Wissenschaft. Edition. Edition Wissenschaft Forschungsgemeinschaft Funk e. V.. G Issue No. 22. October 2005

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1 Edition Wissenschaft Forschungsgemeinschaft Funk e. V.. G Issue No. 22. October 2005 Edition Wissenschaft Jörg Reißenweber, Janine Poess and Eduard David Sensitivity of children to EMF exposure do elevated susceptibilities to high-frequency mobile communication fields exist during discrete developmental phases?

2 Editorial Dear readers, We gladly present you a new and hopefully interesting issue of Edition Wissenschaft. Commissioned by the Forschungsgemeinschaft Funk e. V., a group of physicians describes with great diligence and scientific meticulousness the growth cycles of unborn life resp. infants up to the young adult. This study issue was put in the focus of public interest mainly by the recommendations of the so-called Stewart report that children younger than 16 years should only use mobile phones in emergencies. This carefully crafted report presented by the British Independent Expert Group on Mobile Phones, chaired by Sir William Stewart, on 16 June 2000, has basically confirmed general scientific opinion as well as the ICNIRP-recommendations. However, the response sparked by the broad media coverage especially in English-speaking countries to the recommendations for a thoughtful use of mobile phone especially by children has reopened scientific debate. Within the research program COST 281 a workshop titled Mobile Communication and Children took place on 5 May 2002 in Rome; in addition, a working group chaired by Luc Martens was implemented. A current survey of literature on the topic was presented, and the following topics were discussed: Anatomical properties and biophysical mechanism in children; dielectric properties; dosimetry; biological studies; pattern of usage, risk communication to children. Moreover, the WHO organized a workshop in Istanbul in June 2004, devoted to the question whether children are at a special risk from electromagnetic fields. The workshop was organized in cooperation with the Medical Faculty of Gazi University, Ankara. Further information is found on the WHO website at research/children/en/. The authors of this issue of Edition Wissenschaft, Dr. med. Jörg Reißenweber, Janine Pöss and Prof. Dr. med. Eduard David, have aimed to provide additional scientific facts on the question hotly discussed in the public whether children and adults essentially differ in their physical constitution under the aspect of electromagnetic field exposure and, accordingly, could react differently. The focus is on the medical aspect of the topic. Our special thanks go to the authors, but also to Prof. Dr. med. Siegfried Zabransky, University Clinics Saarland, Medical Clinic for Children and Youth, Homburg/Saar, for revising the manuscript and his advice on the concept and design of this topical issue. As soon as further results are available, we will continue our coverage in adequate form. Sincere greetings Gerd Friedrich 2 Edition Wissenschaft October 2005

3 Contents 1 Scope and Purpose 6 2 Introduction 7 3 The ICP (Infancy Childhood - Puberty) model 8 4 Foetal Growth Assessment of foetal size Measurements Macroscopic and microscopic growth Placenta Epidemiology Nutrition Foetal number Control of foetal growth The Homeobox genes Foetal genome Maternal constraints Endocrine control Other factors that influence size at birth 11 5 Growth during infancy, childhood and adolescence Growth in infancy Growth in childhood Mid-childhood growth spurt Growth at adolescence Differences between the sexes 13 6 Influences on growth in infancy and childhood Prenatal influences Nutritional influences Endocrine influences Conclusion 14 7 Height velocity changes and further physical changes in puberty Body components Normal variations in pubertal growth Bone mineralization and puberty Clinical recognition of normal growth 16 8 Growth Hormone (GH) Hypothalamic control of GH secretion Other factors influencing GH secretion GH and Body mass index (BMI) GH in the circulation Signal transduction Insulin-like growth factors and binding proteins Cellular actions of IGFs 17 9 Control of growth Actions of GH and IGF-I on bone growth Endocrine control in the foetus, the child and during puberty 18 Edition Wissenschaft October

4 10 Growth a linear process? Formation of the embryonic skeleton and the growth plates Structure and function of the growth plate Growth and chemical composition of soft tissues Skin Heart Liver and kidneys Brain Changes in the dielectric properties during growth Brain Skull Brain development Prenatal development Histogenesis Dendritic growth Myelinisation Synaptogenesis Pruning Synaptic density Neuronal density Mean number of synapses/neurons The newborn child Postnatal CNS development Growth spurts Sensitive periods Development of the brainstem Medulla Pons Midbrain Behaviour and cognitive development of the new-born Development of the skull, sutures and fontanelles Fusion of fontanelles and sutures Skull growth Two skull growth possibilities Volume of neurocranium Head circumference Diploic space Auditory tube Discussion of weak points and periods of hypothetically increased sensitivity during the development from embryonal and foetal stages to puberty Growth Nerve fibres Synaptogenesis: Blood brain barrier (BBB): Erythropoesis: 34 4 Edition Wissenschaft October 2005

5 16.6 The skull as antenna: Water content of tissues Proposals for future research projects Compilation of biophysical, biomedical and anatomical parameters and tissue properties worth being investigated more thoroughly in future studies: Specific age-related phenomena and parameters worth being considered in regard of child development under the influence of electromagnetic fields Assessment of the present knowledge and research on health hazards by radiofrequency fields from the medical point of view Summary Selected literature Imprint 42 Edition Wissenschaft October

6 Scope and Purpose Jörg Reißenweber, Janine Poess and Eduard David Sensitivity of children to EMF exposure do elevated susceptibilities to highfrequency mobile communication fields exist during discrete developmental phases? 1 Scope and Purpose The effects of electromagnetic fields in the high frequency ranges of mobile telecommunication systems are currently the subject of vigorous discussion in regard to their putative negative outcome on health. The British Stewart Report and sections of the German Electrotechnical Commission are discussing small skull volume during infancy, childhood and adolescence as possible risk factors in children who use telephones. Thus as the present study explains in detail below an initial precondition has to be established for the future in order to compare the dielectric properties of the human skull during growth in infancy, childhood and puberty on the one hand and during adulthood on the other. At any given point of time during the development of the growing organism, the dielectric properties of the various fatty or connective or bony or nervous tissues within the human skull vary to a considerable extent. The principal reason is that the above-mentioned structures possess different tissue and cell densities, as well as different specific weights and water contents. Additionally, when the skull develops successively, tissue properties are always changing and adapting depending on the stage of growth. Thus, at any given moment during growth, we have to observe novel and different combinations and patterns of ever-changing tissue and cell densities or specific weights and water contents, respectively. Consequently, during infancy, childhood and puberty, the results are changing all the time as far as susceptibility to external electromagnetic influences are concerned. Therefore it seems useful and reasonable to carefully analyse and assess the geometrical and three-dimensional spatial assertions of various biological structures and tissues within the human skull. In this context, the high degree of complexity of overlapping growth processes in skull and nervous system components requires a concise and astute analysis of the available biological and medical databases. The models of complex growth patterns during various periods of organ and organ system development need to be successively investigated. For example, the nerve fibre sheaths might present different degrees of myelination in different depths of the brain and, in consequence, show different dielectric properties. Likewise, connective tissue dependent of its thickness, density and water content produces a variety of shielding effects against external electromagnetic fields. Skin-fold, for instance, something that involves connective tissue is greater in girls than in boys, particularly during puberty. Thus sex differences must be considered in this context, too. It is because of this complexity of human anatomy and development and specifically human skull development that we have undertaken the effort to compile, analyse and assess existing knowledge in the field of neonatal medicine, developmental medicine, biology and paediatrics. This paper provides an overview of human growth, beginning with the prenatal development 6 Edition Wissenschaft October 2005

7 Introduction of human life during the embryonic and foetal stages up to the newborn with a special focus on the nervous system and the hormonal and endocrinological aspects of growth. The latter issue is discussed primarily in the context of effects and interactions of growth hormone (GH), insulin and insulin-like growth factor (IGF) etc., including the evaluation of peak and trough values of hormone secretion at all stages of development. Questions of body mass index (BMI) are also dealt with here. A further focus is on postnatal development during infancy, childhood and adolescence in general. An overview like this seems crucial for the assessment of biological structures such as the blood brain barrier (BBB) during the stages of development towards the adult organism. In an astute and complete analysis, growth processes involved in nervous system development like the fascinating processes of synaptogenesis and pruning etc. by environmental factors are explained. For only a sound and thorough knowledge of the different velocities of development of the various nervous or bony structures can provide a first insight into possible anatomical or histological weaknesses or critical issues in terms of modification or even alteration of physiological or neurophysiological functions by external electromagnetic fields and other environmental agents, for example. One important biomedical endpoint of the present effort should be to identify probable or putative temporal and/or local gaps and sensitive developmental periods and/or regions of the human skull when or where electromagnetic fields if at all could hypothetically have harmful effects on children s health or adolescents well-being and easiness. There is accumulating evidence that human cognitive functions might be positively or negatively influenced by weak external electromagnetic fields in the global system mobile communication (GSM) or universal mobile telecommunication system (UMTS) frequency ranges (see TNO-COFAMstudy by Zwamborn et al., September 2003) although the latter study urgently needs replication before it can be considered relevant and before measures are taken. Given a recent publication on the phenomenon of electromagnetic hypersensitivity (Bioelectromagnetics 24: , 2003) by Leitgeb and Schröttner ( evidence could be found for the existence of a subgroup of people with significantly increased electrosensibility ) further research on this topic is warranted and seems to be justified. The infancy-childhood-puberty (ICP) mathematical model of the human growth curve (Karlberg et al. 1987) is demonstrated, as are the various growth periods including epidemiological aspects and sex differences. The clinical recognition of normal growth and the endocrine control of growth of various tissues such as bone and cartilage are also covered. The question is also discussed of whether growth is a linear process, as are changes in dielectric properties during growth. Likewise, growth and chemical composition of soft tissues are covered, with the focus on organ systems. Brain development is demonstrated in detail (histogenesis and cell differentiation, dendritic growth, myelination, synaptogenesis and pruning). Then, the new-born child and the postnatal CNS development including growth spurts and sensitive periods are presented. The development of the brain stem, the cognitive development of the newborn and - last but not least - that of the skull are elucidated. Finally, putative weaknesses and developmental phases of hypothetically increased sensitivity are outlined, as well as a proposal for possible future research projects - followed by a summary and selected literature. 2 Introduction Effects of electromagnetic fields in the high frequency ranges of mobile communications are currently being discussed intensively - presumably in terms of their possible negative effects on children s health. The discussion has been intensified by the Stewart Report, in which an independent British expert group had expressed its concern that children possibly react more sensitively than adults when exposed to electromagnetic fields in the mobile communications frequency range. This question is even being discussed in other national and international bodies and organisations (German Electrotechnical Commission, World Health Organisation WHO). For this reason, the WHO organised a workshop in Istanbul on this topic entitled Sensitivity of Children to EMF in June 2004, which will be referred to in this text. First, a common but nevertheless detailed overview of paediatric and embryological aspects, as well as aspects of developmental biology and physiology of the human body from the embryonic stage until puberty for different organs and organ systems will be provided. Edition Wissenschaft October

8 The ICP Then the link to high-frequency electromagnetic fields shall be examined. At this point however, it must be stated that at present, there is nothing to suggest an increased sensitivity of organs or organ systems towards electromagnetic fields. In other words: Until now, no facts or clues point towards relevant weaknesses or developmental phases from the embryonal stages to puberty with relation to electromagnetic fields in the mobile communication frequency range. This was also nearly common sense during the WHO workshop on this topic in Istanbul in June Nevertheless the present basic overview could be a starting point at the very beginning for a novel branch of research. Initially it makes sense to characterise the developing human body based on existing literature thoroughly in regard to numerous parameters and measures, primarily from the areas of biophysics, biochemistry, anatomy and physiology during growth from prenatal stages via the small infant, infant, childhood, and youth to the adult stage: 3 The ICP (Infancy Childhood Puberty) model 5 The infancy-childhood-puberty (ICP) model of growth (Karlberg et al. 1987) is a mathematical model of the human growth curve. According to this model, the normal linear growth curve can be broken down into three additive, biologically interpretable components of growth from the immediate postnatal period to adolescence. The infancy component starts in mid-gestation. It is initially rapid but decelerates by the end of the first year to about three to four years of age. The childhood component starts in the second half of the first year and slowly decelerates. It is assumed that the infancy component represents the postnatal contribution of foetal growth and Figure 1 The Infancy-Childhood-Puberty (ICP) model of growth implies a mathematical approach to the human growth curve. According to this model, the normal linear growth curve can be broken down into three additive components of growth from the immediate postnatal period to adolescence: The infancy component (1) starts in mid- gestation. Initially it is rapid but it decelerates by the end of the first year to about three to four years of age. The childhood component (2) starts in the second half of the first year and slowly decelerates. Presumably the infancy component represents the postnatal contribution of foetal growth while the childhood component represents the effect of growth hormone (GH). The puberty component (3) is sigmoid- shaped and involves a spurt in growth during adolescence. The combined effects of the three components result in the normal pattern of growth (Karlberg J. et al., 1987). the childhood component the effect of growth hormone (GH). The puberty component is sigmoid-shaped and involves the adolescent growth spurt. The combined effects of the three components result in the normal pattern of growth. In the Analysis of linear growth using a mathematical model study (Karlberg et al. 1987), growth as Figure 2 Analysis of linear growth using a mathe- matical model: From birth up to the onset of the childhood component most children show a non-linear decrease in velocity. In a majority of the children, abrupt increases in velocity were seen at onset of the childhood component. Most of the children showed fairly constant velocities during the second year of life. Growth is dependent on both infancy and childhood components in this period. During the third year, growth is more stable, being solely dependent on the childhood component (Karlberg J. et al., 1987). 8 Edition Wissenschaft October 2005

9 Foetal Growth measured by supine length was analysed for longitudinally followed healthy infants using the ICP model. The study showed that: the onset of the childhood component was significantly earlier in girls than in boys. This corresponds to the lower initial velocity of their infancy component: The onset of the childhood component seems to be clearly related to the magnitude of the infancy component. the onset of the childhood component occurs between six and 12 months and is typically abrupt. from 12 months of age onwards, the onset of the childhood component occurs in all infants. According to this study, most children s growth follows the most common pattern for the sequence of events before, at and after the onset of the childhood component: From birth up to the age of onset of the childhood component, most children display a smooth, non-linear decrease in velocity. At onset of the childhood component, a majority of the children had abrupt increases in growth velocity and most children showed fairly constant velocities during the second year of life. In this period, growth is dependent on both infancy and childhood components. During the third year of life (when the infancy component has disappeared) growth is more stable, being dependent on the childhood component alone. The ICP model can be used for understanding growth disturbances: From three to six months of age, a healthy child shows a maximum change of about 1 SD in attained supine length. After six months of age, an increase in length of more than 0.2 SD every three months corresponds to the onset of the childhood component. This does not occur after 12 months in a healthy child. During the second year of life a healthy child will not change more than 1 SD in attained length per 6 months. Within two to three years of the cessation of the infancy component, a change of more than 0.75 SD indicates an abnormal development solely in relation to the childhood component. 4 Foetal Growth The foetal phase of prenatal development starts in the ninth week following conception and is characterised by rapid growth and the differentiation of tissues and organ systems formed during the embryonic period (the first eight weeks). Foetal growth until birth depends on the interaction of highly complex processes such as cell division, migration, synaptogenesis and differentiation. 4.1 Assessment of foetal size For a correct interpretation of foetal size, knowledge of the gestational age plays an important role. Gestational age is dated from the first day of the last menstrual period. The expected date of delivery is 40 days later. 4.2 Measurements During the first trimester, crownrump length measurement is the most accurate method of pregnancy dating (ideally between 6.5 and 10 weeks) In the second trimester the biparietal diameter and the femur length are measured (useful until 24 weeks). After that, such measurements become less reliable because of the increasing normal variation. The best measurement for assessing foetal size is the head and the abdominal circumference. 4.3 Macroscopic and microscopic growth Foetal growth is linear except during the embryonic period and in the last few weeks of pregnancy, so that measurement curves have a weak sigmoid shape. During the first trimester, tissues and organ systems are established. Initially (during the first three weeks) the three germ layers (ectoderm, mesoderm, endoderm) are formed. In weeks four to eight there is rapid growth and differentiation with the aim of forming the organ systems. Early embryonic growth is achieved mainly by increasing cell number (hyperplasia). The growth rate is greatest in the first week of development (cell doubling time: 24 to 36 hours). In mid-gestation, growth depends on both hyperplasia and hypertrophy (increase in cell size) while near-term hypertrophy predominates. This explains why insults in early development can provoke irreversible growth restriction whereas growth failure due to a later insult can be reversed post-natally with catch-up growth. Macroscopic growth is characterised by a doubling in average foetal length (from 61 mm to 140 mm), foetal weight increases 14-fold (14 g to 200 g) from the tenth week of gestation to the sixteenth. From 10 weeks to term the foetus Edition Wissenschaft October

10 Foetal Growth shows an accelerating growth rate (weeks four to 12: 33 cm/year). Growth velocity peaks in the second trimester (weeks 12-24: 62 cm/ year) and decelerates after this (last 16 weeks: 48 cm/year). The largest weight gain occurs in the third trimester (weeks kg/ year, weeks kg/year, last 16 weeks 8.7 kg/year). Body proportions change during pregnancy. For example, foetal brain and liver growth occurs mainly in the first half of pregnancy whereas muscle, skin and subcutaneous tissue growth is prominent in the third trimester. Thus, foetal head falls as a proportion of total length from 50 % at 9 weeks to 25% by term. There is a marked variation in timing of growth spurts in different organs. 4.4 Placenta The placenta plays an important role in foetal development. A good correlation between second trimester placental volume and foetal weight at term has been shown, suggesting that early placental development may be important for late foetal growth and development. 4.5 Epidemiology 1. Demographic factors Ethnicity, altitude, pregnancy spacing, age, weight, smoking, and social class correlate with foetal size, but it is difficult to estimate the degree to which these associations are determined by genetic or by environmental factors. Because of this complexity it is not possible to estimate the significance of any one factor. 4.6 Nutrition Severe malnutrition can lead to foetal growth failure. During the first 30 weeks, no increase in energy intake is required. But in the last four to six weeks, foetal weight may increase by 1.5 kg. Maternal malnutrition at this stage may impair liver growth. 4.7 Foetal number Reduced foetal growth is a common consequence of multiple pregnancies. 4.8 Control of foetal growth The Homeobox genes The processes of cell division and differentiation as well as morphogenesis depend on developmental genes belonging to the HOMEOBOX family. They encode for proteins that bind DNA, thereby controlling gene expression and hence cell differentiation and organ development Foetal genome In early development, the foetal genome is the major determinant of foetal growth. Later in pregnancy other factors such as maternal constraint and endocrine controls interact. Genetic differences in birth-weight tend to cause changes in cell number rather than in cell size. As hyperplasia (increase in cell number) predominates in the first half of pregnancy it has been suggested that the foetal genome determines growth in this early phase. But the fact that the correlation between eventual adult height and length at birth is much weaker than the correlation with body length at two years of age (Tanner 1962) suggests that genetic factors have their prominent influence on growth in the postnatal period. Intrauterine environment seems to be of dominant influence Maternal constraints It seems that foetal genetics determine growth until maternal factors such as uterine size begin to interact and constrain growth Endocrine control Foetal GH, glucocorticoids, thyroid hormones, and insulin all play important roles in regulating postnatal growth but, with the exception of insulin, they do not have a major role in controlling foetal growth. Insulin and growth factors are major regulators of foetal and placental growth. The role of insulin-like growth factors (IGFs) in foetal growth has been shown by knockout experiments in mice. Disruption of the IGF gene leads to profound foetal growth restriction (40 % reduction in size at birth). Animals without the receptor type I IGF, which mediates the effects of both IGFs, die at birth. The importance of insulin is shown by the somatic overgrowth of newborns to diabetic mothers and the growth failure caused by insulin deficiency. Insulin promotes the growth process by increasing the uptake and utilisation of glucose and amino acid tissue accretion. It also has mitogenic effects, which are mainly secondary to IGF-I secreted in response to insulin. There is some evidence that the GH axis is already active in the foetus: GHRs that are capable of binding GH are detectable from 15 weeks of gestation. Circulating GH levels are high during mid-gestation. The exact role of GH in this period remains unclear. Placental The part played by the placenta in controlling foetal growth is not 10 Edition Wissenschaft October 2005

11 Growth during infancy... completely understood. The cytokine network has an important role in implantation and early placental development. After this, growth factors may be involved but this aspect has not yet been resolved. The placenta itself is an endocrine gland. Although human placental lactogen does indirectly affect growth, its complete absence does not. Placental growth hormone may control maternal IGF-I levels. Maternal The influence of maternal hormones is unclear. Maternal IGF seems to play a certain role its levels being low in foetal growth restriction associated with abnormal placental function. One possible mechanism may be to reduce the uptake and transport of glucose from the maternal circulation by altering the expression of the specific transporter. This would be an important maternal constraint because glucose is assessed as playing an important role in mediating foetal growth. 5 Growth during infancy, childhood and adolescence 5.1 Growth in infancy As mentioned above, the infancy component is the initially rapid but decelerating growth phase of the first two to three years. It seems to be the continuation of foetal growth and is estimated to be determined nutritionally to a considerable extent with minimal contribution by GH. It is therefore during this period that alterations in energy intake have the greatest influence on growth. The correlation between length and weight and mean parental size at birth is poor. This reflects the fact that during intrauterine development the environment has a dominant and strong influence over the foetal genome. After birth this effect disappears and the infant develops its own growth channel : During the first two years a period of catchup soon after birth commonly occurs, lasting until the age of six to eight months or catch-down (this starts at between three and six months and it is completed by nine to 20 months). The average growth rate is about 25 cm in the first 12 months and most children have doubled their length at birth by the time they are three to four years old Other factors that influence size at birth Maternal factors include maternal size, maternal health, maternal nutrition, and teratogens (smoking, alcohol, and drugs). Placental factors include vascular abnormalities, hypoxia, etc. Foetal factors comprise nutrition, intrauterine infection, chromosomal abnormalities, as well as other syndromes and disorders. Figure 3 Length-for-age and weight-for-age percentiles for boys (birth to 36 months). Normal and aberrant growth can be derived from this figure. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000, source: Figure 4 Head circumference-for-age and weight- for-length percentiles for boys. Again, normal and aberrant growth can easily be derived from this figure. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000, source: Edition Wissenschaft October

12 Growth during infancy... Common interpretation of figures 3-6: The infancy component is the primarily rapid but then decelerating growth phase of the first 2-3 years. Obviously it is the continuation of foetal growth and is assumed to be largely nutritionally determined with only a minimal contribution of growth hormone. Therefore alterations in energy intake have the most influence on growth during this period. Correlation between length and weight and mean parental size at birth is poor. This reflects the fact that during intrauterine development, environment dominantly influences the foetal genome. This effect can no longer be observed after birth and the infant develops its own growth characteristics: During the first two years we normally observe a period of catchup growth (soon after birth until the age of six to eight months) or catch-down growth (starts between three and six months and is completed by nine to 20 months). The average growth rate oscillates about 25 cm in the first 12 months while most children double birth length by three to four years of age. 5.2 Growth in childhood The childhood phase assumes gradually more importance from around six months onwards. Until the age of about three years, both the infancy and childhood components are additive. From then on the childhood phase becomes predominant. It is mainly determined by GH, as well as by thyroid hormone. Without adequate GH secretion, the childhood component will be blunted. An abrupt change in growth velocity at the begin of the childhood component (see above) has been detected in most children. The ICP model suggests that this is the time at which GH becomes active. But there is increasing evidence that GH plays a certain role in infancy or even foetal (see above) growth: It has been shown that infants diagnosed as being affected by GH deficiency before the age of two have an excessive birth-weight and a progressive growth failure. This suggests that congenital GH deficiency can affect intrauterine growth and growth in early infancy. The increasing influence of GH seems therefore to be gradual rather than an on-off phenomenon. By four years of age, average growth velocity has declined to 7 cm/year and thereafter continues to decline until adolescence. During the middle years of childhood a child should grow at a rate of 4 to 7 cm/year. Before puberty, average velocity is 5 to 5.5 cm/year. Figure 5 Length-for-age and weight-for-age percentiles for girls (birth to 36 months) Normal and aberrant growth can be derived from this figure. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000, source: Figure 6 Head circumference-for-age and weight- for-length percentiles for girls. Once again, normal and aberrant growth can easily be derived from this figure. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000, source: Common interpretation of figures 7-8: A mid-childhood spurt in weight gain (and also of growth) can be detected in boys and girls at about six to eight years of age. A characteristic rise in adrenal androgen secretion ( adrenarche ) occurs together with the mid-childhood growth spurt and is coincident with the preadolescent fat spurt. The growth spurt could reflect a direct response of bone and muscle tissue to elevated adrenal androgen levels. Or it might be caused by an indirect 12 Edition Wissenschaft October 2005

13 Growth during infancy... There is little difference in height between girls and boys in this period. But the skeletal maturity of girls at birth is three to six weeks ahead and the onset of puberty occurs about two years earlier in girls than in boys. There is marked sexual dimorphism in pubertal timing. Girls are two years earlier in all aspects of puberty: its onset, the age of peak height velocity, and in completion of growth. The study growth at adolescence from Buckler et al. revealed that girls are taller than boys with a maximum difference of 2.5 cm at 12.5 years. They are also heavier, with a maximum difference of 3.5 kg at 13.5 years. The study of Karlberg et al. (1976) gave the following results: Girls weighed more from six to 14 years but the difference was only statistically significant at 12 and 13 years. The annual increment in weight was also greater in girls. The annual increase in height was significantly greater in girls between the age of 9 and 12 years. But as growth takes longer in boys (the later onset of pubertal growth gives them two additional years of pre-pubertal growth and so they gain 8-10 cm compared to girls) and is of greater magnitude (about 3-5 cm more than the growth spurt in girls), the ultimate height and weight of men are greater than that of women. The Karlberg study showed that from 13 years onwards, the increeffect of these androgens on GH secretion: for at about the age of seven years ( adrenarche ) a change in periodic GH secretion is to be observed in children. 5.3 Mid-childhood growth spurt On an individual basis, a midchildhood growth spurt can be detected. A characteristic rise in adrenal androgen secretion ( adrenarche ) occurs concurrently with the mid-childhood growth spurt and this is also coincident with the preadolescent fat spurt. The growth spurt could reflect a direct response of bone and muscle tissue to the increased adrenal androgen levels. Or it may be caused by an indirect effect of these androgens on GH secretion: at an age of roughly Figure 7 Stature-for-age and weight-for-age percentiles for boys (two to 20 years). Normal and aberrant growth can be derived from this figure. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000, source: seven in children (the adrenarche ) there is also a change in the periodicity of GH secretion. In addition, on an individual basis, oscillations in growth velocity of variable amplitude are observed throughout childhood. They occur within a period of approximately two years. Weight changes appear to show a reciprocal relationship with height changes: Growth stasis is associated with weight gain, whereas growth spurts are accompanied by weight stasis. 5.4 Growth at adolescence The period of puberty can be defined as the transition from a prepubertal stage to adulthood through the development of secondary sexual characteristics. Figure 8 Stature-for-age and weight-for-age percentiles for girls (two to 20 years). Again, normal and aberrant growth can easily be derived from this figure. Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000, source: In certain aspects there is a great variability between individuals, notably in the timing of puberty, so that no particular growth pattern can be defined as normal. 5.5 Differences between the sexes Edition Wissenschaft October

14 Influences on growth... ments of height and weight were greater in boys than in girls but only at the age of 15 to 16 did the values attained by boys exceed those of girls. In the Growth at adolescence study (Buckler) median values at 18 were 13.5 cm and 11 kg. Skeletal dimensions are greater in boys at all ages. Boys gain about 30 kg in weight during puberty (82 % being accounted for by fat-free mass), while girls gain approximately 18.5 kg (68 % FFM). Skin-fold is greater in girls, particularly during puberty. 6 Influences on growth in infancy and childhood 6.1 Prenatal influences External influences are at their maximum during growth in utero (see above). Genetic influences gradually become more important during postnatal growth. A total of 95 % of children will have a height prognosis within ± 8.5 cm of the mid-parental centile. The pattern of growth in utero may be reflected in the postnatal growth pattern and may probably cause catch-up or catch-down growth. Infants born small for gestational age (SGA) may be symmetrically or asymmetrically small. Symmetrically small infants have usually had a prolonged insult or a foetal reason for their poor growth whereas asymmetrically small infants have often had a short time of growth failure. In general, asymmetrically small infants have a better prognosis for catch-up growth. In addition, it can be estimated that the developing endocrine system with the beginning of interaction between GH, the IGFs and their binding proteins may influence growth in early infancy. 6.2 Nutritional influences Growth in the first years of life is mainly dependent on nutrition. Particularly from age six months to three years, the child seems to be at most risk from malnutrition - coinciding with the childhood component. This is a sensitive time for infants and children because growth missed during this time is difficult to regain later. 6.3 Endocrine influences As mentioned above, there is a slow, gradual change from the infancy component of the growth curve to the childhood component from the age of about 6 months. The time until the age of three years is characterised by the addition of the two components and from then onwards the endocrine control of birth (the infancy component), primarily mediated by GH, assumes more importance. There are many other factors that influence the process of growth such as chronic illness or psychosocial deprivation. Growth in infancy and in childhood is not a linear process although growth patterns give the impression of linearity. Many studies have revealed that short-term growth is non-linear. The exact form is still unknown (see: Is growth a linear process?) Figure 9 Proportions of a male person from birth up to age 25 (fusion of the epiphyses): As a consequence of different growth of different limbs/body constituents and dimensions, their relations to one another are changing all the time. This predominantly applies for the heights of discrete body constituents: For example the life-long decreasing share of skull height and to a somewhat smaller extent of trunk height in favour of leg length continues until adulthood (Flügel et al., 1986). 6.4 Conclusion Growth restriction is the final common pathway for many organic and emotional problems. The ICP model shows the major influences on growth in infancy and childhood. Prenatal and postnatal growth in infancy and childhood have longreacting effects, not only on adult height but also on morbidity and mortality. New-borns and infants 14 Edition Wissenschaft October 2005

15 Height velocity changes... who are too small have a higher risk of cardiovascular disease and noninsulin-dependent diabetes in later life. 7 Height velocity changes and further physical changes in puberty Peak height velocity during the puberty growth spurt is comparable to the rate of growth during the second year of life. The average duration of the majority of pubertal growth is about six years in boys and girls. Peak height velocity occurs about two years after the start of acceleration. In most boys, the first sign of puberty is enlargement of the testicles, which usually coincides with the onset of acceleration. Other signs are quite advanced before height velocity begins to slow down. In girls, peak height velocity occurs at an earlier phase of development, about one year after the onset of breast development. The menarche occurs roughly one year after the period of peak height velocity. The shapes of height velocity curves of individuals are very similar, with a wide variation at the age of onset of pubertal growth. 7.1 Body components Growth of body components does not occur in parallel: The most rapid growth of the limbs precedes that of the trunk, predominantly before the age of peak height velocity. Growth of the trunk occurs after the age of peak height velocity. Therefore, the ratio of sitting height (an indicator of trunk height) to leg length alters through puberty, being at its lowest at the age of peak height velocity. Growth in the trunk width coincides with overall growth. Weight changes are dramatic and the body mass index (BMI) increases. But it must not be concluded that an increase in BMI during these years is the result of an increase in fatness. Weight gain during this period is predominantly due to an increase in lean body mass (muscle and bone). 7.2 Normal variations in pubertal growth The age of peak height velocity can be used as the criterion of overall timing of puberty: the average age for boys is 14.1 years, for girls 12 years. In boys there is little difference in the ultimate stature or weight between the groups. The increment in stature from pre-puberty to adulthood is similar in boys, though with the onset of puberty occurring at a different time. In contrast, early developing girls tend to be taller and heavier before puberty than late developers. They remain heavier into adult life with only a small difference in stature and they increase less in stature during puberty. In boys with their different timing of puberty, there is little difference in BMI, whereas the later that girls pass through puberty the less is their weight at comparable stages and the lower their BMI. The proportion of growth that occurs at different stages of puberty varies according to the timing of pubertal development. Early developers show a shorter interval and smaller increment of height before the age of peak height velocity, and compensate with greater values afterwards. This fact is also seen in girls in relation to growth before and after the first menstruation (menarche). Growth in the legs predominates in early stages of puberty, whereas growth of the trunk occurs later. Therefore, late developers, whose legs have more time to grow, have greater leg length : sitting height ratios. These variations in timing are multifactorial but nutrition is an important factor that influences the growth process in this period. There are also familial and racial influences and there has also been a secular trend, with puberty advancing at about one year per generation (Tanner 1962). Extremely competitive sporting activities cause a delay in puberty, too. The process of growth ceases when the epiphyses fuse to the shaft of long bones with the obliteration of the growth plate. 7.3 Bone mineralization and puberty Delays in puberty may impair adequate bone growth. Bone mass is accumulated steadily during childhood and notably in adolescence, reaching a peak after the end of puberty. Bone mineralization is consistently correlated with pubertal development and with androgen/ oestrogen levels. Adolescents with delayed puberty show a lower degree of bone development and less bone mass. Hormone treatment to initiate puberty is associated with an increase in bone mineralization. Therefore earlier hormone treatment is required in patients with delayed puberty. Edition Wissenschaft October

16 Growth Hormone (GH) 7.4 Clinical recognition of normal growth Observations need to be made over a year or even more in order to define the problem. The following are required: height, weight, sitting height, sub-ischial leg length, BMI, height velocity, and head circumference; standards for pubertal timing; wrist radiographs (to estimate bone age) and an orchidometer (to measure the testicular volume). Weight fluctuates quite widely; used alone, it is a poor guide to growth. Length is an excellent marker of infant and childhood growth. height-for-age at three months has been shown to be the best screening method to detect growth failure. Height should be plotted on a growth chart on, which the measured heights of the parents has been entered: if the child is male, the father s height and the mothers height cm will be plotted, the reverse for a girl. Mid-parental height is defined as the midpoint between these corrected values, the target range is ± 8.75 cm. If the child s height falls outside the target range, a growth disorder may exist. Another way is to derive a standard deviation score (SDS). Normal values would be expected to fall between ± 2 SDS in 95 % of cases. Growth velocity should not fall below the twenty-fifth or rise above the seventy-fifth centile in successive years. Bone age is estimated by visualisation of epiphyseal centres in growing bones of the wrist. There have been standards generated for bone maturation in each sex throughout childhood and adolescence. As residual growth depends mainly on the state of the epiphyses, methods of predicting adult stature depend on an estimation of bone age i.e. the state of skeletal maturation. The more delayed the bone age (relative to chronological age) the longer the time before the epiphyse fuses and prevents further growth. BMI - weight (kg) divided by the square of the height (cm²) varies greatly in children, rising gradually in infancy, falling during the preschool years and rising again after around eight years of age, through puberty and into adulthood. The hormones that have the greatest influence on human growth are growth hormone (GH) and insulinlike growth factors (IGFs) but others also contribute to the growth process, such as thyroxine, adrenal androgens, sex steroids, glucocorticoids, and Vitamin D. 8 Growth Hormone (GH) 8.1 Hypothalamic control of GH secretion GH is secreted from the anterior pituitary into the circulation. There are pulses every three to four hours: This pattern of secretion is mainly determined by the interaction of two peptides secreted by the hypothalamus: Growth hormone-releasing hormone (GHRH, also known as somatotropin) and somatostatin (SS). The amplitude of the GH peak is determined by GHRH, which stimulates the release of GH by the pituitary. SS determines the trough levels of GH by inhibiting GHRH release (in the hypothalamus) and GH secretion in the pituitary. 8.2 Other factors influencing GH secretion Other factors such as neuropeptides, hormones, sleep, and physical exercise influence the secretion of GH acting directly on the pituitary (stimulation of GHRH and/or inhibition of SS). GH and IGF-I are both able to regulate GH secretion via negative feedback. 8.3 GH and Body mass index (BMI) There is a negative relationship between BMI and GH secretion. GH secretion increases after weight loss. Therefore, diminished GH seems to be a result of fatness rather than a cause. 8.4 GH in the circulation GH can be detected in the foetal pituitary and in foetal serum before the complete maturation of the hypothalamo-pituitary axis. Serum levels peak at around 24 weeks, then decline through to birth and fall further after the first two weeks of life. The decrease in GH is associated with the development of the inhibitory mechanisms. Cross-sectional data suggests that GH pulse amplitude increases with age. The most important changes occur during the pubertal years. Maximum levels of GH secretion coincide with the timing of peak height velocity, secretion thereafter declines into adulthood. A sexual dimorphism in GH secretion exists: Average daily secretion is greater in women than in men. In men, pulses in daylight hours are small whereas nocturnal pulses are large; in women the pulses are more 16 Edition Wissenschaft October 2005

17 Control of Growth frequent but diurnal variation is weaker. The pattern of GH is complicated by the presence of GHBP. Two forms have been identified that bind GH with low or height affinity. The exact physiological significance of complexed GH is unknown. But one of the consequences is an increase in plasma half-life and probably a potentiation of GH effects. 8.5 Signal transduction GH binds to a specific receptor (GHR), which is particularly markedly expressed in the liver. A single molecule of GH binds to two receptors. The binding of GH to a single receptor is followed by recruitment of a second GHR and then the dimerisation of the two GHR. This results in a phosphorylation cascade. GH signal transduction can proceed through many pathways. The result of GH signal transduction by the pathways mentioned is the activation of genes, in particular the IGF-I gene whose product (IGF-I) mediates many of the growth-promoting effects of GH. 8.6 Insulin-like growth factors and binding proteins IGF-I and IGF-II are polypeptide hormones expressed in many organs and tissues. Both are important in foetal growth and development but only IGF-I seems to influence postnatal growth. This may be because IGF-II, in contrast to IGF-I, does not seem to be regulated by GH. The IGFs bind to the IGF binding proteins (IGFBP). Their role is to prevent the potential insulin-like activity of the IGFs and to extend the half-life of the IGFs, creating a circulation reservoir of IGF activity. In addition, they regulate the movement of IGF across the capillary Figure 10 Y-axis: Growth hormone (GH) in ng/ml; X-axis: Clock time in h. The figure displays changes in the serum concentration of growth hormone (ng/ml) over a time period of 24 hours with samples measured at intervals of a duration of 20 min. One can clearly realise the pulsatile pattern of GH secretion and a maximum value in the morning between a.m. and a.m. (Clayton and Gill, 2001). walls and play a role in controlling IGF distribution. The IGFBP s common feature is their ability to bind IGFs with high affinity. But the binding affinity of IGF-I and IGF-II may differ for a given IGFBP. IGFBP-3 is the major IGFBP in the circulation, accounting for most of the IGF-I binding capacity. Like IGF-I, IGFBP-3 is strongly GH-dependent. 8.7 Cellular actions of IGFs There are two receptors for the IGFs: The IGF-I receptor and the type II or IGF-II receptor. Most actions of both IGF-I and IGF-II are mediated by the IGF-I receptor. The signal transduction path is similar to that used by insulin. IGF-II seems to mediate all of its biological effects through the IGF-I receptor. 9 Control of Growth 9.1 Actions of GH and IGF-I on bone growth The major role of GH during growth is to promote longitudinal bone development. Two hypotheses try to explain the precise nature of the GH s action. The somatomedin hypothesis proposes that GH mediates its effects by stimulating the production of hepatic IGF-I, which acts as a classic endocrine hormone. The dual effector theory proposes that GH directly promotes the differentiation of precursor cells and the development of IGF-I responsiveness. Clonal expansion of these differentiated cells is then mediated by local production of IGF-I in response to GH. Systemic administration of GH and IGF-I in hypophysectomized rats has shown that both GH and IGF-I Edition Wissenschaft October

18 Control of Growth? increase body weight, longitudinal bone growth, cell proliferation and cell productivity. GH has been shown to be more effective. This seems to be due to the effects of GH and IGF-I on IGFBPs: GH creates a more stable complex with the binding proteins. Therefore the reservoir of IGF in circulation can be maintained over a longer period of time. In addition, GH seems to stimulate local production of IGF-I. Optimum growth depends on adequate GH secretion, a stable pool of IGF-I and, in addition, paracrine and /or autocrine actions of IGF-I and GH in peripheral tissues. 9.2 Endocrine control in the foetus, the child and during puberty Foetal growth seems to be primarily determined by nutrition, IGFs and other growth factors being GH independent. Exactly which role GH plays in foetal growth and development remains unclear. As mentioned above, there is some evidence that the GH axis is already active in the foetus. The infancy phase is considered to be largely nutritionally determined with the only minimal contribution of by being the continuation of foetal growth. At about six to 12 months of age the onset of the childhood component occurs, and from then until the age of three years, both the infancy and the childhood component are additive. After three years of age the childhood component and thus endocrine control (GH) predominates. But there is increasing evidence that the influence of GH gradually appears and that there is not an on-off-phenomenon. The childhood phase is mainly determined by the influence of GH. The exact way in which GH mediates growth in normal children in this phase is still not clear. GH secretion increases during the mid-childhood years, mainly due to an increase in pulse amplitude with no change in frequency. The sum of GH pulse amplitudes correlates with the growth rate in an asymptotic manner. GH secretion varies in children who grow at a normal rate. Therefore, additional factors must be responsible for the variation in growth rate when an adequate level of GH secretion has been attained. One of these factors is the responsiveness of IGF-I after GH-stimulation. It has been shown that there are considerable interindividual differences of IGF-I secretion for a given GH level. In addition, IGF-I levels seem to correlate more with peak than with trough levels of GH. This suggests that both the pattern of GH secretion and the responsiveness of the target tissues are important for a normal growth process. The period of puberty is mainly influenced by GH and sex steroids, with each contributing approximately 50% to the gain in height. There is an increase of GH release. Oestrogen is important for skeletal maturation and fusion of the epiphyses. IGF-I concentrations increase markedly during puberty. They peak 1 year later in boys than in girls and at least 2 years after the age of peak height velocity. The interactions between GH, IGF-I and other factors that influence the growth process are complex and dynamic. Knowledge of exactly how the signals of the hormones are translated into normal growth still remains very limited. 10 Control of growth? The more closely growth in an individual is observed, the more non-linear it seems. If we think about the complexity of the growth process, there is no reason to suppose that linearity is anything other than an approximation to reality: If we picture one cell in a single growth plate exposed to 1 GH with feedback, regulation growth would be predictable but non-linear. Then adding the multitude of cells, the complex endocrine events, other factors like daylight hours, pulse generators of the CNS, temperature, nutrients, and control mechanisms it may be suggested that growth cannot be a linear process. Growth is a dynamic process that seems to proceed intermittently with interindividual variations that reflect the complex interactions of the events leading to growth. Its exact form and very nature, like the relative contribution of several factors to this process have not yet been understood. One example is the question of whether seasonal variation in growth rates exists. Some studies have revealed seasonal variations, others have not. Ashizawa and Kawabata (1990) and Gelander et al. (1994) revealed that individual body segments also show seasonal growth. All these effects could be mediated by the higher CNS (melatonin and other hormones with circadian rhythmicity). Butler et al. (1990) revealed growth spurts during the childhood period, some 18 Edition Wissenschaft October 2005

19 Growth and chemical... of which may be related to season while others may reflect the midchildhood growth spurts. This supposed non-linearity shows the impossibility of predicting longterm growth from short-term observations. It can be concluded with a degree of certainty that human growth is irregular down to the daily level (J.K.H. Wales) Formation of the embryonic skeleton and the growth plates 10.1 Formation of the embryonic skeleton and the growth plates: Bone tissue is derived from mesenchyme, specialized mesoderm cells. The first step of synaptogenesis consists thus in the aggregation of mesenchymal cells, which differentiate into chondrocytes (cells that produce cartilage). The chondrocytes draw up cartilage models of the future skeleton. Thus, these mesenchymal cells first form cartilaginous centers in the location where bone will eventually form. The chondrocytes start their terminal differentiation by a clear increase in size. At the same time there is an invasion of vascular cells and other cells with the aim of degrading the cartilage in order to form primary ossification centres. Then a process known as endochondral ossification occurs: The ossification centres increase and become ossification fronts moving from the centres to the ends of the bones. At the outer boundary, the cartilage is degraded whereas bone is deposited proximally. Soon after the ossification fronts reach the end of the bones they become compressed. These complex structures of ordered layers of tissue are known as growth plates. In later life they will be responsible for almost all linear growth. They are established around the end of the first trimester Structure and function of the growth plate The growth plate resides between cartilage located at the end of growing bones and an ossification front (moving outwards from the centres of the bones). It can be divided into different zones and is a highly dynamic structure: The chondrocytes that occupy the different zones are in different phases of their lifecycle. They begin their lives in the epiphyseal cartilage (epiphyseal chondrocyte). In the next phase they become resting chondrocytes of the reserve zone. Soon after that they start to proliferate (proliferative zone). In the last phase, the chondrocytes are in the hypertrophic zone and begin their terminal differentiation, which is characterised by a marked increase in size (hypertrophy). A single chondrocyte does not move relative to the ossification front. In contrast, the ossification front moves through the location occupied by the chondrocyte as it differentiates. The differentiated cells disappear as the ossification front passes. Subsequently, the cartilage matrix becomes degraded by perivascular cells. Osteoblasts (cells that produce bone) deposit osteoid (bone mass) forming primary bone trabeculae. Osteoclasts (cells that remove bone mass, which are needed for building the normal bone structure) degrade the remaining cartilage matrix inside the trabeculae. 11 Growth and chemical composition of soft tissues The development of a tissue or a whole organism involves structural and biochemical changes. The Widdowson and Dickerson study shows that the tissues of foetuses and new-born animals contain a higher proportion of water than those of adults. To some extent this is due to an increase in fat, but even on a fat-free basis the percentage of water falls during the period of growth and development. At a certain age the water content becomes constant. It is suggested that this fall in the water content is to some extent due to a decrease in the proportion of the body occupied by extracellular fluids and, in the same time, to a rise in the concentration occupied by cells. The form and structure of an adult organism is reached by differential growth. Some organs and tissues mature faster than others. Foetal heart muscle, liver and kidneys reach their adult composition before skin and skeletal muscle. It can be suggested that this fact is related to the speed of functional maturation: The foetal heart begins to sound at weeks of gestation, foetal liver functions as an haematopoietic organ during foetal development and the foetal kidneys produce urine. In contrast, the skeletal muscles and skin of the foetus have little work to do Skin Development of the skin is associated with a fall in the concentrations of water, sodium and chloride and an increase in total nitrogen and collagen nitrogen. Cellular constitu- Edition Wissenschaft October

20 Growth and chemical... ents increase during prenatal life to a peak during early postnatal life, and after that decrease in the adult organ. The extracellular phase of a tissue consists of extracellular water and connective- tissue proteins (collagen, reticulin, elastin; and fibrous material). One part of the extracellular water is associated with these proteins and is called fibre-water. The other part is associated with non-fibrous material ( non-fibre water ). During development, the proportions of the extracellular fluid change. Coincident with the increase in collagen is an increase in fibre water whereas non-fibre water decreases. Before birth, there is little collagen in the skin. The collagen in human foetal skin is in the form of reticulin fibres. Since the amount of collagen is small during this period, a correspondingly small part of extracellular water is associated with it. The skin of three to six months old infants shows percentages of water and total nitrogen that correspond to levels in adult organs but it is not mature in terms of the proportion of total nitrogen contributed by collagen. Cell water increases to a peak at the time around birth, then decreases along with the change in the concentration of cellular substances. During postnatal growth, the cell density in the corium decreases whereas the thickness of the skin increases. During development there is a fall in the concentration of water and an increase of the amounts of nitrogenous constituents. Potassium and sodium concentrations change in an unexpected way: The foetal heart shows a higher concentration of potassium and a lower concentration of sodium than does the heart of a new-born at term. There are relatively small changes in the concentration of chloride during development. Taking the amount of chloride as a measure of extracellular fluid, it can be concluded that the heart of the foetus is near its adult composition in the proportion of it that is occupied by intercellular lymph Liver and kidneys There is a fall in the concentration of water and a rise in the amount of nitrogen in liver tissue, too. The fact that livers of foetuses contain a large amount of potassium is probably related to the haematopoietic activity of the organ during intrauterine life. The foetal livers contain more sodium and chloride and therefore seem to contain more intercellular lymph. The kidneys also show a decrease in the water content and an increase in the amount of nitrogen Brain The proportion of water falls from over 90% in the foetal brain to 76 to 77% in the adult. The proportion of nitrogen increases. There is also a decrease in the concentration of sodium and chloride and an increased potassium concentration. None of these levels reach adult levels until after term Heart Table 1 This table indicates chemical and biochemical composition of human brain from foetal to adult stages. The results are expressed in kg of fresh whole brain and average values as well as ranges are given (Widdowson and Dickerson, 1960). Indispensable substances like water in g, total N in g, Na, K, Cl, P, Mg and Ca are classed with the discrete develop- mental phases from foetus via the new-born baby to the adult and their amounts are specified (Widdowson and Dickerson, 1960). 20 Edition Wissenschaft October 2005

21 Changes in the dielectric Changes in the dielectric properties during growth In a study by A. Peyman, A. A. Rezazadeh and C. Gabriel, dielectric measurements have been carried out on different tissues (brain, skull, skeletal muscle, liver, kidney) of rats of different age in the frequency range of 130 MHz to 10 GHz. The data show a general trend towards decreasing permittivity and conductivity with increasing age for most of the tissues. This occurs concurrently with the decrease in water content during the process of growth (see above). The brain, skin and skull show the largest decreases in permittivity and conductivity, this trend being less apparent for abdominal tissues. As mentioned above, the study by Widdowson and Dickerson reveals changes in the ratio of free to bound water, which seem to be due to an increase in bound (fibre) and a decrease in free (non-fibre) water. Common interpretation of figures 11 to 16: Peyman et al. (Peyman et al., 2001) performed dielectric measurements on different rat tissues (brain, skull, skeletal muscle, liver, kidney etc.) of different ages in the frequency range from 130 MHz to 10 GHz. In terms of changes in the dielectric properties during tissue growth, the data show a general trend towards decreasing permittivity and conductivity with increasing age for most tissues. This is coincident and compatible with the decrease in water content during growth. Skull, skin and brain tissues are labelled by the most marked decrease in permittivity and conductivity with increasing tissue age whereas this tendency is less apparent in the case of abdominal tissues. Interesting in this context is a study of Widdowson and Dickerson (Widdowson and Dickerson, 1960), Figure 11 Y-Axis: Permittivity (a), Conductivity in S/m (b); X-Axis: Frequency (Hz). This figure indicates the relative permittivity and conductivity of brain tissue from rats of different ages in the frequency range from 130 MHz to 10 GHz. As the graphs show, the permittivity of rat brain tissue declines with increasing frequency. For any given frequency, permittivity - similarly to skull and skin tissues - is higher the younger the investigated brain is - from new-born rats through rats aged 10, 20, 30, 50 and 70 days. In contrast, conductivity increases with frequency - new-born brains again having the highest values (Peyman et al., 2001). Figure 12 X-Axis: Frequency (Hz). This figure displays the relative permittivity and conductivity of skull tissue from rats of different ages in the frequency range from 130 MHz to 10 GHz. Similarly to brain and skin tissues, the graphs show that permittivity of rat skull tissue declines with increasing frequency. For any given frequency, permittivity is higher the younger the investigated skull bone is - from new born rats through rats aged 10, 20, 30, 50 and 70 days. In contrast, conductivity increases with frequency - new-born skull bones again showing the highest values (Peyman et al., 2001). Edition Wissenschaft October

22 Changes in the dielectric... which exhibits changes in the ratio of free to bound water during development, which might be due to an increase in bound (fibre) and a decrease in free (non-fibre) water Brain In the brain, this process seems to be in line with the gradual change in the ratio of the grey and white matters: The grey matter in the brain tissue contains a higher concentration of water than does the white matter. The new-born brain consists mainly of grey matter whereas an increase in white matter occurs as the brain undergoes major changes during development (see brain development) to become a complex and structured tissue Skull As the skull develops it hardens and its calcium content increases. The decrease in water content is associated with the change from red to yellow bone marrow: Red marrow contains much more water than yellow marrow does. The skull of a new-born contains red marrow (like nearly all the bones of the foetus), which is capable of producing blood cells. After birth the blood cells are gradually replaced by fat cells, which cause the colour of the marrow to change from red to yellow. In adults only a few bones (the ends of certain long bones, the ribs, sternum, vertebrae and pelvis) still contain red marrow. Thus decreases in permittivity and conductivity are high in the skull. The results of this study could be interesting in revealing possible differences in assessing the exposure of children and adults to microwaves. Figure 13 Y-Axis: Permittivity (a), Conductivity in S/m (b); X-Axis: Frequency (Hz). This figure demonstrates the relative permittivity and conductivity of skin tissue from rats of different ages in the frequency range from 130 MHz to 10 GHz. As the graphs show, the permittivity of rat skin tissue is declines with increasing frequency. For any given frequency, permittivity - similarly to brain and skull tissues - is higher the younger the investigated skin is - from new born rats through rats aged 10, 20, 30, 50 and 70 days. In contrast, conductivity increases with frequency - new-born skins again presenting the highest values (Peyman et al., 2001). Figure 14 Y-Axis: Permittivity (a), Conductivity in S/m (b); X-Axis: Age (days). This figure indicates relative permittivity and conductivity of rat tissues (brain, muscle, skull, salivary gland, and skin) as a function of age at 900 MHz (Peyman et al., 2001). 22 Edition Wissenschaft October 2005

23 Brain development 13 Brain development 13.1 Prenatal development Brain development starts in the third week of gestation. The first immature nerve cells are formed soon after that Histogenesis 1. Nerve cells proliferate (second to fourth month of gestation). The first young neurons are born. It is believed that few (or no) new cortical neurons are formed after this. Between the fifth and twentieth week of gestational life, an estimated 50,000 to 100,000 new brain cells are generated each second. The rate of development is not equal in the various parts of the central nervous system, considerable spatiotemporal differences can be observed there. 2. The neurons stop dividing and migrate from the centre of the neural tube to a peripheral location (fourth to ninth month of gestation): This migration across the embryonic cerebral wall to the neocortex takes place from the inside to the outside. On completion of migration, a large number of neurons are eliminated through cell death. The remaining neurons grow, differentiate, and become integrated in the cortical circuitry. This layer nerve cells tends to aggregate immediately, in order to form nuclear cell groups or grisea. 3. Finally, the nerve cells differentiate. During this time the growth of processes (dendrites), myelination and the development of contacts with other neurons (synapses) occur. The brain regions obtain their elements, and a blueprint of the CNS wiring is formed. None of these events are completed until after birth Dendritic growth First, the young nerve cell sends out an axon process that grows forward through the neighbouring brain Figure 15 Y-Axis: Permittivity (a), Conductivity in S/m (b); X-Axis: Age (days). This figure demonstrates relative permittivity and conductivity of rat tissues (as before) as a function of age at 1800 MHz (Peyman et al., 2001). Figure 16 Y-Axis: Permittivity (a), Conductivity in S/m (b); X-Axis: Age (days). This figure indicates relative permittivity and conductivity of rat tissues (as before) as a function of age at 2 GHz (Peyman et al., 2001). Edition Wissenschaft October

24 Brain development areas to a specific target area. The process of dendritic growth begins between days 25 and 30. Early dendrites are formed, which have a primitive appearance, being short and unbranched. Later on a ramification may occur. The process of dendritic growth persists for some time after birth, and it has even been suggested that major changes occur post-natally during weeks 5 and 21. Adult levels are reached around five to six months of age, dendritic growth in frontal areas seems to occur until seven years of age. Therefore, environmental changes during this period may influence the configuration of the dendritic tree. The cellular and molecular mechanisms that guide axonal and dendritic differentiation in the cerebral cortex are only just beginning to be understood. The in-growing axons do form connections with the dendrites, and synapses begin to develop. At the same time, elements of the glia are also developing. The conduction pattern of the axons, however, may be modified considerably during later stages of development, when myelination occurs Myelinisation Myelin is a fatty sheath surrounding the axons. It increases the efficiency of the neural transmission promoting impulse conduction. A myelin sheath enables an axon to conduct an impulse in a saltatory way the conduction velocity of the axon becomes some 20 times faster than in unmyelinated nerve fibres. The process of myelination is hierarchical. It occurs in different regions at different times and at different rates. Myelinisation also called myelination begins during prenatal development. Only the most important nerve centres needed for survival are myelinated at birth, particularly the spinal cord, brainstem and the cerebellar peduncles. The spinal cord completes myelination at the third month of gestation. In the brainstem (medulla, pons, or midbrain) myelination begins at the sixth to seventh week of gestation. Pons and medulla have nearly completed myelination by the seventh gestational month; midbrain myelination is only completed well after birth. The process of myelination is not completed at birth and continues for a long time, in man even up to the third decade. Major changes occur post-natally, the velocity of myelination being greatest during the first three years of life. After birth the primary visual (three months of age) and auditory cortex rapidly undergo myelination. After this, the process of myelination advances to a higher order. During the first year-and-a-half of life, the corticospinal motor tract (part of the CNS, which is responsible for voluntary motor function) receives its myelination. During adolescence until adulthood (20 to 30 years) the final myelination of more complex areas occurs that are responsible for reason and other higher functions (e.g. the frontal and temporal lobe, and the cortical association areas). The step-by-step development of neuropsychological functions in the postnatal period may be associated with the completion of myelinisation in the specific brain areas. Myelin is the major cause of the increase in child brain size. Figure 17 This figure illustrates stages of human brain maturation. A discrete area of brain cortex (middle frontal gyrus, Economo Area FD) is presented in 4 developmental phases from left to right: in the new-born, after 3 months, after 15 months and after 2 years. It is obvious that dendritic growth and arborisation are increasing significantly from left to right (Keidel 1980) Synaptogenesis The connectivity of neurons depends on the development of synapses. These are specialised structures localised at the place of contact between the individual neurons responsible for communication and signal transmission. 24 Edition Wissenschaft October 2005

25 Brain development Synaptogenesis is a process going on both concomitantly with and subsequent to dendrite growth. Just as in the case of dendrite development, synapses may also be transient structures. Synapse formation starts in the mid or late second trimester (in regions responsible for the reflexes needed for survival, synaptogenesis occurs during intrauterine development) but major changes occur during postnatal life. Initially the synapses do not have a function; they are utilised as neural circuits emerge. It appears that during development, synaptic density in the brain follows an inverted U Pattern: Low at birth, highest in childhood and lower in adulthood (Huttenlocher, ; H. and Courten, 1987; H. and Dabholkar 1997). Human new-borns have lower synaptic densities than adults. In the months following birth, the infant begins to form synapses at a rate far in excess of the adult level. The highest rate of synapse formation is reached in childhood. By the age of four, synaptic densities have peaked in all brain areas at levels around 50% of adult levels. Throughout childhood, synaptic densities remain above adult levels. Around the age of puberty, a pruning process begins to eliminate synapses, reducing synaptic densities to adult, mature levels. The timing of this process appears to vary among brain areas in humans. Neuroscientists know relatively little about what this fact could mean for learning and education. It seems that basic movement, vision and memory skills first appear in their most primitive form when synaptic densities begin their rapid increase. Synapse formation occurs at different times in different brain areas. In the visual cortex, the rapid increase occurs at around two months of age, until it reaches a peak at 8 to 10 months. After that there is a steady decline in synaptic density reaching adult levels at about 10 years of age. In the auditory cortex there is also a rapid increase in the months following birth with a peak at approx. three months. Adult levels are not reached before puberty. The frontal cortex is a more complex brain area involved in attention, short-term memory, and planning. The process of synapse formation begins later and lasts longer. Peak densities occur at approx. two years of age and remain at high levels until eight years of age. After this they decline to adult levels at around the age of Pruning The developmental brain is characterised by an initial superabundance of produced cells and of processes. In the prenatal period and during the first few years of life, the brain generates millions of synaptic connections. During later development there is a decline in the density of the synapses, due to the selective pruning of redundant or unused connections. Those connections that are used are strengthened while those connections left unused are pruned away. The brain eliminates the synapses it does not need so that the most important ones grow and expand. If two neurons tend to be electrically active at the same time, they automatically form a connection (Hebb 1949). If they are already weakly connected, the synapse will become strengthened. Synaptic pruning seems to be a universal phenomenon that occurs in almost all brain areas. Most of it seems to take place between the ages of 10 and 16, bringing the density of synapses up to the adult level. The process of pruning is controlled by the environment. The remaining dendrites continue to branch, grow, and form new synapses. The presence of sensitive periods during maturation may be related to this phenomena. It has been suggested that the supernumerary cells could constitute a reserve pool of neurons that makes up for possible developmental errors. Pruning is the primary process by which experience influences the brain of the developing child. Although neurons continue to be generated and to divide during adulthood, it is through environmentally influence and pruning that specific neural networks are established and formed. Early experiences are vital to the formation and retention of synapses Synaptic density In the study Synaptic density in human frontal cortex- developmental changes and effects of ageing (Peter R. Huttenlocher): fairly high levels already existed at birth, comparable with those in adults. Significantly greater density over adult values was observed during late infancy and childhood. No significant decline in synaptic density in the frontal cortex was observed over the adult range of 16 to 72 years Neuronal density This also showed marked age-related variations. It was high in the neonatal brain and fell rapidly during the first six months of life. Between the ages of 1 and 2, neuronal density remained unchanged. The density of neurons showed a slow decline Edition Wissenschaft October

26 The newborn child Figure 18 Y-Axis: Synapses/mm3 X 108; X-Axis: age (years). This figure displays synapse counts in layer 3 of middle frontal gyrus as a function of age. Synaptic density at birth is already fairly high showing levels comparable to those of adults. A significantly increased density over adult values is observed during late infancy and childhood. No significant decline in synaptic density in the frontal cortex is observed over the adult range of 16 to 72 years (Huttenlocher 1979). Figure 19 Y-Axis: Neuronal density/mm3 X 104; X-Axis: age (years). This figure demonstrates neuronal density in layer 3 of the middle frontal gyrus as a function of age. Open circles and closed circles represent data obtained in different studies. Confidence limits = ±1 S.D. Neuronal density was affected by marked age-related variations. It was high in the neonatal brain and fell fast during the first 6 months of life. Between the ages of one and two, neuronal density remained unchanged. The density of neurons showed a slight decrease between two years and maturity (Huttenlocher 1979). between two years and maturity (the density of neurons at the age of two was about 55 % above the adult mean. In the brain of a 7-year-old, neuronal density was about 10 % more than the adult mean) Mean number of synapses/neurons (In layer 3 of middle frontal gyrus) This was 10,000 at birth and 100,000 at the age of one. A slight decrease in the number of synapses per neuron appears to occur between late childhood and adulthood. The data suggest that neurons acquire their full complement of synapses by the age of one, and that some synaptic loss occurs later. In contrast, dendritic arborisation appears to increase considerably past the age of one. In his study, Huttenlocher suggests that it is possible to subdivide postnatal cortical development into two phases: The first phase extends from birth to the age of one. It is characterised by a rapid decline in neuronal density, by an increase in synaptic density and in the number of synapses per neuron, by dendritic growth, and by expansion in the total volume of cerebral cortex. Phase two extends from the age of one to adolescence and is characterised by a slow decline in both synaptic and neuronal density. Dendritic growth continues, and the density of the synapses along the dendrites declines. 14 The newborn child The size of a new-born s brain is one quarter of its adult size. It weighs about 300 grams (10 % of bodyweight) in contrast to the adult brain, which weighs about 1400 grams (2% of body weight). Brain weight reaches adult levels between 6 and 14 years of life. Only the lower portions are developed (spinal cord and brain stem); higher regions (the limbic system and the cortex) are still rather primitive. Only the most essential bodily functions are developed. Regional connections between different brain areas are still immature. Synaptogenesis progresses rapidly in all cortical areas around the time of birth. Regional maturation of brain areas (see above) starts before the first month of age. This is 26 Edition Wissenschaft October 2005

27 The newborn child Figure 20 Y-Axis: Synapses per neuron X 104; X-Axis: age (years). This figure indicates the mean number of synapses per neuron as a function of age. Confidence limits = ±1 S.D. A slight decrease in the mean number of synapses per neuron seems to be observed between late childhood and the adult. The data suggest that neurons gain their full complement of synapses by the age of one, and that some synaptic loss occurs later. In contrast, dendritic arborisation seems to increase considerably past the age of one (Huttenlocher 1979). Figure 21 Y-Axis: Brain weight (grams); X-Axis: age (years). This diagram specifies the weight development of the brain. Its final total weight will be attained asymptotically Confidence limits = ±1 S.D. Thus, the size of a new-born s brain is about one quarter of its adult size. Its weight is about 300 grams (10 % of body-weight) in contrast to the brain of the adult with about 1400 grams (2% of body-weight). Brain weight normally attains adult levels between 6 and 14 years of life (Huttenlocher 1979). demonstrated by the increase in metabolic activities (e.g. the sensomotor cortex and brainstem). Brain growth is not due to the formation of new neurons (human beings are born with their full complement of neurons) but caused by (see above): dendritic arborisation myelinisation synaptogenesis increase in the number of supporting cells Recent research challenged the belief that maximum brain growth occurs in the first three years of life. It has been suggested that there are dramatic anatomical changes in brain structure during childhood and early adolescence. Significant brain growth thus continues during developmental periods after the first three years of life Postnatal CNS development A sequential maturation of the different brain areas occurs during development. After 3 months of age, the cerebellum and different cerebral cortical areas, except the frontal cortex, show rising activities. After about six to eight months of age, the frontal cortex starts to mature. The cerebral metabolic rate rises until 3 to 4 years after birth, remains high until about 9 years of age, and thereafter declines to adult levels during teenage years. By the age of two, the brain has twice as many synapses and needs twice as much energy as an adult brain. Synapses continue to be formed in selected areas during adulthood but the growth of new neurons is limited. Experiences continue to cause the branching of dendrites and synaptogenesis. Studies in humans have established that the adult brain remains highly plastic and capable of being neurally remodelled throughout life. It reorganises itself in response to new experiences Growth spurts Spurts in growth seem to occur. During gestation these may be caused by dendritic arborisation, synaptic development, myelinisation and glial growth. In infancy in particular, myelinisation determines brain growth. Jean Piaget s research identified the cognitive developmental stages individuals may progress through during their development. An amount of data to support his major points exists. The results of research by Herman Epstein and Conrad Toepfer, Jr. in the area of brain Edition Wissenschaft October

28 The newborn child growth periodisation confirm Piaget s findings. The brain grows in stages, with growth spurts occurring between the ages of three to ten months, two - four years, six to eight, 10 to 12 and 14 to ±16 years for most children. There seem to be plateaux at between 10 months and two years, four and six years, and between eight and ten, and 12 and 14 years. There are great interindividual differences, with growth spurts occurring at different times in different children. Their duration may also vary widely Sensitive periods Schore (1994) proposes a sensitive period of between six months and one year for the development of neural circuits in the prefrontal cortex. During this period the development of the infant is dependent on face-to-face contact, vocalisation and smiling. He suggested that a release of a transmitter (dopamine) promotes a growth spurt of synapses and glial cells. Critical periods are usually times of rapid development. Research has shown that the normal development of motor, sensory, and language skills is dependent on certain kinds of experience at specific times during the process of growth and development. It has been shown that there are different critical periods for different specific functions. Neuroscientists have suggested that for each specific function of a sensory system (e.g. vision) the critical period can be divided into three distinct phases: Rapid change, during which a function quickly matures. A second phase, during which sensory deprivation can result in deterioration or loss of that function. After that, the system retains sufficient plasticity to compensate for deprivation and is capable of regaining near-normal function if appropriate sensory experience occurs. Highly sensitive neural systems like vision, need environmental stimuli to perfect their neural circuitry. These neural circuits are more sensitively tuned than they could be if they were influenced only by genetic programs at birth. Experiences are indispensable in order for the human brain to develop normally Development of the brainstem The brainstem begins to mature in the sixth to seventh week of gestation and continues into the first year of postnatal life. It can be divided in three parts: medulla, pons, and midbrain. The brainstem consists of various nuclei and subdivisions, which perform sensory and reflexive motor functions (mediation and control of arousal, orientation, the sleep cycle, heart rate, breathing, gross axial, limb, head and eye movement; visual, gustatory; and acoustic perception, screaming and crying. Many brainstem functions are present before birth, including the most vital functions like regulation of the heart rate, sleep cycle, and respiration Medulla The nuclei of the medulla emerge and myelinate prior to those of the pons, which precede those of the midbrain. Descending spinal-motor tracts are responsible for body movement. Five cranial nerves (8, 9, 10, 11, and 12) control body movement, heart rate, respiration. The major structures of the medulla have been established after the seventh and 8th weeks of gestation Pons The pons begins to mature after the medulla, in around the 8th week of gestation. Maturation of myelination of the pons is more prolonged than the medulla and does not reach advanced levels until around the seventh month of gestation. Many of the functions associated with the pons appear later in foetal development Midbrain The midbrain is the least differentiated segment of the brainstem. Begin of maturation: the sixth and 8th weeks of gestation; development and myelination is nearly complete well after birth Behaviour and cognitive development of the new-born At birth, all reflexes are of brain stem origin with minimal cortical control. The development of the forebrain - the brain region, which generates higher order cognitive activity and which is responsible for the expression of emotions such as pleasure, rage, and fear shows a slower path. Therefore, affective or cognitive processing (thinking, reasoning, and understanding) are absent in the foetus and the new-born. Forebrain influences are limited to signalling distress as a reaction to hunger and thirst. Certain brain regions responsible for higher cognitive processes take well over 7, 10 or 30 years to develop and myelinate. During further development, the forebrain increasingly exerts control over the primitive behaviour of the new-born. 28 Edition Wissenschaft October 2005

29 Development of the Development of the skull, sutures and fontanelles One important characteristic of the foetal skull is the presence of sutures, which are spaces between the different bony plates; fibrous membranes of tissue connect the bones of the new-born skull. The membranous places where the sutures meet are called fontanelles. Sutures and fontanelles are important for the foetal skull because they allow the bones to overlap and the head to deform while it passes through the birth channel. In addition, they make the skull flexible and capable of expanding as the foetal brain grows. Figure 22 Sutures and fontanelles can be easily distinguished in this photograph. When a baby is born, its skull presents two apertures called fontanelles. Thus the skull can remain elastic until the brain attains its final size. At birth, the smaller fontanelle at the occiput is hardly palpable. The fusion of the large fontanelle in the centre of the skull cap occurs mainly between the ninth and eighteenth months and up to two years of age Fusion of fontanelles and sutures Sutures Metopic suture: Sagital suture: Coronal suture: Lambdoidal suture: 6 years 30 years 40 years 50 years Fontanelles Anterior fontanelle: 1-2 years 2 antelateral fontanelles: 6 months - 2 years 2 postolateral fontanelles: 6 months - 2 years Posterior fontanelle: 6 months - 2 years There is no reason for parents concerns as skin protects the brain sufficiently, even in the region of the fontanelles. Otherwise the enormous pressure at birth could not be tolerated without damage. From the medical point of view, the large fontanelle may provide important information. If it is dented, this might indicate disorders of the water balance. If it is elevated it could indicate an inflammatory process (photograph by courtesy of Prof. Dr. med. Wolfgang Arnold, Faculty of Dental Medicine, Witten/ Herdecke University) Skull growth The skull has two parts: The neurocranium, which consists of the calotte (or calvaria) and the cranial base and the splanchnocranium, which comprises the face. Skull development starts during the fifth or sixth week of gestation. Initially the primitive brain is surrounded by a layer of mesenchyme (connective tissue). During later development, the mesenchyme becomes bony tissue. Two different mechanisms have been found for this process: The first is known as desmal ossification. The mesenchyme transforms directly to bone. During this process, the mesenchyme cells differentiate to form osteoblasts. In the seventh gestational week the osteoblasts begin to form bony tissue, and gradually all the mesenchyme is transformed into bone. Once this process is complete, the different bony plates of the skull are formed. The membranous sutures and fontanelles remain between the individual plates. The other mechanism is called chondral ossification. During this process, the mesenchyme first transforms to cartilage and later to bone. A cartilage residue (synchondrose) remains between the bone plates and this is responsible for growth. The ossification of these cartilage models is completed at about 20 years of age Two skull growth possibilities 1: Cartilage growth: growth through expansion at cartilage plates, which fuse in adolescence and form synchondroses. 2: Sutural growth 15.4 Volume of neurocranium The neurocranium of a new-born has a volume of 400 cm³ and 900 cm³ after one year. The volume of an adult skull is about 1300 to 1450 cm³ Head circumference To evaluate and understand the growth of the skull, the craniofacial area can be divided in thirds. The neurocranium (first third of the facial area: from the head to the eyebrows) grows rapidly in the first months of life, being directly related to brain growth. Growth of the Edition Wissenschaft October

30 Development of the... Figure 23 Head circumference als Vorlage einsetzen. Die Originalvorlage zur Weiterverarbeitung durch Frau Kellendonk wird am per Post bei der FGF ankommen). Y-Axis: Head circumference. X-Axis: age (months). Head circumference in boys and girls from age 0 to 4 years is illustrated in this figure. It is obvious that at about 15 to 18 months of age the increase of head circumferences is clearly smaller than before - both in girls and in boys. Additionally - for a given age - average head circumference is slightly smaller in girls than in boys (Niessen 1999). second part of the skull occurs more slowly and is directly related to the expansion of sensory organs and teeth. It is not accomplished until adolescence. The cranial base is the most stable part of the skull because of the entry and the exit of neurovascular structures. This photograph illustrates the bony skull and its remarkable growth during three different developmental stages. At birth, up to 6 fontanelles exist, one anterior and one posterior and there are two at the sphenoid bone and the mastoid process. Only the anterior and posterior fontanelles can attain clinical significance. Anterior fontanelle: Average diameter: 2-3 cm. It fuses between month 9 and 18 after birth. Posterior fontanelle: Average diameter: cm. It is frequently fused by month 3 and may even be fused at birth (photograph by courtesy of Prof. Dr. med. Wolfgang Arnold, Faculty of Dental Medicine, Witten/Herdecke University). Figure 24 Y-Axis: Skull Thickness; X-Axis: Age (months). This figure indicates the regression curve for skull thickness versus age (Koenig WJ, 1995). The data behind this figure reveal that cranial bone thickness may be a function of age, and that the growth velocity of increasing thickness of the (parietal) skull bone decreases with age (Koenig 1995) Diploic space In the study Cranial bone grafting in children (William J. Koenig) computer tomographic scans of patients from new-born to 21 years were reviewed to assess the thickness of the diploic space. Analysis of the data revealed that cranial bone thickness may be a function of age and that the growth velocity of the parietal skull bone decreases with increasing age. The presence of a diploic space may also be predicted reliably as a function of age. A diploic space is estimated to be present in 33 percent of children by 30 Edition Wissenschaft October 2005

31 Development of the... the age of one, in 66 percent by the age of two and in over 80 percent by the age of three Auditory tube At birth and during childhood, the auditory tube is short and positioned about 10 from the horizontal. So nasopharyngeal secretions are refluxed into the middle ear and cause infections. In adults the tube is longer and has a 45 orientation. Ear: The pneumatised cavities of the middle ear are formed under the influence of the cavum tympani s mucosa as ventilated cavities in the petrosal bone. This has a great impact on the later resistance to otitis media because the mucosa within the cavities (also to be found in the jaw and frontal sinuses) have an effective immune function. At the same time, more air is resorbed by the mucosae., i.e. resorbed into the blood and removed. Thus the air pressure is reduced in the cavity of the tympanum continuously and it has to be must be replenished via the eustachian tube from the pharynx. Thus the air pressure in the cavity of the tympanum adapts very quickly to the external air pressure. A strong tension of the tympanum can therefore be avoided. Figure 25 Figure 26 Y-Axis: Probability of the appearance of diploic space; X-Axis: Age (months). This figure demonstrates that a diploic space is estimated to be present in 33 percent of children by at the age of one, in 66 percent by the age of two and in over 80 percent by age 3 years. Thus the presence of a diploic space may be reliably predicted as a function of age (Koenig 1995). Edition Wissenschaft October