Neurocognitive and behavioral development in young children (1–7 years) with sex chromosome trisomy

Introduction

About 1 in 650–1000 children are born with a 47,XXY, 47,XXX, or 47,XYY chromosomal pattern, as a result of having an extra X or Y chromosome (1). Knowledge about the neurocognitive and behavioral phenotypes of these sex chromosome trisomies (SCTs) remains rather limited in comparison to other chromosome trisomies such as trisomy 21. This is somewhat surprising considering the disproportionate amount of genes on the X chromosomes that have been linked to brain functioning (2) and the reported congruent effects of X and Y chromosomes on the proportional size of cortical brain systems involved in adaptive functioning (3).

However, research has been fueled by an increasing awareness that studying gene–brain-behavior pathways in genetic conditions such as SCT may significantly contribute to our understanding of mechanisms of developmental risk that underlie neurobehavioral psychopathology. It has been proposed that such a bottom-up ‘behavioral neurogenetics approach’ (4) may provide a powerful tool that can complement the top-down study of populations identified based on behavioral classification of psychopathology. An advantage of studying SCT is that the genetic condition can be identified already very early in life through noninvasive prenatal screening testing (NIPT), which offers the opportunity to prospectively study early neurodevelopmental markers of individual differences in neurodevelopmental outcome.

The number of children prenatally diagnosed with SCT is expected to rise rapidly with increasing availability of the NIPT (5, 6). This calls for more knowledge about the phenotype of SCT to be able improve counseling, psychoeducation, and clinical care through early support or intervention if needed. There is a gap in knowledge specifically in the neurobehavioral and neurocognitive domain, as traditionally the majority of research studies (about 75%) has focused on the somatic/medical phenotype, with only 25% of the studies focusing on the neurobehavioral phenotype (7). In addition to identifying the range and severity of neurobehavioral problems that may be seen in SCT, it is also of great importance to have a better understanding of the early underlying cognitive mechanisms of behavior problems. Similar behavioral problems may arise from different underlying information processing dysfunctions in the brain. Knowledge about the cognitive processes that drive behavioral problems in SCT is essential for identifying the nature of developmental vulnerability as well as the recognition of specific targets for early intervention.

The TRIXY Early Childhood Study is a longitudinal study designed to identify early neurodevelopmental risks in children with SCT. Based on studies in adolescents and adults with SCT showing increased risk for social dysfunctioning, neurobehavioral problems, and psychopathology, one of the aims of this study was to identify early signs and symptoms in young children with SCT. These early signs include behavioral symptoms of neurodevelopmental disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and communication disorders. Key to the study was investigating the neurocognitive underpinnings of behavior rather than behavioral symptoms alone. Neurocognitive impairments may serve as sensitive early predictors of behavioral problems in later life, may function as markers for children with an ‘at-risk’ development (e.g. identify those that do not meet age-specific norms for language, cognitive, and motor skills), and may thus provide specific targets for early support and intervention.

Therefore, neurocognitive functioning of children with SCT was extensively studied, with a focus on early development in the age range of 1–7 years. Key domains of interest were language/communication, social cognition, emotion regulation, and executive functioning because (i) these are vulnerable domains identified in studies in adolescents and adults with SCT, (ii) these have been found to be key mechanisms driving neurobehavioral problems in adolescents and adults with SCT yet remain largely understudied in children, and (iii) these neurocognitive functions are developing at this young age showing individual differences in maturation (8, 9).

The TRIXY Early Childhood Study is based at the TRIXY Center of Expertise at Leiden University, the Netherlands, including a range of (inter)national recruitment and testing sites, including the Extraordinary Kids Clinic, Children’s Hospital Colorado, Denver, USA, directed by Dr N. Tartaglia. In total, 107 children with SCT aged 1–7 years were recruited with the help of clinical genetic departments, pediatricians, and national advocacy or support groups. All children with SCT had been diagnosed based on standard karyotyping for chromosomal abnormalities, with ≥80% of the cells showing SCT. The SCT group included children showing variation in the SCT karyotype (XXX, XXY, and XYY), time of diagnosis (prenatal and postnatal), or ascertainment/recruitment bias (i.e. the reason for enrollment in research). This variation allowed us to statistically test if specific SCT subgroups were characterized by different risk profiles. Recruitment strategy (‘ascertainment bias’) included a ‘prospective follow-up’ subgroup (51%), including children with a prenatal diagnosis who were actively followed over time, an ‘information-seeking’ subgroup (30%), including families looking for information about SCT but without specific concerns of their child’s development, and a subgroup of ‘clinically referred cases’ (19%), including children from families with specific developmental concerns. Within the SCT group, 33 girls with XXX, 50 boys with XXY, and 24 boys with XYY were included. In terms of the timing of diagnosis, 67% of the children were prenatally diagnosed vs 33% postnatally. An age-matched non-clinical control group of 102 children (58 girls and 44 boys) was recruited in the Netherlands. For all children, the exclusion criteria were a history of traumatic brain injury, severely impaired hearing or sight, neurological illness, or colorblindness. As part of the longitudinal design of the study, children were assessed during an initial baseline assessment and a follow-up assessment 12 months later, with a subgroup participating in additional neurocognitive training with a post-intervention follow-up.

In this review, we present the findings from the TRIXY Early Childhood Study in terms of (i) the broad behavioral profile of young children with SCT aged 1–7 years as well as specific domains of neurocognitive and behavioral functioning: (ii) language and communication, (iii) social cognition, social adaptive behavior, and autism spectrum symptoms, and (iv) emotion regulation, executive functioning, and symptoms of ADHD.

Social cognition, social behavior, and autism spectrum symptoms in young children with SCT

Another key area of research was social cognition, social behavior, and autism spectrum symptoms. Our data in 1- to 7-year-old children with SCT reveal vulnerabilities in social adaptive and communicative behavior at a very early age, expressed in difficulties with responding and initiating early social communication and in daily life social-emotional development (21). We also found more social withdrawal during observed social interactions in a structured play situation in children with SCT, aged 1–7 years. Interestingly, we found that social withdrawal is more pronounced when social load in the interaction is high, meaning that social input and demands from the environment are conditional for the formation of social behavior in interaction with the social environment (22).

To explore the extent to which early social vulnerabilities are associated with symptoms that are typical in ASD, we examined the possible impact of SCT on the early appearance of ASD symptoms. The results demonstrated that ASD symptoms, in particular the domains of social interaction and communication, are substantially higher in children with SCT compared to the general population. In our sample, 22% of the children with SCT were at clinical risk for a clinical diagnosis of ASD (23, 24). Joint attention, a pivotal dimension of infant social cognition that serves as an important milestone in typical social development, showed to be predictive of severe social impairments reflected in ASD symptoms in children with SCT at 1 year follow-up (24).

In order to understand how social cognitive development underlie social vulnerabilities in SCT, we investigated the possible impact of SCT on early social cognitive functions and evaluated developmental effects from a cross-sectional perspective. By using eyetracking (see Fig. 1 for the laboratory setup), we found significant differences between children with SCT and typically developing children in basic social cognitive mechanisms of social orienting to faces and eyes and joint attention, indicating that children with SCT are less inclined to visually orient toward social important information and have difficulties with following gaze and point gestures of a social partner. Also, we found significant differences between children with SCT and typically developing children in more complex and specialized social cognitive abilities: young children with SCT showed vulnerabilities in the ability to understand emotions from facial expressions. Similar, substantial difficulties with understanding mental states of others (i.e. theory of mind) were found in young children with SCT (22). These findings suggest that social behavioral difficulties may be anchored in altered perceiving and processing of social information already early in neurodevelopment.

View Full Size

Illustration of the laboratory setup for eyetracking and arousal measurement in the TRIXY Early Childhood Study.

Citation: Endocrine Connections 12, 5; 10.1530/EC-22-0494

• Download Figure
• Download figure as PowerPoint slide

To date, there has been no research evaluating the potential effects of early neurocognitive training in SCT. Therefore, we aimed to investigate the efficacy of a computer-based neurocognitive training program in 4- to 8-year-old children with SCT, targeting at improving the understanding of social cues from facial expressions. The study showed a significant effect of early neurocognitive training on emotion recognition abilities in 4- to 8-year-old children with SCT, suggesting that there are opportunities for positively supporting the development of social cognition in children with an extra X or Y chromosome (25).

Taken together, the results presented in this section concerning the impact of SCT on early social cognitive development reveal that already very early in development, SCT is associated with vulnerabilities in social behavioral functioning and underlying early social cognitive mechanisms. We found that SCT impacts social behavioral development from the first years of life, reflected in vulnerabilities in early social communication and social withdrawal during social interactions. Early social cognitive dysfunctions that may underlie social adaptive vulnerabilities in SCT include social orienting, joint attention, and more complex social cognitive abilities such as the understanding of emotions from facial expressions and theory of mind. These results suggest a profile of social (cognitive) vulnerabilities in young children with SCT, calling for close evidence-based early monitoring and targeted support when necessary. Also, our study suggests that there are opportunities for positively supporting the development of social cognition, in the domain of facial emotion recognition, in young children with SCT.

Discussion

The findings of this review suggest that early signs of neurocognitive impairments and symptoms of psychopathology can be identified in young children with SCT. The impact of the additional sex chromosome on neurocognitive development was found on all domains of interest, including language, communication, social cognition, emotion regulation, and executive functioning, albeit in some domains more pronounced than others and with a differential role of maturation (age). This review also provides the initial evidence for early symptoms of neurodevelopmental disorders, including ADHD, ASD, and communication disorders, across the full range between 1- and 7-year-olds.

Key to the TRIXY Early Childhood Study was to identify early neurocognitive impairments, as they function as markers for children with an ‘at-risk’ development, which may provide specific targets for early support and intervention. It is important to point out that although differences between children with SCT and controls on average were found with medium to large effect sizes in most of the TRIXY studies, only a subgroup of children with SCT had scores in the clinical range. Thus, while some children with SCT may already be recognized as at risk in their development compared to peers of their age, there are also many children with SCT who do not experience any or only mild impairments. Nevertheless, findings from the TRIXY Early Childhood Study showed a ‘growing into deficit’ phenomenon (31): neurocognitive difficulties in children with SCT that were present from as early as 1 year of age were found to become pronounced with increasing age. This could reflect increasing problems that may emerge and present more profoundly with age, in relation to increasing demands from the environment. One explanation for this phenomenon is that neurocognitive functions come ‘online’ at different and later stages of development, due to the maturation process of the brain, making it possible that the effect of early disturbances on the brain may only become noticeable many years later in development. Important to note here is that most of the studies reported in this review examined the role of age cross-sectionally; longitudinal studies are needed to provide further clarity on the developmental trajectories of children with SCT.

Another key result of the TRIXY study was that neurocognitive skills may present as very relevant candidates to serve as specific targets for early support and intervention in children with SCT. Not only did the results show a predictive value of neurocognitive impairments (in the domain of language and communication) with regard to later psychopathology, our results also provide the initial support for the effectiveness of neurocognitive training (in the domain of social cognition). These promising results suggest that there are opportunities for positively supporting the development of social cognition in children with an extra X or Y chromosome.

The study of genetic conditions, such as sex chromosomal trisomies, comes with specific recruitment and study design challenges. Specific to SCT is the low diagnosis rate, whilst the prevalence of the condition is relatively high, making it difficult to include enough participants that cover the full range of potential phenotypic expression and not only those who experience difficulties in daily life that led to diagnosis of the chromosomal aneuploidy in the first place. The approach that was used in the TRIXY Early Childhood study was to record how families came to learn of the study to correct for potential recruitment bias, and three subgroups were identified: (i) ‘active prospective follow-up’ (largest group in the full cohort), (ii) ‘information-seeking parents’, and (iii) ‘clinically referred cases’ (smallest group in the full cohort). The studies reported in this review controlled for recruitment condition in their analysis and found no significant influence of recruitment bias: how parents enrolled in the study did not affect the study results. This may suggest that the children participating in the TRIXY Early Childhood Study reflect a representative subsample of diagnosed children with SCT and that clinical examination of the developmental impact is highly relevant in children with SCT. Having a (prenatal) diagnosis of SCT does not reliably predict what the exact outcome will be for any given individual, highlighting the importance of close monitoring throughout development and to act promptly with guidance and tailor-made early interventions when needed.

When it comes to the specific karyotypes, 47,XXX, 47,XXY, and 47,XYY, most of the studies included in this review found no significant differences between the specific karyotypes on neurocognitive and behavioral outcomes. The overall absence of significant differences suggests that children with 47,XXX, 47,XXY, and 47,XYY karyotypes may show substantial similarities in their neurocognitive and behavioral outcomes, which fits with findings in neuroimaging studies showing convergent effect of the X and Y chromosomes on brain structure (3). Nonetheless, boys with an extra Y chromosome in our sample at some points also showed a slightly more impaired profile. It should be mentioned, however, that the group of boys with 47,XYY was relatively small compared to the other two karyotype groups, and results that included the comparison of children with 47,XYY and the other groups should be interpreted with caution.

Within the TRIXY Early Childhood study, some of the children were treated with testosterone supplements. Whereas early testosterone treatment is considered evidence-based practice when treating a micro-penis in young infants with Klinefelter’s syndrome, far less is known about the impact of early testosterone treatment on neurocognitive development. In order to address this, Aksglaede and colleagues recommend to wait for larger, randomized, and placebo-controlled studies to investigate the potential beneficial side effects of testosterone in children with Klinefelter syndrome. Within the TRIXY Early Childhood Study, we did not analyze outcomes stratified by testosterone treatment, as treatment was solely provided based on individual clinical evaluation of symptoms, relying on varying clinical guidelines, and therefore not suited for scientific analysis. Preliminary results from studies examining the effects of early testosterone treatment in SCT (Davis, 2022, this issue) showed no significant differences on any neurodevelopmental outcomes measured. Future studies are needed to provide evidence-based recommendations to guide clinical care in infants with Klinefelter syndrome.

The TRIXY Early Childhood Study was made possible by the collaboration and extensive effort of multiple international research sites. In close collaboarion with academic medical centers, researchers, and patient organizations involved, over a 100 families with young children with an additional X and Y chromosome enrolled in the study. It is imperative for empirical studies that examine genetic conditions to include a large enough sample to capture the wide heterogeneity in cognitive and behavioral outcomes so often described in these genetic populations. Thus, we strongly encourage more and closer international collaboration in order to advance the overall research and clinical field regarding sex chromosomal aneuploidies. This is also supported by our data, given that almost all of the reported studies in this review did not find significant differences between recruitment sites (US vs the Netherlands).

When it comes to clinical care, the results of the TRIXY Early Childhood Study have important clinical implications. Working in a clinical setting with children with SCT, professionals need to be aware of the variation in (neurocognitive) functioning between children with SCT just as much as the developmental risk for impaired (neurocognitive) functioning. From a young age, difficulties with neurocognitive functions (including language, emotion regulation, executive functioning, and social cognition) can be part of an individual’s cognitive profile, even in the face of average intelligence. For example, children with SCT might fail to meet age- and gender-specific norms on language or cognitive tests or are considered emotionally immature entering (pre)school. Professionals should be aware that children with SCT can have mild impairments on many different domains (e.g. vocabulary delay, poorer motor skills, and frequent temper tantrums) that in typically developing peers might not be signaled as clinically relevant. However, our results show that ‘a wait-and-see approach’ might not be applicable for this group of children, given that many children with SCT had continuous or increased risk for developmental delays. Identifying risk for impairments in (specific areas of) neurocognitive functions can result in specific guidelines on what function needs to be supported during treatment. For example, speech therapy should be considered for children with predominately language delays. In addition, while these results indicate that neurocognitive training might be a valuable component in treating difficulties in children with SCT, it is crucial not to focus narrowly on these specific neurocognitive functions alone but also address the social, emotional, and behavioral development in relation to the social context in which a child with SCT grows up, such as family and school.

The research field of SCT is in need of more longitudinal designs, in order to study the developmental pathways of individuals with SCT from early childhood into school-age, adolescence, and adulthood. In addition, future studies should investigate the role of environmental factors on the variability in outcomes in SCT, including family and parental factors, which may also pinpoint protective factors. In terms of advancing the clinical care for these individuals, examining which interventions are effective in minimizing the developmental impact of SCT would be an important area of future research as well.

The main conclusion to be drawn is that (a subset of) children with an extra X or Y chromosome are vulnerable from a very early age on to numerous important neurodevelopmental domains, including language/communication, social cognition, and emotional and behavioral regulation. Increased symptoms of neurodevelopmental disorders are found in young children with SCT compared to typically developing peers. Our findings from the TRIXY Early Childhood Study are among the first to show that individual differences between children with SCT already exist in early childhood and that these can be predictive of future psychopathology, including behavioral symptoms. It provides support that neurocognitive functions work as underlying building blocks for future development and that these at-risk markers can also be targeted for early interventions. In addition, these collaborative results demonstrate that genetic populations that can be identified early in life (even before birth) can serve as a natural at-risk model to examine early pathways into psychopathology.

Declaration of interest

None of the authors have conflicts of interest.

Funding

This work was supported by a grant from the Dutch Research Council (NWO) (grant number 016.165.397 to SvR).

Author contribution statement

SvR: conception, design, writing of the manuscript. KK: design, writing of the manuscript. NB: writing of the manuscript. EU: writing of the manuscript. HS: conception, design, and writing of the manuscript. All authors contributed to the article and approved the submitted version.