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

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

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other individuals with a facial resemblance to Crouzon syndrome that occurred in the same family. 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. Only t h r o u g h cephalometry was a minimal expression of features suggestive of Crouzon syndrome evident. 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. In fact, the concepts of variable expressivity and reduced penetrance are applied to dominant traits or conditions, 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, simply discovering the gene mutation will very likely indicate that there will be an effect on craniofacial growth and development, but it does not give a precise picture of what that effect will be only what it may tend to be.

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, defined as the proportion of the total phenotypic variance in a sample that is contributed by genetic variance, v is beyond the scope of this article. For more information on these methods and assumptions, the reader may start with Genetics and Analysis of Quantitative Traits by Lynch and Walsh. s A trait with a heritability of 1 is said to be expressed without any enviromnental influence, whereas a trait with a heritability of 0.5 would have half its variability (from individual to individual) influenced by environmental factors and half by genotypic factors. Values over 1 may occur because the twin m e t h o d o l o g y provides an estimate of heritability, u n d e r several simplifying assumptions, that may be incorrect. Still, the estimation of heritability can provide an indication of the relative importance of genetic factors. 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. 9 A few points should be kept in mind when reviewing heritability estimates. First of all, they refer to a specific sample and do not necessarily pertain to a given individual even from within the sample. Thus, they do not allow one to tell to what degree a particular trait was determined by genetic or environmental factors in a single individual. In addition, heritability estimates are descriptive of variances within a sample at a given time, and they are not predictive. 9 Heritability estimates can change with age; for example, 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, including increases for total anterior face height, u p p e r anterior face height, total posterior face height, and u p p e r posterior face height. Despite the general trend for all the craniofacial skeletal variables to increase, there was a decrease for lower posterior face height. W h e n a comparison was made of the craniofacial skeletal heritability estimates at age 14 years and 20 years, there was an insignificant upward trend for some of the traits. However, 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. 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. 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. An extreme example of this principle is the delayed growth seen from the effects of famine associated with war. n Therefore, a high heritability does not prevent a trait from being substantially influenced by subsequent changes in environmental conditions in that sample.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

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u p p e r anterior face height to lower anterior face height, as well as anterior to posterior face heights, 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 12.0 to 18.8 years, with a m e a n of 15.9 years), and 30 dizygotic like-sex twin pairs (ranging in age f r o m 12.4 to 21.0 years, with a m e a n of 15.5 years) resulted in a heritability estimate of 0.52? 3 Lateral cephalographs of 33 monozygotic and 46 dizygotic twins, who ranged in age f r o m 9 to 16 years (mean, 12.1 years) and had not undergone orthodontic treatment, 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. 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. T h e heritability was 0.71 for u p p e r to lower anterior face height and 0.66 for anterior to posterior face height. The better-fitting model, with additive as opposed to d o m i n a n t gene influence, indicates that genetic influence was the sum of some number of approximately equal gene effects. 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, as o p p o s e d to a m o r e c o m m o n environmental, nature. 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. Analysis of the soft tissue associated with anterior vertical height, 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, p r o d u c e d a heritability estimate of 0.66 for 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, ranging f r o m 13 to 20 years of age who had not undergone orthodontic treatment. ~6 T h e m e a n age of the monozygotic twins was 15.2 years, whereas the m e a n age for the dizygotic twins was 14.7 years. Although the heritability estimate for both the lower anterior face height and total anterior face height was 0.86, it was markedly lower for

u p p e r anterior face height (0.16) and posterior face height (0.26). These two relatively low heritability estimates were probably artifacts caused by r a n d o m variation in a limited sample. T h e likelihood of some r a n d o m variation, expressed in the path analysis used, was reinforced when markedly higher estimates of heritability for upp e r anterior face height (0.81) and posterior face height (0.88) 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. ~ 7 Although attributed to r a n d o m error in the path analysis m e t h o d , 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, 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. The u p p e r anterior face height was essentially the same between each pair of twins, regardless of their zygosity. 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, along with the relatively high heritability of the total anterior face height, infers that it is the lower anterior face height that is primarily responsible for the heritability of the total anterior face height.~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. T h e factor with the largest heritability estimate (0.76) included the lower anterior face height and total anterior face height. T h e heritability estimate for the factor that included u p p e r anterior face height was 0.48, whereas that for total posterior face height and lower posterior face height was 0.31. 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, this suggests that some c o m m o n (cultural) environmental factor(s) have greater

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influence on these traits. 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; however, the presence of r a n d o m variation may also be an explanation for these relatively high comm o n inheritance estimates. 16,17 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. 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 1,763 individuals in 399 families from a rural c o m m u n i t y in A n d h r a Pradesh, India. 21 Considering the effect of breathing on the vertical dimension, 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. 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. T h e analysis revealed that the allergic children had a m o r e divergent facial pattern. 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. 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. 24 If an increase in total anterior face height and lower anterior face height, in particular, are associated with perennial allergic rhinitis and m o u t h breathing, 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, resulting in m o u t h breathing, b e c o m e s a p r e d o m i n a t i n g factor. Again, heritability is a descriptive statistic for a particular sample u n d e r defined environmental conditions. 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; thus,

subjects with an e x t r e m e malocclusion tend to be excluded. 25 In a thought-provoking study of the heritability of cephalometric and occlusal variables in siblings with overt malocclusions, it was f o u n d that, in contrast to a series of similar subjects with naturally occurring good occlusion, the heritability estimates for craniofacial skeletal variables in the subjects with overt malocclusions were significantly lower, and the heritability estimates for occlusal variations were significantly higher25 To quote King et al, 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. T h a t is, given genetically influenced facial types and growth patterns, siblings are likely to respond to environmental factors (eg, reduced masticatory stress, chronic mouthbreathing) in similar fashions." Malocclusions a p p e a r to be acquired, 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, that often lead to d e v e l o p m e n t of similar malocclusions. 25

Does Knowing The Heritability Matter In Treatment?

It has been stated that, "Variables with a lower genetic determination are m o r e o p e n to influence by, for example, orthopedic correction than are variables with a high genetic determination, which are not so easily changed by the environment." 14 This implies that the genetic influence is a p r e d e t e r m i n i n g , unalterable factor. However, as has already b e e n discussed, it may be altered u n d e r different environmental (treatment) conditions. Certainly, t r e a t m e n t depends on the origin of a disorder if that cause is known and specific. However, 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. % What is i m p o r t a n t is the response of the individual to the environmental (treatment) intervention, 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). Genetic factors that influence a trait may also influence the response to intervention designed to

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alter that trait, but that is not inherently known in the estimation of the heritability of a trait. The question is, d e p e n d i n g on the ability of the individual to respond to a given environment (treatment), will the interaction of the new or altered environment, with the genetic factors present, result in a change in the phenotype?

Nature, Nurture, 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, this is true for what estimates of the heritability represent, 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. The basic interpretation of the estimation of heritability is that the genetic and environmental factors are separate, thus they can be portioned and do not interact. This has been typified by the phrase nature versus nurture, which by its very construction defines a separation and even opposition. To say, for example, 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 . 27 This is true even for conditions in which an environmental influence is known to be strong, such as in smoking and oropharyngeal cancer. Everyone who smokes does not develop cancer, which indicates an interaction of smoking with other factors, including genetic susceptibility. 9s Essentially all aspects of normal and abnormal development are in some way the result of the interaction of genetic and environmental factors; thus, there is no compelling reason to label a trait or condition as being either genetic or environmental. 97

Searching For Genetic Factors

Heritability estimates can indicate the relative contribution or influence that genetic factors

have had on a trait, which is a consideration with regard to the feasibility of a search for identifying those factors. 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; however, 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. However, 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. Once a particular gene or genes in an area of the g e n o m e are identified, they b e c o m e candidate genes for specific analysis of their structure to pinpoint the relevant allele (s). 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. 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), which is considered to be an important factor in craniofacial and skeletal growth. Out of a normal Japanese sample of 50 m e n and 50 women, 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. The average mandibular ramus height, in those with the GHR P56IT allele, was 4.65 m m shorter than the average for those without the GHR P56IT allele. This significant correlation between the GHR P56IT allele and shorter mandibular ramus height was confirmed in an additional 80 women29 Interestingly, the association was with the mandibular ramus height but not mandibular body length, maxillary length, or anterior cranial base length. These data suggest an effect that is site, area, or region specific. 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, 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. It would also be interesting to see what effect different diet consistencies have on individuals with and without the GHR P56IT allele, as a way of looking at genetic and environmental interaction.

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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. Unfortunately, at this time, 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. 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. It may be that genetic factors that influenced a trait will 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 envir o n m e n t to gain a more favorable dimension is theoretically possible, even in individuals in which the vertical dimension does have a relatively high genetic influence. However, 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. 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. 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. 3,'e'~ Although mice, the most c o m m o n l y used mammalian species for genetic inbred strain studies, have been used and will continue to be used for the study of genes that cause disease and aberrations in mammalian development, their different craniofacial m o r p h o l o g y (ie, 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. 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. The development of the mouse g e n o m e project, not far behind the human g e n o m e project, 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, which may then be tested for in the h u m a n population. 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 1.4 million sites of variation in the h u m a n g e n o m e sequence. 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. O u r g e n o m e varies from one individual to the next, most often in terms of single-base changes of the DNA called singlenucleotide polymorphisms. 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, nmltifactorial basis. Although the scale of such studies could be daunting and there are still problems to solve, the potential for studying how natural variation leads to each one of our qualities is significant. This approach may be the best opportunity yet to better understand the roles of nature and nurture rather than nature versus nurture in development. 32

Acknowledgment
T h e a u t h o r thanks Dr W. E u g e n e Roberts for reviewing the m a n u s c r i p t a n d Ms. Robyn Tibbs, Ms. Madeline Hawkins, a n d Ms. Claudette Maurer for retrieving a n d copying references.

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