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Aim To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development.
Methods We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R).
Results A comparison of 36 typically developing males (mean age 11y, SD 1y 9mo), 31 males with Klinefelter syndrome (mean age 9y 8mo, SD 1y 8mo), and eight males with XYY syndrome (mean age 11y 6mo, SD 1y 11mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p<0.006; XYY vs males with Klinefelter syndrome, p<0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p<0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD.
Interpretation The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.
XYY syndrome is a genetic disorder characterized by an additional Y chromosome. Affecting only individuals who are phenotypically male, XYY syndrome is a common sex chromosome aneuploidy condition in humans, occurring in approximately one in 1000 live male births.1 XYY syndrome has been associated with subtle physical features including tall stature2 and increased head circumference,3–5 though not all studies have observed the latter finding.6 XYY syndrome is also associated with cognitive-behavioural deficits, most notably impairments in language and motor ability,3,5–7 and is thought to entail increased risk of autism spectrum disorders (ASDs).3,8–10
In contrast, Klinefelter syndrome is a genetic disorder characterized by an additional X chromosome. Also affecting only individuals who are phenotypically male, Klinefelter syndrome has an estimated prevalence of one in 600 live male births1 and often manifests with a characteristic physical phenotype, which includes reduced head circumference,6 tall stature, and hypogonadism.11 Individuals with Klinefelter syndrome exhibit impairments in language and motor ability similar to those observed in XYY syndrome,5 raising the question of why two disorders with identifiably disparate genetic bases produce partially overlapping cognitive phenotypes. The present study addressed this question by highlighting regional neuroanatomical similarities and disparities between the two groups.
Though several neuroimaging studies have revealed abnormal brain structure associated with Klinefelter syndrome, to our knowledge, only one neuroimaging study has specifically addressed XYY neuroanatomy.12 Gross neuroanatomical variation associated with Klinefelter syndrome most prominently includes reduced total brain volume,12–14 though some report no significant difference.15,16 Other independently replicated anatomical imaging findings in Klinefelter syndrome include reduced frontal and temporal grey matter13,14,17 and either increased or spared parieto-occipital grey matter.17,18
In the present study, we used conceptually distinct approaches to compare the neuroanatomy of eight males with XYY, 31 males with Klinefelter syndrome, and 36 typically developing males. First, we analysed total tissue volume using volumetric methods. Second, we explored patterns of regional grey matter and white matter difference using pattern classification analysis. We hypothesized that males with XYY syndrome would have increased total tissue volume, given previous reports of increased head circumference in individuals with XYY syndrome. Because of reports that males with XYY syndrome exhibit impairments in language and motor ability similar to those exhibited in Klinefelter syndrome, we also expected males with XYY syndrome to exhibit patterns of regional brain variation more similar to those observed in males with Klinefelter syndrome than in typically developing males.
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In this study, we show that males with XYY syndrome have a distinctive pattern of neuroanatomical variation, relative to males with Klinefelter syndrome and typically developing participants. Specifically, males with XYY syndrome show significantly increased total grey matter and white matter, relative to both comparison groups. After statistically adjusting for global tissue volumes, males with XYY syndrome also show patterns of regional grey matter and white matter that are more similar to those of participants with Klinefelter syndrome than to those of typically developing participants, chiefly in areas associated with language and motor ability. These neuroanatomical variations putatively represent the downstream correlates of abnormal Y-chromosome gene expression associated with XYY syndrome.
To our knowledge, increased TGMV and TWMV in XYY syndrome have not been reported previously. The only other neuroimaging study of XYY syndrome reported no significant total or regional volumetric differences associated with the condition.12 This discrepancy probably arises from differences inherent in our samples, given that both were relatively small for neuroimaging studies, though the discrepancy may also arise from variations in neuroimaging acquisition and analysis methods, most notably differences in definition of whole brain volume.
The finding of increased TGMV and TWMV in individuals with XYY syndrome reported here deserves particular attention. First, the finding is consistent with previous reports of increased head circumference, often considered a proxy for total brain volume, in individuals with XYY syndrome,3,4 though not all studies report increased head circumference in XYY syndrome.6 However, males with XYY syndrome in our sample did not have significantly increased head circumference compared with typically developing participants, suggesting that head circumference may not be an adequate proxy for brain volume, at least in this case, and highlighting the importance of direct brain volumetric assessment using neuroimaging methods. Small sample size does temper these claims. Second, increased TGMV and TWMV may be related to increased risk of ASD, which has been described in XYY syndrome by independent research groups.8,9 Increased head circumference and brain matter volume represent the most robust and consistent neural findings reported in individuals with autism.31–33 More specifically, increased head circumference has been associated with greater severity of impairments in social functioning as well as delayed language onset in ASD.32 However, it is important to note that, even within ASD populations, there is much variability in the neuroanatomical phenotype.29 More generally, idiopathic ASD is a heterogeneous syndrome from the point of view of aetiological/risk factors and pathogenesis,34–36 whereas XYY syndrome represents a relatively well-defined genetic condition, which may be one among many risk factors for ASD. As such, neuroanatomical differences associated with ASD and XYY syndrome may arise from distinct biological origins. Nevertheless, when considered in light of evidence that sex-differentiating mechanisms play an important role in the development of ASD,37,38 the possibility that downstream neuroanatomical differences, aberrant Y-chromosome dosage, and increased risk of ASD are significantly associated deserves further investigation.
Though increased TGMV and TWMV in the group of individuals with XYY distinguishes XYY syndrome from Klinefelter syndrome, pattern classification analysis suggests that, after controlling for total brain tissue volumes, regional neuroanatomical variation in XYY syndrome is more like that of Klinefelter syndrome than of male typical development. In particular, pattern classification analysis suggests that reduced insular and frontotemporal regional volumes accompanied by increased or spared volumes of parieto-occipital regions represent a pattern of altered neurodevelopment characteristic of both XYY and Klinefelter syndrome. Considerations of brain–behaviour associations in these conditions can be only speculative at this time given the limited size of our XYY sample. However, Klinefelter syndrome-like patterns of insular and frontotemporal grey matter and white matter could be associated with previously described language impairment in XYY syndrome7 as well as our sample’s significantly reduced performance on the DAS verbal assessment, which was very similar to the performance of the participants in the Klinefelter syndrome group (Table I).
Klinefelter syndrome- and XYY-specific pattern weights associated with brain matter differences in language-associated regions appear overtly similar, but it is important to keep in mind that these similarities may not reflect similarities in the pathogenesis of underlying language deficits. Pattern classification merely suggests that XYY syndrome may be similar to Klinefelter syndrome with regard to patterns of volumetric differences in grey matter and white matter and that this finding could provide a tentative description of neuroanatomical variation associated with general language impairment. Indeed, language deficits in these two disorders have been distinguished from one another with increasingly detailed behavioural metrics. For example, a recent study addressed these differences, suggesting that males with XYY syndrome have more severe and pervasive language impairment, specifically with greater deficits in higher-level meta-linguistic abilities.5 Other studies have characterized variations in language ability and behavioural phenotype.8 As such, it seems likely that the biological pathways mediating overall language impairment are at least partially distinct in these two common genetic disorders. However, the observation that patterns of grey matter and white matter difference in XYY syndrome in areas associated with language function are more like those of Klinefelter syndrome offers additional insight into possible neuroanatomical correlates of language impairment in XYY syndrome. Further discrimination of specific genetic risk factors and downstream biological mechanisms in XYY syndrome may contribute to a better understanding of gene–brain–behaviour associations underlying impairment in language, cognition, and behaviour in young children.
Though the present study offers new insight into neuroanatomical variation in XYY syndrome, it has some limitations worth noting. First, as is the case for many other studies of sex chromosome aneuploidies, ascertainment bias probably affects the composition of our sample. Participants with Klinefelter syndrome and those with XYY syndrome were mostly referred for clinical evaluation (of eight males with XYY syndrome, two were diagnosed prenatally), so it is likely that cases involving more severe outward manifestations are preferentially included. It is important to keep this in mind when interpreting the results, as many males with XYY syndrome or Klinefelter syndrome frequently go undiagnosed. Second, some participants with XYY syndrome and Klinefelter syndrome were excluded for in-scanner motion; thus, methodological limitations may have precluded assessment of neuroanatomical differences potentially linked to motion-inducing behaviours. Third, small sample size limits our ability to make inferences from our statistical analyses. In part to address limitations associated with small sample size and relative imbalance among sample sizes, we performed SVM-based pattern classification analysis. This allowed us to assess regional neuroanatomical differences indirectly by comparing them with those already observed in contrasts between Klinefelter syndrome and typical development.17
In addition, the SVM methods that were used here do not reveal XYY-specific regional morphometric differences. Rather, our SVM analyses were designed to determine which group the participants with XYY syndrome most resembled with regard to a neuroanatomical pattern previously defined by comparing participants with Klinefelter syndrome and typically developing participants. Lastly, inclusion of a participant with XYY syndrome with cavum velum interpositum may have influenced results, especially as the optimal number of features discriminating Klinefelter syndrome from typical development was different in subgroup analyses with this participant excluded. However, analyses on that same subgroup yielded an XYY classification probability similar to that of the main analyses, suggesting that inclusion of the participant did not inordinately influence our conclusion, namely that regional patterns of neuroanatomical variation observed in XYY syndrome are more like those observed in Klinefelter syndrome than in typical development.
This study represents an important step towards understanding neurodevelopmental consequences associated with XYY syndrome. More generally, the research offers insight into the effects of a supernumerary Y chromosome on structural brain development, suggesting a putative relationship with language and motor abilities. In addition, the results suggest a relationship between Y-chromosome gene dosage and brain structural abnormalities that have previously been associated with ASD. In the future, we plan to conduct a voxel-based morphometry study of neuroanatomy in XYY with a larger sample. Continued research of this nature is important, both for its potential future benefit to individuals with XYY syndrome and for its ability to elucidate genetic influences on cognition, behaviour, and brain development.