The goal of this study was to compare and contrast behavioral and social phenotypes in boys with the sex chromosome disorders, 47,XYY and 47,XXY (KS) versus age-matched controls. The current study extends previous findings by providing data on a larger sample of boys with XYY or KS who were recruited from a wide geographic region on the basis of karyotype rather than psychological diagnoses. An advantage to comparing the XYY and KS groups in this study is that they have similar general cognitive abilities.15
Importantly, in previously published newborn screening studies and in the current study, there is significant variability within the groups, and many of the boys with XYY or KS did not show significant behavioral problems. Our results do indicate, however, that there is increased risk for significant behavioral problems in a subset of boys from the XYY and KS groups, in agreement with previous reports.5,23,24,53
The behavioral phenotypes in the XYY and KS groups differed somewhat in that problem behaviors were more significant in the XYY versus the KS group. There did not seem to be increased anxiety or depressive symptoms in either group.
The behavioral phenotype previously described in XYY syndrome includes an increased risk of impulsivity,5,23,24
poor adaptation to social situations, and behavioral problems related to externalizing behaviors.16,17,24–30
Although our results support these increased risks, it is important to underscore that past research linking XYY to increased risk for criminality must be viewed with extreme caution, given their reliance on small sample sizes and selected rather than broader-based sampling approaches.
In our study, 62% of boys with XYY and 42% of boys with KS had significantly elevated symptoms of ADHD, based on the CPRS-R, compared with a 4% to 5% prevalence rate of ADHD in the general population.54,55
Previous studies also report an increased risk for ADHD, including 11% of a cohort of 26 males with XYY,11
and 63% in a group of 51 males with KS based on standardized DSM-IV interview.56
Half of the XYY group in the current study scored above the cutoff score on the SCQ for screening for ASD, versus 12% of the KS and none of the control group. These frequencies differ from the overall prevalence of ASD in the general population of ~1 of 125,57
and are consistent with previous reports,11,32–34
suggesting there may be an increased risk for ASD features, particularly in the XYY group. The behavioral phenotype of both XYY and KS includes features that overlap considerably with ASD, such as language disorders, other social deficits, and anxiety/withdrawal symptoms. Additional diagnostic studies are needed to determine whether male subjects with XYY or KS indeed meet criteria for ASD by using standardized autism assessments.
Interestingly, the XYY but not the KS group tended to have increased head circumference relative to the control group, in agreement with most,11,17,33
but not all58
previous studies. Brain imaging studies have demonstrated relatively reduced brain volumes in boys with KS.59
In contrast, increased head circumference and increased brain volumes have also been reported in a subset of children with autism.60–62
Future imaging studies will define the underlying brain structure related to these findings in XYY.
Potential factors related to the observed behavioral differences in the XYY and KS groups are their age at diagnosis and the reason for diagnosis. Ascertainment from clinic samples referred for developmental and behavioral issues63
could affect the description of the XYY phenotype. Previous studies have supported better neurodevelopmental outcomes in prenatally versus postnatally diagnosed KS cohorts,25
likely reflecting differences in SES, genetic, and environmental factors in the 2 groups and less bias toward behavioral/developmental findings in boys diagnosed prenatally. In agreement, we also noted relatively better outcomes in prenatally versus postnatally diagnosed boys with KS. We did not find a significant impact of prenatal diagnosis in the XYY group, most likely reflecting the smaller sample size and fewer prenatally diagnosed subjects in this group. Most (59%) of our KS cohort but only 23% of the boys with XYY were diagnosed prenatally. Most (77%) of the boys with XYY were diagnosed postnatally on the basis of developmental or behavioral issues, which would create a sampling bias for more severe behavioral features in our sample. Also, in contrast to KS, the diagnosis of XYY is often delayed.11,30,64
Milder behavioral findings would perhaps also have been found in a larger, prenatally diagnosed XYY cohort; however, subsets of boys with XYY ascertained without bias from newborn screening studies also have behavior findings,18,40,65
suggesting that the association with the karyotype is genuine.
We previously noted considerable overlap in the XYY and KS groups for cognitive function.15
The similarity of findings in these 2 genetic disorders may be related to overlapping gene dosage abnormalities in the pseudoautosomal region (PAR1), a 2.6-Mb interval at the tips of Xp and Yp, where genes are equally expressed.66,67
Similarly, tall stature in both of these populations is thought to be attributable to increased expression from 3 instead of 2 copies of the height-determining SHOX gene.68
The distinctions in behavioral phenotypes of KS and XYY may be related to hormonal and/or genetic factors that differ between the 2 groups. The clearest hormonal difference is normal testosterone in XYY versus testosterone deficiency in KS; behavioral effects of testosterone are well known.69
Genetic factors that differ in XYY versus KS are related to the extra X chromosome in KS versus the extra Y chromosome in XYY. Because a substantial fraction of genes on the X escape X-inactivation to some degree,70
these genes would be overexpressed in the KS group only. The parental origin of the extra chromosome may differentially affect KS and XYY because in KS, the supernumerary X chromosome may be maternal or paternal, whereas in males with XYY, the extra Y chromosome is always paternal in origin. Notably, no parent of origin difference in the KS phenotype has been conclusively demonstrated.71–74
The extra Y chromosome in XYY remains active, and expression of all Y-linked genes is increased in the XYY group only. Previously, the Y chromosome was thought to have a relatively small number of sex-determining and testicular function genes, but is now known to contain additional genes.75,76
Given the increased proportion of boys with XYY versus KS with elevated screening SCQ scores, we hypothesize that the ASD-like behavioral features in XYY are based on an abnormal dosage of 1 or more of these Y-specific genes. Y chromosome candidate genes with potential neural impact include PCDH11Y
(transducin β-like 1, Y-linked),78,79
(neuroligin 4 Y).78,79
Mutations of the closely related, X-linked gene NLGN4×
(neuroligin 4 X) have been firmly implicated in autism/ASD and mental retardation (reviewed in ref 80