DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study.

BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.

Cognitive Profile, Emotional-Behavioral Features, and Parental Stress in Boys With 47,XYY Syndrome.

OBJECTIVE: To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents. METHODS: We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods. RESULTS: All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers' stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not. CONCLUSIONS: Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.

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.

Positive effects of early androgen therapy on the behavioral phenotype of boys with 47,XXY.

47, XXY occurs in up to 1 in 650 male births and is associated with androgen deficiency, neurodevelopmental delays, and atypical social-behaviors. Previously, we showed that young boys with 47, XXY who received early hormonal therapy (EHT) had significantly improved neurodevelopment. The objective of this follow-up study was to examine the effects of EHT on social behavior in boys with 47, XXY. The study consisted of boys prenatally diagnosed with 47, XXY who were referred for evaluations. Twenty-nine boys received three injections of 25 mg testosterone enanthate and 57 controls did not receive EHT. Behavioral functioning was assessed using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, 2nd Ed., and the Child Behavior Checklist for Ages 6-18. The hypothesis that EHT may affect behavior was formulated prior to data collection. Questionnaire data was prospectively obtained and analyzed to test for significance between two groups. Significant differences were identified between group's scores over time in Social Communication (P=0.007), Social Cognition (P=0.006), and Total T-score (P=0.001) on the SRS-2; Initiation (P=0.05) on the BRIEF; and Externalizing Problems (P=0.024), Affective Problems (P=0.05), and Aggressive Behaviors (P=0.031) on the CBCL. This is the third study revealing positive effects of EHT on boys with XXY. There was a significant improvements associated with the 47, XXY genotype in boys who received EHT. Research is underway on the neurobiological mechanisms, and later developmental effects of EHT.

Social deficits in male children and adolescents with sex chromosome aneuploidy: a comparison of XXY, XYY, and XXYY syndromes.

We compare social skills in three groups of males with sex chromosome aneuploidies (SCAs) using the Social Responsiveness Scale (SRS). Participants included males with XXY (N=102, M=10.08 years), XYY (N=40, M=9.93 years), and XXYY (N=32, M=11.57 years). XXY had lower (better) SRS scores compared to XYY and XXYY. Scores were not significantly different between XYY and XXYY. In all groups, there were significantly more with SRS scores in the severe range compared to the SRS normative sample. All groups scored lowest (better) on Social Motivation. Relationships between SRS scores and demographic and clinical variables were examined. Results describe the social skills in males with SCA, and suggest that an additional Y chromosome may contribute to increased risk of autistic behaviors.

XYY chromosome abnormality in sexual homicide perpetrators.

In a retrospective investigation of the court reports about sexual homicide perpetrators chromosome analysis had been carried out in 13 of 166 (7.8%) men. Three men (1.8%) with XYY chromosome abnormality were found. This rate is much higher than that found in unselected samples of prisoners (0.7-0.9%) or in the general population (0.01%). The three men had shown prepubescent abnormalities, school problems, and had suffered from physical abuse. The chromosome analysis in all cases had been carried out in connection with the forensic psychiatric court report due to the sexual homicide. However, two men had earlier psychiatric referrals. All were diagnosed as sexual sadistic, showed a psychopathic syndrome or psychopathy according to the Psychopathy Checklist-Revised [Hare RD, 1991, The Hare Psychopathy Checklist-Revised, Toronto, Ontario, Canada: Multi-Health Systems]. Two were multiple murderers. Especially forensic psychiatrists should be vigilant of the possibility of XYY chromosome abnormalities in sexual offenders.

Criminality and antisocial behaviour in unselected men with sex chromosome abnormalities.

BACKGROUND: Previous studies on male patients with sex chromosome abnormalities (SCA), namely XYY and XXY, suggest that such patients commit criminal acts more frequently than expected. Most of these studies are affected by ascertainment bias. METHODS: Using a population-based sample of men with SCA, identified by screening 34380 infants at birth between 1967 and 1979, comparison between 16 XYY men, 13 XXY men and 45 controls were made in terms of frequency of antisocial personality disorder (APD) using the Schedule for Affective Disorders and Schizophrenia lifetime version. Rates of criminal convictions were examined in 17 XYY men, 17 XXY men and 60 controls. RESULTS: XYY males showed a significantly higher frequency of antisocial behaviour in adolescence and adulthood and of criminal convictions than the controls, but multiple regression analysis showed this to be mediated mainly through lowered intelligence. Property offences constituted the majority of offences in all groups. The XXY men did not show an increased rate of criminal convictions. It is possible that this apparently negative result relates to the relatively small numbers of cases and hence low power of this study. CONCLUSIONS: The findings of this study carry the advantage of not being affected by ascertainment bias and the disadvantage of having low power. It provides evidence for a slightly increased liability to antisocial behaviour in XYY men.

Evaluation of antecedent stimulus parameters for the treatment of escape-maintained aberrant behavior.

We evaluated a methodology for identifying the range of stimulus features of antecedent stimuli associated with aberrant behavior in demand contexts in natural settings. For each participant, an experimental analysis of antecedents (Phase 1) was conducted to confirm the hypothesis that task instructions occasioned increases in aberrant behavior. During Phase 2, specific stimulus features associated with the presentation of task instructions were assessed by evaluating the child's behavior across two distinct settings, therapists, and types of tasks in a sequential fashion. Aberrant behavior occurred immediately across settings and therapists, presumably because the presence of a discriminative stimulus for escape-maintained behavior (the delivery of a task instruction) occasioned aberrant behavior. However, aberrant behavior decreased initially across tasks, suggesting that familiarity with the task might be a variable. During Phase 3, an experimental (functional) analysis of consequences was conducted with 2 participants to verify that aberrant behavior was maintained by negative reinforcement. During Phase 4, a treatment package that interspersed play with task instructions was conducted to disrupt the ongoing occurrence of aberrant behavior. Immediate and durable treatment effects occurred for 2 of the 3 participants.

[47,XYY syndrome. Is diagnosis of significance?]. / Syndromet 47,XYY. Har diagnosen betydning?

Over a 10-year period, from 1984-1995, in the Norwegian county of Vest-Agder, five patients in a paediatric clinic were diagnosed as having chromosome constitution 47,XYY. There are 1,250 males born a year in Vest-Agder. The patients were identified with bias, and not in a routine or prospective screening programme. All patients except one, a child who was diagnosed by chance at the age of one week; were admitted because of moderate conduct disorders or problems at school and striking tallness of stature. The half-brother of one of the 47,XYY boys had Klinefelter's syndrome 47,XYY. We conclude that identification of 47,XYY syndrome and information about it were of significance and help in counselling the patients and their families.

Chromosomes in autism and related pervasive developmental disorders: a cytogenetic study.

Few studies have examined the occurrence of chromosome abnormalities in a large sample of patients with autism and related pervasive developmental disorders (PDDs). In the present report, the authors examined a consecutive series of 92 children with PDDs (DSM-III-R; 75 males and 17 females). A cytogenetic examination, including growth in folate deficient medium, was performed in all cases. Three patients (3.2%) (two females and one male) showed chromosome abnormalities: deletion of the long arm of chromosome 8; tetrasomy of chromosome 15; and XYY syndrome. Only the subject who had tetrasomy 15 met the criteria for autistic disorder, while the other were diagnosed as suffering from a PDD not otherwise specified (PDDNOS). Another patient showed an abnormal fragile site at Xq27 in three out of 100 cells. However, subsequent molecular studies did not confirm the presence of fragile-X syndrome. These results suggest that chromosome abnormalities are uncommon in traditional autism and may be relatively more common in people with PDDNOS.

Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders.

OBJECTIVE: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DMS-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI). METHOD: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine. RESULTS: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed. CONCLUSIONS: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine.

XYY chromosome anomaly and schizophrenia.

Sex chromosome anomalies have been associated with psychoses, and most of the evidence is linked to the presence of an additional X chromosome. We report a patient with XYY chromosome anomaly who developed schizophrenia.

[Hebephrenic symptoms as an expression of an XYY chromosome abnormality? Case report of a patient with suspected sexual abuse of his own 2 minor children]. / Hebephrene Symptomatik als Ausdruck einer XYY-Chromosomenanomalie? Kasuistik über einen Patienten mit Verdacht auf sexuellen Missbrauch zweier leiblicher, minderjähriger Kinder.

A 48 year old patient was hospitalised because of parasuicidal behaviour and suicidal ideation. He was under suspicion of having sexually abused his 4-year old daughter and his 4-year old son. At the age of 17, he was hospitalised in a psychiatric ward under the diagnosis of hebephrenic schizophrenia. He successfully received an insulin coma therapy. Because of his increased height (1.89 m), mental retardation and other psychical disorders in his youth, we now suspected him of having an extra Y chromosome which was confirmed by chromosome analysis. The non-uniform symptomatology of XYY-individuals includes a hebephrenic aspect. Concerning the different therapeutical and juridical consequences, we considered a critical investigation of the former diagnosis "Hebephrenic Schizophrenia".

A transsexual male with 47,XYY karyotype.

Transsexuals are usually found to have a normal chromosome complement. The literature to date documents four transsexuals with 47,XYY pattern. This paper reports a fertile male with major cell line of 47,XYY and a gender identity disorder.

XYY genotype and crime: 2 cases.

The presence of 47, XYY genotype has stimulated much debate as to whether these men are more likely to indulge in criminal and violent behaviour than 46, XY males. Two cases of XYY men who had committed murder are described, and the current literature regarding criminality and psychopathology in XYY males is reviewed. It is important that Forensic Psychiatrists with XYY patients are aware of these issues as the link between XYY genotype and criminality may be raised in court.

[A child with XYY syndrome as experienced by his mother. A report of daily journal recordings]. / Ein Kind mit XYY-Syndrom im Erleben seiner Mutter. Ein Bericht nach Tagebuchaufzeichnungen.

A mother's experiencing of the development of her son with "XYY syndrome" is presented based on notes from the mother's diary. According to recent findings in unselected longitudinal studies the boy clearly belonged to a subgroup of the more severely affected children. His developmental language and motor delays, other language problems and problems at school were typical, whereas his slightly reduced IQ, in the lower normal range, and aggressive and autistic symptoms were atypical. In many ways the mother's experience is comparable to that of parents of mentally retarded children. Complicating factors were the inconspicuous phenotype, late diagnosis and lack of professional help. It is shown that parental adaptation to a "handicapped" child can occur in phases. These can be understood through models of mourning or coping. It would be of great help to these families if self-help groups would be established.