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.

Maternal input to children with sex chromosome trisomies.

BACKGROUND: Although language difficulties are one of the most distinctive characteristics of the neuropsychological profile of children with sex chromosome trisomies (SCT), the analysis of the maternal input addressed to them is a neglected topic. AIMS: The present study aims to analyse the lexical, morphosyntactic, and functional features of the input addressed to children with SCT comparing them with those of the input directed to typically developing children (TD). METHODS & PROCEDURES: Participants were 38 mothers and their 8-month-old children, 19 with SCT and 19 TD children. Maternal utterances, collected during video-recorded play sessions, have been transcribed and coded. OUTCOMES & RESULTS: No significant differences between groups have been found in the lexical and syntactic characteristics of maternal input. However, considering the input functional features, the proportion of directives and questions was significantly higher in the maternal input addressed to children with SCT than in the input addressed to TD children whereas the opposite pattern was found in the proportion of affect-salient speech. CONCLUSIONS & IMPLICATIONS: The awareness of a possible delay in their children's language development could influence the way the mothers speak to them. In particular, the functional features of maternal input could be affected. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development. What this paper adds What is already known on the subject Studies in the literature identified a high percentage of language delays or impairments in children with SCT. To date, according to our knowledge, there are no studies that analyse the linguistic input addressed to these children. What this study adds The lexical and syntactic features of maternal input addressed to 8-month-old children with SCT are adequate to the children's communicative skills. However, the mothers of children with SCT seem to provide additional scaffolding in their verbal input, using a lower proportion of affect-salient speech and a higher proportion of questions. In addition, a higher proportion of directives suggests the use of a more demanding style. Clinical implications of this study The awareness of possible language delays could influence the functional features of input leading mothers to use a more supportive and demanding input. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development.

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.

A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47, XYY).

PURPOSE OF REVIEW: About one in 650-1000 children is born with an extra X or Y chromosome, referred to as sex chromosome trisomies (SCTs). Studying SCTs may uncover unique insights in neurodevelopmental pathways underlying the risk for neurobehavioral problems and psychopathology. There is also a clinical need for more knowledge about the phenotype of SCT with the recent introduction of noninvasive prenatal screening. RECENT FINDINGS: The reviewed studies illustrate an increased vulnerability for psychopathology such as (symptoms of) autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, depression and, to a lesser degree, psychotic disorders. Although traditionally the primary focus has been on language and learning problems, recent research suggests that impairments in executive functioning, social cognition and emotion regulation may also be key factors underlying the risk for neurobehavioral problems. SUMMARY: The research field of SCT is in need of a more longitudinal perspective to identify early markers of 'at risk' development, and to assess the effectiveness of early interventions. Neurocognitive markers that signal compromised neurodevelopment may prove to be helpful in this. Variability in the SCT phenotype provides a unique opportunity to identify not only genetic but also environmental factors that shape neurodevelopmental outcome, calling for studies focused on understanding individual differences.

Health professionals' involvement and information provision in genetic counseling following prenatal diagnosis of sex chromosome aneuploidy in Hong Kong.

This study supports training in genetic counseling for obstetricians and adoption of a multidisciplinary approach in the counseling process following prenatal diagnosis of sex chromosome aneuploidy.

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.

Children with sex chromosome trisomies: parental disclosure of genetic status.

Sex chromosome trisomies (SCTs) are frequently diagnosed, both prenatally and postnatally, but the highly variable childhood outcomes can leave parents at a loss on whether, when and how to disclose genetic status. In two complementary studies, we detail current parental practices, with a view to informing parents and their clinicians. Study 1 surveyed detailed qualitative data from focus groups of parents and affected young people with either Trisomy X or XYY (N=34 families). These data suggested that decisions to disclose were principally affected by the child's level of cognitive, social and emotional functioning. Parents reported that they were more likely to disclose when a child was experiencing difficulties. In Study 2, standardised data on cognitive, social and emotional outcomes in 126 children with an SCT and 63 sibling controls highlighted results that converged with Study 1: logistic regression analyses revealed that children with the lowest levels of functioning were more likely to know about their SCT than those children functioning at a higher level. These effects were also reflected in the likelihood of parents to disclose to unaffected siblings, schools and general practitioners. In contrast, specific trisomy type and the professional category of the clinician providing the original diagnosis did not affect likelihood of disclosure. Our study emphasises the complex weighing up of costs and benefits that parents engage in when deciding whether to disclose a diagnosis.

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.

Long-term management of patients with disorders of sex development (DSD).

Differences or disorders of sex development (DSD) describe a biological discrepancy between chromosomal, gonadal, and phenotypical sex, often affecting the morphology of the genito-reproductive organs. DSD is most often due to genetic abnormalities affecting chromosomal composition or single genes. Most children with 46,XX karyotype and DSD have congenital adrenal hyperplasia due to 21-hydroxylase deficiency and should be regarded as unchallenged females. For children with 46,XY DSD, the situation is even much more complicated since indeed an exact genetic diagnosis is still missing. Depending on the phenotype, this may be true for more than 80% of children with severe hypospadias, in contrast in post-pubertal patients with clinical evidence of complete androgen insensitivity, whom 95% show an underlying mutation within the androgen receptor gene. DSD and numerical aberrations of sex chromosomes, especially 45,X/46,XY mosaicism depends essentially on the assessment of the exact clinical morphology with a focus of the external and internal genital structures and of the endocrine and reproductive function of the gonads with the aim for a best prognosis of the child. This assessment should be done in a center of expertise.

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.

Parents' perspectives on the unforeseen finding of a fetal sex chromosomal aneuploidy.

OBJECTIVE: To investigate the parental perspectives of being confronted with an unforeseen fetal sex chromosomal aneuploidy (SCA), in light of the fact that this accidental finding is avoidable by rapid aneuploidy detection (RAD). METHODS: Exploratory qualitative interview study. We conducted 16 semi-structured interviews with parents who decided to continue pregnancy after the unforeseen finding of a fetal SCA. RESULTS: The communication of the unforeseen finding of SCA; the informed decision-making process concerning the pregnancy follow-up and the child and its future were the extracted themes. Parents were not prepared to accidental findings in routine prenatal diagnostics. All started an unguided search on the Internet. It is not at all clear whether parents have preference for an RAD test with X and Y probes Parents were satisfied with the post-test professional information they received to make an informed decision, whereas after birth questions still remained to be answered. CONCLUSION: Parents' perspectives may serve as major contributors to research on the question whether or not the X and Y probes should be standard included for purposes of RAD. The fact that RAD has the possibility to avoid accidental findings of SCAs, brings up the question whether any benefits outweigh the potential harms.

48,XXYY, 48,XXXY and 49,XXXXY syndromes: not just variants of Klinefelter syndrome.

UNLABELLED: Sex chromosome tetrasomy and pentasomy conditions occur in 1:18,000-1:100,000 male births. While often compared with 47,XXY/Klinefelter syndrome because of shared features including tall stature and hypergonadotropic hypogonadism, 48,XXYY, 48,XXXY and 49,XXXXY syndromes are associated with additional physical findings, congenital malformations, medical problems and psychological features. While the spectrum of cognitive abilities extends much higher than originally described, developmental delays, cognitive impairments and behavioural disorders are common and require strong treatment plans. Future research should focus on genotype-phenotype relationships and the development of evidence-based treatments. CONCLUSION: The more complex physical, medical and psychological phenotypes of 48,XXYY, 48,XXXY and 49,XXXXY syndromes make distinction from 47,XXY important; however, all of these conditions share features of hypergonadotropic hypogonadism and the need for increased awareness, biomedical research and the development of evidence-based treatments.

Parental decisions regarding prenatally detected fetal sex chromosomal abnormality and the impact of genetic counselling: an analysis of 57 cases in Taiwan.

OBJECTIVE: To analyse parental decisions regarding pregnancies with sex chromosome abnormalities (SCA). METHODS: Collected and reviewed records from our hospital for 1991-2005. Genetic counselling was provided by obstetricians or perinatologists. RESULT: Among 57 fetuses with SCA were 36 non-mosaic cases (four of 36, 45,X; 12 of 36, 47,XXY; seven of 36, 47,XYY, 13 of 36, 47,XXX) and 21 mosaic cases (15 of 21, 45,X mosaicism). Only 20% of 45,X mosaic pregnancies were continued, whereas all other mosaic pregnancies (100%) were continued (P = 0.004). Of 32 SCA cases counselled by a perinatologist, 66% (21 of 32) were continued. In contrast, 36% (nine of 25) of cases counselled by a general obstetrician were continued, a barely significant difference (P = 0.048). More couples chose to continue pregnancies in recent years. CONCLUSION: Genetic counselling by well-trained specialists is valuable, and the trend towards fewer terminations at our centre suggests improved parental knowledge of pathology associated with SCA.

Tall stature, insulin resistance, and disturbed behavior in a girl with the triple X syndrome harboring three SHOX genes: offspring of a father with mosaic Klinefelter syndrome but with two maternal X chromosomes.

AIMS: To describe the tall stature and its possible underlying mechanism in a Caucasian girl (age 12 years and 10 months) with 46,XX (28%)/47,XXX (72%) mosaicism and to identify the parental origin of her extra X chromosome. METHODS: The fasting glucose-to-insulin ratio was studied. The karyotypes of the girl and her parents as well as the presence of SHOX copies and the parental origin of her extra X chromosome were assessed. RESULTS: Clinical examination revealed a tall stature and severe acne, and endocrinological/metabolic assessment revealed insulin resistance. Fluorescence in situ hybridization cytogenetic analysis depicted the presence of three SHOX genes in the 47,XXX cell line of the patient. Karyotyping of her parents showed a normal 46,XX karyotype in the mother and 46,XY(93%)/47,XXY(7%) Klinefelter mosaicism in the father. However, DNA analysis unequivocally showed maternal origin of the extra X chromosome of the patient. CONCLUSIONS: This report suggests that SHOX gene triplication may produce a tall stature, even in the presence of preserved ovarian function. X triplication might predispose to insulin resistance and behavioral disorders.

A role for 5alpha-reductase activity in the development of male homosexuality?

Higher body hair with lower mesmorphism ratings were observed in Caucasian homosexual men compared with the general male population, reflecting elevated 5alpha-reductase (5alphaR) activity, and higher dihydrotestosterone-to-testosterone (DHT-to-T) ratio, in sharp contrast to 46,XY 5alphaR 2 deficiency subjects, who are often born with ambiguous, or female genitalia, but tend to grow up to be muscular, heterosexual men with very little body hair, or beard. One study also showed them scoring around dull normal IQs. A greater prevalence of liberal body hair growth in men with higher IQs and/or educational levels was also observed in several samples. The exceptions to this statistical trend are too unsettling, however. Nevertheless, the results of a number of published studies, including one showing higher DHT-to-T ratio in homosexual men, done with different objectives over a span of 80 years, together strongly support these findings. Furthermore, in an animal model, "cognitive-enhancing effects" of "5alpha-reduced androgen [metabolites]" were recently demonstrated.

Chromosomal abnormalities in a clinic sample of individuals with autistic disorder.

We examined data from the largest reported sample of autistic individuals who have been karyotyped with the aim of providing additional information in the search for autism disease genes. Individuals seen in the University of Iowa's Child and Adolescent Psychiatry Clinic since 1980 who had been diagnosed with autism were cross-referenced with the University of Iowa's Cytogenetics Laboratory database. We determined the number of individuals referred for cytogenetic testing and, of these, the number found to have gross cytological abnormalities. Medical records were reviewed for all cases with such abnormalities. Between 1980 and 1998, 898 subjects seen in the clinic were diagnosed with autism. Of these, 278 (30.1%) were referred for cytological studies; 25 (9.0%) of these were found to have chromosomal abnormalities. The most common chromosomal abnormalities were Fragile X, other sex chromosome anomalies, and chromosome 15 abnormalities. These data support the contribution of chromosomal abnormalities to a small but significant number of cases of autism, and highlight the involvement of chromosome 15 and the sex chromosomes.