The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 88, Issue 10

Scientific Articles | October 01, 2006

Prevalence, Concordance, and Heritability of Scheuermann Kyphosis Based on a Study of Twins

Frank Damborg, MD¹; Vilhelm Engell, MD¹; Mikkel Andersen, MD¹; Kirsten Ohm Kyvik, MD, PhD²; Karsten Thomsen, MD, DMSc¹

¹ Department of Orthopaedic Surgery, The Spine Section (RC), University Hospital of Odense, Soender Boulevard 29, DK-5000 Odense, Denmark. E-mail address for F. Damborg: Damborg@Dadlnet.dk
² The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Soender Boulevard 29, DK-5000 Odense, Denmark

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In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the Sahva Foundation. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Investigation performed at the Department of Orthopaedic Surgery, The Spine Section (RC), University Hospital of Odense, Odense, Denmark

The Journal of Bone and Joint Surgery, Incorporated

J Bone Joint Surg Am, 2006 Oct 01;88(10):2133-2136. doi: 10.2106/JBJS.E.01302

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Abstract

Background: The purpose of this study was to establish a cohort of symptomatic twins with Scheuermann kyphosis to provide estimates of prevalence, concordance, odds ratio, and heritability. These estimates indicate to what extent genetic factors contribute to the etiology of this disease.

Methods: The Odense-based Danish Twin Registry is unique in that it contains data on all 73,000 twin pairs born in Denmark over the last 130 years. For the present study, all 46,418 twins born from 1931 through 1982 received a seventeen-page questionnaire, in which one question was "Have you been diagnosed with Scheuermann disease by a doctor"? The prevalence of self-reported Scheuermann disease was calculated, with the total number of answers used as the general population. Pairwise and probandwise concordance, odds ratio, tetrachoric correlations, and heritability were calculated.

Results: We found that the overall prevalence of Scheuermann disease was 2.8%, with a prevalence of 2.1% among women and 3.6% among men (p < 0.0001). The pairwise concordance for monozygotic twins was 0.19 compared with 0.07 for dizygotic twins. The probandwise concordance was 0.31 for monozygotic twins and 0.13 for dizygotic twins. The odds ratios were 32.92 and 6.25 in the monozygotic and dizygotic twins, respectively. These differences were significant (p < 0.01). Heritability was 74%.

Conclusions: In a large cohort of twins that included almost 35,000 individuals, the self-reported overall prevalence of Scheuermann disease was 2.8% and the male-to-female ratio was close to 2:1. Because the pairwise and probandwise concordance and the odds ratio were two to three times higher in monozygotic than in dizygotic twins and the heritability was high, we concluded that there is a major genetic contribution to the etiology of Scheuermann disease.

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The etiology of Scheuermann kyphosis remains uncertain. It is also unclear whether theories suggesting a genetic background^1-4 or an environmental effect^5-7 are correct.

Studies of twins are advantageous in determining whether a disorder is genetic in etiology. Monozygotic twins have identical genes while dizygotic twins are like siblings and share 50% of their segregating genes. An increased ratio of doubly affected monozygotic compared with dizygotic twins indicates that the disorder in question has at least a partial genetic etiology. Both monozygotic and dizygotic twin pairs share a common environment, so only genetic factors should account for a greater similarity in monozygotic twins compared with dizygotic twin partners.

The purpose of this study was to evaluate a cohort of twins who were symptomatic for Scheuermann kyphosis to enable us to estimate the prevalence, concordance, odds ratio, and heritability of this disease.

Materials and Methods

Materials and Methods | Results | Discussion | References

The Odense-based Danish Twin Registry contains data on all 73,000 pairs of twins born in Denmark over the last 130 years. Celebrating its fiftieth anniversary in 2004, it was the first population-based twin registry and is today one of the two largest in the world⁸. The important distinction between monozygotic and dizygotic twins is based on four questions of similarity with a calculated accuracy of approximately 95%^9,10. All of the scientific ethical committees of Denmark have approved this study.

All 46,418 Danish twins registered in the Danish Twin Registry born from 1931 through 1982 received a seventeen-page omnibus questionnaire in the spring of 2002. One question was "Have you been diagnosed with Scheuermann disease by a doctor?"

The prevalence of self-reported Scheuermann disease was calculated with the total number of answers used as the general population, and the twins with Scheuermann kyphosis were stratified according to gender.

We compared monozygotic and dizygotic same-sex twin pairs to calculate the pairwise and probandwise concordance¹¹, odds ratio, and tetrachoric correlations with confidence intervals. Pairwise concordance estimates the risk of both twins being affected in a pair in which at least one is affected, and probandwise concordance estimates the risk of a twin becoming affected, given that his or her monozygotic or dizygotic twin partner has the phenotype. Both the odds ratios and differences between monozygotic or dizygotic pairs were calculated with the stratified Mantel-Haentzel test. The odds ratio estimates the risk of a twin having the phenotype condition his or her monozygotic or dizygotic twin partner may or may not have. Tetrachoric correlations, estimation of heritability, and determination of the best-fit etiology by means of univariate structural equation modeling was carried out with use of an MX software program¹². These calculations were based on a liability model, which assumes that the dichotomous distribution of Scheuermann kyphosis (affected compared with not affected) reflects an underlying, normally distributed likelihood of having the condition, or liability, in the population. When a threshold value of the liability is exceeded, an individual is affected; otherwise, he or she is not. The threshold reflects the prevalence of the trait. These are standard assumptions in quantitative genetic analysis of categorical traits¹³. Structural equation modelling quantifies sources of individual variation by separating the observed phenotypic variance into genetic and environmental variance¹². The genetic contribution can be further divided into an additive (A) genetic variance component (representing the influence of alleles at several loci acting in an additive manner) and a nonadditive (D) genetic variance component (representing intralocus and interlocus interaction). With a potential for measurement error, the environmental component is subdivided into a common (C) environmental variance component (representing environmental factors affecting both twins in a pair as a source of similarity) and an individual and/or unique environmental variance component (E) (environmental factors not shared by twins and making them dissimilar). Heritability is defined as the proportion of the total phenotypic variance that is attributable to genetic variance.

The tetrachoric correlations are used to decide which etiology models fit best. The selection of the best-fitting submodel is based on a balance between goodness-of-fit and parsimony¹². Parsimony is a scientific rule that states that if there are two answers to a problem or a question, and if, for one answer to be true, well-established laws of logic and science must be rewritten, ignored, or suspended to allow it to be true, while for the other answer to be true no such accommodation need be made, then the simpler of the two answers is much more likely to be correct.

SPSS (version 6; SPSS, Chicago, Illinois) and Epi Info (Centers for Disease Control and Prevention, Atlanta, Georgia) software packages were used to evaluate the data.

Results

Materials and Methods | Results | Discussion | References

A total of 34,944 (75.3%) of the 46,418 twins responded to the omnibus questionnaire, and 34,007 (97.3%) of the respondents answered the question about Scheuermann disease. Nine hundred and forty-three twin individuals, representing 380 females and 563 males, reported having Scheuermann disease, indicating an overall prevalence of 2.8% (95% confidence interval, 2.6 to 3.0). There was a prevalence among females of 2.1% (95% confidence interval, 1.9 to 2.3) compared with a prevalence among males of 3.6% (95% confidence interval, 3.2 to 4.1); the difference was significant (chi square with one degree of freedom = 67.8; p < 0.0001). The prevalence of Scheuermann disease was not significantly different between the cohorts of monozygotic and dizygotic twins.

Of the 34,007 individuals who responded to the Scheuermann disease question, 11,436 were twin pairs in which both twins answered the question and 645 of those 22,872 individuals reported that they had been diagnosed as having Scheuermann disease.

Concordance, odds ratios, and tetrachoric correlations are presented in Table I. All variables were significantly higher in the monozygotic than in the dizygotic twins (p < 0.01). The tetrachoric correlation in the monozygotic twins was twice as high as that in the dizygotic twins, indicating that an AE submodel, a combination of genetic variance and environmental factors (see the Materials and Methods section for definitions of A, D, C, and E), fits the data best.

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TABLE I Concordance, Odds Ratio, and Tetrachoric Correlations in Twins with Scheuermann Disease*

	No. of Pairs (Concordant/Discordant/Unaffected)	Pairwise Concordance	Probandwise Concordance	Odds Ratio	Tetrachoric Correlations
Monozygotic pairs	34/57/3146	0.19 (0.13-0.25)	0.31 (0.25-0.37)	32.92 (19.40-55.84)	0.79 (0.70-0.86)
Dizygotic pairs	16/100/3908	0.07 (0.04-0.25)	0.13 (0.09-0.17)	6.25 (3.41-11.31)	0.39 (0.25-0.51)

All variables were significantly higher in monozygotic than in dizygotic pairs (p < 0.01). The 95% confidence intervals are given in parentheses.

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TABLE I Concordance, Odds Ratio, and Tetrachoric Correlations in Twins with Scheuermann Disease*

	No. of Pairs (Concordant/Discordant/Unaffected)	Pairwise Concordance	Probandwise Concordance	Odds Ratio	Tetrachoric Correlations
Monozygotic pairs	34/57/3146	0.19 (0.13-0.25)	0.31 (0.25-0.37)	32.92 (19.40-55.84)	0.79 (0.70-0.86)
Dizygotic pairs	16/100/3908	0.07 (0.04-0.25)	0.13 (0.09-0.17)	6.25 (3.41-11.31)	0.39 (0.25-0.51)

All variables were significantly higher in monozygotic than in dizygotic pairs (p < 0.01). The 95% confidence intervals are given in parentheses.

The heritability derived from this model was 74% (95% confidence interval, 65% to 81%).

Discussion

Materials and Methods | Results | Discussion | References

Scheuermann kyphosis was first described in 1920⁶, and the reported prevalence has ranged from 1% to 8% in the general population^7,14. We regard the self-reported prevalence of 2.8% in this large cohort as a reliable figure for the overall prevalence of symptomatic Scheuermann disease.

The reported prevalence of Scheuermann kyphosis in males and females has varied in the literature. The male-to-female ratio has been reported to be 1:2¹⁵, 1:1^16-18, 2:1^19,20, or 7.3:1⁶. In the present cohort, the prevalence in males was almost twice that of the prevalence in females (1.7:1). We know of no report in the literature on either an increased or a decreased risk of Scheuermann kyphosis in twins, and, in the present study, the prevalence was not significantly different between monozygotic and dizygotic twins.

The cause of this disorder, which affects the patients both with visible deformity and with an increased risk of pain⁷, is unknown. The present study demonstrates that the likelihood of the development of Scheuermann kyphosis is largely genetically determined, but the environment also has a role to play.

Studies of twins are accepted as relatively unique in distinguishing the contribution of genetic from environmental factors in the phenotypic variance of a given medical condition. It is essential that the cohort of twins is population-based since the disease-based studies have a tendency toward overrepresentation of monozygotic and concordant pairs^21,22. The present cohort from the Danish Twin Registry is both very large and population-based, thereby supporting strongly the rationale for this type of study. The zygosity was determined by a standard twin questionnaire that is used for studies of this size, with a frequency of misclassification of the twins of =5%^9,10.

Another important assumption in studies of twins is the assumption of an equal environment. This has been questioned repeatedly, and while there is no doubt that monozygotic twins are treated more similarly than dizygotic twins, it is questionable whether this environmental similarity causes increased phenotypic concordance. Environmental similarity during childhood does not predict twin similarity in personality, attitudes, or a range of psychiatric disorders²³, and thus it is our opinion that it does not predict Scheuermann disease similarity.

The cardinal challenge in this study was the correct identification of the patients. Although this was done by means of a questionnaire, the patient identification of Scheuermann kyphosis was not simply self-reported since the disorder had to be diagnosed by a doctor. It appears that the patients would have to have had symptoms or have had cosmetic complaints to be examined by a doctor in the first place. The patients would then have had to recall that they had been diagnosed as having Scheuermann disease. Patients with unrecognized kyphosis may not have sought medical attention, and the diagnosis would not have been made. In addition, some of these patients were born in the 1930s and 1940s, and, for those patients, the diagnosis may not have been made, since Scheuermann disease was first described in 1920 and may not have been well accepted in that era. There is, therefore, a risk that individuals who had milder cases of Scheuermann kyphosis with no symptoms or cosmetic problems were not included and that the prevalence is underestimated in this study.

Different theories based mainly on genetic^1-4 and mechanical^5-7 factors have been proposed to explain the cause of Scheuermann kyphosis. In our study, all estimates of risk in twins, as well as the tetrachoric correlations, were higher in monozygotic than in dizygotic twins. These differences were significant and confirm a genetic contribution to the etiology of Scheuermann disease, substantiated by the calculated heritability of 74%. We think that this estimate of the heritability of Scheuermann disease will be valuable in the design of future genetic studies.

Kewalramani et al.²⁴ were the first, as far as we know, to report a possible mode of autosomal dominant inheritance in a family with Scheuermann kyphoscoliosis in combination with Charcot-Marie-Tooth syndrome. Halal et al.³ described five families in which the prevalence of Scheuermann kyphosis seemed to follow an autosomal dominant pattern, and later studies have supported this theory^2,4. In 2001, Axenovich et al.¹ reported on ninety pedigrees with Scheuermann disease and concluded, on the basis of analysis with the transmission probability model, that the inheritance could be described within the framework of a dominant major gene diallele model. According to this model, Scheuermann disease should never occur in the absence of the mutant allele so that all the male carriers and only half of the female carriers of the mutant allele have the disease develop. The findings in our study primarily support a multifactorial inheritance pattern of Scheuermann disease, but we cannot rule out the role of a major gene as an etiologic factor.

In conclusion, in a large twin cohort of almost 35,000 individuals, the self-reported overall prevalence of Scheuermann disease was 2.8% and the male-to-female ratio was close to 2:1. The pairwise and probandwise concordance and the odds ratio were highly significant, as they were between two and three times higher in monozygotic than in dizygotic twins. The heritability was 74%. The findings confirm a major genetic contribution to the etiology of Scheuermann disease. ?

References

Materials and Methods | Results | Discussion | References

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Scheuermann HW. Kyfosis dorsalis juvenalis. Ugeskr Laeger. 1920;82: 385-93.82385 1920

Sørensen KH. Scheuermann's juvenile kyphosis: clinical appearances, radiography, etiology and prognosis. Copenhagen: Munksgaard; 1964. 1964

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Topics

scheuermann's disease ; twins

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Frank Damborg, Vilhelm Engell, Mikkel Andersen, Kirsten Ohm Kyvik, Karsten Thomsen; Prevalence, Concordance, and Heritability of Scheuermann Kyphosis Based on a Study of Twins. The Journal of Bone & Joint Surgery. 2006 Oct;88(10):2133-2136.

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