficult than superimposition of cephalometric tracings but is necessary to detect the amount of change and can be used to see changes in exquisite detail. These images are based on a superimposition of two volumetric images registered on the cranial base. The green posttreatment volume is superimposed on the brown posttreatment volume. The changes are due to a combination of growth and treatment. The most dramatic change is the downward-forward growth of the mandible and eruption of the maxillary teeth. (Courtesy Drs. C. Nurko and D. Grauer.)
FIGURE 2-11 Images from a single photograph with a 3dMD camera. Both profile and oblique and frontal views can be captured at the same head position, and measurements of soft tissue dimensions and proportions can be made with great accuracy at any orientation of the face, which makes such a 3-D camera a valuable research tool.
Both anthropometric and cephalometric data can be expressed cross-sectionally rather than longitudinally. Obviously, it would be much easier and quicker to do a cross-sectional study, gathering data once for any individual and including subjects of different ages, rather than spending many years on a study in which the same individuals are measured repeatedly. For this reason, most studies are cross-sectional. When this approach is used, however, variability within the sample can conceal details of the growth pattern, particularly when there is no correction for timing variation (Figure 2-12). Fluctuations in the growth curve that may occur for nearly every individual would be seen in a cross-sectional study only if they occurred at the same time for each person, which is unlikely. Longitudinal studies are efficient in the sense that a great deal of information can be gained from a relatively small number of subjects, fewer than would be needed in a cross-sectional study. In addition, the longitudinal data highlight individual variations, particularly variations caused by timing effects.
FIGURE 2-12 If growth velocity data for a group of individuals with a different timing of the adolescent growth spurt are plotted on a chronologic scale, it is apparent that the average curve is not an accurate representation of the pattern of growth for any particular individual. This smoothing of individual variation is a characteristic of cross-sectional data and a major limitation in use of the cross-sectional method for studies of growth. Only by following individuals through time in a longitudinal study is it possible to see the details of growth patterns.
Measurement data can be presented graphically in a number of different ways, and frequently, it is possible to clarify growth changes by varying the method of display. For example, we have already seen that growth data can be shown either by plotting the size attained as a function of age, which is called a “distance” curve, or as a “velocity” curve, showing not the total length but the increment added each year (see Figure 2-5). Changes in the rate of growth are much more easily seen in a velocity curve.
Various other mathematical transformations can be used with growth data to make them easier to understand. For instance, the growth in weight of any embryo at an early stage follows a logarithmic or exponential curve because the growth is based on division of cells; the more cells there are, the more cell divisions can occur. If the same data are plotted using the logarithm of the weight, a straight-line plot is attained (Figure 2-13). This demonstrates that the rate of multiplication for cells in the embryo is remaining more or less constant.
FIGURE 2-13 Data for the increase in weight of early embryos, with the raw data plotted in green and the same data plotted after logarithmic transformation in blue. At this stage, the weight of the embryo increases dramatically, but, as shown by the straight line after transformation, the rate of multiplication of individual cells remains fairly constant. When more cells are present, more divisions can occur, and the weight increases faster. (From Lowery GH. Growth and Development of Children. 8th ed. Chicago: Year Book Medical Publishers; 1986.)
More complex mathematical transformations were used many years ago by D’Arcy Thompson5 to reveal similarities in proportions and growth changes that had not previously been suspected (Figure 2-14). To correctly interpret data after mathematical transformation, it is important to understand how the data were transformed, but the approach is a powerful one in clarifying growth concepts. Thompson’s classic presentation remains stimulating reading.
FIGURE 2-14 In the early 1900s, D’Arcy Thompson showed that mathematical transformation of a grid could account for the changes in the shape of the face from man (A) to chimpanzee (B), monkey (C), dog (D), or other animals. Application of this method revealed previously unsuspected similarities among various species. (Redrawn from Thompson DT. On Growth and Form. Cambridge: Cambridge University Press; 1961.)
Much has been learned about skeletal growth using the technique called vital staining, in which dyes that stain mineralizing tissues (or occasionally, soft tissues) are injected into an animal. These dyes remain in the bones and teeth and can be detected later after sacrifice of the animal. This method was originated by the great English anatomist John Hunter in the eighteenth century. Hunter observed that the bones of pigs that occasionally were fed textile waste were often stained in an interesting way. He discovered that the active agent was a dye called alizarin, which still is used for vital staining studies. Alizarin reacts strongly with calcium at sites where bone calcification is occurring. Since these are the sites of active skeletal growth, the dye marks the locations at which active growth was occurring when it was injected. Bone remodels rapidly, and areas from which bone is being removed also can be identified by the fact that vital stained material has been removed from these locations (Figure 2-15). Highly detailed vital staining studies of bony changes in craniofacial development in experimental animals, from work done at the National Institute of Dental Research, are available.6
FIGURE 2-15 A, The mandible of a growing rat that received four injections of alizarin (red-blue-red-blue) at 2-week intervals and was sacrificed 2 weeks after the last injection (so the bone formed since then is white). Remodeling of the bone as it grows blurs some of the lines of intensely colored bone created by each injection, but the red-blue sequential lines in the condylar process can be seen clearly. B, Section through the zygomatic arch, from the same animal. The zygomatic arch grows outward by apposition of bone on the outer surface and removal from the inner surface. The interruptions in the staining lines on the inner surface clearly show the areas where bone is being removed. What was the outer surface of the zygomatic arch at one point becomes the inner surface a relatively short time later, and then is removed.
Although studies using vital stains are not possible in humans, vital staining can occur. Many children born in the late 1950s and early 1960s were treated for recurrent infections with the antibiotic tetracycline. It was discovered too late that tetracycline is an excellent vital stain that binds to calcium at growth sites in the same way as alizarin. The discoloration of incisor teeth that results from tetracycline given when the teeth are mineralizing has been an esthetic disaster for some individuals (Figure 2-16). Although this should not occur now, it still is seen occasionally.
FIGURE 2-16 Tetracycline staining in the teeth of a boy who received large doses of tetracycline because of repeated upper respiratory infections in early childhood. From the location of the staining, it is apparent that tetracycline was not administered in infancy but was given in large doses beginning when the crowns of the central incisors were about half formed, or at approximately 30 months.
With the development of radioactive tracers, it has become possible to use almost any radioactively labeled metabolite that becomes incorporated into the tissues as a sort of vital stain. The location is detected by the weak radioactivity given off at the site where the material was incorporated. The gamma-emitting isotope 99mTc can be used to detect areas of rapid bone growth in humans, but these images are more useful in diagnosis of localized growth problems (see Chapter 19) than for studies of growth patterns. For most studies of growth, radioactively labeled materials in the tissues of experimental animals are detected by the technique of autoradiography, in which a film emulsion is placed over a thin section of tissue containing the isotope and then is exposed in the dark by the radiation. After the film is developed, the location of the radiation that indicates where growth is occurring can be observed by looking at the tissue section through the film (Figure 2-17).
FIGURE 2-17 Autoradiograph of fetal rat bones growing in organ culture, with 14C-proline and 3H-thymidine incorporated in the culture medium. Thymidine is incorporated into DNA, which is replicated when a cell divides, so labeled nuclei are those of cells that underwent mitosis in culture. Because proline is a major constituent of collagen, cytoplasmic labeling indicates areas where proline was incorporated, primarily into extracellularly secreted collagen.
Another experimental method applicable to studies of humans is implant radiography. In this technique, inert metal pins are placed in bones anywhere in the skeleton, including the face and jaws. These metal pins are well tolerated by the skeleton, become permanently incorporated into the bone without causing any problems, and are easily visualized on a cephalogram (Figure 2-18). If they are placed in the jaws, a considerable increase in the accuracy of a longitudinal cephalometric analysis of growth pattern can be achieved. This method of study was developed by Professor Arne Björk and coworkers at the Royal Dental College in Copenhagen, Denmark, and was used extensively by workers there (see Chapter 4). It provided important new information about the growth pattern of the jaws. Before radiographic studies using implants, the extent of remodeling changes in the contours of the jaw bones was underestimated, and the rotational pattern of jaw growth described in Chapter 4 was not appreciated.
FIGURE 2-18 Lateral cephalometric radiograph from the archives of Björk’s implant studies, showing a subject with six maxillary and five mandibular tantalum implants. (Courtesy Department of Orthodontics, University of Copenhagen, Denmark.)
At this point, precise evaluation of dentofacial growth in humans using implant cephalograms has largely been superseded by 3-D imaging via computed tomography (CT) or MRI, but it still can be helpful to use implants to provide landmarks for superimposition.
Rapid advances in molecular genetics are providing new information about growth and its control. For example, homeobox Msx genes, which are known to be critically important in the establishment of body plan, pattern formation, and morphogenesis, have been found to be expressed differentially in growth of the mandible. Msx1 is expressed in basal bone but not in the alveolar process, while Msx2 is strongly expressed there.7 It is known now that a decrease in Hedgehog pathway activity causes holoprosencephaly (failure of the nose to develop) and hypotelorism and that excessive activity due to truncating primary cilia on cranial neural crest cells causes hypertelorism and frontonasal dysplasia.8 It also has been shown recently that hedgehog signaling acts at two distinct steps in disk morphogenesis: condyle initiation and disc-condyle separation during the formation of the temporomandibular (TM) joint.9 The proper functioning of families of growth factors and their cognate receptors is essential in regulating embryonic processes of cell growth and organ development, as well as a myriad of postnatal processes that include growth, wound healing, bone remodeling, and homeostasis.
Interaction between different tissues within the craniofacial complex creates yet another level of regulation of growth and development. One example of this is the convergence of the development of the muscles that attach to the mandible and the bony areas to which they attach. While there are a number of genes involved in determining mandibular size, genetic alterations in muscle development and function translate into changes in the forces on areas of bone where muscles attach, and this leads to modification of skeletal areas like the coronoid process and gonial angle area of the mandible. Genetic alterations that affect muscle also would affect these skeletal areas. To understand this, it is necessary both to identify specific genes involved and to deduce how their activity is modified, but already it is apparent that gene expression can be upregulated or downregulated by mechanical stresses.
An exciting prospect is a better understanding of how patients with orthodontic problems that are known to have a genetic component (Class III malocclusion being the best example) will respond to treatment. Chromosomal loci associated with Class III malocclusion have been identified.10 It is clear that there are multiple subtypes of Class III, and a necessary first step is better characterization of these phenotypes. Establishing phenotypic markers (distinct clinical characteristics) makes it possible to establish definitive correlations with modes of inheritance and is necessary for linkage studies that will clarify the genetic basis for the problem. At this point, the mutation leading to primary failure of eruption (PFE) has been identified,11 and for the first time, an orthodontic problem can be diagnosed from a sample of blood or saliva. It is likely that in the future, genetic screening of blood or other tissue samples will be used to identify patients with orthodontic problems who are likely to respond well or poorly to specific treatment modalities, in the same way that the likely response to drug therapies already is being determined.12
Experiments that clarify how growth is controlled at the cellular level offer exciting prospects for better control of growth in the future. It is estimated that about two-thirds of the 25,000 human genes play a role in craniofacial development, so complex patterns of genetic activity obviously are involved, and complex genetic interactions interact with external influences on growth. It is unlikely that genetic analysis will ever be applicable to planning treatment for the majority of orthodontic problems, but it could yield valuable information about the best approach to some of the most difficult skeletal malocclusions and perhaps the application of gene therapy to growth problems.13
At the cellular level, there are only three possibilities for growth. The first is an increase in the size of individual cells, which is referred to as hypertrophy. The second possibility is an increase in the number of the cells, which is called hyperplasia. The third is secretion of extracellular material, thus contributing to an increase in size independent of the number or size of the cells themselves.
In fact, all three of these processes occur in skeletal growth. Hyperplasia is a prominent feature of all forms of growth. Hypertrophy occurs in a number of special circumstances but is a less important mechanism than hyperplasia in most instances. Although tissues throughout the body secrete extracellular material, this phenomenon is particularly important in the growth of the skeletal system, where extracellular material later mineralizes.
The fact that the extracellular material of the skeleton becomes mineralized leads to an important distinction between growth of the soft or nonmineralized tissues of the body and the hard or calcified tissues. Hard tissues are bones, teeth, and sometimes cartilages. Soft tissues are everything else. In most instances, cartilage, particularly the cartilage significantly involved in growth, behaves like soft tissue and should be thought of in that group, rather than as hard tissue.
Growth of soft tissues occurs by a combination of hyperplasia and hypertrophy. These processes go on everywhere within the tissues, and the result is what is called interstitial growth, which simply means that it occurs at all points within the tissue. Although secretion of extracellular material can also accompany interstitial growth, hyperplasia primarily and hypertrophy secondarily are its characteristics. Interstitial growth is characteristic of nearly all soft tissues and of uncalcified cartilage within the skeletal system.
In contrast, when mineralization takes place so that hard tissue is formed, interstitial growth becomes impossible. Hyperplasia, hypertrophy, and secretion of extracellular material all are still possible, but in mineralized tissues, these processes can occur only on the surface, not within the mineralized mass. Direct addition of new bone to the surface of existing bone can and does occur through the activity of cells in the periosteum—the soft tissue membrane that covers bone. Formation of new cells occurs in the periosteum, and extracellular material secreted there is mineralized and becomes new bone. This process is called direct or surface apposition of bone. Interstitial growth is a prominent aspect of overall skeletal growth because a major portion of the skeletal system is originally modeled in cartilage. This includes the basal part of the skull, as well as the trunk and limbs.
Figure 2-19 shows the cartilaginous or chondrocranium at 8 and 12 weeks of intrauterine development. Cartilaginous skeletal development occurs most rapidly during the third month of intrauterine life. A continuous plate of cartilage extends from the nasal capsule posteriorly all the way to the foramen magnum at the base of the skull. It must be kept in mind that cartilage is a nearly avascular tissue whose internal cells are supplied by diffusion through the outer layers. This means, of course, that the cartilage must be thin. At early stages in development, the extremely small size of the embryo makes a chondroskeleton feasible, but with further growth, such an arrangement is no longer possible without an internal blood supply.
FIGURE 2-19 Development and maturation of the chondrocranium (cartilage: light blue; bone: stippled dark blue). A, Diagrammatic representation at about 8 weeks. Note that an essentially solid bar of cartilage extends from the nasal capsule anteriorly to the occipital area posteriorly. B, Skeletal development at 12 weeks. Ossification centers have appeared in the midline cartilage structures, and in addition, intramembranous bone formation of the jaws and brain case has begun. From this point on, bone replaces cartilage of the original chondrocranium rapidly so that only the small cartilaginous synchondroses connecting the bones of the cranial base remain.
During the fourth month in utero, there is an ingrowth of blood vascular elements into various points of the chondrocranium (and the other parts of the early cartilaginous skeleton). These areas become centers of ossification, at which cartilage is transformed into bone in the process called endochondral ossification, and islands of bone appear in the sea of surrounding cartilage (see Figure 2-19, B). The cartilage continues to grow rapidly but is replaced by bone with equal rapidity. The result is that the amount of bone increases rapidly and the relative (but not the absolute) amount of cartilage decreases. Eventually, the old chondrocranium is represented only by small areas of cartilage interposed between large sections of bone, which assume the characteristic form of the ethmoid, sphenoid, and basioccipital bones. Growth at these cartilaginous connections between the skeletal bones is similar to growth in the limbs.
In the long bones of the extremities, areas of ossification appear in the center of the bones and at the ends, ultimately producing a central shaft called the diaphysis and a bony cap on each end called the epiphysis. Between the epiphysis and diaphysis is a remaining area of uncalcified cartilage called the epiphyseal plate (Figure 2-20, A). The epiphyseal plate cartilage of the long bones is a major center for their growth, and in fact, this cartilage is responsible for almost all growth in length of these bones. The periosteum on the surfaces of the bones also plays an important role in adding to thickness and in reshaping the external contours.
FIGURE 2-20 A, Endochondral ossification at an epiphyseal plate. Growth occurs by proliferation of cartilage, occurring here at the top. Maturing cartilage cells are displaced away from the area of proliferation, undergo hypertrophy, degenerate, and are replaced by spicules of bone, as seen in the bottom. B and C, Endochondral ossification in the head of the condyle. A layer of fibrocartilage lies on the surface, with proliferating cells just beneath. Maturing and degenerating cartilage cells can be seen toward the area of ossification.
Near the outer end of each epiphyseal plate is a zone of actively dividing cartilage cells. Some of these, pushed toward the diaphysis by proliferative activity beneath, undergo hypertrophy, secrete an extracellular matrix, and eventually degenerate as the matrix begins to mineralize and then is rapidly replaced by bone. As long as the rate at which cartilage cells proliferate is equal to or greater than the rate at which they mature, growth will continue. Eventually, however, toward the end of the normal growth period, the rate of maturation exceeds the rate of proliferation, the last of the cartilage is replaced by bone, and the epiphyseal plate disappears. At that point, the growth of the bone is complete, except for surface changes in thickness, which can be produced by the periosteum.
Endochondral ossification also occurs at the mandibular condyle, which superficially looks like half an epiphyseal plate (Figure 2-20, B and C). As we will see, however, the cartilage of the condyle does not behave like an epiphyseal plate—and the difference is important in understanding mandibular growth.
Not all bones of the adult skeleton were represented in the embryonic cartilaginous model, and it is possible for bone to form by secretion of bone matrix directly within connective tissues, without any intermediate formation of cartilage. Bone formation of this type is called intramembranous ossification. This type of bone formation occurs in the cranial vault and both jaws (Figure 2-21).
FIGURE 2-21 The bones of the skull of a 12-week-old fetus, drawn from a cleared alizarin-stained specimen. (Redrawn from Sadler TW, Langman J. Langman’s Medical Embryology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2003.)
Early in embryonic life, the mandible of higher animals develops in the same area as the cartilage of the first pharyngeal arch—Meckel’s cartilage. It would seem that the mandible should be a bony replacement for this cartilage in the same way that the sphenoid bone beneath the brain replaces the cartilage in that area. In fact, development of the mandible begins as a condensation of mesenchyme just lateral to Meckel’s cartilage and proceeds entirely by intramembranous bone formation (Figure 2-22). Meckel’s cartilage disintegrates and largely disappears as the bony mandible develops. Remnants of this cartilage are transformed into a portion of two of the small bones that form the conductive ossicles of the middle ear but not into a significant part of the mandible. Its perichondrium persists as the sphenomandibular ligament. The condylar cartilage develops initially as an independent secondary cartilage, which is separated by a considerable gap from the body of the mandible (Figure 2-23). Early in fetal life, it fuses with the developing mandibular ramus.
FIGURE 2-22 Diagrammatic representation of the relation of initial bone formation in the mandible to Meckel’s cartilage and the inferior alveolar nerve. Bone formation begins just lateral to Meckel’s cartilage and spreads posteriorly along it without any direct replacement of the cartilage by the newly forming bone of the mandible. (Redrawn from Ten Cate AR. Oral Histology: Development, Structure, and Function. 5th ed. St. Louis: Mosby; 1998.)
FIGURE 2-23 The condylar cartilage (blue) develops initially as a separate area of condensation from that of the body of the mandible and only later is incorporated within it. A, Separate areas of mesenchymal condensation at 8 weeks. B, Fusion of the cartilage with the mandibular body at 4 months. C, Situation at birth (reduced to scale).
The maxilla forms initially from a center of mesenchymal condensation in the maxillary process. This area is located on the lateral surface of the nasal capsule, the most anterior part of the chondrocranium, but endochondral ossification does not contribute directly to formation of the maxillary bone. An accessory cartilage, the zygomatic or malar cartilage, which forms in the developing malar process, disappears and is totally replaced by bone well before birth, unlike the mandibular condylar cartilage, which persists.
Whatever the location for intramembranous bone formation, interstitial growth within the mineralized mass is impossible, and the bone must be formed entirely by apposition of new bone to free surfaces. Its shape can be changed through removal (resorption) of bone in one area and addition (apposition) of bone in another (see Figure 2-15). This balance of apposition and resorption, with new bone being formed in some areas while old bone is removed in others, is an essential component of the growth process. The formation of new bone from a cartilaginous predecessor or direct bone formation within mesenchyme often is referred to as modeling; changes in the shape of this new bone due to resorption and replacement are referred to as remodeling. Keeping this distinction in mind can make it easier to understand the following sections of this chapter.
To understand growth in any area of the body, it is necessary to understand (1) the sites or location of growth, (2) the type of growth occurring at that location, (3) the mechanism of growth (i.e., how growth changes occur), and (4) the determinant or controlling factors in that growth.
In the following discussion of sites and types of growth in the head and face, it is convenient to divide the craniofacial complex into four areas that grow rather differently: the cranial vault, the bones that cover the upper and outer surface of the brain; the cranial base, the bony floor under the brain, which also is the dividing line between the cranium and the face; the nasomaxillary complex, made up of the nose, maxilla, and associated small bones; and the mandible. The sites and types of growth are discussed in the following section of this chapter. The mechanism and determinants for growth in each area, as they are viewed from the perspective of current theories of growth control, are discussed in the following section.
The cranial vault is made up of a number of flat bones that are formed directly by intramembranous bone formation, without cartilaginous precursors. From the time that ossification begins at a number of centers that foreshadow the eventual anatomic bony units, the growth process is entirely the result of periosteal activity at the surfaces of the bones. Remodeling and growth occur primarily at the periosteum-lined contact areas between adjacent skull bones, the cranial sutures, but periosteal activity also changes both the inner and outer surfaces of these platelike bones.
At birth, the flat bones of the skull are rather widely separated by loose connective tissues (Figure 2-24). These open spaces, the fontanelles, allow a considerable amount of deformation of the skull at birth. This is important in allowing the relatively large head to pass through the birth canal (see Chapter 3 for more detail). After birth, apposition of bone along the edges of the fontanelles eliminates these open spaces fairly/>