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Development of the Vertical Dimension: Nature and Nuture

James K. Hartsfield, Jr
The relevance of analyzing the development of the vertical dimension to clinical practice is first to determine if there is a vertical dimension component to the malocclusion, then ascertain what factors are having the greatest influence on the vertical dimension problem. Unfortunately, studies on the genetic and environmental factors that influence the development of vertical dimension are representative of the samples, not necessarily of any particular individual. In addition, the extent that a particular trait is influenced by genetic factors may have little if any effect on success of environmental (treatment) intervention. Genetic factors that influenced a trait may also influence the response to intervention to alter that trait, or other genetic factors may be involved in the response. Therefore, the possibility for altering the environment to gain a more favorable dimension is theoretically possible, even in individuals with a relatively high genetic influence on the vertical dimension. However, the question of how environmental and genetic factors interact (a question that essentially cannot be answered in estimates of heritability), is most relevant to clinical practice because it may explain why a particular alteration of the environment (treatment) in one compliant patient may be successful and not in another. (Semin Orthod 2002;8:113-119.) Copyright 2002, Elsevier Science (USA). All rights reserved.

onsideration of factors that influence, determine, or even drive d e v e l o p m e n t usually involves a discussion of nature versus nurture, as if they were mutually exclusive. However, develo p m e n t is not the result of genetic and environmental (nongenetic) factors working in isolation or i n d e p e n d e n t of one another. Before proceeding, a couple of basic definitions are required. Genotype generally refers to the set of genes that an individual carries and, in particular, usually refers to the particular pair of alleles (alternative forms of a particular gene) at a given region of the g e n o m e . In contrast, p h e n o t y p e is the observable properties and physical characteristics of an individual, 1 as d e t e r m i n e d by genotype

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a n d the e n v i r o n m e n t in which the individual develops.

Even Gene Mutations For D o m i n a n t Traits Are Not Predetermining
T h e craniosynostosis syndromes (along with their effect on craniofacial growth and development) are autosomal d o m i n a n t traits associated with single-gene mutations. They provide good examples of how, even with the strong influence of a single gene, the p h e n o t y p e can vary markedly. Contrary to an earlier p r e s u m p t i o n that a particular mutation in a given gene would always result in a specific syndrome, several identical mutations in the fibroblast growth factor receptor 2 gene have b e e n f o u n d in patients diagnosed with the three clinical entities of Crouzon, Pfeiffer, and Jackson-Weiss syndrome. 2,-~ A n o t h e r example of the individual variability of these autosomal d o m i n a n t phenotypes associated with a single-gene mutation occurred in individuals with the classic phenotypes of Pfeiffer and Apert syndrome, as well as in seven

l~}rmz the Indiana University &hool of Dentistu, Indianapolis, IN. Address correspondence to James K. Hartsfield, Jr, DMD, MS, MMedSci, PhD, Indiana University School of Dentistry, 1121 W Michigan, IrMianapolis, IN 46202-5186. Copyright 2002, Elsevier Science (USA). All *Jghts *~served. 1073-8746/02/0803-0002535.00/0 doi:10.1053/sodo. 2002.125430

Seminars in Orthodontics, Vol 8, No 3 (September), 2002: pp 113-119

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they refer to a specific sample and do not necessarily pertain to a given individual even from within the sample. and they are not predictive. 9 A few points should be kept in mind when reviewing heritability estimates. the estimation of heritability can provide an indication of the relative importance of genetic factors. defined as the proportion of the total phenotypic variance in a sample that is contributed by genetic variance.12 E s t i m a t i o n Of Vertical D i m e n s i o n Heritability Clinical consideration of the vertical dimension may include the evaluation of the ratio of the . a longitudinal analysis of 30 sets of siblings that had not u n d e r g o n e orthodontic treatment showed a significant increase in heritability estimates between the ages of 4 and 14 years for 29 craniofacial skeletal variables. In fact.5 would have half its variability (from individual to individual) influenced by environmental factors and half by genotypic factors. that may be incorrect. simply discovering the gene mutation will very likely indicate that there will be an effect on craniofacial growth and development. Values over 1 may occur because the twin m e t h o d o l o g y provides an estimate of heritability. 4 The phenotype may be so variable that an individual may appear to be clinically normal yet have the same gene mutation associated with Crouzon syndrome in three of his children and two of his grandchildren. Hartsfield. In addition. Despite the general trend for all the craniofacial skeletal variables to increase. a high heritability does not prevent a trait from being substantially influenced by subsequent changes in environmental conditions in that sample. . and u p p e r posterior face height. Only t h r o u g h cephalometry was a minimal expression of features suggestive of Crouzon syndrome evident. Still. u n d e r several simplifying assumptions. First of all. for example. 10 The heritability of a trait c a n n o t necessarily be extrapolated from one sample and set of environmental conditions to another. 9 Heritability estimates can change with age. 5 The phenotypic variation present in these examples may be caused by modifying factors such as environment and other (modifying) genes in the g e n o m e that interact with the effect of a specific mutation associated with a d o m i n a n t trait. whereas a trait with a heritability of 0. s A trait with a heritability of 1 is said to be expressed without any enviromnental influence. heritability estimates are descriptive of variances within a sample at a given time.]r other individuals with a facial resemblance to Crouzon syndrome that occurred in the same family. total posterior face height. An extreme example of this principle is the delayed growth seen from the effects of famine associated with war. u p p e r anterior face height. For more information on these methods and assumptions. including increases for total anterior face height. they do not allow one to tell to what degree a particular trait was determined by genetic or environmental factors in a single individual. W h e n a comparison was made of the craniofacial skeletal heritability estimates at age 14 years and 20 years. the reader may start with Genetics and Analysis of Quantitative Traits by Lynch and Walsh. but it does not give a precise picture of what that effect will be only what it may tend to be. Confirming that there is a certain degree of genetic influence on a trait is a preliminary step to fur- ther specific genetic linkage studies (using DNA markers) to determine areas of the g e n o m e that appear to be associated with the characteristics of a given trait. However. acknowledging the potentially variable phenotype that may not be evident at all in an individual with the gene mutation3 ~These examples give a clear message that even for a generally extreme autosomal d o m i n a n t phenotype. there was an insignificant upward trend for some of the traits. n Therefore. v is beyond the scope of this article. there was a decrease for lower posterior face height.114 James K. there was a decrease in the heritability estimate from the age of 14 for u p p e r anterior face height and an increase for lower posterior face height to that estimated at age 4 years. the concepts of variable expressivity and reduced penetrance are applied to dominant traits or conditions. Thus. 7 An adverse environment can alter the phenotypic expression that the genes would have p r o m o t e d u n d e r more favorable conditions. E s t i m a t i n g t h e I n f l u e n c e of G e n e t i c and E n v i r o n m e n t a l Factors o n P h e n o t y p e A discussion of the methods and assumptions made to estimate heritability.

hwestigation of the anterior u p p e r face height to anterior lower face height in 30 monozygotic twin pairs (ranging in age from 12. 14 The analysis indicated that additive genes and the specific e n v i r o n m e n t influenced all the facial proportions. this suggests that some c o m m o n (cultural) environmental factor(s) have greater . m If there are relatively high c o m m o n inheritance estimates for the u p p e r anterior face height a n d posterior face height as c o m p a r e d to the lower anterior face height and total anterior face height. The u p p e r anterior face height was essentially the same between each pair of twins. along with the relatively high heritability of the total anterior face height. Analysis of the soft tissue associated with anterior vertical height. it was markedly lower for u p p e r anterior face height (0. with a m e d i a n age of 24) in which there was a significant difference in the intrapair differences (variance) between the monozygotic and dizygotic twins for total anterior face height and lower anterior face height but not for u p p e r anterior face height. regardless of their zygosity. T h e heritability was 0. with a m e a n of 15. whereas the m e a n age for the dizygotic twins was 14.31. nature.Development of the Vertical Dimension 115 u p p e r anterior face height to lower anterior face height. It was concluded that the dichotomy of the heritability between the u p p e r anterior face height and the lower anterior face height.~5 Lateral cephalographs were used in a path analysis study to c o m p a r e the heritability of horizontal and vertical distances (as o p p o s e d to proportions or ratios) on 55 pairs o f twins of the same gender. 12. as well as anterior to posterior face heights. This is consistent with the prevailing c o n c e p t that malocclusion has a multifactorial origin (combination of a n u m b e r of genetic and environmental factors) and implies that specific environmental (treatment) factors might have some effect on the traits. Although the heritability estimate for both the lower anterior face height and total anterior face height was 0. These two relatively low heritability estimates were probably artifacts caused by r a n d o m variation in a limited sample.5 years) resulted in a heritability estimate of 0. with a m e a n of 15.81) and posterior face height (0. T h e heritability estimate for the factor that included u p p e r anterior face height was 0. T h e likelihood of some r a n d o m variation. and 30 dizygotic like-sex twin pairs (ranging in age f r o m 12. whereas that for total posterior face height and lower posterior face height was 0.66 for anterior to posterior face height.76) included the lower anterior face height and total anterior face height. ranging f r o m 13 to 20 years of age who had not undergone orthodontic treatment.66 for anterior face height. were used in genetic m o d e l fitting to d e t e r m i n e the heritability of anteroposterior and vertical facial proportions. as o p p o s e d to a m o r e c o m m o n environmental.4 to 21. indicates that genetic influence was the sum of some number of approximately equal gene effects.0 to 18.8 years.7 years. ~ 7 Although attributed to r a n d o m error in the path analysis m e t h o d . expressed in the path analysis used.71 for u p p e r to lower anterior face height and 0. with additive as opposed to d o m i n a n t gene influence. was reinforced when markedly higher estimates of heritability for upp e r anterior face height (0.48.9 years). p r o d u c e d a heritability estimate of 0.0 years.1 years) and had not undergone orthodontic treatment.26). the dichotomy of the heritability between the u p p e r anterior face height and the lower anterior face height echoed the findings of an earlier study on 35 pairs of monozygotic twins and 21 pairs of like-sex dizygotic twins (ranging in age f r o m 18-55 years. The specific e n v i r o n m e n t aspect of the fitted m o d e l implies that the environmental influences were of a m o r e individual. infers that it is the lower anterior face height that is primarily responsible for the heritability of the total anterior face height. T h e factor with the largest heritability estimate (0.16) and posterior face height (0.~s T h e dichotomy was also suggested when lateral cephalometric m e a s u r e m e n t s were m a d e of 67 monozygotic twin pairs and 29 dizygotic twin pairs and investigated through factor analysis with subsequent estimation of heritability.86. as m e a s u r e d on the facial profile of lateral p h o t o g r a p h s taken of 42 pairs of monozygotic twins and 37 pairs of dizygotic twins. ~6 T h e m e a n age of the monozygotic twins was 15.88) were d e t e r m i n e d in the same sample by using weighted means of monozygotic and dizygotic twin estimates instead of path analysis. who ranged in age f r o m 9 to 16 years (mean.2 years.52? 3 Lateral cephalographs of 33 monozygotic and 46 dizygotic twins. The better-fitting model.

chronic mouthbreathing) in similar fashions. resulting in m o u t h breathing. that often lead to d e v e l o p m e n t of similar malocclusions. These results are based on path analysis of family resemblance using craniofacial a n t h r o p o m e t r i c m e a s u r e m e n t s of 1. T h e analysis revealed that the allergic children had a m o r e divergent facial pattern." 14 This implies that the genetic influence is a p r e d e t e r m i n i n g . 22 This is consistent with the findings in a study of 100 ll-year-old Finnish children in which there was an increase in the vertical dimension in m o d e r a t e and severely allergic subjects." Malocclusions a p p e a r to be acquired. T h a t is. 16 O n e conjecture m i g h t be diet consistency 9° on the posterior face height and the d e v e l o p m e n t of nasal airway patency on the u p p e r anterior face height.116 James K. However. subjects with an e x t r e m e malocclusion tend to be excluded. which may be similar for c o m p a r a b l e genotypes (or at least the genes that are going to influence the response to the particular intervention). however. India. and the heritability estimates for occlusal variations were significantly higher25 To quote King et al. reduced masticatory stress. as has already b e e n discussed. Certainly. why do some (although not all) studies indicate a d i c h o t o m y in the estimates of heritability of the u p p e r anterior face height and the lower posterior face height? O n e hypothesis is that the lower anterior face height may have a relatively greater heritability than the u p p e r anterior face height in some individuals unless increased nasal obstruction. Genetic factors that influence a trait may also influence the response to intervention designed to . which are not so easily changed by the environment. thus. orthopedic correction than are variables with a high genetic determination. t r e a t m e n t depends on the origin of a disorder if that cause is known and specific. 25 Does Knowing The Heritability Matter In Treatment? It has been stated that. it may be altered u n d e r different environmental (treatment) conditions.763 individuals in 399 families from a rural c o m m u n i t y in A n d h r a Pradesh. the presence of r a n d o m variation may also be an explanation for these relatively high comm o n inheritance estimates. unalterable factor. "Variables with a lower genetic determination are m o r e o p e n to influence by. Harlsfield. are associated with perennial allergic rhinitis and m o u t h breathing. the heritability estimates for craniofacial skeletal variables in the subjects with overt malocclusions were significantly lower. 25 In a thought-provoking study of the heritability of cephalometric and occlusal variables in siblings with overt malocclusions. given genetically influenced facial types and growth patterns. in contrast to a series of similar subjects with naturally occurring good occlusion.fi influence on these traits. These a p p a r e n t m o u t h breathers were c o m p a r e d with their 25 siblings who apparently were not m o u t h breathers and did not have perennial allergic rhinitis and 14 nasal breathing control subjects. b e c o m e s a p r e d o m i n a t i n g factor. it has also b e e n pointed out that contrary to p o p u l a r opinion the extent that a particular trait is influenced (or if you wish even d e t e r m i n e d ) by genetic factors may have little if any effect on the success of environmental (treatment) intervention. in particular. it was f o u n d that. % What is i m p o r t a n t is the response of the individual to the environmental (treatment) intervention. 16. 25 "We p r o p o s e that the substantive measures of intersib similarity for occlusal traits reflect similar responses to environmental factors c o m m o n to b o t h siblings. However. . 23 An additional report with similar findings was based on a study of 37 children with perennial allergic rhinitis (ages 5-10 years) and m a t c h e d controls. Again. for example. the most striking difference was f o u n d in a comparison of cephalometric facial dimensions in 25 white children with perennial allergic rhinitis. 24 If an increase in total anterior face height and lower anterior face height. siblings are likely to respond to environmental factors (eg. 21 Considering the effect of breathing on the vertical dimension. Studies that estimate heritability of craniofacial structures may have a bias because they have generally b e e n p e r f o r m e d with subjects who had not u n d e r g o n e orthodontic treatment. heritability is a descriptive statistic for a particular sample u n d e r defined environmental conditions. but the f u n d a m e n t a l genetic control of craniofacial f o r m predisposes siblings into c o m p a r a b l e physiologic responses.17 In support of the environmental effect on nasal d e v e l o p m e n t is the rejection of the null hypothesis that there is no c o m m o n sibling effect on nasal height.

there is no compelling reason to label a trait or condition as being either genetic or environmental. However. Once a particular gene or genes in an area of the g e n o m e are identified. result in a change in the phenotype? Nature. including genetic susceptibility.65 m m shorter than the average for those without the GHR P56IT allele. . thus they can be portioned and do not interact. the association was with the mandibular ramus height but not mandibular body length. Study of the influence of particular genetic factors on development may be performed by using a candidate gene chosen for the function of its associated protein. which is considered to be an important factor in craniofacial and skeletal growth.Development of the VerticalDimension 117 alter that trait. will the interaction of the new or altered environment. The question is. but that is not inherently known in the estimation of the heritability of a trait. the search for markers linked with certain phenotypes can indicate areas of the g e n o m e that contain influential genes that were previously not known or even suspected to have an influence on the phenotype. however. Nurture. d e p e n d i n g on the ability of the individual to respond to a given environment (treatment). maxillary length. 97 Searching For Genetic Factors Heritability estimates can indicate the relative contribution or influence that genetic factors have had on a trait. such as in smoking and oropharyngeal cancer. Out of a normal Japanese sample of 50 m e n and 50 women. which by its very construction defines a separation and even opposition. was 4. Everyone who smokes does not develop cancer. which indicates an interaction of smoking with other factors. with the genetic factors present. those who did not have the GHR P56IT allele had a significantly greater mandibular ramus length (condylion-gonion) than did those with the GHR PB6IT allele. or Both? It has been stated that analyses of craniofacial structures have led to the conclusion that they have moderate to high estimated heritabilities and that they are primarily a consequence of nature rather than nurtureY 5 In a sense. The basic interpretation of the estimation of heritability is that the genetic and environmental factors are separate. or region specific. To say. The search for DNA markers linked with certain phenotypes may indicate areas of the g e n o m e that have a gene or genes that influence the phenotype. this process does not necessarily precisely define what gene in the area is contributing or what allele of that gene may be more influential than others. as a way of looking at genetic and environmental interaction. based o n heritability estimates of a particular sample that the anterior face height is 70% genetic and 30% environmental gives a misleading dichotomy between genetic and environmental factors and obscures the fact that most if not all h u m a n disease (and development) results from the interaction between genetic susceptibility and environmentalmoderating f a c t o r s . in those with the GHR P56IT allele. it is not clear if the effect is directly on the mandible a n d / o r on a n o t h e r nearby tissue or matrix. this is true for what estimates of the heritability represent. An example is a study of the association of the Pro561Thr (P56IT) variant in the growth h o r m o n e receptor gene (GHR). This has been typified by the phrase nature versus nurture. 9s Essentially all aspects of normal and abnormal development are in some way the result of the interaction of genetic and environmental factors. for example. 27 This is true even for conditions in which an environmental influence is known to be strong. or anterior cranial base length. This significant correlation between the GHR P56IT allele and shorter mandibular ramus height was confirmed in an additional 80 women29 Interestingly. Although it was concluded that the GHR P56IT allele may be associated with decreased growth of mandibular height and can be a genetic marker for it. area. These data suggest an effect that is site. but it is often interpreted that genetic factors are influencing development independently of the environment and that genetic factors have controlled or determined the development. which is a consideration with regard to the feasibility of a search for identifying those factors. they b e c o m e candidate genes for specific analysis of their structure to pinpoint the relevant allele (s). thus. The average mandibular ramus height. It would also be interesting to see what effect different diet consistencies have on individuals with and without the GHR P56IT allele.

4 million sites of variation in the h u m a n g e n o m e sequence. The main use of this h u m a n single-nucleotide polymorphism map will be to determine the contributions of genes to diseases (or nondisease phenotypes) that have a complex. Ms. Animal studies using inbred strains compare the different responses of an environmental factor against consistent genotypes and the effect of different b a c k g r o u n d genotypes on the phenotypic expression of a specific gene mutation. Robyn Tibbs. their different craniofacial m o r p h o l o g y (ie. the possibility for altering the envir o n m e n t to gain a more favorable dimension is theoretically possible. Therefore. O u r g e n o m e varies from one individual to the next. It may be that genetic factors that influenced a trait will also influence the response to intervention to alter that trait. Bixler D: O)1 the classification of the acrocephalosyndactyly syndromes. 1995 3. Hartsfield. not far behind the human g e n o m e project. . Unfortunately. the most c o m m o n l y used mammalian species for genetic inbred strain studies. Study of these environmental and genetic factors has been difficult at the clinical level because of the relatively small sample sizes and lack of markers to analyze genetic diversity from one patient to the next. at this time. Clin Genet 12:169-178. 1977 5. 2001 2. References 1. Escobar V. which may then be tested for in the h u m a n population. However. Madeline Hawkins. or other genetic factors may be involved in the response.118 James K. nmltifactorial basis. Bellus GA. Everett ET. In addition. The h u m a n g e n o m e project resulted in not only a single h u m a n g e n o m e sequence composed o f overlapping parts from many humans but also cataloged some 1. even in individuals in which the vertical dimension does have a relatively high genetic influence. Park WJ. Ward RE. have been used and will continue to be used for the study of genes that cause disease and aberrations in mammalian development. will increase the n u m b e r of known DNA markers that may be used in the study of putative relevant genetic factors and genetic-environmental interactions.labs EW: Mutations in fibroblast growth factor receptors: phenotypic c o n s e q u e n c e s during eukaryotic development. Mulvihill. Britto DA. studies on the genetic and environmental factors that influence the development of vertical dimension are representative of the samples studied and not necessarily of any particular individual. Nature Gcnet 9:101-103. Am J H u m Genet 57:748754.][|: Craniofacial syndromes: no such thing as a single gene disease. most often in terms of single-base changes of the DNA called singlenucleotide polymorphisms. Claudette Maurer for retrieving a n d copying references. This approach may be the best opportunity yet to better understand the roles of nature and nurture rather than nature versus nurture in development. Although the scale of such studies could be daunting and there are still problems to solve. a n d Ms. Baltimore D: O u r g e n o m e unveiled. 32 Acknowledgment T h e a u t h o r thanks Dr W. Nature 409:814-816. This increased n u m b e r of variations (or polymorphisms) may be used as markers to perform genetic (including genetic-environment interaction) analysis in an outbred population such as h u m a n beings. the potential for studying how natural variation leads to each one of our qualities is significant. 1995 4. Studies using mating crosses of various inbred strains of mice help estimate the n u m b e r of genes that influence a phenotype.'e'~ Although mice. 3°. E u g e n e Roberts for reviewing the m a n u s c r i p t a n d Ms. the question of how environmental and genetic factors interact (a question that essentially c a n n o t be answered in estimates of heritability) is most relevant to clinical practice because it may explain why a particular alteration of the environm e n t (treatment) in one compliant patient may be successful and not in another.f l Summary and Conclusion The relevance of analyzing the development of the vertical dimension to clinical practice is first to determine if there is a vertical dimension c o m p o n e n t to the malocclusion and then ascertain what factors are having the greatest influence on the vertical dimension problem in that individual. the presence of snouts and single dentition with incisors and molars only) may not be readily applicable to some of the clinical questions orthodontists have regarding craniofacial growth in humans. et al: A novel FGFR2 gene mutation in Crouzon syndrome associated with . the extent that a particular trait is influenced by genetic factors may have little if any effect on success of environmental (treatment) intervention. The development of the mouse g e n o m e project.

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