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.

Delivering the Diagnosis of Sex Chromosome Aneuploidy: Experiences and Preferences of Parents and Individuals.

Increased prenatal diagnoses of sex chromosome aneuploidies (SCAs) amid limited knowledge of their prognoses heighten the need to understand how families contend with the implications of an SCA. To explore the experiences of parents and individuals who received a genetic diagnosis of an SCA (excluding Turner syndrome), we conducted semistructured qualitative telephone interviews with 43 participants affected by these conditions. Parents (n = 35) and individuals (n = 8) expressed almost unanimous interest in more optimistic portrayals of their condition from their providers, even when the prognosis is uncertain. While some participants reported success in receiving accurate information from their provider and identifying supportive resources, numerous families received outdated or misleading information about their condition and lacked direction in accessing follow-up care and support. Parents desire greater coordination of their child's medical care and access to care that approaches an SCA holistically. Opportunities remain to improve the diagnosis and care of individuals with SCAs.

Behavioral and psychological features in girls and women with triple-X syndrome.

Triple-X syndrome is a common sex chromosome aneuploidy, which appears in 1 out of 1,000 females. The aim of our study was to describe the behavioral features of a large group of girls and women with triple-X in comparison to a control group. A total of 72 subjects with triple-X and 69 subjects of an age-matched control group were included. Psychological and behavioral questionnaires were allocated to three age groups, representing a range of ages from young childhood to adulthood. Regarding the females between 4 and 7 years of age, we found significant differences for social problems, attention problems, and school performance. For the age group 8-17 years, we found larger significant differences for the majority of the scales listed in the child behavior checklist. The most significant differences (p < .001) were from total behavior problems, internalizing problems, and four other scales. Young females with triple-X have significantly lower general self-esteem, especially concerning school and family. In the adults, there were significant differences concerning psychological symptoms and distress, with higher scores in the triple-X subjects. Regardless, their mean scores were still in the normal range. We did not find clinical evidence for more than 50% of the triple-X females in any age group, indicating that approximately half of them do not have behavioral problems, and that more than 60% do not differ in their competence from the control group. However, our findings suggest that triple-X influences mental health and the overall well-being of the individuals across their whole life spans.

Vocal and gestural productions of 24-month-old children with sex chromosome trisomies.

BACKGROUND: Children with sex chromosome trisomies (SCT) frequently show problems in language development. However, a clear description of the communicative patterns of these children is still lacking. AIMS: To describe the first stages of language development in children with SCT in comparison with those in typically developing (TD) children. The purpose was to verify the existence of possible differences in communicative skills (in both vocal and gestural modality) and identify the presence of possible early predictors (i.e., low vocabulary size and low gesture production) of later language impairment in children with SCT. METHODS & PROCEDURES: Fifteen 24-month-old children with SCT (eight males with Klinefelter syndrome (KS) and seven females with triple X syndrome (TX)) and fifteen 24-month-old TD children (eight males and seven females) participated in the study. Their spontaneous communicative productions were assessed during a semi-structured play session in interaction with a parent. In addition, their vocabulary size was assessed using a parental report (the Italian version of the MacArthur Communicative Development Inventories). OUTCOMES & RESULTS: With regards to their vocabulary size, 60% of children with SCT (75% of children with KS and 43% of children with TX) were at risk for language impairments (i.e., they had a vocabulary size smaller than 50 words). In addition, TD children showed better lexical and syntactic skills than children with SCT in their spontaneous communicative productions. However, the production of communicative gestures was higher in children with SCT than in TD children. Boys with KS appeared to differ from TD males in more aspects of communication than girls with TX differed from TD females. CONCLUSIONS & IMPLICATIONS: The study showed the importance of early detection of language risk factors in children with SCT, while also considering the use of compensatory strategies (e.g., the use of communicative gestures).

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.

A case-control study of brain structure and behavioral characteristics in 47,XXX syndrome.

Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under-recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age- and sex-matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi-structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention-deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population-based studies of Trisomy X and also found in our sample.

[MALE, FEMALE, NEUTRUM. SEXUAL IDENTITY, UNCERTAIN SEX AND BIOLOGY]. / MASCHILE, FEMMINILE E NEUTRO IDENTITÁ SESSUALE, SESSO INCERTO E BIOLOGIA.

For almost 2000 years, human beings have been discussing about gender. New scientific evidences give interesting new points of view, partially subverting the normal dichotomy described by the "two-gender" theory. In this article, we are going to critically review the history of the approach towards people born with a Sexual-Differentiation-Disorder, passing through the analysis of the Italian National Ethics Committee's opinion, describing the modern scientific evidences on the gender-identity development, furthermore ruling out the new approach borned from the femminist philosophies, and the new biogiuridical experiments borned in Australia and Germany. Would it be possible a world where a person could be more then a male or a female?

The social behavioral phenotype in boys and girls with an extra X chromosome (Klinefelter syndrome and Trisomy X): a comparison with autism spectrum disorder.

The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106 controls, aged 9 to 18 years. We used the Autism Diagnostic Interview, Social Responsiveness Scale, Social Anxiety Scale and Social Skills Rating System. In the extra X group, levels of social dysfunction and autism symptoms were increased, being in between controls and ASD. In contrast to the ASD group, the extra X group showed increased social anxiety. The effects were similar for boys and girls with an extra X chromosome.

The psychiatric phenotype in triple X syndrome: new hypotheses illustrated in two cases.

BACKGROUND: Triple X syndrome (47,XXX or trisomy X) is a relatively frequent cytogenetic condition with a large variety of physical and behavioural phenotypes. METHOD: Two adult patients with a triple X karyotype are described. RESULTS: Their karyotype was unknown until some years ago. What these patients have in common is that they were diagnosed with a broader autism phenotype, they were sexually abused, they suffer from psychotic illness and they show challenging behaviour, suicidality and a decline in occupational capacity. DISCUSSION: These gene-environment interactions are discussed. Gene-environment interactions may explain the variety of behavioural and psychiatric phenotypes in triple X syndrome. Ongoing atypical development in adults is hypothesized. CONCLUSIONS: Gene-environment interactions and ongoing atypical development in adults should be taken into account in research concerning the psychiatric phenotype of developmental disorders, especially those involving triple X syndrome.