The Effect of Hormonal Therapy on the Behavioral Outcomes in 47,XXY (Klinefelter Syndrome) between 7 and 12 Years of Age.

47,XXY, also known as Klinefelter syndrome, is the most commonly occurring sex chromosomal aneuploidy (SCA). Hormonal replacement therapy (HRT) has been associated with improved neurodevelopmental capabilities in boys with 47,XXY, although studies investigating HRT's possible positive effect on behavioral outcomes are scarce. This study explores the association between behavioral outcomes and HRT in boys ages 7-12. Patients were divided into 4 groups based on HRT status: untreated, early hormonal treatment (EHT), hormonal booster therapy (HBT), and both EHT and HBT. Analysis of Variance (ANOVA) and Kruskal-Wallis tests were conducted to determine group differences on the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF). The treated groups were found to have better scores in emotional control, initiative, organization of materials, behavioral rating index, metacognition index, and global executive composite than the untreated group on the BRIEF. On the CBCL, the treated groups presented better scores for somatic complaints, social problems, thought problems, attention problems, aggressive behavior, internalizing problems, total problems, affective problems, somatic problems, ADHD problems, oppositional defiant problems, and sluggish problems in comparison to the untreated group. These results offer evidence that HRT, specifically the combination of both EHT and HBT, may be successful in mitigating some undesirable behavioral outcomes. Further research is necessary to determine the efficacy of the combination of EHT and HBT regarding dosage, specific ages, and long-term benefits.

Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY).

Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.

Quality of life in Klinefelter patients on testosterone replacement therapy compared to healthy controls: an observational study on the impact of psychological distress, personality traits, and coping strategies.

PURPOSE: We aimed to verify if 1 year-testosterone-replacement therapy could produce a psychopathological recovery and a satisfactory quality of life in Klinefelter syndrome (KS) patients compared to matched healthy controls. Further, we analyzed personality traits and coping strategies, an issue not yet examined in androgen-treated KS patients. We also enquired whether any of the sociodemographic and psychological variables might predict a patient's general and sexual life satisfaction. METHODS: The Quality of Life Enjoyment and Satisfaction Questionnaire and the Temperament and Character Inventory-Revised were administered to both 23 KS patients and matched healthy subjects. Psychopathology was investigated by the Symptom Checklist-90-Revised (SCL-90-R) and the Mini-mental State Examination. The COPE Inventory was used to identify cognitive and behavioral strategies to manage disease-related distress. RESULTS: In testosterone-treated KS patients, when compared with controls, SCL-90-R subscales analysis evidenced high psychological distress, mainly presented as obsessive thoughts, hanger-hostility, phobias, and psychoticism. Self-directedness and self-transcendence, along with the prevalent use of emotion-focused coping strategies, outlined the personality of our KS patients. Depression and somatization proved to be predictors of general life dissatisfaction. Depression, anger-hostility, and paranoid ideation, instead, emerged as predictors of sexual life dissatisfaction. CONCLUSION: Endocrinologists should cooperate with mental health providers to foster a better outcome of the disease in KS patients.

Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome.

Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non-verbal and visuo-spatial domains, executive dysfunction and social impairments, and by an increased vulnerability toward psychiatric disorders. The neurobiological underpinnings of the observed neuropsychological profile have not been established. A distinct pattern of both global and regional brain volumetric differences has been demonstrated in addition to preliminary findings of functional brain alterations related to auditory, motor, language and social processing. When present, the combination of cognitive, psychological and social challenges has the potential to negatively affect quality of life. This review intends to provide information and insight to the neuropsychological outcome and brain correlates of KS. Possible clinical intervention and future directions of research will be discussed.

Behavioral phenotype of 49,XXXXY syndrome: Presence of anxiety-related symptoms and intact social awareness.

49,XXXXY is a rare X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births and is notable for variable motor, speech, and behavioral deficits. Case studies have described boys with this disorder as shy, impulsive, and aggressive with low frustration tolerances; however, previous studies have been limited due to cohort size. This study reports on the largest cohort of boys with 49,XXXXY to date with an emphasis on the prevalence of anxiety-related symptoms and sociability from preschool to adolescence. The Child Behavior Checklist, Behavior Rating Inventory of Executive Function, 2nd edition, and Social Responsiveness Scale, 2nd edition were completed by parents on a cohort of 69. The cohort demonstrated deficits in social cognition and communication beginning in preschool, however, presented with consistent social awareness and motivation for social activities not previously appreciated in this disorder. In addition, signs of anxiety presented during preschool years and increased in severity with age, particularly in internalizing problems. Boys with 49,XXXXY presented with wide behavioral variability across all ages and domains. Further research into the potential influences of culture, birth order, biological treatment, and frequency of services is needed to better define the behavioral phenotype of children with this disorder.

Emotion regulation in adults with Klinefelter syndrome (47,XXY): Neurocognitive underpinnings and associations with mental health problems.

OBJECTIVES: The aim of this study is to evaluate if language and executive functioning deficits in individuals with the 47,XXY chromosomal pattern contribute to emotion regulation problems and related symptoms of psychopathology. METHODS: A group of 26 adult men with 47,XXY completed measures of cognitive emotion regulation strategies, neurocognitive functioning, and symptoms of psychopathology. RESULTS: Atypical emotion regulation strategies were found in the XXY group, with increased expression of emotions (69%), avoiding (65%), distraction seeking (54%), and passive coping (54%). More difficulties in mental flexibility and attention regulation, and speeded responding were associated with more pronounced emotion expression (emotional outbursts). Emotion regulation problems were associated with symptoms of anxiety, depression, thought problems, and hostility. CONCLUSION: This study has identified emotion regulation as a potential target for treatment and intervention, with a specific focus on executive functions in the management of emotions in individuals with 47,XXY.

High-level language competencies and Theory of Mind in a group of children with Klinefelter syndrome.

Klinefelter syndrome (KS) is a genetic anomaly involving the presence of one or more supernumerary X chromosomes in male individuals. In the cognitive profile of these individuals, strengths are found in nonverbal abilities, whereas weaknesses are observed in executive function, language, and academic performance. Our study is based on a comparison between eight children diagnosed with KS (47,XXY) (age range: 9-13 years; IQ range: 80-123), with no delay in language development, and eight typically developing (TD) controls. We explored a range of high-level language competencies and Theory of Mind (ToM) in addition to basic language competency. High-level language competencies were assessed by a battery that measures pragmatic language skills and a metaphor comprehension test (MCT). To assess ToM, we administered the corresponding subtest of the NEPSY II. Basic language competence was assessed by the NEPSY II Comprehension of Instructions subtest. Although basic language performance did not differentiate the individuals with KS from the TD controls, relevant differences appeared in some of the high-level language competencies as well as in the ToM task. All tasks in which the individuals with KS performed less well were characterized by complex inferential processes. Some possible clinical and educational implications are discussed.

The incidence of anxiety symptoms in boys with 47,XXY (Klinefelter syndrome) and the possible impact of timing of diagnosis and hormonal replacement therapy.

47,XXY (Klinefelter syndrome) is the most common X and Y chromosomal variation (1:660 males). The incidence of anxiety disorders and the impact of hormonal replacement therapy (HRT) is not well understood. Child Behavior Checklist and Screen for Childhood Anxiety Related Emotional Disorders were completed by parents of 80 boys with 47,XXY. Forty received HRT prior to 10 years of age while 40 did not. HRT (22.5%) received early hormonal treatment prior to 18 months. About 32.5% received hormone booster treatment between 5 and 10 years. The remaining 42.5% received both. There were fewer reported social (p = .015), thought (p = .012), and affective problems (p = .048) in treated boys when compared to untreated. Boys with both treatments demonstrated fewer symptoms on anxious/depressed scale (p = .001) compared to those with early treatment only. Within the treated group, prenatally diagnosed showed fewer indications of anxiety problems (p = .02) than their postnatal counterparts. This comparative, cross-sectional study expands previous findings on the possible positive effect of HRT in boys with 47,XXY. Anxiety disorders appear to be a penetrant aspect of the 47,XXY phenotype. Further investigation is warranted to explore the relationship between biological treatment and individual responses to HRT to develop more personalized and precise medicine.

Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies.

The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

[Klinefelter'syndrome: A predisposition to sexual crime?] / Le syndrome de Klinefelter : une prédisposition au crime sexuel ?

BACKGROUND: Several studies have reported over-representation of psychiatric disorders among patients with Klinefelter' Syndrome (KS), with forensic complications. OBJECTIVE: Consider determinants of sexual assault in patient with KS. REVIEW: In this work, we present the case of Jules, 23 years old, with KS, benefiting from steroid replacement therapy, convicted of rape of a minor and evaluated in this context. We question here the role of his genetic pathology and of his hormonal treatment in this sexual assault. FINDINGS: According to evidence from the literature, it is not possible to determine with certainty the fair value of each factor and their impact on the occurrence of the sexual criminal act. Indeed, although the crime rate among KS subjects is higher than in the general population, the majority of them have never been in trouble with the law; moreover, these subjects were no more likely to commit violent sexual acts than were criminals without KS. As for hormonal treatment, it seems that testosterone is better viewed as a facilitator of initiating an aggressive response than as a primary inductor. CONCLUSION: In conclusion, the onset of sexual violence that accompanied the introduction of hormonal treatment into a patient with KS suggests an effective involvement of steroid replacement therapy, even small, in the criminal act. This must incite clinicians to extreme prudence and to take account of multidisciplinary expertise (psychiatrist, endocrinologist) in order to reconsider the continuation of the treatment in this particular forensic context. Finally, we discuss other factors that can precipitate such a violent act.

Neuropsychiatric Aspects in Men with Klinefelter Syndrome.

BACKGROUND AND OBJECTIVE: Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy (47, XXY) and cause of male hypergonadotropic hypogonadism. It is characterized by an extreme clinical heterogeneity in presentation, including infertility, hypogonadism, language delay, metabolic comorbidities, and neurocognitive and psychiatric disorders. Since testosterone is known to have organizational, neurotrophic and neuroprotective effects on brain, the condition of primary hypogonadism could play a role. Moreover, given that KS subjects have an additional X, genes on the extra-chromosome could also exert a significant impact. The aim of this narrative review is to analyze the available literature on the relationship between KS and neuropsychiatric disorders. METHODS: To extend to the best of published literature on the topic, appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. RESULTS: Both morphological and functional studies focusing on the brain showed that there were important differences in brain structure of KS subjects. Different psychiatric disorders such as Schizophrenia, autism, attention deficit hyperactivity disorder, depression and anxiety were frequently reported in KS patients according to a broad spectrum of phenotypes. T supplementation (TRT) was not able to improve the psychotic disorders in KS men with or without overt hypogonadism. CONCLUSION: Although the risk of psychosis, depression and autism is increased in subjects with KS, no definitive evidence has been found in studies aiming at identifying the relationship between aneuploidy, T deficit and the risk of psychiatric and cognitive disorders in subjects affected by KS.

Anxiety and depression in Klinefelter syndrome: The impact of personality and social engagement.

Klinefelter syndrome (KS) (47, XXY) is the most common sex chromosome disorder, with a prevalence of 1 in every 660 newborn males. Despite the profound adverse effects of anxiety and depression, and their greater prevalence in KS populations, no research has been conducted to date to identify the determinants of anxiety and depression among patients with KS. We examined the relationships between personality traits, social engagement, and anxiety and depression symptoms among KS patients (n = 69) and a group of male controls (n = 69) matched for age and years of education. KS patients experienced more anxiety and depression symptoms than control participants. Neuroticism was the strongest and most consistent mediator between KS and both anxiety and depression symptoms. This research suggests that neuroticism may play a central role in attention switching, anxiety and depression among patients with Klinefelter syndrome. The central role of neuroticism suggests that it may be used to help identify and treat KS patients at particularly high-risk for attention-switching deficits, anxiety and depression.

[The Klinefelter syndrome: a systematic review of secondary psychiatric comorbidities]. / Het klinefeltersyndroom: een systematisch overzicht van de secundaire psychiatrische aandoeningen.

BACKGROUND Klinefelter syndrome (ks) is the most common type of sex chromosome aneuploidy and is associated with psychiatric comorbidities. ks is only diagnosed in less than half of the cases due to the heterogeneous phenotype.
AIM: This study investigates the prevalence of secondary psychiatric diseases and their treatment in ks patients.
METHOD: Relevant articles were identified using the PubMed database. We included articles published in the last ten years, concerning ks patients who were assessed for comorbidities.
RESULTS: A total of 50 articles were included. The most prevalent comorbidities were language disorders and autism spectrum symptoms. Only half the ks population was treated (50.4%) with the primary treatment consisting of hormone therapy. 14% of patients were never treated hormonally.
CONCLUSION: Psychiatric comorbidities were observed in many patients with ks. The early diagnosis of ks in patients is important, given that inadequate treatment of ks patients can lead to reduced social functioning.

Male and Female Hypogonadism.

Hypogonadism is a clinical syndrome that results in hormone deficiency in men and women. Primary hypogonadism is caused by gonadal (testicular or ovarian) failure. Secondary hypogonadism is the result of a dysfunction within the hypothalamus and/or pituitary. Diagnosis of hypogonadism requires a comprehensive health history, evaluation of the signs and symptoms, complete physical examination, as well as laboratory and diagnostic testing for both sexes. Hormone replacement is the hallmark of hypogonadism treatment. Restoring and/or maintaining quality of life is a major consideration in the management of patients with hypogonadism.

The nature of social cognitive deficits in children and adults with Klinefelter syndrome (47,XXY).

About 1 in 650 boys are born with an extra X chromosome (47,XXY or Klinefelter syndrome). 47,XXY is associated with vulnerabilities in socio-emotional development. This study was designed to assess types of cognitive deficits in individuals with 47,XXY that may contribute to social-emotional dysfunction, and to evaluate the nature of such deficits at various levels: ranging from basic visuospatial processing deficits, impairments in face recognition (FR), to emotion expression impairments. A total of 70 boys and men with 47,XXY, aged 8 to 60 years old, participated in the study. The subtests feature identification, FR and identification of facial emotions of the Amsterdam Neuropsychological Tasks were used. Level of intellectual functioning was assessed with the child and adult versions of the Wechsler Intelligence Scales. Reaction time data showed that in the 47,XXY group, 17% had difficulties in visuospatial processing (no social load), 26% had difficulties with FR (medium social load) and an even higher number of 33% had difficulties with facial expressions of emotions (high-social load). Information processing impairments increased as a function of "social load" of the stimuli, independent of intellectual functioning. Taken together, our data suggest that on average individuals with XXY may have more difficulties in information processing when "social load" increases, suggesting a specific difficulty in the higher-order labeling and interpretation of social cues, which cannot be explained by more basic visuospatial perceptual skills. Considering the increased risk for social cognitive impairments, routine assessment of social cognitive functioning as part of neuropsychological screening is warranted.

Endocrine and psychological aspects of sexual dysfunction in Klinefelter patients.

Klinefelter syndrome is a frequent cause of hypogonadism, but despite hundreds of publications on different aspects of Klinefelter syndrome, only a few studies dealt with sexual dysfunction. In particular, testosterone is critical for various aspects of sexual response, but its role on sexuality in Klinefelter syndrome patients is debatable and no studies have evaluated the efficacy of testosterone treatment on sexual dysfunction in these subjects. Furthermore, the impact of psychological and relational aspects on sexual function of Klinefelter syndrome subjects is poorly defined. In this study, we aimed to determine the presence and type of sexual dysfunctions in Klinefelter syndrome subjects; to correlate them with testosterone levels and psychosexological and relational domains; and to evaluate the effects of testosterone therapy. We studied 62 non-mosaic naïve Klinefelter syndrome patients and 60 age-matched controls by means of medical history, psychosexological history, 15-item International Index of Erectile Function questionnaire, endocrine assessment, and dynamic penile color Doppler ultrasound. Twenty-five hypogonadal Klinefelter syndrome patients were studied after 6 months of testosterone replacement therapy. Klinefelter syndrome subjects have reduced 15-item International Index of Erectile Function scores regarding sexual desire, intercourse satisfaction, and overall satisfaction with respect to controls, and these aspects were significantly associated with testosterone levels. Klinefelter syndrome subjects had also higher prevalence of erectile dysfunction, but no relation with testosterone levels was evident. A high prevalence of a range of psychological disturbances was present in Klinefelter syndrome subjects with erectile dysfunction with respect to those without erectile dysfunction. No statistical difference in the prevalence of premature and delayed ejaculation was observed between Klinefelter syndrome and control subjects. Testosterone replacement therapy improved sexual desire, intercourse satisfaction, and overall satisfaction scores, but had no effect on erectile function. Penile color Doppler ultrasound was normal in all subjects. This study shows that sexual dysfunction in Klinefelter syndrome is multifactorial and related only in part to hypogonadism and largely to psychological disturbances. Evaluation and therapy of sexual dysfunction should include a combined andrological and psychosexological approach.

International investigation of neurocognitive and behavioral phenotype in 47,XXY (Klinefelter syndrome): Predicting individual differences.

47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty-four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures.

The effect of early life stress on the cognitive phenotype of children with an extra X chromosome (47,XXY/47,XXX).

Studies on gene-environment interactions suggest that some individuals may be more susceptible to life adversities than others due to their genetic profile. This study assesses whether or not children with an extra X chromosome are more vulnerable to the negative impact of early life stress on cognitive functioning than typically-developing children. A total of 50 children with an extra X chromosome and 103 non-clinical controls aged 9 to 18 years participated in the study. Cognitive functioning in domains of language, social cognition and executive functioning were assessed. Early life stress was measured with the Questionnaire of Life Events. High levels of early life stress were found to be associated with compromised executive functioning in the areas of mental flexibility and inhibitory control, irrespective of group membership. In contrast, the children with an extra X chromosome were found to be disproportionally vulnerable to deficits in social cognition on top of executive dysfunction, as compared to typically-developing children. Within the extra X group the number of negative life events is significantly correlated with more problems in inhibition, mental flexibility and social cognition. It is concluded that children with an extra X chromosome are vulnerable to adverse life events, with social cognition being particularly impacted in addition to the negative effects on executive functioning. The findings that developmental outcome is codependent on early environmental factors in genetically vulnerable children also underscores opportunities for training and support to positively influence the course of development.

Klinefelter's syndrome and sexual offending - A literature review.

BACKGROUND: Klinefelter's syndrome is a sex chromosome abnormality affecting approximately 1 in 1000 men. There have been suggestions that it is associated with a higher than average prevalence of sexual offending but to what extent does research evidence support this assertion? AIMS: This study aimed to conduct a systematic review of published research to establish the prevalence of sexual offending in men with Klinefelter's syndrome. METHOD: The databases MEDLINE, PsycINFO and EMBASE were searched from inception until 31 December 2016 by using a range of terms for Klinefelter's syndrome and for sexual offending. All selected papers were examined for quality by using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. RESULTS: We identified 53 relevant papers of which 10 met our inclusion criteria. All but one were prevalence studies conducted in a prison or hospital setting. The one, Danish, register-based cohort study did suggest an increased risk of sex offending among Klinefelter men, probably established before the diagnosis was made and, therefore, any hormone replacement instituted. CONCLUSION: There is insufficient evidence to date to support concerns about exceptional risk of sex offending among men with Klinefelter's syndrome. Rather, it is arguable that there is a research gap in understanding how the experience of and treatment for their condition may affect them. Copyright © 2017 John Wiley & Sons, Ltd.