case study of xyy syndrome

Understanding the phenotypic spectrum and family experiences of XYY syndrome: Important considerations for genetic counseling

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• Published: 07 January 2023
• Volume 14 , pages 17–25, ( 2023 )

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• Colleen Jodarski   ORCID: orcid.org/0000-0001-6640-8963 1 ,
• Rylee Duncan 2 ,
• Erin Torres 2 ,
• Rachel Gore   ORCID: orcid.org/0000-0002-8253-5441 1 ,
• Armin Raznahan 2 &
• Morgan Similuk 1  

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A Correction to this article was published on 10 February 2023

This article has been updated

XYY syndrome is characterized by a variable neurodevelopmental phenotype, with features including developmental delays, cognitive impairments, and an increased risk for mental health conditions. There are two recent developments that have primarily motivated this review. The first is the increased use of non-invasive prenatal screening (NIPS), which will likely result in more individuals being diagnosed with XYY prenatally. As such, health care providers (HCPs) both within genetics and outside of the specialty are more likely to encounter this diagnosis in the future. The second is advances in the understanding of the phenotypic variability of XYY through biobank and deep phenotyping efforts. As the phenotypic spectrum of XYY syndrome continues to expand, families will face greater uncertainty when receiving this diagnosis. Given both of these developments, HCPs will need to have up-to-date and accurate information about XYY to better counsel families. Furthermore, the ability to employ effective counseling techniques, such as anticipatory guidance, will aid in supporting and guiding families through the diagnostic journey. This review aims to provide insight on the neurodevelopmental and psychosocial aspects of XYY syndrome by discussing current research and borrowing from the relevant psychosocial literature of other genetic conditions. In this way, we hope to equip HCPs with the ultimate goal of improving the care and support provided to individuals with XYY and their families.

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Introduction

XYY syndrome, also known as Jacob’s syndrome, is a sex chromosome aneuploidy (SCA) condition with an estimated prevalence of about 1/1000 male births, though recent studies show that it is underdiagnosed (Abramsky and Chapple 1997 ; Abramsky et al. 2001 ; Berglund et al. 2020a , 2019 ; Nielsen and Wohlert 1991 ; Zhao et al. 2022 ). Physical characteristics tend to be less prominent and vary greatly amongst affected individuals but can include tall stature, macroorchidism, macrocephaly, and hypertelorism (Bardsley et al. 2013 ). While the physical features of this condition tend to be less evident, the neurodevelopmental phenotype is more pronounced and can present challenges for affected individuals and their families.

Historically, most individuals were diagnosed with XYY postnatally after seeking medical care due to concerns such as developmental delay or behavioral issues (Abramsky et al. 2001 ). This led to early reports of the XYY phenotype being enriched for cognitive and behavioral issues as well as other mental health conditions. While useful in understanding the “severe” end of the spectrum of XYY syndrome, it also created an issue of ascertainment bias within the literature. Recent biobank studies have shed light on the degree of phenotypic variability by providing insight into the “mild to asymptomatic” end of the spectrum. For instance, a recent study of the UK Biobank found that only 1 out of 143 men with 47, XYY had previously known of their abnormal karyotype, further emphasizing the degree to which this condition is underdiagnosed (Zhao et al. 2022 ).

Additionally, with the advent of non-invasive prenatal screening (NIPS), SCA can now be routinely detected early in pregnancy. Currently, the American College of Obstetricians and Gynecologists (ACOG) recommends that NIPS be offered to all pregnant individuals regardless of age or baseline risk of aneuploidy (ACOG 2020). The increased use of NIPS will likely result in more individuals diagnosed with XYY syndrome in the future, thus increasing the likelihood that health care providers (HCPs) both in the genetics specialty and outside of it will provide care for individuals with XYY. Therefore, it is important for those providing prenatal care to have updated and accurate information to counsel expecting parents and provide appropriate anticipatory guidance. Additionally, pediatric HCPs must better understand the needs of children with XYY and their families to provide them with the necessary resources and care.

Given the recent expansion of the phenotypic spectrum of 47, XYY from large biobank efforts and deep phenotyping of affected individuals, families face the potential of greater uncertainty when receiving a diagnosis of XYY syndrome. Furthermore, with the number of individuals diagnosed with XYY growing due to the increased use of NIPS, HCPs in prenatal and pediatric settings must be equipped to help families navigate the diagnostic journey. As such, the goal of this review is to:

Summarize the neurodevelopmental phenotypes of XYY syndrome

Highlight relevant management guidelines

Discuss the individual and family experiences of the diagnostic journey

Provide recommendations for genetic counseling

Consider high-priority areas for future clinical research

In doing so, we hope to improve the support provided by the medical community to individuals with XYY and their families.

Neurodevelopmental features

The neurodevelopmental features of XYY include a mixed picture of language delays, cognitive impairments, and increased risk for mental health conditions. However, the condition is best characterized by marked variability in the presence and severity of the neurodevelopmental phenotype. Individuals may experience developmental delays early in life that persist into childhood and adolescence, while others experience a more subtle phenotype that may go undetected. Here, we outline common cognitive and psychiatric features to increase awareness regarding the neurodevelopmental profile of XYY syndrome.

Some of the earliest manifestations of XYY syndrome are delays in achieving developmental milestones, including language development and motor skills (Joseph et al. 2018 ; Lalatta et al. 2012 ; Ross et al. 2009 ; Urbanus et al. 2022a , 2022b ). Language development delay may be the most characteristic sign in preschool-age children, with marked delay observed in both prenatally and postnatally diagnosed children (Geerts et al. 2003 ; Urbanus et al. 2022a , 2022b ). When compared to individuals with XXY syndrome, one study found that, on average, children with XYY have more severe and pervasive language impairment at both simple and complex levels of oral and written language (Ross et al. 2009 ). Regarding motor milestones, children with XYY have been noted to have mild delays in the areas of fine motor and gross motor tasks, strength, speed and agility, coordination, and independent walking (Joseph et al. 2018 ; Ross et al. 2009 ).

A consistent finding regarding the cognitive phenotype in children with XYY is the wide range in general intelligence (IQ) that trends toward the lower end of normal (Bardsley et al. 2013 ; Berglund et al. 2020b ; S.M. Davis et al. 2020b ; Joseph et al. 2018 ). While both verbal and nonverbal IQ are typically reported in the low-average range, verbal ability tends to be more severely impaired (S.M. Davis et al. 2020b ; Joseph et al. 2018 ; Lee et al. 2012 ). Individuals with XYY can also have reduced verbal comprehension, working memory, and processing speed, which are associated with increased difficulty maintaining attention and concentration that may result in challenges with other executive functions (Operto et al. 2019 ).

The speech delay and verbal difficulties observed early in development may contribute to the later onset of learning disabilities (Operto et al. 2019 ). Academic difficulties among individuals with XYY are common, and individuals often receive special education (Geerts et al. 2003 ; Linden and Bender 2002 ). However, it should be noted that individuals with XYY possess other strengths in the academic setting, such as curiosity, humor, and teamwork (Thompson et al. 2022 ). Additionally, individuals were reported to possess strengths in the areas of science, technology, engineering, and mathematics (Linden and Bender 2002 ; Thompson et al. 2022 ).

Psychiatric

As previously mentioned, individuals with XYY are at an increased risk for mental health conditions (Berglund et al. 2020b ). Numerous studies have found that individuals with XYY are more likely than the general population and other SCA conditions to receive a diagnosis of attention deficit-hyperactivity disorder (ADHD) (Bardsley et al. 2013 ; Kuiper et al. 2021 ; Ross et al. 2015 ; Tartaglia et al. 2012 ). Individuals tend to have greater issues in the domains of inattention and hyperactivity/impulsivity, which may contribute to lower adaptive functioning overall (Bardsley et al. 2013 ; Joseph et al. 2018 ; Kuiper et al. 2021 ; Ross et al. 2015 ; Tartaglia et al. 2012 ). Similarly, children with XYY show deficits in both internalizing and externalizing behaviors, with externalizing behaviors such as impulsivity, behavioral regulation, thought and attention problems, and aggression tending to be worse (Fjermestad et al. 2017 ; Operto et al. 2019 ; Ross et al. 2012 ). Although externalizing behaviors are more prominent, some individuals with XYY also show internalizing behavior problems, such as withdrawal (Fjermestad et al. 2017 ; Lalatta et al. 2012 ; Operto et al. 2019 ). Comorbid mood disorders, such as anxiety and depression, tend to be more common in instances where there is a diagnosis of another neurodevelopmental disorder (Bardsley et al. 2013 ; Tartaglia et al. 2012 ). Other psychiatric diagnoses reported in individuals with XYY include bipolar disorder and oppositional defiant disorder (Bardsley et al. 2013 ; Berglund et al. 2020b ).

In addition to ADHD, many studies report an increased incidence of autistic behaviors and autism spectrum disorder (ASD) in individuals with XYY compared to the general population and other SCA conditions (Bardsley et al. 2013 ; Berglund et al. 2020b ; Cordeiro et al. 2012 ; Joseph et al. 2018 ; Lee et al. 2012 ; Ross et al. 2012 , 2015 ; Tartaglia et al. 2017 ). One study reported that individuals with XYY are about five times more likely to have ASD than individuals with XXY and 20 times more likely than the general population (Tartaglia et al. 2017 ). Importantly, autism symptoms may contribute to social difficulties experienced by individuals with XYY (Cordeiro et al. 2012 ; Lee et al. 2022 , 2012 ). However, social motivation generally remains intact, suggesting that individuals with XYY are motivated by social interactions, but have trouble in social situations due to social communication deficits and autistic mannerisms (Bouw et al. 2022a , 2022b ; Cordeiro et al. 2012 ; Lee et al. 2022 , 2012 ).

Management recommendations and multidisciplinary care

There are several management recommendations that were identified during our review of the literature. With respect to developmental delays, caregivers and HCPs should monitor language development to identify any early delays or difficulties (Lalatta et al. 2012 ; Urbanus et al. 2022a , 2022b ). Early identification of language delays allows for early interventions, such as speech therapy, to minimize any long-term detriment (Lalatta et al. 2012 ; Urbanus et al. 2022a , 2022b ). Similarly, it is recommended that children with XYY receive comprehensive neuropsychological and educational screening to evaluate for learning disabilities, ASD, ADHD, and other behavioral or social cognitive difficulties, so that they can receive appropriate interventions, treatments, and services early in development, which allows for improved outcomes (Bouw et al. 2022a , 2022b ; Kuiper et al. 2021 ; Lalatta et al. 2012 ; Operto et al. 2019 ; Ross et al. 2012 ; Tartaglia et al. 2012 ). In addition to aiding in the development of an individualized education plan for school-aged children, neuropsychological testing may also identify significant impairment in fine motor, gross motor, or self-help skills, in which case physical therapy and/or occupational therapy may be recommended (Thompson et al. 2020 ; Visootsak and Graham 2006 ). Additionally, individuals with XYY are at an increased risk of physical comorbidities, such as dystonia and mild tremor, which may require additional care from a neurologist (Bardsley et al. 2013 ; J.L. Davis et al. 2020a ,). Overall, comprehensive screening allows for targeting of each child’s unique needs, and thus, provides the opportunity to create a tailored management plan. In the case of prenatal diagnosis, clinicians should outline these recommendations, so that expecting parents can appropriately plan for follow up, which will aid in bridging the gap between pre- and postnatal care (Lalatta et al. 2012 ).

The eXtraordinarY Kids Clinic in Colorado presents a model for providing multidisciplinary care to children with SCA (Tartaglia et al. 2015 ). Their interdisciplinary team consists of developmental-behavioral pediatrics, child psychology, pediatric neuropsychology, speech-language therapy, occupational therapy, genetic counseling, nursing, pediatric endocrinology, and social work (Tartaglia et al. 2015 ). Such interdisciplinary teams provide the opportunity for comprehensive and individualized care that is tailored to the unique needs of the child. Importantly, parents report that this model of care for their child with SCA improved their understanding of their child, the diagnosis, and the necessary supports to aid in their success (Tartaglia et al. 2015 ). Given the reported benefits of this care model, implementing similar interdisciplinary clinics in other locations is needed to support the increasing number of individuals diagnosed with SCA as genetic testing implementation continues to expand (Tartaglia et al. 2015 ).

While early intervention and multidisciplinary care are key to improving outcomes in children with XYY, a recent study also described the importance of interventions that highlight the strengths of children with XYY rather than solely targeting deficits (Thompson et al. 2022 ). With respect to academic support, strengths-based approaches have been shown to improve student wellbeing, aid academic achievement, and build student capacity (Thompson et al. 2022 ). Additionally, strength-based approaches in the academic setting help set up students with XYY for success by increasing positive affect, reducing depressive symptoms, and enhancing quality of life (Schutte and Malouff 2019 ; Seligman et al. 2005 ). One can easily focus on the potential deficits created by a diagnosis of XYY, but appreciating the strengths and capabilities possessed by these individuals is important as well.

Individual and family experiences of the diagnostic journey

Whether identified prenatally or postnatally, a diagnosis of XYY can be difficult for families to process. For many families, the diagnosis comes as a surprise, as most parents report not having prior knowledge of SCA at the time of diagnosis (Riggan et al. 2020 , 2021 ). Thus, receiving a diagnosis of XYY can present as a traumatic event and often lead to feelings of grief, distress, and guilt (Lalatta et al. 2012 ; Riggan et al. 2021 ). Much of the uncertainty and worry that parents experience at the time of diagnosis can be mitigated by improving their understanding of the diagnosis and its prognosis (Jaramillo et al. 2019 ; Lalatta et al. 2012 ; Riggan et al. 2021 ). While it is common for families to experience feelings of worry and uncertainty, some families, especially those with children diagnosed postnatally, may feel relieved after receiving a diagnosis (Riggan et al. 2020 , 2022 ). Conversely, parents who receive a prenatal diagnosis are at an increased risk of feeling depressed, anxious, and less optimistic (Jaramillo et al. 2019 ; Riggan et al. 2020 , 2021 ).

In addition to the timing of diagnosis and indication for testing, family experiences of the diagnostic journey can vary based on the information provided during disclosure. For example, parents who report negative experiences at the time of diagnosis often report that their HCP was unprepared, had little information specific to the SCA to share with them, or provided information that they later found was inaccurate, whereas parents with positive diagnostic experiences report that their HCP stressed the phenotypic spectra and connected them with other parents or advocacy groups (Jaramillo et al. 2019 ; Riggan et al. 2021 ). The way in which the diagnosis is initially communicated to parents is extremely important because it can influence if additional information is sought and how subsequent information is perceived (Abramsky et al. 2001 ; Riggan et al. 2021 ). Despite advances in our understanding of SCA, parents are reporting that they are not presented with materials that are up-to-date and easy to understand at the time of diagnosis (Jaramillo et al. 2019 ; Riggan et al. 2020 , 2021 ). Another concern is the imbalance of information, as many parents feel that the negative aspects of the condition are emphasized over positive aspects and that the language used was negative or apologetic (Jaramillo et al. 2019 ; Riggan et al. 2020 , 2021 ). Poor and imbalanced communication at the time of diagnosis may lead families to feel like they do not have the necessary emotional support or information to make informed decisions. As a result, parents may conduct their own internet searches to gather information, which can result in a biased and outdated understanding of XYY (Riggan et al. 2021 ). HCPs counseling XYY families should be prepared to address any misinformation parents have about the XYY diagnosis and inform them of the limitations in the literature (e.g., institutionalized populations, ascertainment bias, etc.) As access to prenatal genetic screening and testing increases, the likelihood that non-genetics providers will have to disclose results and provide pre- or post-test counseling increases. Since HCPs’ knowledge and beliefs about XYY likely vary significantly, they should be equipped with a disclosure protocol that is based on up-to-date information and follows professional guidelines and input from the XYY community (Abramsky et al. 2001 ).

As a lifelong diagnosis, parents are continually adapting to what it means to have a child with XYY. Compared to children with XYY, parents perceive their child’s diagnosis as having a larger negative impact on their child’s mental health and well-being, as shown by higher parent-report compared to self-report scores of depression and anxiety (Bardsley et al. 2013 ). Parents also perceive their children as having greater difficulty in different psychosocial domains compared to how children perceive their challenges (S.M. Davis et al. 2020b ). Together, these findings suggest that individuals with XYY may be adapting more positively to their condition than their parents. Parental coping is of particular concern, as reports indicate clinically significant levels of parental stress and anxiety associated with XYY (Lalatta et al. 2012 ; Operto et al. 2019 ). While all parents of children with XYY may experience some level of stress, parents of children who have more emotional and behavioral problems (e.g., parents of children diagnosed postnatally) may be of highest concern (Operto et al. 2019 ). Regardless of the degree of their child’s emotional and behavioral challenges, HCPs must evaluate and monitor parents for signs of stress and anxiety. Additionally, it is important that they acknowledge possible parental anxiety related to a difficult relationship with their child and feelings of inadequacy in aspects of their parental role (Operto et al. 2019 ).

Following diagnosis, families are commonly faced with the difficult questions of if, when, and how to disclose the XYY diagnosis to their child, other family members, teachers, and care providers. For many families, these decisions are complicated by the variable cognitive, emotional, and behavioral prognoses. Additionally, parents report that their own knowledge and understanding of the condition are barriers to their decision-making (Gratton et al. 2016 ). Although parents report feeling unsure about how to make decisions about disclosure, research suggests that there are consistent factors upon which parents base their decisions (Gratton et al. 2016 ). One of the most influential factors is the child’s level of functioning, with parents being more likely to disclose the diagnosis to their child and others if they experience more behavioral, social, and language challenges (Gratton et al. 2016 ). Although age does not seem to be as important as the child’s functioning, parents were more likely to disclose the diagnosis to older children (Gratton et al. 2016 ). Many parents of children with XYY must navigate decisions about disclosure on their own, as few received counseling about disclosure at the time of diagnosis (Gratton et al. 2016 ).

HCPs who interact with children with XYY have an opportunity to support families by helping them navigate the potential benefits and drawbacks of diagnosis disclosure. HCPs should be prepared to address some of the reasons why parents might decide not to disclose, such as fear of stigmatization, feeling like the diagnosis gives an excuse for bad behavior, and needless anxiety if the child is not clinically affected (Gratton et al. 2016 ). Importantly, part of the counseling discussion regarding disclosure should involve discussion about the variation in outcomes associated with XYY, especially since the child’s functioning plays an important role in the decision-making process. As parents are more likely to disclose the diagnosis if their child is more severely affected, HCPs should be prepared with disclosure resources that are appropriate for all levels of functioning (for examples, see Bishop 2014 ; Gratton et al. 2014 ).

Genetic counseling for XYY

Whether to evaluate the sex chromosomes as part of NIPS has been an area of professional debate due to important considerations on both sides. Reasons one may argue not to screen for SCA include concerns regarding sex selection for non-medical reasons, test inaccuracies, and the less severe and highly variable phenotype of these conditions that result in counseling challenges (Dondorp et al. 2015 ). For the purposes of this review, we will focus on addressing the latter two issues. At this time, NIPS has a lower positive predictive value (PPV) for SCA compared to trisomies 21, 18, and 13 (Bevilacqua et al. 2018 ; Guo et al. 2022 ; Ramdaney et al. 2018 ). Recent studies report a PPV ranging from 37 to 46% for SCA, which is much lower than the PPV for the other autosomal trisomies with sensitivity and specificity close to 100% (Bevilacqua et al. 2018 ; Guo et al. 2022 ; Ramdaney et al. 2018 ). Additionally, as outlined above, the phenotypic spectrum and severity of XYY are broad with other SCA conditions facing a similar counseling challenge. As such, one may argue to reserve NIPS for only screening for those conditions that have a more severe phenotype. However, in reviewing the literature, parents of children with SCA provide insight into the benefits of early diagnosis.

Firstly, early diagnosis of SCA during pregnancy allows expecting parents more time to prepare and earlier access to recommended therapies and interventions (Bevilacqua et al. 2018 ; Jaramillo et al. 2019 ; Riggan et al. 2021 ). These benefits cannot be understated, as earlier intervention allows for improved outcomes in children with SCA and additional time for parents to adapt to the diagnosis. Additionally, screening for SCA during pregnancy shortens the potential diagnostic odyssey for children who do present with a more severe SCA phenotype. Parents of children with SCA who received a pediatric diagnosis expressed frustration as the early signs of these conditions were missed by medical professionals (Riggan et al. 2022 ). Furthermore, parents reported that diagnostic delay led to several important negative outcomes for their child, including missed opportunity to access interventions and supports earlier, lack of understanding from others, inability to develop effective parenting strategies at an earlier age, and inability to proactively advocate for their child (Riggan et al. 2022 ). Given these challenges, one can see how prenatal screening and diagnosis can be of immense benefit to parents in being able to better provide for their child with SCA and adapt to their diagnosis.

Furthermore, studies have shown that current counseling regarding prenatal screening of SCA has room for improvement. For example, parents of children with SCA have reported being unaware of SCA as a possible result from prenatal screening or diagnosis or that a positive NIPS result requires follow up confirmatory testing (Ramdaney et al. 2018 ; Riggan et al. 2021 ). Additionally, parents receiving a prenatal diagnosis express a desire for supportive communication concerning parental education and transparency regarding the variable phenotype of SCA conditions (Riggan et al. 2021 ). Some of the uncertainty of these diagnoses relates to our current understanding of the phenotypic spectrum that will never be fully realized unless SCA is routinely screened for during pregnancy (Berglund et al. 2020a , 2020b ). So, while there are currently limitations to screening for SCA with NIPS, we argue that the response to these challenges is not to obscure desired information from expecting parents, but rather to provide accurate and comprehensive pre- and post-test counseling related to SCA.

Recommendations for clinical practice

The wide variability in the neurodevelopmental phenotype associated with XYY syndrome poses challenges with counseling and providing anticipatory guidance. One of the factors that has been associated with the variability in phenotype is the timing of diagnosis. Individuals who are postnatally diagnosed tend to be more severely affected due to a presenting issue leading them to seek care, whereas individuals diagnosed prenatally are less likely to receive special education or speech therapy services (Bardsley et al. 2013 ; Lalatta et al. 2012 ; Linden and Bender 2002 ). Therefore, the wide variability reported in the prenatally diagnosed population is thought to best reflect the true diversity of the phenotype (Bardsley et al. 2013 ). As such, HCPs should be flexible in their counseling practices based on timing of diagnosis and indication for testing. Here, we outline recommendations for providing genetic counseling that considers the variability in outcomes and family experiences.

Uncertainty is often a large factor at play within the field of genetics and counseling for XYY syndrome is no different. Given the variability of the phenotype, uncertainty regarding the severity of XYY syndrome, especially in the prenatal setting, is an important concept to discuss with families. The variability in phenotype can also contribute to how well a family is able to adapt to having a child with XYY. For example, Linden and Bender ( 2002 ) interviewed families who had a prenatally diagnosed child with XYY and found that while some parents were not concerned about the implications of the diagnosis, others reported concerns about the future welfare of their children and disclosing the diagnosis to others.

When providing information about XYY, HCPs counseling families should strive to offer balanced and accurate information. However, the idea of “balanced” is difficult to define, as shown by relevant literature examining the responses of parents of children with Down syndrome (DS) (Hippman et al. 2012 ). When asked to provide a “balanced description”, parents provided a wide variety of narratives that likely reflects the differences in their lived experiences with the condition (Hippman et al. 2012 ). Accordingly, Hippman et al. ( 2012 ) provide recommendations for HCP communication that can be strengthened to address challenges related to variability in family experiences. While these recommendations were pulled from the literature on DS, we suggest that they can be utilized when counseling families of children with XYY. HCPs counseling families should recognize the potential variability in a family’s reaction to receiving a diagnosis (Hippman et al. 2012 ). Regardless of their reaction, exploring previously helpful coping skills can aid in providing anticipatory guidance for families, particularly in the prenatal context (Hippman et al. 2012 ). Another counseling recommendation is to have expecting parents imagine what their life might be like with an affected child. While XYY is less well known in the general population compared to DS, the lesson still applies, where having parents imagine the similarities and differences of their anticipated life with a child who has XYY can aid in processing the diagnosis and integrating it into the greater framework of their lives.

Additionally, communication surrounding a diagnosis of XYY should be driven by the parent and their specific emotional and informational needs by continuing to ask them for their questions (Hippman et al. 2012 ). As described above, families are often in need of accurate and up-to-date information about XYY. Awareness of support groups, such as the Association for X and Y Chromosome Variations (AXYS), is a valuable resource for providers and patients alike. Through engaging with the greater community of individuals with XYY, HCPs will be better able to counsel families by providing a nuanced description of the range of possibilities related to life with XYY. So, while “balanced” may be a difficult goal to achieve, providing up-to-date information that is non-judgmental and responsive to the specific needs of the family will be imperative to better counseling families of a child with XYY.

As previously discussed, individuals with XYY are at an increased risk of developing certain psychiatric conditions. While not all children with XYY will develop psychiatric issues, it is important to equip parents to identify symptoms so that they can better manage their child’s mental health. Drawing from the lessons learned from 22q11.2 deletion syndrome (22qDS) and “awareness to act”, HCPs can empower parents of children with XYY to be their child’s best advocate. Carrion et al. ( 2022 ) define “awareness to act” as confidence in being alert and equipped to protect and/or manage their child’s mental health. Parents of children with 22qDS described worry and stress over missing “red flags” of mental illness and a limited awareness as to what symptoms they should be watching out for (Carrion et al. 2022 ). One can easily see how this could apply to other conditions that carry a risk of psychiatric conditions, which are more difficult to screen for at times than physical symptoms. Parents in this study reported that psychiatric genetic counseling helped them achieve awareness to act in several important domains: increased confidence in awareness of red flags, strategies to protect their child’s mental health, and empowerment in their ability to articulate and advocate for services their child needed (Carrion et al. 2022 ). Most importantly, providing anticipatory guidance promoted parents’ sense of agency in reducing the risk of psychiatric problems and improving outcomes for their child with 22qDS (Carrion et al. 2022 ). Since parents of children with XYY may experience a great deal of stress related to their child’s diagnosis and perceived mental health, they may also benefit from a similar form of anticipatory guidance. Given that most of the presentations of XYY are “unseen” physically, empowering families in a similar way is important so that they can advocate effectively for their child’s mental health needs.

Areas for future research

While this is not an exhaustive list of areas for of future research, our review of the literature identified significant gaps in our current understanding of XYY syndrome and its impact on individuals and their families. Firstly, future research should focus on qualitative reports from the families themselves about their experiences of having a child with XYY. In this way, we can learn what is most helpful and most challenging about living with XYY as well as identify family needs that are currently unmet by HCPs. Furthermore, most of the referenced studies include data obtained from parental report, which at times was shown to differ from what was reported by individuals with XYY (Bardsley et al. 2013 ; S.M. Davis et al. 2020b ). Future research should also focus on the experiences of individuals with XYY to gauge their understanding of the diagnosis and what their specific needs are.

Additionally, more longitudinal studies, such as the eXtraordinarY babies study, are needed to enhance our understanding of XYY across the lifespan (Tartaglia et al. 2020 ). Similarly, there are few studies to date about the impacts of an XYY diagnosis in adulthood and the challenges that may occur during this transition. The transition to adulthood marks a time of great change and uncertainty, and better understanding of how individuals with XYY adapt during this time is essential. In this way, HCPs can provide appropriate support and counseling regarding specific concerns, such as fertility and family planning.

Future work should also aim to distinguish possible biological and familial predictors of phenotypic variability. For example, multiple linear regression models have shown that individuals with XYY and their family members are correlated on certain traits, such as IQ, vocabulary, and social awareness (Wilson et al. 2021 ). Efforts to understand the clinical utility of these models in the genetic counseling setting will be useful in providing anticipatory guidance for families. As such, HCPs will be able to better counsel families about the issues surrounding diagnosis, both medically and psychosocially.

In conclusion, XYY syndrome is characterized by a neurodevelopmental phenotype that is variable in nature. Given that the primary manifestations of this condition are largely ‘unseen’, individuals and their families must navigate unique challenges, such as disclosure of diagnosis. An XYY diagnosis can lead to a range of experiences and emotions for family members, with parental coping being of particular concern. As such, anticipatory guidance and preparing families with an “awareness to act” are useful counseling interventions. Additionally, it is vital that families be provided with resources about the diagnosis that are developmentally appropriate for their child. There is room to grow in our understanding of the many facets of an XYY diagnosis and the associated psychosocial challenges. With future research focusing on the phenotypic spectrum of this condition across the lifespan, special attention will also need to be paid to how this diagnosis also impacts the family system. XYY syndrome is a diagnosis that has significant implications on not only the affected individual, but the family as well. It is therefore imperative that HCPs fully understand the range of lived experiences with XYY so that we can better counsel and care for affected individuals and their families.

Change history

10 february 2023.

A Correction to this paper has been published: https://doi.org/10.1007/s12687-023-00636-0

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This work was supported with funds from the NIAID Division of Intramural Research and from the National Institute of Mental Health (NIMH).

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Colleen Jodarski, Erin Torres, and Morgan Similuk conceptualized this review. Colleen Jodarski and Rylee Duncan performed the literature search and analysis and wrote the original draft. Armin Raznahan, Morgan Similuk, Rachel Gore, and Erin Torres provided critical reviews and edits. Colleen Jodarski and Rylee Duncan wrote revisions. All authors reviewed the final manuscript.

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Jodarski, C., Duncan, R., Torres, E. et al. Understanding the phenotypic spectrum and family experiences of XYY syndrome: Important considerations for genetic counseling. J Community Genet 14 , 17–25 (2023). https://doi.org/10.1007/s12687-022-00630-y

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• Volume 2, Issue 1
• Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study
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• Kirstine Stochholm 1 ,
• Anders Bojesen 2 ,
• Anne Skakkebæk Jensen 1 ,
• Svend Juul 3 ,
• Claus Højbjerg Gravholt 1
• 1 Department of Endocrinology and Internal Medicine, Aarhus University Hospital NBG, Aarhus C, Aarhus, Denmark
• 2 Department of Clinical Genetics, Vejle Hospital, Sygehus Lillebaelt, Vejle, Denmark
• 3 Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
• Correspondence to Dr Claus Højbjerg Gravholt; ch.gravholt{at}dadlnet.dk

Objective To investigate the criminal pattern in men between 15 and 70 years of age diagnosed with 47,XXY (Klinefelter's syndrome (KS)) or 47,XYY compared to the general population.

Design Register-based cohort study comparing the incidence of convictions among men with KS and with 47,XYY with age- and calendar-matched samples of the general population. Crime was classified into eight types (sexual abuse, homicide, burglary, violence, traffic, drug-related, arson and ‘others’).

Setting Denmark 1978–2006.

Participants All men diagnosed with KS (N=934) or 47,XYY (N=161) at risk and their age- and calendar-time-matched controls (N=88 979 and 15 356, respectively).

Results The incidence of convictions was increased in men with KS (omitting traffic offenses) compared to controls with a HR of 1.40 (95% CI 1.23 to 1.59, p<0.001), with significant increases in sexual abuse, burglary, arson and ‘others’, but with a decreased risk of traffic and drug-related offenses. The incidence of convictions was significantly increased among men with 47,XYY compared to controls with a HR of 1.42 (95% CI 1.14 to 1.77, p<0.005) in all crime types, except drug-related crimes and traffic. Adjusting for socioeconomic variables (education, fatherhood, retirement and cohabitation) reduced the total HR for both KS and 47,XYY to levels similar to controls, while some specific crime types (sexual abuse, arson, etc) remained increased.

Conclusion The overall risk of conviction (excluding traffic offenses) was moderately increased in men with 47,XYY or KS; however, it was similar to controls when adjusting for socioeconomic parameters. Convictions for sexual abuse, burglary, arson and ‘others’ were significantly increased. The increased risk of convictions may be partly or fully explained by the poor socioeconomic conditions related to the chromosome aberrations.

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Article summary

Article focus.

To investigate crime rates of men with an extra sex chromosome (47,XXY and 47,XYY). Based on previous small studies, we hypothesised that an increased crime rate would be present in men with an extra sex chromosome and investigated this in a nationwide registry study.

Key messages

Using a nationwide approach, we show that men diagnosed with KS (47,XXY) and 47,XYY are more frequently convicted for sexual abuse, burglary, arson and other reasons. Traffic offenses are seen less frequently in both groups.

Whether early diagnosis and improved clinical care can lead to a decrease in convictions is not clear.

The increased crime rate may be partly or fully mediated by poor socioeconomic conditions.

Strengths and limitations of this study

The study clearly delineates a pattern of increased crime rates among men diagnosed with an extra sex chromosome. The strength of the present study is the large number of men with sex chromosomes and the large control group and the merging of several registries.

The limitations are that we were not able to control for concomitant medicinal use, especially testosterone use in KS, nor to include clinical data.

Introduction

The sex chromosome trisomies 47,XXY (Klinefelter's syndrome (KS)) and 47,XYY are the most common male sex chromosome aneuploidies compatible with live birth. KS affects 167 per 100 000 men, 1–3 while the prevalence estimates of 47,XYY are highly variable, ranging in live born men from 26 per 100 000 4 to 375 per 100 000, 5 although many are not diagnosed or diagnosed late. 6 Both KS and 47,XYY are much more frequent when studied in a tall population, 7 which is readily explained by the presence of additional copies of the SHOX gene (and possibly also other genes related to stature) in men with KS and 47,XYY. 8 As with 47,XYY, many KS are not diagnosed, and a considerable delay in diagnosis exists for those who get a diagnosis. 2

The 47,XYY sex chromosome abnormality has been described in various settings 6 9 since the first descriptions of a group of men with 47,XYY in 1965 by Jacobs et al 10 who conducted a chromosome survey of male patients at the State Hospital in Carstairs, Scotland, and found that men with the 47,XYY karyotype were particularly frequent among inmates in penal institutions. During the 1960s and 1970s, studies of persons with KS and 47,XYY identified an increased frequency in hospitals for mentally handicapped, 11 and men with 47,XYY seemed to be over-represented in prisons. 12 Several of these studies reported a general increased rate of criminal behaviour and increased crime rates among both cohorts, especially due to sexual crimes. 13 These studies were associated with selection problems as they investigated institutionalised individuals. Two relatively new studies of criminal behaviour among sex chromosome trisomies have been published. Götz et al 14 found an increased rate of criminal behaviour among persons with 47,XYY but not among persons with KS. Another study from 1988 15 linked young KS males with arson. However, both studies include a very limited number of persons. The study by Witkin et al 7 in tall persons concluded that there was no evidence of an increased crime rate among KS and 47,XYY, but again with very few study subjects. Long-term follow-up of a cohort of KS (n=19) and 47,XYY (n=19) indicated that persons with 47,XYY had a fourfold increase in convictions, mostly due to minor offenses. 16 All investigations conducted so far on this issue are limited by the study of selected groups, either institutionalised or clinic patients, in addition to methodological shortcomings, such as self-report of crimes, poorly defined definition of crime type and poorly defined control groups. All studies have also been conducted in very small groups comprising <20 persons with a chromosome abnormality. The full spectrum of all types of crime has never been reported. As mentioned, diagnosis of both syndromes is usually delayed and more than half of the expected individuals are never diagnosed, 2 6 and a more thorough knowledge of all aspects these syndromes would most likely facilitate earlier diagnosis and possibly better clinical care.

In order to examine the crime characteristics of men with KS and 47,XYY, we undertook the present nationwide study, focusing not only on the total number of convictions but also on various crime types. Thus, we investigated the criminal pattern of all men diagnosed with 47,XYY and KS compared with a large age- and calendar-time-matched control group. We compared HRs without and with adjustment for socioeconomic variables in order to assess whether any increased risk of conviction could be explained by the poorer socioeconomic conditions of men with KS and 47,XYY. Furthermore, the criminal pattern before and after the diagnosis of the chromosomal aberration was investigated.

The present study is a register-based study combining information from the Danish Cytogenetic Central Register, Statistics Denmark and the Danish Central Crime Registry.

Study population

Using the Danish Cytogenetic Central Register, we identified all men diagnosed with a karyotype compatible with KS, 47,XYY or variants thereof in Denmark by January 2009. These men are hereafter referred to as index-persons. The register was founded in 1967 and contains information regarding all cytogenetic analyses performed in Denmark since 1960, including date of diagnosis. Unique identification numbers (ID numbers) from the Civil Registration System enabled identification of every single person diagnosed with an aberrant chromosomal analysis. ID numbers are given to all Danish citizens since 1968. The ID numbers ensured a one-to-one linkage between the registries.

For each index-person, Statistics Denmark identified up to 100 age- and calendar-time-matched controls (matched on month and year of birth) from the male background population. All dates of emigration and death were retrieved. All controls were alive and living in Denmark when their index-person was diagnosed. All controls emigrated or deceased before the index-person turned 15 years were excluded.

Convictions

The Danish Central Crime Register has previously been described as possibly the most thorough, comprehensive and accurate crime register in the Western world. 17 Since the register was digitalised on 1 November 1978, all charges and decisions for any reported offense in Denmark have been registered. We had access to annual information, and a person could be registered with multiple convictions the same year. We defined 1 July the relevant year as the date of the conviction. The study period was from 1 November 1978 to 31 December 2006, as 2006 was last year with available information.

In Denmark, the age of criminal responsibility is 15 years. All solved criminal acts committed by individuals born after 1 November 1963 has been registered in the crime register. We considered only persons between 15 and 70 years during the study period to be at risk of an event. We categorised the offenses into eight groups, that is, (1) sexual-related convictions including rape; (2) homicides; (3) violent convictions; (4) robbery, burglary and theft; (5) traffic offenses; (6) drug-related convictions not including violence; (7) arson and (8) ‘others’.

All convictions of an index-person or a control were retrieved from the crime register. We defined an event as the first conviction in any group and in each of the eight groups separately. Thus, only the first event was analysed, and all succeeding events in the same group were excluded.

We discriminated between events before and after the diagnosis of a chromosome aberration. Also, in order to analyse whether the conviction and the diagnosis could be related, we excluded all convictions up to 2 years before and 2 years after the diagnosis in a separate analysis. We also discriminated between persons diagnosed early and late in life, using the median age at diagnosis as cut-point.

Socioeconomic outcome parameters

From Statistics Denmark, we retrieved information regarding time of the following events, as previously described 18 : cohabitation with a partner, achievement of an education, fatherhood and retirement.

Cohabitation and marriage

We retrieved all persons' marital and cohabitational status each 1st of January. Data were available from 1980 through 2007. The event was first change from being single to be cohabitating with a partner.

Data were category of education and dates for achieved education. An achieved bachelor degree or higher was considered ‘an education’. The event was first achieved bachelor degree for a person between 18 and 40 years.

All children born or adopted were registered from 1942 until 2007, with a linkage to both of their registered parents. Fatherhood was defined as the event of the first fathering of a child.

We defined retirement as due to age, sickness or voluntary choice. A person was considered retired, the first year payment was received due to retirement, regardless of a later return to the labour market.

The study protocol was approved by the Danish Data Protection Agency.

Kaplan–Meier estimates were constructed for time of first conviction. Time at risk started at age of 15 years or at start of registration, whichever came last, and ended at the date of first event, at the age of 70 years, at emigration/death or 31 December 2006, whichever came first.

HRs were calculated using stratified Cox proportional hazards regression, where each case and his matched controls were one stratum. For the analyses, time at risk started on the 15th birthday or 1 November 1978, whichever came last, and time at risk ended 1 July the year we registered an event for the first time, on the date of emigration, on the 70th birthday, on the date of death or 31 December 2006, whichever came first. For analyses before the diagnosis, time at risk ended no later than the date of diagnosis. For analyses after the diagnosis, time at risk started no earlier than the date of diagnosis.

For the analyses excluding all convictions 2 years before and after the diagnosis, all persons who had a first registration of a conviction of the relevant crime type during this period were excluded. We analysed convictions adjusted for cohabitation, education, fatherhood and retirement.

To examine a potential bias associated with undiagnosed KS and 47,XYY cases, we performed a sensitivity analysis, assuming that the risk of conviction among undiagnosed cases is smaller than the risk observed among diagnosed cases, and we applied the statistical uncertainty from the observed data expressed by the SE of the ln(HR) estimate.

All results are shown with 95% CI, and p<0.05 was considered statistically significant. We made no formal correction for multiple comparisons. We used Stata V.10.0 (Stata Corp.) for all calculations.

We identified 1049 persons with KS, whereof 934 were at risk of an event due to age between 15 and 70 years during the registration period; similarly, 208 persons with 47,XYY were identified, and 161 were at risk of an event. For details on both cohorts of index-persons and their controls, see table 1 .

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Basic characteristics of persons with Klinefelter's syndrome (KS) or 47,XYY

Persons with KS

The risk of any conviction was similar in persons with KS and controls with a HR of 0.95 (95% CI 0.86 to 1.05, p=0.28) but was increased to 1.40 (95% CI 1.23 to 1.59) when excluding traffic offenses ( table 2 ). Convictions of sexual abuse, burglary, arson and ‘other’ were moderately increased in persons with KS ( figures 1 and 2 ). When excluding convictions within 2 years before and after the diagnosis, the HRs did not change substantially (supplemental figure 1). The HRs were significantly increased for convictions of sexual abuse, burglary and arson both before and after the KS diagnosis (supplemental table 1). The HRs were lower in the cohort diagnosed late in life (supplemental figure 2). Adjusting for socioeconomic parameters reduced the total HR (excluding traffic offenses) to a HR of 1.05 (95% CI 0.90 to 1.23) ( table 2 ), but it was still significantly increased in the subgroups sexual abuse and arson. The HR for convictions of traffic offenses was significantly decreased both before and after adjustment for socioeconomic parameters.

HRs (95% CI) for overall cause-specific convictions without and with adjustment for education, retirement, cohabitation and fatherhood in men with KS and 47,XYY

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Kaplan–Meier plot of proportion of persons convicted (excluding traffic offenses) for the first time in the background population (thin line) and in men with Klinefelter's syndrome (bold line). All were 15–70 years of age.

HRs of convictions due to cause in Klinefelter's syndrome (KS) compared to age-matched men (see the Materials and methods section for details). Actual numbers of offenders (KS/controls) are given in parentheses.

Persons with 47,XYY

In total, the risk of convictions was moderately increased in persons with 47,XYY compared to controls (HR 1.42 (95% CI 1.14 to 1.77), p<0.005) and even more pronounced (HR 2.09 (95% CI 1.61 to 2.71), p<0.001) when excluding traffic offenses ( figure 3 and table 2 ). A significantly increased HR was identified for convictions of sexual abuse, homicide, violence, burglary, arson and ‘others’ ( figure 4 ). In none of the eight conviction groups did the estimate change substantially when excluding convictions 2 years before or after the diagnosis (supplemental figure 3). Before the diagnosis, the HRs were significantly increased for convictions of sexual abuse only, and there were no events among the persons with 47,XYY in homicides, drug-related convictions and the arson group (supplemental table 1). After the diagnosis, the HRs were significantly increased in all offense groups, except for the traffic offenses (data not shown). There were no significant differences between HRs for those diagnosed younger and older than the median age at diagnosis (supplemental figure 4). Adjusting for socioeconomic parameters reduced the total HR (excluding traffic offenses) to 1.04 (95% CI 0.68 to 1.61) ( table 2 ), and all other subgroup HRs but sexual abuse decreased.

Kaplan–Meier plot of proportion of persons convicted (excluding traffic offenses) for the first time in the background population (thin line) and in men with 47,XYY (bold line). All were 15–70 years of age.

HRs of convictions due to cause in 47,XYY syndrome compared to age-matched men (see the Materials and methods section for details). Actual numbers of offenders (47,XYY/controls) is given in parentheses.

This large study in persons with KS and 47,XYY covering all diagnosed individuals in Denmark demonstrates that persons with 47,XYY and KS are convicted of a number of specific offenses more frequently than the background population. The total number of convictions, however, was not increased in persons with KS, primarily due to a significantly decreased number of traffic-related convictions. The study also demonstrates that unfavourable socioeconomic conditions may be part of the explanation for the increased rate of convictions since adjustment for socioeconomic variables reduced the HR in both cohorts. We could also demonstrate an association between convictions and age at diagnosis in persons with KS, that is, the earlier the diagnosis had been made, the greater the likelihood of having been convicted of an offense.

Men with KS and 47,XYY are to a large extent diagnosed late or not diagnosed at all, 2 6 and we have previously estimated that only 25% of KS and 15% of 47,XYY get a diagnosis. The same pattern is seen in other countries. 19 20 Thus, the results of the present study apply to the studied cohort—in other words, patients with KS and 47,XYY seen in daily clinical practice, and risk estimates may therefore not be applicable to groups of yet undiagnosed men with sex chromosome trisomies or even patients from other countries. We are well aware that the results of the present study may stigmatise persons with KS and 47,XYY due to the over-representation of convictions of sexual abuse and arson. But instead of suppressing such data, we believe that they are pivotal in furthering the understanding of these syndromes.

We found a significantly increased cause-specific risk of convictions due to sexual abuse, burglary, arson and ‘others’ among men with 47,XYY and KS. Furthermore, the cause-specific risk of convictions due to homicide and violence was increased among persons with 47,XYY. We then studied the impact of socioeconomic factors by adjusting for level of education, fatherhood, retirement and cohabitation. This adjustment lead to reductions in most HR, and only the risk of convictions for sexual abuse and arson among persons with KS and only sexual abuse among persons with 47,XYY remained significantly elevated. Among persons with KS, we found a significantly decreased risk of traffic-related convictions.

In general, information about sexual function in men with sex chromosome aberrations is sparse. Schiavi et al 21 found that fewer men with 47,XYY, but not men with KS, were married, experienced greater sexual dissatisfaction in general, acknowledged unconventional sexual experiences compared to a control group and demonstrated a less masculine gender role. Furthermore, men with 47,XYY have been described as immature, having interpersonal and sexual difficulties. 22 Thus, men with KS and 47,XYY have been described with increased frequency of different or deviating sexual behaviour, although it is important to stress that only few and small studies have investigated this subject. In addition, an increased vulnerability to psychiatric disorders and deviant behaviour, 23–25 psychophysiological dysfunction 26 and increased levels of autism traits in KS 27 28 together with a lower educational level and poor socioeconomic status 18 may result in a increased susceptibility to commit a crime. We did not expect the finding of significantly increased risk of convictions for sexual abuse, and we believe this to be of considerable importance. The reason for the increased frequency of sexual abuse convictions is of course speculative but may be due to the previously described feeling of being sexually different, which may end up in misinterpreting sexual cues, or possibly frustration leading to socially and legally unacceptable ways of achieving sexual satisfaction. Further studies are needed to clarify whether early diagnosis, sex steroid treatment, psychological therapy or other initiatives may alter this finding.

Our findings of an increased frequency of convictions other than traffic offenses were not corroborated by the long-term follow-up study by Ratcliffe, 16 who only found increased criminality among persons with 47,XYY (n=19), but not among persons with KS (n=19), and that this increase primarily was due to minor offenses.

Previous reports have linked persons with KS with arson, 15 29 and a case report identified improvement on treatment for hypergonadotropic hypogonadism. 30 There have only been case reports of arson in men with 47,XYY. 14 31 We have no specific explanation as to why this specific tendency is present, but it is possible that some of the psychopathological traits mentioned above, especially for the KS group, may prove explanatory in future studies.

Previously, lower intelligence has been pointed out as a contributing factor to the increased criminal behaviour in men with 47,XYY. 14 Götz et al 14 investigated criminality and antisocial behaviour in unselected men with KS and 47,XYY and showed that men with 47,XYY were more likely to have a criminal record compared to controls and found this to be due to lower IQ (n=16). They found no increase in the number of criminal records among persons with KS compared with controls, possibly due to low power (n=13). 14 Witkin et al 7 found a significantly increased rate of criminality in 47,XYY (n=12) even after adjusting for social class and intelligence, while the crime rate among KS (n=16) after adjustment was similar to the background population.

We did find that the association between the crime rate (excluding traffic offenses) and either KS or 47,XYY was reduced when adjusting for socioeconomic variables, such as level of education, retirement, cohabitation and fatherhood. In other words, the increased risk of conviction among the cases may partly or fully be explained by disadvantageous socioeconomic conditions. However, although there may be a relationship between increased convictions and poor socioeconomic status in persons with sex chromosomal abnormal phenotype, the causal relationship cannot be established.

We matched the current large group of patients with approximately 100 controls for each case. We did not match on other variables, such as socioeconomic factors, since these factors could easily be causally involved in how the chromosome abnormality leads to a deviant pattern of criminality. Indeed, matching on socioeconomic factors would likely lead to overmatching—which ‘is potentially capable of biasing study results beyond any hope of repair’. 32 The current approach allowed us to use subsequent adjustments to clarify whether socioeconomic factors were involved, which they in fact turned out to be. We did correct for level of education, fatherhood, retirement and cohabitation, although it can be problematic to control for social factors, because the chromosome aberrations per se can be the very reason for social problems, while the reverse is not possible. In addition, social problems—marginalisation, lack of education, poverty, etc—can affect the risk of criminal behaviour and of being detected and convicted. In other words, social problems may be part of a chain of events and adjustment would therefore introduce confounding. However, having controlled for these factors, we found that the total HRs for being convicted decreased and were no longer statistically significant for either group. Being well aware of the deviant behaviour and learning difficulties present in both cohorts from a very young age, we hypothesise that these difficulties are part of the background for the identified increased number of convictions. We then performed a sensitivity analysis to examine a potential bias arising if the severity of the syndrome affects both the risk of conviction and the probability of being diagnosed. 33 In one analysis, we assumed that the excess hazard among undiagnosed cases was half the excess hazard seen among diagnosed cases, and we applied the statistical uncertainty from the observed data. In another similar analysis, we assumed that the excess hazard among undiagnosed cases was similar to that in the background population. For KS, we assumed that 25% of all cases had been diagnosed. In the sensitivity analyses, the HRs were reduced, but still significantly elevated for all convictions (excluding traffic offenses), and for sexual abuse, burglary and arson (supplementary table 2). For 47,XYY, we observed a similar pattern. Here, we assumed that 15% of all cases had been diagnosed. In the sensitivity analysis, the HRs were reduced, but still significantly elevated for all convictions (excluding traffic offenses), and for sexual abuse, violence, burglary and arson (supplementary table 2). In other words, it is highly likely that the crime rate would remain significantly increased in an entirely unbiased population of both KS and 47,XYY with complete diagnosis of all cases.

We identified an association between age at diagnosis and convictions in some groups in both cohorts. The findings of a more ‘normal’ number of convictions in persons with KS in those diagnosed when older than the median age of diagnosis might be explained by a less typical phenotype, both physical and, perhaps more importantly, cognitive phenotype. However, this finding was not present in the persons with 47,XYY. We find no reason to believe that a late diagnosis per se is positive. Due to the reported increased criminal problems, we undertook analyses excluding those convicted in close proximity to the diagnosis. We hereby intended to avoid detection bias by excluding those who were diagnosed due to a conviction and who may bias the results towards an increased number of convictions in the index-persons. As exclusion of such persons hardly changed the findings, we believe that this type of bias can be ignored. The drawback of this study is the lack of clinical information, including IQ level, treatment with sex steroids, number of persons with a driving license and access to a car and for instance psychiatric diagnoses. The advantages are the nationwide inclusion of all diagnosed men at risk with sex chromosome trisomies and the close matching of the controls.

We were not able to control for concomitant medicinal use. There are usually no known hormonal deficits among men with 47,XYY, while men with KS often receive testosterone substitution therapy due to hypergonadotrophic hypogonadism. It has been speculated that early testosterone substitution in KS 34 35 would partially attenuate the impact of the syndrome on intellectual functioning and possibly other factors, but this remains to be studied. Others have speculated that testosterone substitution therapy could cause psychological disturbances, such as aggressive behaviour and occasionally lead to violent crime, especially at supraphysiological doses, 36 although a placebo controlled study of androgen treatment in healthy young men showed no or minimal change in mood or behaviour. 37 38 We cannot fully exclude the possibility that the pattern of criminality among KS could be related to testosterone substitution therapy, while it seems unlikely that medicinal use among men with 47,XYY is related to criminality. We note that the pattern of criminality in 47,XYY, who have a normal testosterone production, was equal or higher than among KS, and furthermore that criminality among KS was elevated even before diagnosis and thus before commencement of supplementation with testosterone, making it unlikely that testosterone supplementation is causally involved in the excess criminality in KS. In addition, in many men with KS, conventional testosterone supplementation is often not sufficient, and many men with KS are also not compliant, at least not all the time, resulting in hypotestosteronemia, elevated luteinizing hormone and diseases, symptoms and signs related to hypogonadism. 39–41

In conclusion, this study on all diagnosed men with a sex chromosome trisomy in Denmark identified a significantly increased number of convictions, excluding traffic offenses, both in persons with KS and 47,XYY. When adjusting for socioeconomic factors, the adjusted risk was similar to controls for both cohorts. We interpret this as indicating that a main explanation of the increased risk of conviction is due to unfavourable living conditions associated with these syndromes. In both cohorts, we found a significantly increased number of convictions due to sexual offense and arson. Further studies are needed to identify whether these findings can be prevented by improved clinical care, including earlier diagnosis.

Acknowledgments

KS had full access to all the data in the study, and KS and CHG take responsibility for the integrity of the data, the accuracy of the data analysis and the decision to publish.

• Nielsen J ,
• Bojesen A ,
• Gravholt CH
• Handelsman DJ
• Robinson A ,
• Sergovich F ,
• Valentine GH ,
• Stochholm K ,
• Witkin HA ,
• Mednick SA ,
• Schulsinger F ,
• Ottesen AM ,
• Aksglaede L ,
• Bender BG ,
• Salbenblatt JA ,
• Brunton M ,
• Melville M ,
• McDanal CJ ,
• Schroder J ,
• de la Chapelle A ,
• Johnstone EC ,
• Ratcliffe SG
• Miller ME ,
• Ratcliffe S
• Hodgins S ,
• Brennan PA ,
• Higgins CD ,
• Swerdlow AJ ,
• Schoemaker MJ ,
• Schiavi RC ,
• Theilgaard A ,
• Christensen AL ,
• Schultz-Larsen J ,
• Birkebaek NH ,
• Bruining H ,
• DeLisi LE ,
• Maurizio AM ,
• Svetina C ,
• van Rijn S ,
• Tartaglia N ,
• Cordeiro L ,
• Paoloni-Giacobino A ,
• Thorens G ,
• Rothman KJ ,
• Greenland S ,
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• Aminorroaya A ,
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• Kristensen K ,
• Birkebaek N ,

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Files in this Data Supplement:

• Data Supplement - Manuscript file of format pdf

To cite: Stochholm K, Bojesen A, Jensen AS, et al . Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study. BMJ Open 2012; 2 :e000650. doi: 10.1136/bmjopen-2011-000650

Contributors KS, AB, SJ and CHG participated in the conception and design of the study. KS, AB, SJ, ASJ and CHG participated in the analysis and interpretation of data. KS and CHG drafted the article, and KS, AB, SJ, ASJ and CHG approved the final version to be published.

Funding Funded by Central Region Denmark; Danish Ministry of Science, Technology and Innovation, grant number 1-45-72-7-07; 271-09-0907.

Competing interests None.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement There are no additional data from the present study available.

Read the full text or download the PDF:

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XYY Syndrome

Last updated: October 03, 2012 Years published: 1990, 1992, 1998, 1999, 2002, 2012

Acknowledgment

NORD gratefully acknowledges Professor Rhoshel K. Lenroot, MD, Chair of Infant, Child, and Adolescent Psychiatry, University of New South Wales; Director of Child and Adolescent Mental Health Services, South Eastern Sydney Local Health District; Neuroscience Research Australia (NeuRA), for assistance in the preparation of this report.

XYY syndrome is a rare chromosomal disorder that affects males. It is caused by the presence of an extra Y chromosome. Males normally have one X and one Y chromosome. However, individuals with this syndrome have one X and two Y chromosomes. Affected individuals are usually very tall. Many experience severe acne during adolescence. Additional symptoms may include learning disabilities and behavioral problems such as impulsivity. Intelligence is usually in the normal range, although IQ is on average 10-15 points lower than siblings.

Introduction

In the past, there were many misconceptions about this disease. It was sometimes called the super-male disease because men with this syndrome were thought to be overly-aggressive and lacking in empathy. Recent studies have shown that this is not the case. Although individuals with XYY syndrome have an increased risk for learning disabilities and behavioral problems, they are not overly aggressive, nor are they at an increased risk of any serious mental illness. Because these boys are at a higher risk for having learning disabilities, they may benefit from speech therapy, tutoring, and general awareness of the specific issues they struggle with. Although the first years of school may be more challenging for boys with XYY syndrome, they generally go on to lead full, healthy, and normal lives.

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• 47, XYY syndrome
• Jacob's syndrome
• XYY karyotype
• YY syndrome

Characteristics of XYY syndrome are often subtle and do not necessarily suggest a serious chromosomal disorder. Thus, males with this condition are often undiagnosed or misdiagnosed. The most common physical difference is increased height, which usually becomes apparent after the age of five or six, and results in an average height of about 6 feet, 3 inches by adulthood. Some individuals with XYY also develop severe cystic acne during adolescence. Fertility and sexual development are normal. Besides the potential for increased height, most affected individuals typically have a normal physical appearance (phenotype).

Boys with XYY syndrome typically have normal intelligence, although, on average, IQ is 10 to 15 points lower than siblings. Affected boys may exhibit mild delays in reaching developmental milestones. Learning disabilities have been reported in up to 50 percent of cases, most commonly speech delays and language problems. Reading difficulties are common due to an increased incidence of dyslexia.

In some cases, affected individuals develop behavioral problems such as an explosive temper, hyperactivity, impulsivity, defiant actions, or, in some cases, antisocial behavior. There is a higher rate of attention deficit and hyperactivity disorder and a smaller increased risk for having an autism spectrum disorder.

XYY syndrome is a rare chromosomal disorder caused by the presence of an extra Y chromosome. Normally, males have 46 chromosomes including one X and one Y chromosome. Males with XYY syndrome have 47 chromosomes, two of which are Y chromosomes. Most cases of XYY syndrome are due to a cell division error in the sperm prior to conception. Rarely, the cell division error occurs after conception resulting in a mosiac of cells with 46 chromosomes and 47 chromosomes. The exact cause for why these errors in cell division occur is not understood.

Affected populations

XYY syndrome is a rare chromosomal disorder present at birth that affects only males. It is estimated to occur in approximately one in 1,000 live births.

Symptoms of the following disorders can be similar to those of XYY syndrome. Comparisons may be useful for a differential diagnosis:

Klinefelter syndrome is associated with a group of chromosomal disorders in males in which one or more extra X chromosomes are present. Males with the classic form of the disorder have one extra X chromosome. Males with variant forms of Klinefelter syndrome have additional X and/or Y chromosomes. The extra X and/or Y chromosome can affect physical, developmental, behavioral, and cognitive functioning. Common physical features may include tall stature, lack of secondary pubertal development, small testes (hypogonadism), delayed pubertal development, and breast development (gynecomastia) in late puberty. These features may be associated with low testosterone level and elevated gonadotropin levels. (For more information on this disorder, choose “Klinefelter” as your search term in the Rare Disease Database.)

Sotos syndrome is a variable genetic disorder characterized by excessive growth before and after birth. One of the major features of Sotos syndrome is a particular facial appearance that includes facial flushing, an abnormally prominent forehead (frontal bossing), down-slanting eyelid folds (palpebral fissures), prominent, narrow jaw, a long narrow face and a head shape that is similar to an inverted pear. Height and head circumference are measured to be greater than average for most affected children. Developmental delays are present in most children with Sotos syndrome and can include motor and language delays as well as mental retardation ranging from mild to severe. Other problems associated with Sotos syndrome include jaundice in newborns, curved spine (scoliosis), seizures, crossed eyes (strabismus), conductive hearing loss, congenital heart defects, kidney abnormalities and behavioral problems. Affected individuals also have a slightly increased risk to develop specific types of tumors. Sotos syndrome is caused by an abnormality (mutation) in the NSD1 gene. (For more information on this disorder, choose “Sotos” as your search term in the Rare Disease Database.)

Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from case to case. Marfan syndrome is inherited as an autosomal dominant trait. Defects or disruptions (mutations) of the fibrillin-1 (FBN1) gene have been linked to Marfan syndrome and related disorders.. (For more information on this disorder, choose “Marfan” as your search term in the Rare Disease Database.)

A diagnosis of XYY syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and specialized tests (i.e., chromosomal analysis) that detect the presence of an extra Y chromosome (47,XYY karyotype).

A diagnosis of XYY syndrome may be made before birth (prenatally) through amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such fluid or tissue samples may reveal the presence of an extra Y chromosome.

Clinical Testing and Work-Up

Speech and language assessment should occur during the first 24 months. Reading assessment should occur by school age to rule out dyslexia. Behavioral assessment should be considered for children who are having difficulty with symptoms such as impulsivity, poor attention, or social skills.

Treatment of XYY syndrome is symptomatic and supportive. Speech therapy, occupational therapy, or assistance for learning disabilities in the school setting may be of benefit. In most cases, affected individuals are very responsive to early intervention and treatment, and problems may resolve altogether within a few years. Treatment of acne may help an affected individual’s self-image. Attention deficit and hyperactivity disorder, difficulties with social interactions, or other behavioral problems can be treated with therapy or medication the same as in individuals who do not have XYY.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

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For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

Contact for additional information about XYY syndrome:

Professor Rhoshel K. Lenroot, M.D.

Chair of Infant, Child, and Adolescent Psychiatry

University of New South Wales

Director of Child and Adolescent Mental Health Services

South Eastern Sydney Local Health District

Neuroscience Research Australia

Corner of Barker and Easy Streets

Randwick, Sydney NSW 2031

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[email protected]

JOURNAL ARTICLES

Leggett V, Jacobs P, Nation K, et al. Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review. Dev Med Child Neurol. 2010;52:119-129.

Ross J, Zeger M, Kushner H, et al. An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Dev Disabil Res Rev. 2009;15:209-317.

Visootsak J, Graham J. Social function in multiple X and Y chromosome disorders: XXY, XYY, XXYY, XXXY. Dev Disabil Res Rev. 2009;15:328-332.

Aksglaede L, Skakkebaek N, Juul A. Abnormal sex chromosome constitution and longitudinal growth: Serum levels of insulin-like growth factor (IGF)-1, IGF binding protein-3, luteinizing hormone, and testosterone in 109 males with a 47,XXY, 47,XYY, or sex-determining region of the y chromosome (SRY)-positive 46,XX karyotypes. J Clin Endocrin Metab. 2008;93 (1):169-176.

Shi Q, Martin RH. Multicolor fluorescence in situ hybridization analysis of meiotic chromosome segregation in a 47,XYY male and a review of the literature. Am J Med Genet. 2000;93:40-6. Erratum in: Am J Med Genet. 2001;99:76.

47, XYY Syndrome, Genetics Home References. https://ghr.nlm.nih.gov/condition/47xyy-syndrome. Updated January 2009. Accessed October 3, 2012.

Lenroot RK. XYY Syndrome. Society For The Study Of Behavioural Phenotypes. https://www.ssbp.org.uk/site/images/stories/ssbp/downloads/XYY.pdf. 2010. Accessed October 3, 2012.

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The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Ontology. Please consult with a healthcare professional for medical advice and treatment.

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• Published: 25 February 1967

Criminal Behaviour and the XYY Male

• W. H. PRICE 1 &
• P. B. WHATMORE 2  

Nature volume  213 ,  page 815 ( 1967 ) Cite this article

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IN 1965, Jacobs et al. published their preliminary findings of a chromosome survey conducted at a maximum security hospital, The State Hospital, Lanarkshire, Scotland 1 . The most remarkable finding in the completed survey was the discovery among 315 men of nine patients with an XYY sex chromosome constitution. Their behaviour, together with their pattern of crime, has now been closely studied. The full clinical details of this investigation will be published elsewhere by us, and this communication directs attention to the ways in which the XYY males differ from males with an XY sex chromosome complement at the same hospital.

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Jacobs, P. A., Brunton, M., Melville, M., Brittain, R. P., and McClemont, W. F., Nature , 208 , 1351 (1965).

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PRICE, W., WHATMORE, P. Criminal Behaviour and the XYY Male. Nature 213 , 815 (1967). https://doi.org/10.1038/213815a0

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Issue Date : 25 February 1967

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The XYY syndrome. Review with a case study

• PMID: 5448146
• DOI: 10.1177/070674377001500408

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• Plasma testosterone levels in males with the 47,XYY karyotype. Price WH, van der Molen HJ. Price WH, et al. J Endocrinol. 1970 May;47(1):117-22. doi: 10.1677/joe.0.0470117. J Endocrinol. 1970. PMID: 5428907 No abstract available.
• The 47,XYY male with special reference to behavior. Price WH, Jacobs PA. Price WH, et al. Semin Psychiatry. 1970 Feb;2(1):30-9. Semin Psychiatry. 1970. PMID: 4950051 Review. No abstract available.
• 47,XYY and 46,XY males with antisocial and/or sex-offending behavior: antiandrogen therapy plus counseling. Money J, Wiedeking C, Walker P, Migeon C, Meyer W, Borgaonkar D. Money J, et al. Psychoneuroendocrinology. 1975;1(2):165-76. doi: 10.1016/0306-4530(75)90008-6. Psychoneuroendocrinology. 1975. PMID: 1234655 No abstract available.
• The 47,XYY male: a review. Owen DR. Owen DR. Psychol Bull. 1972 Sep;78(3):209-33. doi: 10.1037/h0033068. Psychol Bull. 1972. PMID: 4560789 Review. No abstract available.
• Psychological and sociological investigation of XYY prisoners. Griffiths AW, Richards BW, Zaremba J, Abramowicz T, Stewart A. Griffiths AW, et al. Nature. 1970 Jul 18;227(5255):290-2. doi: 10.1038/227290a0. Nature. 1970. PMID: 5428201 No abstract available.

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Reproductive outcomes of 3 infertile males with XYY syndrome

Retrospective case series and literature review.

Editor(s): Pang., Myung-Geol

Center for Reproductive Medicine, Center of Prenatal Diagnosis, First Hospital of Jilin University, Changchun, China.

∗Correspondence: Yang Yu, Centre for Reproductive Medicine, Centre for Prenatal Diagnosis, The First Hospital, Jilin University, 71 Xin-min Street, Changchun 130021, Jilin Province, P.R. China (e-mail: [email protected] ).

Abbreviations: β-HCG = β-human chorionic gonadotropin, ART = assisted reproductive technology, GnRH = gonadotrophin-releasing hormone agonist, ICSI = intracytoplasmic sperm injection, ISCN = international system for chromosome nomenclature, PCR = polymerase chain reaction, STS = sequence-tagged site.

How to cite this article: Zhang X, Liu X, Xi Q, Zhu H, Li L, Liu R, Yu Y. Reproductive outcomes of 3 infertile males with XYY syndrome: Retrospective case series and literature review. Medicine . 2020;99:9(e19375).

This work was supported by the Finance Department Health Special Project of Jilin Province, China (JLSCZD2019-022).

The authors have no conflicts of interest to disclose.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

The aim of this study is to evaluate the pregnancy outcomes of males with a 47, XYY karyotype following assisted reproductive treatment.

A retrospective study was performed using data from infertile men with 47, XYY at a center for reproductive medicine in 2004 to 2017. Of the 19,842 infertile males treated, a total of 21 showed the 47, XYY karyotype and were included in the present study. Clinical variables were collected. Three men were under treatment with their partner before either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

The incidence of 47, XYY in infertile men is 1/945 (21/19842). Most men are azoospermic or severely oligospermic. Three men and their partners underwent IVF or ICSI treatment with fresh ejaculate samples. The fertilization rate was 52.94% to 83.33%. The embryo cleavage rate was 50% to 90%. One man had abnormal sex hormonal levels and his partner had no clinical pregnancy. The other 2 couples had healthy baby boys.

Live spermatozoa can be gathered and fertility is possible for infertile males with 47, XYY syndrome when IVF or ICSI treatment is used. It is recommended that genetic counseling is provided in such cases.

1 Introduction

Sex chromosome aneuploidies (SCA) such as Klinefelter syndrome (47, XXY), Turner syndrome (45, X), 47, XXX and 47, XYY syndromes occur approximately once in every 420 live births. [1] The 47, XYY syndrome is a common sex chromosomal genetic syndrome that occurs approximately once in every 1000 live male births. Because of the diverse phenotype of the syndrome and potential lack of symptoms, identification, and diagnosis of men with 47, XYY syndrome is difficult. Common symptoms include greater risk of behavioral problems, mild learning difficulties, delayed speech and language development, and tall stature. [3] Most males with 47, XYY, approximately 85%, are not diagnosed until they present with fertility problems. [4] This means that the majority of 47, XYY men have a delayed diagnosis, with a median age of 17.1 years at diagnosis. [2] The study reported 47, XYY syndrome occurs more frequent in infertile men. These men have a 4-fold increased infertility risk compared to men with 46, XY. [5]

Several studies demonstrated that men with 47, XYY syndrome have variable sperm counts, ranging from normozoospermia to azoospermia [6,7] and increased sperm chromosomal abnormalities. [8] While carriers of the 47, XYY syndrome can produce offspring without medical intervention, even passing the extra Y chromosome to offspring. A few of men with 47, XYY syndrome had difficulty to achieve pregnancy. Assisted reproductive technologies (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) may be required to produce offspring. [9] However, methods for evaluating and treating XYY syndrome have not been established. In this study, the medical records of 21 men with 47, XYY syndrome, and their clinical and laboratory sperm parameters, were investigated. Of these patients, the results of in IVF or ICSI cycles performed in 3 men diagnosed infertility are also reported.

2 Materials and methods

2.1 patients.

A retrospective study was performed using data from infertile men with 47, XYY at the Center for Reproductive Medicine, First Hospital of Jilin University from 2004 to 2017. The average age of the patients was 28.1 ± 5.2 years (range 21–41 years). Three men were undergoing fertility treatment with their partners, before either IVF or ICSI. A questionnaire, designed to obtain information on smoking history, alcohol intake, working conditions, past medical history, injuries, and any familial conditions, was completed by all subjects. The patients’ gave written informed consent, and the study was approved by the ethics committee of the First Hospital of Jilin University.

2.2 Semen analysis

Semen samples were collected by masturbation after 3 to 5 days of sexual abstinence and semen characteristics were detected within 1 hour of ejaculation using computer-assisted semen analysis ( http://www.wei-li.com/ ). Semen analysis was performed according to the World Health Organization standard protocol (fifth edition) ( http://www.who.int/en/ ). Patients were diagnosed with oligozoospermia if their semen samples (taken at intervals of 1–3 weeks) had sperm counts <20 × 10 6 /mL, moderate oligozoospermia if their sperm counts were >5 × 10 6 /mL and <10 × 10 6 /mL, severe oligozoospermia if their sperm counts were <5 × 10 6 /mL, azoospermia if no sperm were present in at least 3 ejaculates after centrifugation and asthenospermia if sperm progressive motility [(a + b)%] was <50%.

2.3 Hormonal analysis

Peripheral blood samples were drawn from the majority of patients. Serum was collected from centrifuged blood samples at 1000 g for 15 minutes. The concentrations of plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) were measured using electrochemiluminescence immunoassay (Elecsys 2010 Chemistry Analyser, Mannheim, Germany). Normal reference ranges for these hormones in the male are as follows FSH, 1.5 to 12.4 mIU/mL; LH, 1.7 to 8.6 mIU/mL; and T, 9.9 to 27.8 nmol/mL.

2.4 Karyotype analysis

Peripheral blood lymphocytes from all patients were collected and cultured in lymphocyte culture medium (Yishengjun, Guangzhou Baidi Biotech Co. Ltd, China) at 37°C for 72 hours and then treated with colcemid (Sigma, Uk) for 1 hour. Peripheral blood lymphocytes were harvested and processed by hypotenic treatment, fixation, trypsinization, and Giemsa banding (GTG-banding). For each patient, a minimum of 20 metaphase cells were counted, and at least 3 cells were analyzed.

2.5 Y chromosome microdeletion analysis

Genomic DNA was isolated from Ethylene Diamine Tetraacetic Acid-treated peripheral blood using a commercially available whole-blood DNA extraction kit (TIAN amp Blood DNA kit, Beijing Tiangen Biotech, Beijing, China). Y chromosome microdeletion analysis was performed by polymerase chain reaction (PCR) amplification of sequence tagged sites (STS) or gene-specific sequences, according to the recommendations of the European Academy of Andrology and the European Molecular Genetics Quality Network. Specific STS markers spanning the entire azoospermia factor region were used: sY84, sY86, sY127, sY134, sY143, sY254, and sY255. ZFX/ZFY loci were used as internal controls. For cases with no band visualized, PCR analysis was performed a minimum of 2 times to verify the deletion.

2.6 Ovarian stimulation and ART procedure

Ovarian induction was performed using a gonadotrophin-releasing hormone (GnRH) analog suppression (Tryptorelin, Ferring, Germany) protocol (short or long), a GnRH agonist protocol. Ovarian stimulation was performed as previously reported. [10] Oocyte retrieval was performed 36 to 40 hours after human chorionic gonadotropin (HCG) injection. IVF or ICSI was performed at 40 hours and 42 hours post-hCG, respectively. 16 to 18 hours after IVF or ICSI, the presence of 2 pronuclei (PN) and 2 polar bodies indicated fertilization. The fertilization rate was calculated as the proportion of metaphase II oocytes forming 2 PN. At 72 hours after oocyte retrieval, embryos were classified according to cleavage and morphology score. [11]

The embryo cleavage rate was calculated as the percentage of fertilized oocytes that reached the cleavage stage. Two embryos were transferred into the woman's uterine cavity on day 3 after oocyte retrieval or transferred after cryopreservation and a thawing–warming procedure.

3.1 Clinical findings from 21 infertile men

Of the 19,842 infertile males, a total of 21 with karyotype 47, XYY were included in the present study. Therefore, the incidence of 47, XYY in this infertile male population was 1/945 (21/19,842). Semen analysis findings included: 5 cases of azoospermia, 8 cases of severe oligozoospermia (including 5 asthenospermia), 3 cases of moderate oligozoospermia and asthenospermia, 1 case of oligozoospermia and asthenospermia, 2 cases of normozoospermia (including 1 asthenospermia). The results of semen analysis for the other 2 cases were not available (1 performed Y chromosome microdeletions analysis does not absent any STS loci). Y chromosome microdeletion analysis showed that 7 severe oligozoospermia and 4 azoospermia were not deletions of STSs ( Table 1 ). The flow chart of genetic counseling for these males are shown in Figure 1 .

3.2 Reproductive hormone assays

Of the 21 infertile men, 10 patients underwent serum sex hormonal analysis. Of these 10 cases, 5 cases had abnormal hormonal level. In these 5 cases, 3 cases (patient numbers 15, 18, 20) had levels of FSH and LH that were higher than normal reference ranges and one of these (patient number 15) also had lower T levels compared with normal reference ranges. Two cases (patient number 6, 11) had higher FSH or higher LH levels and both had lower T levels compared with normal references ranges ( Table 2 ).

3.3 ART outcomes for 3 infertile males with 47, XYY

Three treatment cycles were performed using fresh ejaculate samples from the 3 male patients (patient number 4, 5, 13). All of the 3 couples had a history of primary infertility. The chromosome karyotype results of the 3 female partners were normal. Female aetiologies of infertility were ovulation dysfunction or polycystic ovary syndrome. Based on the paternal semen concentration, 2 couples performed conventional IVF and the other couple underwent conventional ICSI. Because our clinic was not able to perform preimplantation genetic diagnosis for aneuploidy screening (PGS) procedures they were advised to seek PGS from any authorized provider in China before ART. Nevertheless, for personal reasons these couples chose to undergo IVF/ICSI without PGD.

Clinical outcomes of the ICSI or IVF performed are presented in Table 3 . The fertilization rate was 52.94% to 83.33%. The embryo cleavage rate was 50% to 90%. Embryo transfer (ET) was conducted with patient number 5 using 2 fresh embryos (6 IV, 4 IV) and a phenotype normal boy was delivered at 38 weeks gestation. Patient number 4 and number 13 underwent ET with frozen–thawed embryos. Patient number 4 gave birth to a phenotype normal boy at 39 weeks gestation. Genetic information of these born boys showed normal karyotype and no deletions on the Y chromosome.

4 Discussion

Nonmosaic 47, XYY syndrome is an aneuploidy of sex chromosomes. It is often associated with male infertility. In our study the incidence rate was 0.1% (21/19,842) which is in accordance with a previously reported incidence rate. [12] Our study on infertile nonmosaic 47, XYY patients confirms that, if spermatozoa can be gathered, fertility is possible with the use of IVF or ICSI treatment.

Individuals with 47, XYY karyotype present with variable phenotypes and the majority of cases are phenotypically normal. About 75% of patients with this syndrome are not prenatally or postnatally detected, and diagnosis is often delayed or absent. [13,14] DNA polymorphism analysis has shown that most cases of SCA occur due to meiotic errors arising in the paternal germline. [15,16] In the case of 47, XYY the syndrome always involves a paternal error as the embryo inherits 2 Y chromosomes. Semen analysis of the patients in this study showed that 47, XYY syndrome carriers can have highly variable sperm counts that range from normal to azoospermia, though most men were azoospermic or severely oligospermic ( Table 1 ), which is in accordance with previous reports ( Table 4 ). There were also reports that males with the 47, XYY karyotype have normal testosterone levels. [29] However, another study found that males in prison had an increased frequency of the 47, XYY karyotype and higher testosterone levels. [4] In our study, 10 patients with XXY syndrome underwent serum sex hormonal analysis and, of these, 5 cases had abnormal hormonal levels ( Table 2 ). Three of the 5 patients had a T level that was lower than normal reference ranges, and all 5 patients had higher FSH and/or LH levels, similar to a previous report. [26] Therefore, abnormal semen analysis results or hormonal level may be an indicator of chromosomal defects in infertile males.

Although fertility may vary in XYY men, the studies have reported an increased incidence of chromosomally abnormal spermatozoa in their semen. Studies had found that XYY infertile men often have an impaired chromosome synapsis and are missing a meiotic recombination site. These errors may make the cells susceptible to meiotic arrest and increase the levels of aneuploidy within spermatozoa. [30–32] If spermatozoa is present, studies have reported a majority of pachytene cells (58%–100%) in the ejaculate of patients that contain the extra Y chromosome. [8] Thus in theory, there is a significant risk of fetal demise and transmission of a SCA in future offspring, at frequency of 50%. However, in clinical practice, the incidence of abnormal karyotype of offspring in published studies is highly variable. In fact, previous studies have reported that descendants of 47, XYY syndrome rarely had chromosomal abnormalities, with an incidence rate of less than 1%. [22,33]

The purported mechanism behind this correction is a loss of the extra Y chromosome germ cell during the spermatogonial stages. [15] The study indicated that an arrest point for genetically abnormal germ cells may reside at the primary and secondary spermatocyte or spermatid stages of development leading to a continuous elimination of these cells during spermatogenesis. [16] Solari et al [34] observed a high level of germ cell death at, or immediately after, the meiotic divisions. Milazzo et al [24] also observed a large number of apoptotic round spermatids and impaired meiotic division. Therefore, the presence of the extra Y chromosomes in spermatocytes may cause varying degrees of maturation arrest as well as heterogeneous sperm concentrations.

Men with 47, XYY syndrome that show normal semen parameters can achieve pregnancy spontaneously. However, for infertile men who have difficulty achieving pregnancy, IVF or ICSI may be required. The studies are also demonstrate these findings causing different reproductive outcomes ( Table 4 ). The use of ART can provide an opportunity for these men to father children but the techniques may elevate the risk of conceiving offspring with genetic anomalies. [35] Therefore, genetic counseling is recommended for infertile patients with 47, XYY syndrome. Sperm fluorescence in situ hybridization or PGS can also be considered to better understand the potential risks to the offspring. [16,25] A flow chart of the genetic counseling procedure for these males is shown in Figure 1 .

Studies have provided preliminary evidence to suggest higher levels of sperm aneuploidy in 47, XYY men are related to recurrent miscarriage and repetitive ICSI failure. [30,36] In the present study, spermatozoa from three 47, XYY men were used for IVF or ICSI and 2 couples of these patients delivered healthy offspring. The other couple did not have a clinical pregnancy after transfer of 2 frozen–thawed embryos ( Table 3 ). The present study revealed that the fertilization rates of the 3 cases were between 52.94% and 83.33%. This is in accordance with previous reports of 66% [37] and 54.2%, [38] and these results did not show lower fertilization rates as others have reported. [30]

In conclusion, men with a 47, XYY karyotype are often phenotypically normal and difficult to diagnose. The methods for precisely evaluating and treating 47, XYY syndrome have not been established. For now, there were no systematic studies have been published showing that how those infertile males with 47, XYY syndrome to fathered a healthy baby, and in such cases, genetic counseling is also recommended.

Author contributions

Yang Yu and Xinyue Zhang contributed to the design of the article. Xiangyin Liu and Xinyue Zhang contributed to the analysis of data and wrote the manuscript. Qi Xi, Haibo Zhu, and Linlin Li contributed to the collection of data. RuiZhi Liu was the research advisor.

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The XYY Controversy

This historical case study discusses how a paper published in 1961 that purported to link men with XYY chromosomes to being predisposed to violent and criminal behavior. The case discusses issues related to genetic screening and other applications of genetics and biotechnology research. 

This is one of six cases from Michael Pritchard and Theodore Golding's instructor guide, " Ethics in the Science Classroom ." 

Categories of Ethics/Values Issues Illustrated by This Case: Issues related to genetic screening and other applications of genetics and biotechnology research.

1. Introduction

Efforts to make use of increasing knowledge about the genetic component of human development and behavior have been a frequent source of serious ethical controversies. Support among geneticists, other scientists and the educated public for the eugenics movement, which advocated efforts to improve the human race by controlling presumed heritable characteristics, resulted in such misguided governmental policies early in this century as the large-scale sterilization of "inferior" individuals. Legislation authorizing such forms of social engineering was met with increasing criticism from those who questioned the morality of such practices as well as those who doubted the validity of simplistic biologically determinist models of complex human social behavior.

The reaction to the extreme and horrific use of eugenics measures by the Nazis in their campaign to promote the superiority of a cleansed Aryan "race" resulted in a temporary hiatus in research and development in applied human genetics. By the 1960s, however, increasing understanding about the genetic causes of such specific conditions as Down's Syndrome and sickle cell anemia were again arousing support for efforts to seek genetic explanations - and perhaps improvements - for a wide range of human "deficiencies" from various sorts of socially deviant behavior to susceptibility to environmental hazards.

The explosive growth of facile genetic engineering technologies and, in particular, the potential applications of the information gained through the Human Genome Project is destined to greatly amplify both the quantity and the variety of ethical concerns related to attempts to screen, control, manipulate or modify people based on their genetic predispositions.

A frequent underlying theme in disputes over "progress" in applied human genetics is rooted in the nature-nurture controversy. Those who do research into the genetic factors related to complex human problems are seen by their opponents as diverting attention from and ultimately undermining attempts to ameliorate the socioeconomic conditions related to the problems. In the view of these opponents, genetic differences are likely to be less important than social inequalities in determining most human behavior. Furthermore, they argue that the end result of a biological determinist perspective is discrimination against, rather than help for, those who are deemed inferior or defective.

The XYY controversy offers a case study that dramatically illustrates many of the ethical issues that arise when efforts are made to explore the social implications of human genetic differences.

2. Background

In 1961, a paper was published in the medical journal Lancet reporting the first man to be discovered with an extra Y chromosome in his cells, in addition to the normal male complement of one X and one Y. Within the next few years research reports appeared that purported to show that XYY males were predisposed to violent and criminal behavior. This claim was widely publicized in the news media. By the mid-1960s XYY was being referred to as the criminal chromosome. In 1968 lawyers in at least two cases succeeded in persuading juries that their clients were less culpable for their crimes because they were XYY males. If this was not sufficient to persuade the public that XYY individuals were potentially dangerous social misfits, the erroneous report that a vicious serial killer of eight student nurses in Chicago was an XYY male surely had that result.

As is often the case for sensationalized, premature publicity about unproven scientific findings, the subsequent research that debunked the connection between the XYY karyotype and any demonstrable link to anti-social behavior received very little publicity. Thus the myth persisted that males with an extra Y chromosome were likely to manifest excessive violence and other undesirable social traits. This fallacious association even made its way into biology textbooks.

Several research projects underway during the 1960s were aimed at examining the actual prevalence of the XYY karyotype in the general population and attempting to explore whether there were any phenotypic consequences, including predisposition to any form of abnormal social behavior. One such study was carried out by Harvard child psychiatrist Stanley Walzer and Harvard Medical School geneticist Park Gerald. By 1968 they were screening all newborn males at Boston Hospital for Women and following up by studying the development of those with abnormal karyotypes like XYY or XXY. The research was funded by a grant from the Centers for Studies of Crime and Delinquency of the National Institute for Mental Health.

3. The Case

In 1974 the Walzer and Gerald research project became the subject of sharp criticism orchestrated by a study group from the organization Science for the People and led by Harvard microbiology professor Jonathan Beckwith and MIT molecular biology professor Jonathan King. Their criticism was based on claims that the research seriously stigmatized those infants found to be XYY, that efforts to obtain informed consent were flawed, that the research served no potentially useful purpose for either the subjects or society as a whole, that the research design could not produce any valid scientific conclusions, and that the only possible consequences of the work would be to undermine appropriate efforts to deal with social problems.

After failing in their attempt to have the research stopped by appealing to Harvard's internal institutional review boards, the Science for the People Group went to the press and successfully enlisted the help of other organizations concerned about the welfare of children. This tactic ultimately achieved their goal of getting Walzer and Gerald (as well as other researchers) to stop screening newborns for XYY. The victory was won at the expense of alienating many biomedical researchers who objected to the tactic of using public pressure to stop a research project.

4. Readings

To prepare yourself to consider the issues raised by this case you should read the following documents:

• "The XYY Controversy: Researching Violence and Genetics," a Special Supplement to the Hastings Center Report , August 1980.
• "Behavioral Implications of the XYY Genotype," by Ernest B. Cook, Science, 179, pp 139-150, January 12, 1973.
• "Patients' Rights: Harvard Is Sight of Battle Over X and Y Chromosomes," by Barbara Culliton, Science , 186, pp 715-717, November 22,1974.
• "XYY: Harvard Researcher Under Fire Stops Newborn Screening," by Barbara J. Culliton, Science , 188, pp 1284-1285, June 27, 1975.
• Part III of The Code of Codes , edited by Daniel J. Kevles and Leroy Hood (Harvard University Press, Cambridge, 1992) contains several essays that discuss many of issues concerning ethical, legal and social implications of human genetics research and technology.
• An excellent discussion of issues related specifically to genetic screening of workers is "Genetic Testing in the Workplace" by Paul Billings and Jon Beckwith, Trends in Genetics , 8, pp. 198-202, June 1992.

5. The Issues

Significant ethical questions raised by this case:

• How should the principle of informed consent be interpreted when the subject of a research project is newborn infants?
• What possible outcomes would justify a research project that will have the inevitable outcome of stigmatizing the subjects in a way that may result in serious restrictions on their personal freedom?
• Is it an inappropriate intrusion for a researcher to offer anticipatory guidance to subjects of a research study where no scientific basis exists for expecting the need for this help?
• Is it possible to design an ethical, valid research project aimed at establishing a genetic component for the predisposition to some socially unacceptable behavior?
• Is it ethical to ban or refuse to use public monies to support certain types of research because of their potential social consequences, even if the research may have scientific merit?
• Is it ethical for scientists (or anyone else) to organize public opposition, with the help of the press, to halt a research project that has won the approval of the public funding agency and all of the review procedures within the institutions where it is being carried out?
• To what extent should the principle of academic freedom be invoked to protect researchers from the scrutiny of the public?
• Under what circumstances is it ethical to deny human subjects of research projects information about the results of that research?
• To what extent should the public be represented on institutional review boards set up to approve research that may have serious social or political consequences?
• Should there be any limits to the genetic information that a pregnant women can use in deciding whether to interrupt a pregnancy.

Additional ethical questions related to applications of genetic research results not covered by this case study:

• What are the ethical issues related to such concerns as rights of privacy, pregnancy counseling, public education, equal access and public welfare that are raised by existing or proposed screening programs for debilitating or fatal diseases resulting from genetic defects, such as Down's syndrome, cystic fibrosis, Huntington's disease and Tay-Sach's disease?
• What are the ethical implications of using genetic screening in the workplace to exclude candidates from eligibility for jobs?
• Is it ethically permissible to use genetic susceptibility to various diseases as a basis for determining eligibility for health care coverage?
• Is the use of genetic information to increase the social categories to which people can be assigned likely to lead to various forms of discrimination, and to what has been referred to as a genetic underclass?
• Can the potential invasions of privacy that may result from the increased use of genetic screening in forensics be avoided?

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This material is based upon work supported by the National Science Foundation under Award No. 2055332. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

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Intracortical myelin across laminae in adult individuals with 47,XXX: a 7 Tesla MRI study

Sriranga Kashyap and Claudia Vingerhoets shared last authorship.

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Chaira Serrarens, Julia Ruiz-Fernandez, Maarten Otter, Bea C M Campforts, Constance T R M Stumpel, David E J Linden, Therese A M J van Amelsvoort, Sriranga Kashyap, Claudia Vingerhoets, Intracortical myelin across laminae in adult individuals with 47,XXX: a 7 Tesla MRI study, Cerebral Cortex , Volume 34, Issue 8, August 2024, bhae343, https://doi.org/10.1093/cercor/bhae343

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47,XXX (Triple X syndrome) is a sex chromosome aneuploidy characterized by the presence of a supernumerary X chromosome in affected females and is associated with a variable cognitive, behavioral, and psychiatric phenotype. The effect of a supernumerary X chromosome in affected females on intracortical microstructure is currently unknown. Therefore, we conducted 7 Tesla structural MRI and compared T1 (ms), as a proxy for intracortical myelin (ICM), across laminae of 21 adult women with 47,XXX and 22 age-matched typically developing females using laminar analyses. Relationships between phenotypic traits and T1 values in 47,XXX were also investigated. Adults with 47,XXX showed higher bilateral T1 across supragranular laminae in the banks of the superior temporal sulcus, and in the right inferior temporal gyrus, suggesting decreases of ICM primarily within the temporal cortex in 47,XXX. Higher social functioning in 47,XXX was related to larger inferior temporal gyrus ICM content. Our findings indicate an effect of a supernumerary X chromosome in adult-aged women on ICM across supragranular laminae within the temporal cortex. These findings provide insight into the role of X chromosome dosage on ICM across laminae. Future research is warranted to further explore the functional significance of altered ICM across laminae in 47,XXX.

Triple X syndrome is a relatively common sex chromosome aneuploidy (SCA) characterized by the presence of a supernumerary X chromosome, resulting in a karyotype of 47,XXX in affected females, and has an estimated incidence of about one in 1,000 female newborns ( Otter et al. 2010 ). 47,XXX is not typically associated with facial dysmorphology or distinct physical features and the phenotype is generally mild ( Tartaglia et al. 2010 ). Therefore, it is estimated that only 16% of cases are clinically diagnosed ( Viuff et al. 2015 ). It is hypothesized that overexpression of genes on the X chromosome that escape X-inactivation, as well as incomplete X chromosome inactivation, may result in the phenotypic traits associated with 47,XXX ( Nielsen et al. 2020 ; Raznahan and Disteche 2021 ). However, minor physical findings can be present in some individuals with 47,XXX including clinodactyly, epicanthal folds, and tall stature, with body segment proportions typically showing a short sitting height and long legs ( Tartaglia et al. 2010 ). Sex hormone levels are usually normal in individuals with 47,XXX ( Green et al. 2018 ; Skuse et al. 2018 ). Deficits in children and adolescents with 47,XXX have been found in several domains, including motor skills, speech, receptive and expressive language, educational achievement, and interpersonal relationships ( Leggett et al. 2010 ; Lenroot et al. 2014 ; Urbanus et al. 2021 ; Capelli et al. 2023 ). Additionally, women with 47,XXX are at increased risk for developing autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder, as well as other psychiatric disorders including psychotic, anxiety, and depressive disorders ( Otter et al. 2010 ; Green et al. 2018 ; van Rijn 2019 ; Berglund et al. 2022 ; Sánchez et al. 2023 ). Previous studies in adult women with 47,XXX showed psychiatric disorders in about 50% of the participating cases ( Freilinger et al. 2018 ; Otter et al. 2022 ). Children and adolescents with 47,XXX often present with a variable cognitive phenotype, including mild learning disabilities and manifestations of executive dysfunction ( Tartaglia et al. 2010 ; van Rijn and Swaab 2015 ; van Rijn et al. 2016 ). Lower mean full-scale IQ (FSIQ) has been reported in children, adolescents, and adults with 47,XXX, with the normal curve shifted to the left compared to healthy controls. Verbal IQ (VIQ) is generally more impaired compared to performance IQ (PIQ) ( Otter et al. 2010 ; Tartaglia et al. 2010 ; Otter et al. 2022 ). Lastly, social functioning and social cognition deficits have been reported in children and adults with 47,XXX ( Lee et al. 2012 ; van Rijn et al. 2014 ; Wilson et al. 2019 ; Otter et al. 2021 ).

In the last three decades, interest in the neurobiological effects in SCAs, including 47,XXX, has increased, including effects on brain structure and brain function as they can serve as promising models for examining the effects of sex chromosomes on brain development and clinical disease in the general population. Previous neuroimaging studies have revealed alterations in brain gray matter structure and function in children, adolescents, and adults with 47,XXX ( Warwick et al. 1999 ; Patwardhan et al. 2001 ; Lenroot et al. 2014 ; Fish et al. 2016 ; Reardon et al. 2016 ; Mankiw et al. 2017 ; Nadig et al. 2018 ; Serrarens et al. 2022 ; Serrarens et al. 2023 ). More specifically, individuals with 47,XXX showed alterations of total brain volume ( Warwick et al. 1999 ; Patwardhan et al. 2001 ; Lenroot et al. 2014 ; Fish et al. 2016 ; Reardon et al. 2016 ; Mankiw et al. 2017 ; Nadig et al. 2018 ), cortical gray matter volume ( Lenroot et al. 2014 ), cortical white matter volume ( Lenroot et al. 2014 ), subcortical nuclei volume ( Reardon et al. 2016 ; Nadig et al. 2018 ; Serrarens et al. 2022 ), cortical thickness and surface area ( Lenroot et al. 2014 ; Serrarens et al. 2022 ), and cortical folding ( Fish et al. 2016 ). Moreover, adult individuals with 47,XXX showed altered frontoparietal functional connectivity at rest ( Serrarens et al. 2023 ). However, intracortical (gray matter) microstructure has not been investigated in children, adolescents, or adults with 47,XXX. Moreover, studies investigating intracortical microstructure in other SCAs, including 45,X0 (Turner syndrome), 47,XXY (Klinefelter syndrome), and 47,XYY (XYY syndrome), are still lacking.

The human cerebral cortex is a complex structure comprising 6 morphologically and functionally distinct layers, also known as laminae, that differ in the density and arrangement of neuronal cells, and their pattern of myelination ( Trampel et al. 2019 ). Myelin is a lipid- and protein-rich sheath formed by oligodendrocytes and wrapped around axons in the nervous system that greatly enhances the speed of action potential propagation, provides nutritional support for axons, and is necessary for maintaining proper brain function ( Nave 2010 ; Orthmann et al. 2020 ; Guo et al. 2023 ). White matter myelin has been found to play a key role in cognitive functioning ( O'Muircheartaigh et al. 2014 ; Chevalier et al. 2015 ; Dai et al. 2019 ; Gong et al. 2023 ), and abnormalities in white matter myelination have been linked with multiple sclerosis ( Lemus et al. 2018 ), Alzheimer’s disease ( Nasrabady et al. 2018 ), and several psychiatric disorders ( Lewandowski et al. 2014 ; Ho et al. 2021 ). Although primarily concentrated in white matter, myelinated axons are also present in the cortex. Recently, there has been a growing interest in assessing the content of intracortical myelin (ICM), and advances in neuroimaging techniques have enabled the noninvasive visualization of ICM content in vivo. Several MRI contrasts are sensitive to ICM content ( Glasser and Van Essen 2011 ; Cohen-Adad et al. 2012 ; De Martino et al. 2015 ), and studies have demonstrated alterations in ICM in patients with multiple sclerosis ( Barletta et al. 2021 ), Alzheimer’s disease ( Pelkmans et al. 2019 ), and several psychiatric disorders ( Baranger et al. 2021 ; Suh et al. 2023 ; Zhang et al. 2023 ; Chen et al. 2024 ). Quantitative T1 maps are also sensitive to ICM content ( Stüber et al. 2014 ; Waehnert et al. 2016 ). T1, which is the time constant (in ms) governing the recovery of the longitudinal component of the magnetization following radio-frequency excitation, is an MRI parameter that is closely related to tissue myelination ( Koenig et al. 1990 ). It has been suggested that myelin and compounds colocalized to myelin influence the longitudinal T1, with cortical regions with higher myelination showing reduced T1 (ms) ( Haast et al. 2016 ). T1 maps have, for example, been used to visualize myelination patterns in the auditory and visual cortices, regions that are characterized by high myelination and low T1 ( Waehnert et al. 2016 ). Moreover, T1 map values have also been shown to vary across cortical laminae ( Tardif et al. 2015 ; Waehnert et al. 2016 ; Sprooten et al. 2019 ).

To the best of our knowledge, there have been no ICM studies conducted in 47,XXX. Therefore, it remains unclear whether intracortical microstructure across laminae is affected in individuals with 47,XXX. Hence the effect of X chromosome dosage on ICM across laminae is unknown. The present study aimed to compare quantitative T1 maps of gray matter across laminae between adult individuals with 47,XXX and typically developing females using ultra-high field (7 Tesla) structural MRI. Furthermore, given previous evidence of lower IQ, impaired social functioning and social cognition, we explored whether the variability of these (cognitive) outcomes was related to variability in T1 across laminae in 47,XXX.

All procedures in this study were performed in accordance with the ethical standards established by the respective national and institutional committees regarding human experimentation and in accordance with the Declaration of Helsinki. All procedures involving human subjects were approved by the Medical Ethics Committee of the Maastricht University Medical Centre, Maastricht, the Netherlands (METC143051/NL46871.068.14). Written informed consent was obtained from all participants.

Participants

Twenty-one adults with 47,XXX and 22 age-matched typically developing females, aged 18 to 59, were included in this study. The Dutch (NL) and Flemish (B) individuals with 47,XXX were recruited through the 47,XXX support group, clinicians, clinical geneticists, pediatricians, and gynecologists. Typically developing females were recruited independently through local advertisement. General inclusion criteria were (i) 18 years or older of age, (ii) mental capacity to give informed consent, and (iii) a sufficient command of the Dutch language. Individuals with 47,XXX were included if a 47,XXX karyotype or a mosaic 46,XX/47,XXX karyotype with at least 85% cells with an extra X chromosome was genetically confirmed. Exclusion criteria for all study participants were (i) being under legal guardianship, (ii) contraindications for MRI, and (iii) pregnancy.

Instruments

A shortened version of the Dutch Wechsler Adult Intelligence Scale, Third Edition (WAIS-III; Velthorst et al. 2013 ) was administered to all participants to estimate the level of intellectual functioning. The Emotion Recognition Task (ERT) of the Cambridge Neuropsychological Test Automated Battery (CANTAB; Cambridge Cognition, Cambridge, UK; see www.cambridgecognition.com ) was used to assess social cognition in all participants. The total number of correctly identified emotions, with a maximum score of 180, was included as the outcome measure of the ERT ( Cambridge Cognition 2014 ). The Dutch translation of the informant/observer version of the Social Responsiveness Scale for adults (SRS-A) was used to assess social responsiveness (which is considered a screening instrument for ASD) in all participants ( Constantino et al. 2012 ). The SRS-A questionnaire is subdivided into 4 subscales including (i) social awareness, (ii) social communication, (iii) social motivation, and (iv) rigidity and repetitive behavior. SRS-A scales are reported as T-scores with scores <40 indicating high social functioning, scores between 40 and 59 indicating normal social functioning, scores between 60 and 75 indicating mild to moderate social deficits, and scores ≥76 indicating severe deficits.

MRI data acquisition

MRI data acquisition was carried out at Scannexus B. V. ( https://scannexus.nl ) on a Siemens Magnetom 7 T scanner (Siemens Healthineers, Erlangen, Germany) using a 1Tx/32Rx commercial head coil (Nova Medical Inc., Wilmington, MA, USA). Anatomical data were acquired using a 3D-MP2RAGE sequence ( Marques et al. 2010 ); repetition time (TR) = 5,000 ms; echo time (TE) = 2.51 ms; inversion times TI1/TI2 = 900/2,750 ms; α 1 /α 2  = 5°/3°; phase partial Fourier = 6/8; GRAPPA = 2 with 24 reference lines; bandwidth = 248 Hz/Px; nominal voxel size = 0.7 × 0.7 × 0.7 mm 3 ; acquisition time = 10:57 min. When using a 3D-MP2RAGE sequence, images at the two inversion times (TI1/TI2) are used to calculate the UNI (or T1w), and the quantitative T1 maps. These maps can be obtained directly from the scanner.

Preprocessing of imaging data

Preprocessing of anatomical data was first carried out using presurfer scripts ( https://github.com/srikash/presurfer , Kashyap 2021 ) to first remove the background noise from the MP2RAGE UNI (T1w) image ( presurf_MPRAGEise.m ) and then, an accurate brainmask (“stripmask”) was obtained using SPM12’s unified segmentation approach ( presurf_UNI.m ) ( Ashburner and Friston 2005 ). The stripmasks were visually inspected in each participant and manually corrected using ITK-SNAP ( Yushkevich et al. 2016 ) in cases in which the automatic masking was suboptimal ( Kashyap et al. 2021 ). The T1w image and corrected mask were supplied as input to the recon-all pipeline of FreeSurfer ( v7.3.2) to perform segmentation and cortical surface reconstruction ( https://surfer.nmr.mgh.harvard.edu/ , Fischl 2012 ) in native submillimeter resolution ( https://surfer.nmr.mgh.harvard.edu/fswiki/SubmillimeterRecon ).

Laminar analysis

The pial and white surfaces from FreeSurfer were further processed using FreeSurfer and LayNii (v2.4.0.; Huber et al. 2021 ) ( https://github.com/srikash/surf_laynii/ , Kashyap 2023 ). In brief, the white and pial surfaces were shifted toward the white matter and cerebrospinal fluid, respectively, by 30% of the cortical thickness using FreeSurfer’s mris_expand tool to account for any small discrepancies in the placement of the boundaries when using 3D-MP2RAGE for automatic segmentation ( Fujimoto et al. 2014 ; Kashyap et al. 2021 ). The surfaces were then transformed into volumetric space, upscaled, and relabeled as per LayNii requirements. Finally, a total of nine intracortical equivolume laminae were delineated using LayNii’s LN2_LAYERS ( Waehnert et al. 2014 ; Huntenburg et al. 2017 ) , where the first lamina is the deepest and closest to the white matter boundary, and the last lamina is the most superficial and closest to the pial surface. The number of nine laminae was chosen based on a compromise between computational feasibility and smoothness (please see https://layerfmri.com/2019/02/22/how-many-layers-should-i-reconstruct/ ).

Correction of quantitative T1

B1 + maps acquired during scanning were used to correct the quantitative T1 map images ( Marques and Gruetter 2013 ; Haast et al. 2018 ) using publicly available scripts ( https://github.com/JosePMarques/MP2RAGE-related-scripts ). The corrected T1 maps and FreeSurfer’s parcellation schemes based on the Desikan–Killiany atlas ( Desikan et al. 2006 ) were also upsampled to 0.3 mm isotropic resolution for further laminar analysis. Quantitative T1 laminar profiles were obtained from 68 (34 left and 34 right hemisphere) cortical regions of interest. Mean T1 values (ms) were sampled from each region of interest of the Desikan–Killiany atlas for the 9 intracortical laminae.

Statistical analysis

Statistical analyses were performed in R, version 3 ( R Core Team 2020 ). First, differences in group demographics including age, FSIQ, VIQ, and PIQ were examined using Mann–Whitney U tests and independent-samples t -tests according to the normality of data distribution. Second, ERT scores were transformed into standardized Z-scores to identify outliers (Z-scores smaller than −3 or larger than 3) and no outliers were detected. Normally distributed raw scores on the ERT of the CANTAB were compared between groups using the independent-samples t -test. Normally and non-normally distributed total SRS-A T-scores and T-scores for SRS-A subscales were compared using independent-samples t -tests and Mann–Whitney U tests, respectively. Group differences in T1 values were examined using multiple linear regression models via the lm function in R, with per region of interest and per lamina each mean T1 value as the dependent variable and group (i.e. diagnosis) as the independent variable, adjusted for FSIQ. Cohen’s d effect size estimates were derived from the t -statistic of the group variable from the multiple linear regression model. Bonferroni correction was applied to correct for multiple comparisons [0.05/(2(hemispheres)]. Consequently, a P -value < 0.025 was considered significant. In case cognitive outcome measure scores or social functioning scores were significantly different between individuals with 47,XXX and typically developing females, relationships between these cognitive and social functioning parameters and mean T1 values extracted from significant region of interest laminae were calculated using Pearson’s or Spearman’s rank correlation coefficients, separately for individuals with 47,XXX and typically developing females.

Demographics

Sample demographics are presented in Table 1 . There was no significant difference in age between groups. Individuals with 47,XXX had a significantly lower FSIQ, VIQ, and PIQ compared to typically developing females.

Sample demographics.

Numbers in bold reflect significant between group differences. TD, typically developing; FSIQ, full-scale intelligence quotient; VIQ, verbal intelligence quotient; PIQ, performance intelligence quotient.

a No significant difference between VIQ and PIQ in either 47,XXX or 46,XX (typically developing females).

Social cognition and social responsiveness

Social cognition and SRS-A T-scores are summarized in Table 2 . Individuals with 47,XXX had significantly lower ERT scores compared to age-matched typically developing females. Women with 47,XXX scored significantly higher on 3 SRS-A subscales: social awareness, social communication, and social motivation, as well as on total SRS-A score. There was no significant difference between groups in score of SRS-A subscale rigidity and repetitive behavior.

Between-group differences in social cognition and social responsiveness.

Numbers in bold reflect significant between group differences. TD, typically developing; ERT, emotion recognition task.

T1 profiles across intracortical laminae

Laminar analyses applied to T1 maps showed significantly higher mean T1 in lamina 9 of the banks of the superior temporal sulcus (Cohen’s d  = 0.745) of the left hemisphere, as well as higher mean T1 in laminae 8 and 9 of the banks of the superior temporal sulcus (Cohen’s d  = 0.924; 1.038 respectively) of the right hemisphere in 47,XXX compared to typically developing females ( Table 3 and Fig. 1A and B ). In addition, 47,XXX subjects showed higher mean T1 in laminae 7 and 8 of the inferior temporal gyrus (Cohen’s d  = 0.709; 0.779, respectively) of the right hemisphere compared to typically developing females ( Table 3 and Fig. 1C ).

Results for mean T1 map values of significant regions of interest in 47,XXX compared to typically developing females.

TD, typically developing.

Original T1 maps, corrected T1 maps, equivolume laminae projected on corrected T1 maps, and intracortical laminae T1 profiles of 47,XXX and typically developing (TD) females of a) banks of the superior temporal sulcus of the left hemisphere, b) banks of the superior temporal sulcus of the right hemisphere and c) inferior temporal gyrus of the right hemisphere. Intracortical laminae T1 profiles show mean T1 (ms) values and standard deviations for intracortical (gray matter) laminae 1 to 9, with lamina 1 closest to the white matter/gray matter boundary and lamina 9 closest to the gray matter/cerebrospinal fluid boundary. WM: white matter; GM: gray matter; CSF: cerebrospinal fluid; WM/GMB: white matter/gray matter boundary; GM/CSFB: gray matter/cerebrospinal fluid boundary.

Relationship with IQ, social cognition, and social behavior

We found significant positive correlations between mean T1 values in lamina 7 of the right hemisphere inferior temporal gyrus and social awareness scores ( r  = 0.496, P  = 0.026), social communication scores ( r  = 0.512, P  = 0.021), social motivation scores ( r  = 0.489, P  = 0.029), and social functioning total scores ( r  = 0.581, P  = 0.007) within individuals with 47,XXX, but not in typically developing females. In addition, we found significant positive correlations between mean T1 values in lamina 8 of the right hemisphere inferior temporal gyrus and social awareness scores ( r  = 0.466, P  = 0.038), social communication scores ( r  = 0.513, P  = 0.021), social motivation scores ( r  = 0.470, P  = 0.037), and social functioning total scores ( r  = 0.560, P  = 0.010) within individuals with 47,XXX, but not in typically developing females. However, only the positive correlation between lamina 7 mean T1 of the inferior temporal gyrus of the right hemisphere and social functioning total scores did survive correction for multiple comparisons [ P  = 0.002; = 0.05/5 (laminae) × 5 (social cognition and social functioning tasks)]. Correlations between T1 values and IQ and ERT scores were not present in 47,XXX.

To the best of our knowledge, this is the first MRI study investigating ICM in 47,XXX using ultra-high field 7 T structural MRI. Using laminar analyses applied to quantitative T1 maps, we demonstrated significantly lower ICM across supragranular laminae in 47,XXX bilaterally in the banks of the superior temporal sulcus and in the right inferior temporal gyrus. Moreover, better social functioning was associated with larger ICM in supragranular laminae of the right inferior temporal gyrus in adult individuals with 47,XXX.

We reported significantly higher T1 across supragranular cortical laminae in 47,XXX bilaterally in the banks of the superior temporal sulcus and in the inferior temporal gyrus of the right hemisphere with high effect sizes, possibly indicating less ICM content in these cortical gray matter structures. Given that intracortical T1 values of these cortical brain regions are within the expected range of gray matter T1 at 7 T ( Kashyap et al. 2018 ; Sanchez Panchuelo et al. 2021 ; Gulban et al. 2022 ), there is no possibility of potentially having sampled nongray matter tissue (e.g. cerebrospinal fluid) in these supragranular cortical laminae. Based on findings of previous neuroimaging studies, the superior temporal sulcus is associated with speech, language processing, and social cognition ( Redcay 2008 ; Saitovitch et al. 2012 ; Specht and Wigglesworth 2018 ; Wilson et al. 2018 ; Nourski et al. 2021 ), and the inferior temporal gyrus is associated with visual information processing, language, emotion regulation, and social cognition ( Lin et al. 2020 ; Balgova et al. 2022 ). Myelination of axons, which increases the speed of signal transmission between neurons and facilitates information integration, has been found to play a key role in the development of many aspects of cognition, including language ability and social cognition ( O'Muircheartaigh et al. 2014 ), and alterations in cortical myelin have been demonstrated in patients with depressive disorders ( Baranger et al. 2021 ; Zhang et al. 2023 ), bipolar disorder ( Suh et al. 2023 ), schizophrenia ( Wei et al. 2020 ), Alzheimer’s disease ( Pelkmans et al. 2019 ), and multiple sclerosis ( Mangeat et al. 2018 ; Barletta et al. 2021 ). Therefore, abnormalities in myelin can lead to dysregulation of neuronal circuits and may (partially) underly the behavioral phenotype associated with 47,XXX. Speech, language, and visual information processing abilities of 47,XXX individuals were not assessed in the current study. However, speech and language deficits have previously been described in children and adolescents with 47,XXX ( Leggett et al. 2010 ; Urbanus et al. 2021 ; Capelli et al. 2023 ). Using macromolecular proton fraction as a marker of myelin, significant positive correlations between early language skills and myelin density were shown in typically developing toddlers in gray matter of frontal, parietal, and temporal lobes using neuroimaging data ( Corrigan et al. 2022 ). Therefore, more research is necessary to investigate the contribution of altered superior temporal sulcus and inferior temporal gyrus ICM content across laminae to speech and language problems in 47,XXX.

Although our results showed significantly worse scores on social cognition (ERT) in adults with 47,XXX compared to typically developing females, we did not show any significant associations between ERT scores and T1 across laminae in the superior temporal sulcus or inferior temporal gyrus in 47,XXX. However, other aspects of social cognition, including theory of mind and joint attention, were not assessed in the present study. Therefore, future studies are necessary to investigate potential relationships between other aspects of social cognition and altered ICM in the superior temporal sulcus and inferior temporal gyrus in adult individuals with 47,XXX. Nevertheless, we reported a significant positive correlation between inferior temporal gyrus intracortical T1 and total social functioning scores in 47,XXX, indicating that higher social functioning in 47,XXX is related to larger ICM content. A previous study investigating ICM trajectories of social–emotional brain regions, including the superior temporal sulcus, in typically developing toddlers using the myelin water fraction reported a steep increase in ICM content in delineated brain regions throughout the first 3 years of life ( Schneider et al. 2021 ). Moreover, they showed a significant correlation between this pattern of myelination and their social–emotional development as observed and rated by parents ( Schneider et al. 2021 ). In addition, social cognitive training in typically developing individuals was associated with decreases in T1 in superficial depths in the parietal and temporal cortices and sensory-motor areas ( Valk et al. 2023 ). Previous studies in individuals with psychiatric disorders have not directly related ICM to social functioning or social cognition. Therefore, more research is necessary to investigate the contribution of altered ICM in the superior temporal sulcus and inferior temporal gyrus to social functioning and social cognition in 47,XXX.

Alterations of ICM in the temporal cortex as reported here in 47,XXX have also been shown in individuals with schizophrenia. More specifically, increases in ICM were shown in supragranular laminae of the parietal–temporal cortex including the supramarginal and superior temporal gyri in individuals with schizophrenia compared to typically developing individuals ( Wei et al. 2020 ). Psychotic symptoms and psychotic disorders have been reported in individuals with 47,XXX ( Otter et al. 2010 ; Green et al. 2018 ; Otter et al. 2022 ). Thus, these results may indicate potentially shared neurodevelopmental pathways contributing to the 47,XXX phenotype and idiopathic psychotic disorders. Alterations in brain morphology and brain function in the superior temporal sulcus ( Boddaert et al. 2004 ; Redcay 2008 ; Saitovitch et al. 2012 ; Nomi and Uddin 2015 ) and inferior temporal gyrus ( Cai et al. 2018 ; Kim et al. 2021 ) have previously also been reported in individuals with ASD. Yet, most of these studies have focused disproportionately on males with ASD rather than females with ASD. However, these parallels in altered brain (micro)structure and brain function between individuals with 47,XXX and those with ASD may suggest potentially shared neurodevelopmental pathways underlying both conditions. Nevertheless, an investigation of ICM in young children with ASD using the T1w/T2w ratio as an estimate of ICM content found no significant differences between individuals with ASD and typically developing children, also not while controlling for sex ( Chen et al. 2022 ). Yet, children with ASD showed altered developmental timing of myelination across several posterior cortical regions ( Chen et al. 2022 ). This alteration may suggest long-term effects that may manifest as differences in ICM in adulthood in ASD. It might be interesting for future studies to compare ICM across laminae using T1 between individuals with 47,XXX with and without ASD across different developmental periods. Unfortunately, we could not examine these potential differences as a result of an insufficient sample size resulting in decreased power to detect statistically significant differences between individuals with 47,XXX with and without ASD.

In a previous study using a largely overlapping sample, we showed smaller subcortical nuclei volumes and lower surface area in the superior temporal gyrus and superior frontal gyrus of the right hemisphere in adult women with 47,XXX ( Serrarens et al. 2022 ). Here, we demonstrate altered ICM across supragranular laminae bilaterally in the banks of the superior temporal sulcus, which separates the superior temporal gyrus from the middle temporal gyrus. It has been hypothesized that surface area and ICM are neurodevelopmentally related ( Cafiero et al. 2019 ). Although we did not observe significant differences in surface area of the banks of the superior temporal sulcus in 47,XXX in our previous study, further investigation is warranted to investigate the potential relationship between ICM and surface area in 47,XXX.

The deeper layers of the cortex closer to the white matter boundary are generally the most heavily myelinated and have an MRI signal that is distinct from the signal in the superficial gray matter, which has fewer myelinated fibers ( Rowley et al. 2015 ). Yet, here we showed ICM alterations in superficial cortical laminae of the superior temporal sulcus and inferior temporal gyrus in 47,XXX. Given that superficial cortical laminae tend to contain the supragranular layers that are rich in feed-forward sensory connections on pyramidal neurons and contain neurons that project their axons to other cortical areas of the same hemisphere (associative), decreased myelination in 47,XXX may lead to disrupted neuronal connectivity with other cortical regions ( Wei et al. 2020 ). ICM content in deeper cortical laminae (infragranular) of the superior temporal sulcus and inferior temporal gyrus was not statistically altered in individuals with 47,XXX. However, medium effect sizes were observed for deeper cortical laminae in the banks of the superior temporal sulcus and the inferior temporal gyrus in the right hemisphere, also showing higher T1 values in 47,XXX compared to typically developing females. Decreasing T1 value trajectories were observed from supragranular to infragranular laminae, trajectories that are comparable to the results of previous studies using T1 map values ( Tardif et al. 2015 ; Waehnert et al. 2016 ; Sprooten et al. 2019 ; Gulban et al. 2022 ). Future studies including larger sample sizes are required to further investigate ICM in deeper cortical laminae in the superior temporal sulcus and inferior temporal gyrus in 47,XXX.

Using diffusion tensor imaging data, X chromosome dosage effects on white matter microstructure were previously shown in individuals with 45,X0 ( Molko et al. 2004 ; Holzapfel et al. 2006 ; Yamagata et al. 2011 ; Xie et al. 2015 ) and 47,XXY ( Goddard et al. 2015 ). Altered radial diffusivity, which is an indirect measure of white matter myelination, was reported in children with 45,X0 in widespread white matter regions and tracts ( Yamagata et al. 2011 ). Additionally, children and adolescents with 47,XXY showed altered radial diffusivity in the anterior corona radiata and sagittal striatum ( Goddard et al. 2015 ). Combined, these results suggest X chromosome dosage effects on white matter microstructure across the lifespan. The results in 47,XXX presented here increase our understanding of X chromosome dosage effects on gray matter microstructure, more specifically on ICM across laminae. However, comparison data from structural MRI studies investigating ICM in other SCAs, including 45,X0 and 47,XXY, are currently not available. To elucidate the direct impact of X chromosome dosage on ICM across laminae in more depth, future studies including a more diverse group of SCAs are required. Moreover, longitudinal studies investigating ICM across laminae in SCAs, including 47,XXX, across developmental trajectories are warranted.

Our study is the first to investigate ICM across laminae in individuals with 47,XXX. Our work in 47,XXX presented here offers a better understanding of how X chromosome dosage impacts ICM. Another important strength of this study is the use of ultra-high field 7 T MRI data. MRI at 7 T offers increased signal-to-noise ratio and increased contrast-to-noise ratio compared to 3 T MRI, allowing imaging with submillimeter spatial resolutions and mapping of laminar profiles, improving the delineation of anatomical structures, providing clearer tissue boundaries which results in improved segmentation accuracy and minimizing partial volume effects ( Marques et al. 2010 ; Choi et al. 2011 ; Bahrami et al. 2017 ; Vachha and Huang 2021 ). In addition, our study is the first to examine relationships between ICM across laminae and IQ, and social cognition and social functioning in 47,XXX. Despite the strong merits and novelty of our study, some limitations should be mentioned as well. First, our sample size was relatively small, resulting in decreased power to detect statistically significant differences. When having a small sample size, P values are particularly vulnerable to small deviations in the number of outcomes ( Mitani and Haneuse 2020 ). Since this is the first explorative study investigating intracortical myelin across laminae in 47,XXX, we chose to be comprehensive and report statistical significance at P  < 0.025 (corrected for the number of hemispheres). The relatively small sample size could be a potential explanation for our not observing alterations in ICM across deeper laminae of the banks of the superior temporal sulcus and the inferior temporal gyrus. However, 47,XXX is considered an underrepresented and understudied population ( Tuke et al. 2019 ). Given the variability in clinical phenotype and the assumption that many individuals with 47,XXX are not clinically diagnosed, recruitment of large sample sizes is difficult and requires international collaborative consortia. Ascertainment bias is also a well-known limitation in research in genetic disorders in general. This also applies to 47,XXX studies as patients presenting more severe phenotypes are more likely to be clinically diagnosed, and recognized and enrolled in research. Therefore, our sample may not be representative of all individuals with 47,XXX. Moreover, the cross-sectional nature of our data makes it difficult to assess possible age-varying patterns of ICM across laminae in 47,XXX, stressing the need for longitudinal studies investigating ICM across laminae and its potential relationships with clinical symptoms in 47,XXX. Individuals with 47,XXX had a confirmed 47,XXX diagnosis through DNA testing, which was verified by their general practitioner. However, genetic/genomic information was not collected for this study. Therefore, future studies are necessary to investigate the effect of these factors on intracortical myelin in 47,XXX. While X chromosome dosage effects on ICM across laminae were elucidated in 47,XXX at adult age, alterations in brain structure may also be the result of indirect sex hormonal effects. Sex hormone levels in 47,XXX are usually normal, but were not investigated in this study, and therefore, future research is warranted. We acknowledge the inherent limitation that T1 values do not directly represent myelin concentrations, but rather serve as a close approximation. T1 values are also influenced by other factors, such as iron or susceptibility. However, work by Stüber ( Stüber et al. 2014 ) suggests that the value of T1 within the cortex is mostly dominated by myelin content. In laminar analysis using MRI, cortical laminae that are used to calculate laminar profiles do not directly correspond to cytoarchitectonic layers (in a histological sense). The geometrical depth might not consistently align with a cortical lamina based on cytoarchitecture across regions or individuals, as demonstrated by variations in laminar volumes along functional gradients by Wagstyl and colleagues ( Wagstyl et al. 2020 ). Lastly, 7 T MRI is fraught with challenges posed by transmit field (B1 + )-related inhomogeneities that need to be corrected using additionally acquired data and/or image processing. In the present study, we were able to correct quantitative T1 map images for B1 + inhomogeneities in postprocessing using a dedicated B1 + acquisition. Future studies can consider employing methods outlined here or recent advances in MR acquisition methods like pTx and Universal Pulses to remediate some of these issues associated with imaging inhomogeneities ( Gras et al. 2016 ; Choi et al. 2024 ).

In conclusion, our results indicate an effect of a supernumerary X chromosome in adult-aged women on ICM across supragranular laminae of the banks of the superior temporal sulcus, and the inferior temporal gyrus. These findings provide insight into the role of X chromosome dosage on ICM across laminae. Future research is warranted to further explore the functional significance of altered ICM across laminae in 47,XXX.

We would like to thank all the women for participating in this study. We would also like to thank Truda Driesen for coordinating the study.

Chaira Serrarens (Data curation, Formal analysis, Methodology, Software, Visualization, Writing—original draft, Writing—review & editing), Julia Ruiz-Fernandez (Data curation, Formal analysis, Methodology, Software, Writing—review & editing), Maarten Otter (Conceptualization, Investigation, Project administration, Resources, Writing—review & editing), Bea C.M. Campforts (Investigation, Project administration, Resources, Writing—review & editing), Constance T.R.M. Stumpel (Conceptualization, Project administration, Supervision, Writing—review & editing), David Linden (Supervision, Writing—review & editing), T.A.M.J. van Amelsvoort (Conceptualization, Project administration, Supervision, Writing—review & editing), Sriranga Kashyap (Formal analysis, Methodology, Software, Supervision, Visualization, Writing—original draft, Writing—review & editing), and Claudia Vingerhoets (Methodology, Supervision, Visualization, Writing—original draft, Writing—review & editing).

The work of C.S. was supported by the National Institute of Mental Health (NIMH 5U01MH119740-05). STEVIG, Oostrum, the Netherlands, contributed financially to the work of co-author M.O.

Conflict of interest statement: None declared.

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• v.2(1); 2012

Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study

Kirstine stochholm.

1 Department of Endocrinology and Internal Medicine, Aarhus University Hospital NBG, Aarhus C, Aarhus, Denmark

Anders Bojesen

2 Department of Clinical Genetics, Vejle Hospital, Sygehus Lillebaelt, Vejle, Denmark

Anne Skakkebæk Jensen

3 Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark

Claus Højbjerg Gravholt

Associated data.

To investigate the criminal pattern in men between 15 and 70 years of age diagnosed with 47,XXY (Klinefelter's syndrome (KS)) or 47,XYY compared to the general population.

Register-based cohort study comparing the incidence of convictions among men with KS and with 47,XYY with age- and calendar-matched samples of the general population. Crime was classified into eight types (sexual abuse, homicide, burglary, violence, traffic, drug-related, arson and ‘others’).

Denmark 1978–2006.

Participants

All men diagnosed with KS (N=934) or 47,XYY (N=161) at risk and their age- and calendar-time-matched controls (N=88 979 and 15 356, respectively).

The incidence of convictions was increased in men with KS (omitting traffic offenses) compared to controls with a HR of 1.40 (95% CI 1.23 to 1.59, p<0.001), with significant increases in sexual abuse, burglary, arson and ‘others’, but with a decreased risk of traffic and drug-related offenses. The incidence of convictions was significantly increased among men with 47,XYY compared to controls with a HR of 1.42 (95% CI 1.14 to 1.77, p<0.005) in all crime types, except drug-related crimes and traffic. Adjusting for socioeconomic variables (education, fatherhood, retirement and cohabitation) reduced the total HR for both KS and 47,XYY to levels similar to controls, while some specific crime types (sexual abuse, arson, etc) remained increased.

The overall risk of conviction (excluding traffic offenses) was moderately increased in men with 47,XYY or KS; however, it was similar to controls when adjusting for socioeconomic parameters. Convictions for sexual abuse, burglary, arson and ‘others’ were significantly increased. The increased risk of convictions may be partly or fully explained by the poor socioeconomic conditions related to the chromosome aberrations.

Article summary

Article focus.

• To investigate crime rates of men with an extra sex chromosome (47,XXY and 47,XYY). Based on previous small studies, we hypothesised that an increased crime rate would be present in men with an extra sex chromosome and investigated this in a nationwide registry study.

Key messages

• Using a nationwide approach, we show that men diagnosed with KS (47,XXY) and 47,XYY are more frequently convicted for sexual abuse, burglary, arson and other reasons. Traffic offenses are seen less frequently in both groups.
• Whether early diagnosis and improved clinical care can lead to a decrease in convictions is not clear.
• The increased crime rate may be partly or fully mediated by poor socioeconomic conditions.

Strengths and limitations of this study

• The study clearly delineates a pattern of increased crime rates among men diagnosed with an extra sex chromosome. The strength of the present study is the large number of men with sex chromosomes and the large control group and the merging of several registries.
• The limitations are that we were not able to control for concomitant medicinal use, especially testosterone use in KS, nor to include clinical data.

Introduction

The sex chromosome trisomies 47,XXY (Klinefelter's syndrome (KS)) and 47,XYY are the most common male sex chromosome aneuploidies compatible with live birth. KS affects 167 per 100 000 men, 1–3 while the prevalence estimates of 47,XYY are highly variable, ranging in live born men from 26 per 100 000 4 to 375 per 100 000, 5 although many are not diagnosed or diagnosed late. 6 Both KS and 47,XYY are much more frequent when studied in a tall population, 7 which is readily explained by the presence of additional copies of the SHOX gene (and possibly also other genes related to stature) in men with KS and 47,XYY. 8 As with 47,XYY, many KS are not diagnosed, and a considerable delay in diagnosis exists for those who get a diagnosis. 2

The 47,XYY sex chromosome abnormality has been described in various settings 6 9 since the first descriptions of a group of men with 47,XYY in 1965 by Jacobs et al 10 who conducted a chromosome survey of male patients at the State Hospital in Carstairs, Scotland, and found that men with the 47,XYY karyotype were particularly frequent among inmates in penal institutions. During the 1960s and 1970s, studies of persons with KS and 47,XYY identified an increased frequency in hospitals for mentally handicapped, 11 and men with 47,XYY seemed to be over-represented in prisons. 12 Several of these studies reported a general increased rate of criminal behaviour and increased crime rates among both cohorts, especially due to sexual crimes. 13 These studies were associated with selection problems as they investigated institutionalised individuals. Two relatively new studies of criminal behaviour among sex chromosome trisomies have been published. Götz et al 14 found an increased rate of criminal behaviour among persons with 47,XYY but not among persons with KS. Another study from 1988 15 linked young KS males with arson. However, both studies include a very limited number of persons. The study by Witkin et al 7 in tall persons concluded that there was no evidence of an increased crime rate among KS and 47,XYY, but again with very few study subjects. Long-term follow-up of a cohort of KS (n=19) and 47,XYY (n=19) indicated that persons with 47,XYY had a fourfold increase in convictions, mostly due to minor offenses. 16 All investigations conducted so far on this issue are limited by the study of selected groups, either institutionalised or clinic patients, in addition to methodological shortcomings, such as self-report of crimes, poorly defined definition of crime type and poorly defined control groups. All studies have also been conducted in very small groups comprising <20 persons with a chromosome abnormality. The full spectrum of all types of crime has never been reported. As mentioned, diagnosis of both syndromes is usually delayed and more than half of the expected individuals are never diagnosed, 2 6 and a more thorough knowledge of all aspects these syndromes would most likely facilitate earlier diagnosis and possibly better clinical care.

In order to examine the crime characteristics of men with KS and 47,XYY, we undertook the present nationwide study, focusing not only on the total number of convictions but also on various crime types. Thus, we investigated the criminal pattern of all men diagnosed with 47,XYY and KS compared with a large age- and calendar-time-matched control group. We compared HRs without and with adjustment for socioeconomic variables in order to assess whether any increased risk of conviction could be explained by the poorer socioeconomic conditions of men with KS and 47,XYY. Furthermore, the criminal pattern before and after the diagnosis of the chromosomal aberration was investigated.

The present study is a register-based study combining information from the Danish Cytogenetic Central Register, Statistics Denmark and the Danish Central Crime Registry.

Study population

Using the Danish Cytogenetic Central Register, we identified all men diagnosed with a karyotype compatible with KS, 47,XYY or variants thereof in Denmark by January 2009. These men are hereafter referred to as index-persons. The register was founded in 1967 and contains information regarding all cytogenetic analyses performed in Denmark since 1960, including date of diagnosis. Unique identification numbers (ID numbers) from the Civil Registration System enabled identification of every single person diagnosed with an aberrant chromosomal analysis. ID numbers are given to all Danish citizens since 1968. The ID numbers ensured a one-to-one linkage between the registries.

For each index-person, Statistics Denmark identified up to 100 age- and calendar-time-matched controls (matched on month and year of birth) from the male background population. All dates of emigration and death were retrieved. All controls were alive and living in Denmark when their index-person was diagnosed. All controls emigrated or deceased before the index-person turned 15 years were excluded.

Convictions

The Danish Central Crime Register has previously been described as possibly the most thorough, comprehensive and accurate crime register in the Western world. 17 Since the register was digitalised on 1 November 1978, all charges and decisions for any reported offense in Denmark have been registered. We had access to annual information, and a person could be registered with multiple convictions the same year. We defined 1 July the relevant year as the date of the conviction. The study period was from 1 November 1978 to 31 December 2006, as 2006 was last year with available information.

In Denmark, the age of criminal responsibility is 15 years. All solved criminal acts committed by individuals born after 1 November 1963 has been registered in the crime register. We considered only persons between 15 and 70 years during the study period to be at risk of an event. We categorised the offenses into eight groups, that is, (1) sexual-related convictions including rape; (2) homicides; (3) violent convictions; (4) robbery, burglary and theft; (5) traffic offenses; (6) drug-related convictions not including violence; (7) arson and (8) ‘others’.

All convictions of an index-person or a control were retrieved from the crime register. We defined an event as the first conviction in any group and in each of the eight groups separately. Thus, only the first event was analysed, and all succeeding events in the same group were excluded.

We discriminated between events before and after the diagnosis of a chromosome aberration. Also, in order to analyse whether the conviction and the diagnosis could be related, we excluded all convictions up to 2 years before and 2 years after the diagnosis in a separate analysis. We also discriminated between persons diagnosed early and late in life, using the median age at diagnosis as cut-point.

Socioeconomic outcome parameters

From Statistics Denmark, we retrieved information regarding time of the following events, as previously described 18 : cohabitation with a partner, achievement of an education, fatherhood and retirement.

Cohabitation and marriage

We retrieved all persons' marital and cohabitational status each 1st of January. Data were available from 1980 through 2007. The event was first change from being single to be cohabitating with a partner.

Data were category of education and dates for achieved education. An achieved bachelor degree or higher was considered ‘an education’. The event was first achieved bachelor degree for a person between 18 and 40 years.

All children born or adopted were registered from 1942 until 2007, with a linkage to both of their registered parents. Fatherhood was defined as the event of the first fathering of a child.

We defined retirement as due to age, sickness or voluntary choice. A person was considered retired, the first year payment was received due to retirement, regardless of a later return to the labour market.

The study protocol was approved by the Danish Data Protection Agency.

Kaplan–Meier estimates were constructed for time of first conviction. Time at risk started at age of 15 years or at start of registration, whichever came last, and ended at the date of first event, at the age of 70 years, at emigration/death or 31 December 2006, whichever came first.

HRs were calculated using stratified Cox proportional hazards regression, where each case and his matched controls were one stratum. For the analyses, time at risk started on the 15th birthday or 1 November 1978, whichever came last, and time at risk ended 1 July the year we registered an event for the first time, on the date of emigration, on the 70th birthday, on the date of death or 31 December 2006, whichever came first. For analyses before the diagnosis, time at risk ended no later than the date of diagnosis. For analyses after the diagnosis, time at risk started no earlier than the date of diagnosis.

For the analyses excluding all convictions 2 years before and after the diagnosis, all persons who had a first registration of a conviction of the relevant crime type during this period were excluded. We analysed convictions adjusted for cohabitation, education, fatherhood and retirement.

To examine a potential bias associated with undiagnosed KS and 47,XYY cases, we performed a sensitivity analysis, assuming that the risk of conviction among undiagnosed cases is smaller than the risk observed among diagnosed cases, and we applied the statistical uncertainty from the observed data expressed by the SE of the ln(HR) estimate.

All results are shown with 95% CI, and p<0.05 was considered statistically significant. We made no formal correction for multiple comparisons. We used Stata V.10.0 (Stata Corp.) for all calculations.

We identified 1049 persons with KS, whereof 934 were at risk of an event due to age between 15 and 70 years during the registration period; similarly, 208 persons with 47,XYY were identified, and 161 were at risk of an event. For details on both cohorts of index-persons and their controls, see table 1 .

Basic characteristics of persons with Klinefelter's syndrome (KS) or 47,XYY

Persons with KS

The risk of any conviction was similar in persons with KS and controls with a HR of 0.95 (95% CI 0.86 to 1.05, p=0.28) but was increased to 1.40 (95% CI 1.23 to 1.59) when excluding traffic offenses ( table 2 ). Convictions of sexual abuse, burglary, arson and ‘other’ were moderately increased in persons with KS ( figures 1 and ​ and2). 2 ). When excluding convictions within 2 years before and after the diagnosis, the HRs did not change substantially (supplemental figure 1). The HRs were significantly increased for convictions of sexual abuse, burglary and arson both before and after the KS diagnosis (supplemental table 1). The HRs were lower in the cohort diagnosed late in life (supplemental figure 2). Adjusting for socioeconomic parameters reduced the total HR (excluding traffic offenses) to a HR of 1.05 (95% CI 0.90 to 1.23) ( table 2 ), but it was still significantly increased in the subgroups sexual abuse and arson. The HR for convictions of traffic offenses was significantly decreased both before and after adjustment for socioeconomic parameters.

HRs (95% CI) for overall cause-specific convictions without and with adjustment for education, retirement, cohabitation and fatherhood in men with KS and 47,XYY

KS, Klinefelter's syndrome; NA, a HR could not be computed due to lown.

Kaplan–Meier plot of proportion of persons convicted (excluding traffic offenses) for the first time in the background population (thin line) and in men with Klinefelter's syndrome (bold line). All were 15–70 years of age.

HRs of convictions due to cause in Klinefelter's syndrome (KS) compared to age-matched men (see the Materials and methods section for details). Actual numbers of offenders (KS/controls) are given in parentheses.

Persons with 47,XYY

In total, the risk of convictions was moderately increased in persons with 47,XYY compared to controls (HR 1.42 (95% CI 1.14 to 1.77), p<0.005) and even more pronounced (HR 2.09 (95% CI 1.61 to 2.71), p<0.001) when excluding traffic offenses ( figure 3 and table 2 ). A significantly increased HR was identified for convictions of sexual abuse, homicide, violence, burglary, arson and ‘others’ ( figure 4 ). In none of the eight conviction groups did the estimate change substantially when excluding convictions 2 years before or after the diagnosis (supplemental figure 3). Before the diagnosis, the HRs were significantly increased for convictions of sexual abuse only, and there were no events among the persons with 47,XYY in homicides, drug-related convictions and the arson group (supplemental table 1). After the diagnosis, the HRs were significantly increased in all offense groups, except for the traffic offenses (data not shown). There were no significant differences between HRs for those diagnosed younger and older than the median age at diagnosis (supplemental figure 4). Adjusting for socioeconomic parameters reduced the total HR (excluding traffic offenses) to 1.04 (95% CI 0.68 to 1.61) ( table 2 ), and all other subgroup HRs but sexual abuse decreased.

Kaplan–Meier plot of proportion of persons convicted (excluding traffic offenses) for the first time in the background population (thin line) and in men with 47,XYY (bold line). All were 15–70 years of age.

HRs of convictions due to cause in 47,XYY syndrome compared to age-matched men (see the Materials and methods section for details). Actual numbers of offenders (47,XYY/controls) is given in parentheses.

This large study in persons with KS and 47,XYY covering all diagnosed individuals in Denmark demonstrates that persons with 47,XYY and KS are convicted of a number of specific offenses more frequently than the background population. The total number of convictions, however, was not increased in persons with KS, primarily due to a significantly decreased number of traffic-related convictions. The study also demonstrates that unfavourable socioeconomic conditions may be part of the explanation for the increased rate of convictions since adjustment for socioeconomic variables reduced the HR in both cohorts. We could also demonstrate an association between convictions and age at diagnosis in persons with KS, that is, the earlier the diagnosis had been made, the greater the likelihood of having been convicted of an offense.

Men with KS and 47,XYY are to a large extent diagnosed late or not diagnosed at all, 2 6 and we have previously estimated that only 25% of KS and 15% of 47,XYY get a diagnosis. The same pattern is seen in other countries. 19 20 Thus, the results of the present study apply to the studied cohort—in other words, patients with KS and 47,XYY seen in daily clinical practice, and risk estimates may therefore not be applicable to groups of yet undiagnosed men with sex chromosome trisomies or even patients from other countries. We are well aware that the results of the present study may stigmatise persons with KS and 47,XYY due to the over-representation of convictions of sexual abuse and arson. But instead of suppressing such data, we believe that they are pivotal in furthering the understanding of these syndromes.

We found a significantly increased cause-specific risk of convictions due to sexual abuse, burglary, arson and ‘others’ among men with 47,XYY and KS. Furthermore, the cause-specific risk of convictions due to homicide and violence was increased among persons with 47,XYY. We then studied the impact of socioeconomic factors by adjusting for level of education, fatherhood, retirement and cohabitation. This adjustment lead to reductions in most HR, and only the risk of convictions for sexual abuse and arson among persons with KS and only sexual abuse among persons with 47,XYY remained significantly elevated. Among persons with KS, we found a significantly decreased risk of traffic-related convictions.

In general, information about sexual function in men with sex chromosome aberrations is sparse. Schiavi et al 21 found that fewer men with 47,XYY, but not men with KS, were married, experienced greater sexual dissatisfaction in general, acknowledged unconventional sexual experiences compared to a control group and demonstrated a less masculine gender role. Furthermore, men with 47,XYY have been described as immature, having interpersonal and sexual difficulties. 22 Thus, men with KS and 47,XYY have been described with increased frequency of different or deviating sexual behaviour, although it is important to stress that only few and small studies have investigated this subject. In addition, an increased vulnerability to psychiatric disorders and deviant behaviour, 23–25 psychophysiological dysfunction 26 and increased levels of autism traits in KS 27 28 together with a lower educational level and poor socioeconomic status 18 may result in a increased susceptibility to commit a crime. We did not expect the finding of significantly increased risk of convictions for sexual abuse, and we believe this to be of considerable importance. The reason for the increased frequency of sexual abuse convictions is of course speculative but may be due to the previously described feeling of being sexually different, which may end up in misinterpreting sexual cues, or possibly frustration leading to socially and legally unacceptable ways of achieving sexual satisfaction. Further studies are needed to clarify whether early diagnosis, sex steroid treatment, psychological therapy or other initiatives may alter this finding.

Our findings of an increased frequency of convictions other than traffic offenses were not corroborated by the long-term follow-up study by Ratcliffe, 16 who only found increased criminality among persons with 47,XYY (n=19), but not among persons with KS (n=19), and that this increase primarily was due to minor offenses.

Previous reports have linked persons with KS with arson, 15 29 and a case report identified improvement on treatment for hypergonadotropic hypogonadism. 30 There have only been case reports of arson in men with 47,XYY. 14 31 We have no specific explanation as to why this specific tendency is present, but it is possible that some of the psychopathological traits mentioned above, especially for the KS group, may prove explanatory in future studies.

Previously, lower intelligence has been pointed out as a contributing factor to the increased criminal behaviour in men with 47,XYY. 14 Götz et al 14 investigated criminality and antisocial behaviour in unselected men with KS and 47,XYY and showed that men with 47,XYY were more likely to have a criminal record compared to controls and found this to be due to lower IQ (n=16). They found no increase in the number of criminal records among persons with KS compared with controls, possibly due to low power (n=13). 14 Witkin et al 7 found a significantly increased rate of criminality in 47,XYY (n=12) even after adjusting for social class and intelligence, while the crime rate among KS (n=16) after adjustment was similar to the background population.

We did find that the association between the crime rate (excluding traffic offenses) and either KS or 47,XYY was reduced when adjusting for socioeconomic variables, such as level of education, retirement, cohabitation and fatherhood. In other words, the increased risk of conviction among the cases may partly or fully be explained by disadvantageous socioeconomic conditions. However, although there may be a relationship between increased convictions and poor socioeconomic status in persons with sex chromosomal abnormal phenotype, the causal relationship cannot be established.

We matched the current large group of patients with approximately 100 controls for each case. We did not match on other variables, such as socioeconomic factors, since these factors could easily be causally involved in how the chromosome abnormality leads to a deviant pattern of criminality. Indeed, matching on socioeconomic factors would likely lead to overmatching—which ‘is potentially capable of biasing study results beyond any hope of repair’. 32 The current approach allowed us to use subsequent adjustments to clarify whether socioeconomic factors were involved, which they in fact turned out to be. We did correct for level of education, fatherhood, retirement and cohabitation, although it can be problematic to control for social factors, because the chromosome aberrations per se can be the very reason for social problems, while the reverse is not possible. In addition, social problems—marginalisation, lack of education, poverty, etc—can affect the risk of criminal behaviour and of being detected and convicted. In other words, social problems may be part of a chain of events and adjustment would therefore introduce confounding. However, having controlled for these factors, we found that the total HRs for being convicted decreased and were no longer statistically significant for either group. Being well aware of the deviant behaviour and learning difficulties present in both cohorts from a very young age, we hypothesise that these difficulties are part of the background for the identified increased number of convictions. We then performed a sensitivity analysis to examine a potential bias arising if the severity of the syndrome affects both the risk of conviction and the probability of being diagnosed. 33 In one analysis, we assumed that the excess hazard among undiagnosed cases was half the excess hazard seen among diagnosed cases, and we applied the statistical uncertainty from the observed data. In another similar analysis, we assumed that the excess hazard among undiagnosed cases was similar to that in the background population. For KS, we assumed that 25% of all cases had been diagnosed. In the sensitivity analyses, the HRs were reduced, but still significantly elevated for all convictions (excluding traffic offenses), and for sexual abuse, burglary and arson (supplementary table 2). For 47,XYY, we observed a similar pattern. Here, we assumed that 15% of all cases had been diagnosed. In the sensitivity analysis, the HRs were reduced, but still significantly elevated for all convictions (excluding traffic offenses), and for sexual abuse, violence, burglary and arson (supplementary table 2). In other words, it is highly likely that the crime rate would remain significantly increased in an entirely unbiased population of both KS and 47,XYY with complete diagnosis of all cases.

We identified an association between age at diagnosis and convictions in some groups in both cohorts. The findings of a more ‘normal’ number of convictions in persons with KS in those diagnosed when older than the median age of diagnosis might be explained by a less typical phenotype, both physical and, perhaps more importantly, cognitive phenotype. However, this finding was not present in the persons with 47,XYY. We find no reason to believe that a late diagnosis per se is positive. Due to the reported increased criminal problems, we undertook analyses excluding those convicted in close proximity to the diagnosis. We hereby intended to avoid detection bias by excluding those who were diagnosed due to a conviction and who may bias the results towards an increased number of convictions in the index-persons. As exclusion of such persons hardly changed the findings, we believe that this type of bias can be ignored. The drawback of this study is the lack of clinical information, including IQ level, treatment with sex steroids, number of persons with a driving license and access to a car and for instance psychiatric diagnoses. The advantages are the nationwide inclusion of all diagnosed men at risk with sex chromosome trisomies and the close matching of the controls.

We were not able to control for concomitant medicinal use. There are usually no known hormonal deficits among men with 47,XYY, while men with KS often receive testosterone substitution therapy due to hypergonadotrophic hypogonadism. It has been speculated that early testosterone substitution in KS 34 35 would partially attenuate the impact of the syndrome on intellectual functioning and possibly other factors, but this remains to be studied. Others have speculated that testosterone substitution therapy could cause psychological disturbances, such as aggressive behaviour and occasionally lead to violent crime, especially at supraphysiological doses, 36 although a placebo controlled study of androgen treatment in healthy young men showed no or minimal change in mood or behaviour. 37 38 We cannot fully exclude the possibility that the pattern of criminality among KS could be related to testosterone substitution therapy, while it seems unlikely that medicinal use among men with 47,XYY is related to criminality. We note that the pattern of criminality in 47,XYY, who have a normal testosterone production, was equal or higher than among KS, and furthermore that criminality among KS was elevated even before diagnosis and thus before commencement of supplementation with testosterone, making it unlikely that testosterone supplementation is causally involved in the excess criminality in KS. In addition, in many men with KS, conventional testosterone supplementation is often not sufficient, and many men with KS are also not compliant, at least not all the time, resulting in hypotestosteronemia, elevated luteinizing hormone and diseases, symptoms and signs related to hypogonadism. 39–41

In conclusion, this study on all diagnosed men with a sex chromosome trisomy in Denmark identified a significantly increased number of convictions, excluding traffic offenses, both in persons with KS and 47,XYY. When adjusting for socioeconomic factors, the adjusted risk was similar to controls for both cohorts. We interpret this as indicating that a main explanation of the increased risk of conviction is due to unfavourable living conditions associated with these syndromes. In both cohorts, we found a significantly increased number of convictions due to sexual offense and arson. Further studies are needed to identify whether these findings can be prevented by improved clinical care, including earlier diagnosis.

Supplementary Material

Acknowledgments.

KS had full access to all the data in the study, and KS and CHG take responsibility for the integrity of the data, the accuracy of the data analysis and the decision to publish.

To cite: Stochholm K, Bojesen A, Jensen AS, et al . Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study. BMJ Open 2012; 2 :e000650. doi: 10.1136/bmjopen-2011-000650

Contributors: KS, AB, SJ and CHG participated in the conception and design of the study. KS, AB, SJ, ASJ and CHG participated in the analysis and interpretation of data. KS and CHG drafted the article, and KS, AB, SJ, ASJ and CHG approved the final version to be published.

Funding: Funded by Central Region Denmark; Danish Ministry of Science, Technology and Innovation, grant number 1-45-72-7-07 ;; 271-09-0907 .

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

Data sharing statement: There are no additional data from the present study available.