This study characterizes and compares the profile of social skills and autism symptomatology in a large cohort of three most common SCA conditions in males, including Klinefelter/XXY, XYY, and XXYY syndromes at two study sites. Overall, the KS group had fewer reports of social difficulties and fewer significant differences from the normative sample compared to the XYY and XXYY groups. However, even in the KS group, the mean SRS subscale results were in low end of the mild-to-moderate range with wide variability in scores, and there was a significantly higher percentage (almost 20%) of participants with scores in the severe range compared to the normative sample. These findings are consistent with other studies showing higher rates of social difficulties and autistic behaviors in males with SCA (Bishop, D. V. et al., 2010
; Geerts, M. et al., 2003
; Tartaglia, N. et al., 2010
; van Rijn, S., Aleman, A., De Sonneville, L., & Swaab, H., 2009
; van Rijn, S., Swaab, H., Aleman, A., & Kahn, R., 2006
; van Rijn, S. et al., 2008
When we examined factors within the SCA study groups that may be related to SRS scores, we found that lower verbal cognitive abilities (in the KS and XXYY groups), a postnatal diagnosis of SCA (in the KS and XYY groups), and a previous clinical diagnosis of ASD (in all three groups) were all associated with greater impairment in social responsiveness. There were no significant correlations between age, nonverbal cognitive abilities, or SES and SRS scores in any of the study groups.
4.1 Social Responsiveness and Verbal Abilities
When considering correlations between cognitive abilities and SRS scores in the three study groups, there was a relatively weak but significant correlation between verbal cognitive scores and SRS scores (τ=−.21 to −.34) in KS and XXYY groups, but not the XYY group. Thus, the poorer language abilities among individuals with KS and XXYY may be contributing to their social difficulties. This finding is similar to the 2009 study by Bruining et. al (2009)
where children with KS who had an ASD were more likely to have a comorbid language disorder (Bruining, H. et al., 2009
). From a clinical perspective, these results suggest that when individuals with SCA are presenting with concerns related to social functioning and possible ASD diagnosis, evaluation of verbal cognitive abilities and speech-language skills are important since they may be a factor contributing to social difficulties that can be targeted in an intervention plan.
In the XYY group, our results suggest that the social difficulties and autism symptomatology are more independent of their verbal abilities since verbal/VIQ scores were not significantly correlated with deficits in social responsiveness. This finding may be partly related to the more significant social and behavioral difficulties in XYY compared to KS (Ross, J. et al., in press
). Thus, individuals with XYY with social and behavioral disorders but normal verbal cognitive abilities would be more likely to be ascertained compared to KS.
4.2 Social Responsiveness and Timing of SCA Diagnosis
When comparing subgroups of participants with KS and XYY diagnosed in the prenatal period to those in the postnatal period, the subgroups with a prenatal diagnosis had fewer social difficulties compared to those diagnosed in the postnatal period. This is consistent with previous literature of improved outcomes in individuals with a prenatal diagnosis.(Linden, M. G., Bender, B., & Robinson, A., 1996
; Linden, M. G. & Bender, B. G., 2002
) These differences are likely due to a variety of factors including an increased likelihood of prenatal care, increased family supports, increased awareness of possible neurodevelopmental problems, and earlier initiation of early intervention therapies and supports in the prenatally diagnosed groups. In this study, SES was not significantly different between those with a prenatal or postnatal diagnosis of XYY, nor was SES significantly correlated to SRS scores for any of 3 the study groups.
In individuals with a postnatal diagnosis, the SCA condition was ascertained due to the presence of features that were concerning to medical professionals. In most cases, the indications for genetic testing are related to moderate to severe developmental delays or cognitive impairments, behavioral disorders, or the presence of autism spectrum disorders, all of which would contribute to the higher SRS scores in this subgroup. These study results are important in genetic counseling of individuals with a prenatal diagnosis of SCA. It is important to point out that while the risk for delays and social difficulties is increased compared to the general population, there is a wide spectrum of involvement and not all individuals have significant delay, social deficits, or autism spectrum disorders.
4.3 Social Responsiveness and Previous Clinical Diagnoses of ASD
While it makes sense that those with a previous clinical diagnosis of ASD would have higher SRS scores than those without a previous diagnosis, it was interesting to find that a large percentage of individuals with SCA without a previous diagnosis of ASD also had elevations in SRS scores compared to what is expected in the general population (over 40% in the KS group, and over 70% in the XYY and XXYY groups). These results suggest that many of these participants have social skills difficulties and autistic symptomatology that are subthreshold for a classification of ASD or who may indeed meet criteria for ASD upon further evaluation.
4.4 Social Motivation in SCA
Another interesting finding was the general preservation of skills in the Social Motivation subscale compared to the other subscales of the SRS in the three SCA study groups. The Social Motivation subscale of the SRS includes behaviors such as desire for social interactions, withdrawal or avoidance of social settings, and confidence in social situations. This finding suggests that most children and adolescents with SCA have an interest in and are motivated by social interactions, however their deficits in social cognition, social communication, and autistic mannerisms are stronger contributors to their overall social difficulties.
This finding is consistent with a series of previous reports in an adult cohort with KS where van Rijn et al. reported that the frequency of social interactions (i.e. social motivation) did not differ between a KS group and control group (van Rijn, S. et al., 2008
). However, the study did find that the KS group exhibited social cognitive deficits in multiple other areas such as recognition of facial expressions, processing of social cues (van Rijn, S. et al., 2006
), and understanding of affective prosodic language cues (tone of voice) (van Rijn, S. et al., 2007
). Similar studies that deconstruct different aspects of social skills in XYY and XXYY have not been reported, and would be an important contribution since social difficulties are more common in these groups.
The apparent relative strengths and preservation of social motivation is important for two other reasons. First, an interest in reciprocal social interactions does not exclude diagnosis of an ASD. Children and adolescents with SCA, despite typical social motivation and a desire for friendships and social interactions, may still have deficits in social awareness, social cognition, communication, and other autistic behaviors that are still causing enough impairment to meet criteria for diagnosis of an ASD. Thus, the presence of social motivation in the SCA population should not be used by clinicians as a reason to dismiss or not pursue further ASD evaluation in children with SCA who have social difficulties. This would result in under diagnosis of ASDs in SCA, and those undiagnosed may then not receive or qualify for services and interventions targeting the social and communication deficits. Second, these results show that children with SCA may be more socially motivated than would be expected in the typical profile of children with social deficits or ASD, and this positive interest in social engagement can be used in developing intervention strategies for the SCA group.
4.5 The Effect of Extra “X” or “Y” Chromosomes
When comparing SCA groups and phenotypic features, questions arise around whether differences between the groups are due to gene dosage effects from the extra X and/or Y chromosomes, or whether differences in exposure to androgens may be contributing to differences. In both XXY/KS and XXYY, the extra X chromosome leads to testicular dysfunction and decreased overall testosterone levels compared to typical males with XY and to males with XYY who have normal testosterone levels. These differences in testosterone levels are usually present by mid-puberty and throughout adulthood, when the majority of individuals with KS and XXYY are treated with testosterone replacement therapy. There is also some evidence that prepubertal testosterone levels are lower in male children with KS (Lahlou, N., Fennoy, I., Carel, J. C., & Roger, M., 2004
; Ross, J. L. et al., 2005
), which may play a role in neurodevelopmental differences. While it could be proposed that some of the social difficulties and language deficits in KS and XXYY may be associated with neurodevelopmental effects of lower androgen levels, our results suggest that the effect of the extra Y chromosome in the XYY and XXYY groups is more strongly associated with social deficits and ASD symptoms compared to the extra X chromosome and androgen deficiency effects.
To further consider the effects from the extra X and/or Y chromosomes on social functioning, the most interesting comparisons are between the XXY/KS and XYY groups (two sex chromosome trisomy groups with similar cognitive abilities), and the comparison between the XYY and XXYY groups (where the extra sex chromosome in the XXYY group leads to significantly lower cognitive scores of 10 or more points in both verbal and nonverbal domains compared to XYY). First, for age-matched groups with similar verbal and nonverbal cognitive abilities (KS versus XYY), the XYY group presents with significantly more social deficits and autistic symptomatology compared to the KS group. This, combined with the lack of relationship between all IQ measures and SRS scores in XYY, provides evidence that the socialdeficits in XYY may be independent of cognitive abilities.
In the second comparison (XYY vs. XXYY), despite greater clinical involvement characteristic of XXYY, our study found SRS Total and subscale scores (averages, score distributions and category proportions) are nearly identical in XYY and XXYY. This finding suggests that the effect of the extra Y chromosome on social skills and autistic behaviors is more significant than the effect of the extra X chromosome, and, again, is also relatively independent of cognitive abilities.
The phenotype of the SCA conditions results from overexpression of genes on the sex chromosomes, however the specific genes associated with the behavioral phenotype of SCAs are not yet known. There are several genes on the sex chromosomes important in neuronal development and neurotransmission, and which have been associated with ASD. For example, the ASMT
gene codes for the enzyme which catalyzes the final step of melatonin synthesis, and both polymorphisms and duplications in the ASMT
gene have been associated with an increased risk for ASD.(Cai, G. et al., 2008
; Jonsson, L. et al., 2010
; Melke, J. et al., 2008
) Neuroligins are cell adhesion molecules involved in synapse formation and function, and neuroligin 4 (NLGN4
) gene mutations have also been associated with autism (Jamain, S. et al., 2003
; Laumonnier, F. et al., 2004
; Yan, J. et al., 2005
), and have been proposed as being important in the language disorders in children with SCAs (Bishop, D. V. & Scerif, G., 2011
). The protocadherin 11 (PCDH11Y
) gene on the Y chromosome is expressed primarily in brain tissue during synaptogenesis (Durand, C. M. et al., 2006
), and abnormal expression of protocadherin proteins may result in abnormal synapse formation related to ASD. Further studies of how these and other X&Y chromosome genes contribute to the neurodevelopmental phenotype of SCA is an important next step in this research, and results may also help us to better understand the biological basis for the male bias in ASD.
There are some important limitations of this study. Our study samples were largely clinically referred and therefore, may represent a group of males with SCAs with more clinical involvement. However, not all participants were clinically referred for behavioral or social issues, as many were ascertained by endocrinology clinics. Also, though the SRS is psychometrically sound and able to measure a range of autistic symptomatology without floor effects, it is not able to diagnose ASDs. Additional studies of autism in SCAs are needed and should include other well-validated measures and not rely solely upon parent-report questionnaire and historical autism diagnosis information.
In summary, our results show that males with KS, XYY and XXYY are at increased risk for social deficits and do demonstrate a range of autistic behaviors. While in the cognitive domains males with XYY often fare better than XXYY, there was an almost identical profile of social deficits in the XYY and XXYY groups. These results point to the need for further genetic studies of the relationships between genes on the Y chromosome and autistic behaviors.
- This study compares social skills in three groups with sex chromosome aneuploidies.
- In XXY, XYY and XXYY a significant proportion of participants had social deficits.
- Lower verbal abilities (in XXY and XXYY) were significantly related to social skills.
- Findings in XYY and XXYY suggest the Y chromosome may contribute to social deficits.