Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome

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 parietooccipital 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.