1. Response to comments to "Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study"

    We thank Steve Hammett, Jim Moore and Gary Glissman for their interest in our paper and for their comments. They all express the opinion, to a varying degree, that the content should be detrimental for patients with KS and 47,XYY syndrome. We understand this point, but we disagree, and we can iterate that as physicians caring for hundreds of patients with sex chromosome disorders through many years, being involved in research and the generation of information material for patients and relatives, that we apparently see the plight of our patients differently. We firmly believe that clinicians caring for these patients will be better suited to do so with these data at hand, and likewise that other health care professionals will benefit from comprehensive and holistic knowledge of the syndrome. Before submission of our paper we had a general discussion of the results of our study within the group of authors and with other colleagues and everybody agreed that it would be unethical not to publish the data! We have seen a similar situation with patients with schizophrenia which also have a high rate of criminality. There is a large body of evidence to support this high rate of criminality, and this knowledge has led to the development of tools to estimate risk of criminality, as well as an increased focus on improved medicinal treatment of those with an estimated high risk of future criminality 1. In other words, the knowledge of an increased rate of criminality has been used in a constructive way to improve patient care. We and others have through the very recent years expanded the clinical phenotype of these syndromes, and one of our reviewers, Nicole Tartaglia, has also within the last year contributed with valuable information concerning the social deficits present in many persons with KS and 47,XYY 2, 3 in clinical studies, while we have presented compelling data from epidemiological studies showing that the socio-economic situation of males with these syndromes is inferior in comparison with the background population 4, 5. We are confident that all these studies with different approaches will help better define and characterize these two syndromes. This will in due course lead to better treatment and hopefully also to earlier diagnosis. Suppression of data such as we have presented, we believe, will be detrimental for these two groups of patients in the long run. Stigmatization of groups of patients, a concern voiced by our commenters, is of course always a concern, and is also a concern for us. However, we do not think and believe that our paper will lead to stigmatization of patients. Steve Hammett mentions that a link between gay communities and sexual offenses to children have been propelled by the religious right (in the USA, we presume), and states that he does not hope that our data will lead to a similar link. The gay community, we believe, was never harmed by openness, rather it seems that openness has been and is the way to increased understanding and tolerance of gay people. In the same way, we see our study as a step towards greater understanding and treatment of people with KS and 47,XYY. We see our data as the foundation for future and better studies of how to alleviate some of the inherent social, psychiatric and psychological problems related to the syndromes. We also believe that openness, presentation of factual concerns based on sound data and the free dissemination of data as the foundation for scientific progress. Steve Hammett and Jim Moore have concerns about our approach of not matching for socio-economic status, as was also voiced by our reviewers. This kind of thinking is based on misconceptions about which kinds of answers epidemiology can offer. Our approach in this epidemiological study is methodologically sound and we can only reiterate that matching is not necessarily the right thing to do when the factors (socio-economy parameters) that one matches on are pivotal in understanding the phenomenon of interest, in this case - "criminality". There is a considerable body of research on matching in case-control studies, showing that it is dangerous and sometimes outright wrong to match on factors that, like in the current setting, may be causally involved in the chain of events leading to increased criminality. This can lead to overmatching 6 - "matching on factors that are affected by the study exposure or disease (i.e being KS or control) is almost never warranted and is potentially capable of biasing study results beyond any hope of repair. It is therefore crucial to understand the nature of such overmatching and why it needs to be avoided". And since we have previously shown that having KS or 47,XYY is related to poorer socio-economic outcome 4, 5, one cannot match on such factors since we do not know the precise causal relationship between these factors, the diseases (i.e. KS or 47,XYY) and criminality. Such an approach may even lead to "an irreparable form of selection bias" 6. Thus, there is nothing "contentious" or "problematic" about our data. They are generated in a society with a much lower crime rate than in the USA (70 murders per year per 5.6 million people) and with a much higher detection rate of crimes committed. Steve Hammett also voices concern in relation to the fact that only 25% of the expected number of males with Klinefelter syndrome is present in our analysis. Although we do discuss this issue at length, being the ones that originally presented the issue some years ago 7, we would like to point to the fact that we actually present a sensitivity analysis as Supplementary data. Here, we present two different scenarios. One, where we assume that the rate of criminality among the non-diagnosed would be half that observed among the cases, and another analysis where we assume that the rate of criminality would be similar to that of the controls. On the background of these analyses we show that it is highly likely that the crime rate would remain significantly increased among an entirely unbiased population of both KS and 47,XYY with complete diagnosis of all cases. However, it is clear that only diagnosis of all cases with KS and 47,XYY would fully elucidate this important question. Gary Glissman rightly points to neurobiology as an area where we need new information in relation to KS and 47,XYY. We can only agree with this notion, and we believe that ongoing studies will help in deciphering the somewhat scattered information currently at hand in relation to changes observed on MRI of the brain, neurocognitive changes and genetics. Clearly, this is a very interesting area which poses hope for better understanding, treatment and coupling with endocrinology. Finally, we would like to add a comment on the nature of a study as ours. We have utilized existing registers and merged these in order to better delineate the course of rare syndromes 4, 5, 7-14. Epidemiology is a powerful tool in this context. Epidemiology offers interesting insight, poses new questions, and can present challenging dilemmas. But rarely epidemiological studies can offer solutions, new treatment strategies or prove the superiority of a new drug. Here, we need clinical studies, preferably randomized placebo-controlled clinical trials. A range of studies like ours should therefore serve as part of the background for future clinical studies. Such clinical studies, we are ourselves, engaged in.

    Reference List

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    (2) Cordeiro L, Tartaglia N, Roeltgen D, Ross J. Social deficits in male children and adolescents with sex chromosome aneuploidy: a comparison of XXY, XYY, and XXYY syndromes. Res Dev Disabil 2012 July;33(4):1254-63.

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    (4) Bojesen A, Stochholm K, Juul S, Gravholt CH. Socioeconomic trajectories affect mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2011 May 11;96(7):2098-104.

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    (10) Stochholm K, Bojesen A, Jensen AS, Juul S, Gravholt CH. Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study. BMJ Open 2012 February 22;2(1):e000650.

    (11) Stochholm K, Juul S, Juel K, Naeraa R.W., Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006 July 18;91:3897-902.

    (12) Stochholm K, Juul S, Gravholt CH. Mortality and incidence in women with 47,XXX and variants. Am J Med Genet A 2010 February;152A(2):367 -72.

    (13) Stochholm K, Juul S, Gravholt CH. Diagnosis and mortality in 47,XYY persons: a registry study. Orphanet J Rare Dis 2010 May 29;5:15.

    (14) Stochholm K, Hjerrild B, Mortensen KH, Juul S, Frydenberg M, Gravholt CH. Socio-economic parameters and mortality in Turner syndrome. Eur J Endocrinol 2012;166(6):1013-9.

    Conflict of Interest:

    None declared

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