Sex differences in rates and manifestations of mental illness have been receiving increasing attention for their potential to inform diagnosis, clinical course and treatment in a broad range of neuropsychiatric disorders. Recent literature suggests that underlying mechanisms for these sex dimorphisms arise from: (1) differential expression of genes on the sex chromosomes and, (2) extensive influence of sex hormones on the brain during critical windows of development. Though the independent and interactive effect of these influences on brain development and function are thought to contribute significantly to sexually dimorphic patterns of cognition and behavior, research in this area is limited. Further investigation is essential to increase our understanding of how sex chromosome gene expression and sex hormone exposure influence neural processes underlying sex differences in both typical development and in mental illness. Sex chromosome aneuploidies such as Turner syndrome ('TS', 45,X) and Klinefelter syndrome ('KS', 47,XXY) represent unique paradigms for elucidating the influences of sex chromosome gene expression and sex hormone exposure on neural development and function. Each condition is characterized by an abnormal number of X chromosomes and affected (genotypic non-mosaic) individuals typically demonstrate greatly reduced levels of sex hormone production. Because TS and KS are associated with specific profiles of neuroanatomical and cognitive-behavioral variation, the study of these conditions can potentially provide unique information about sexually dimorphic brain differences occurring in typical development (where males have 46,XY genotype and females have 46,XX genotype). Although TS and KS have been previously studied independently, there has been no prospective, direct comparison of these cohorts to date, and no studies have compared these groups singly or together to both typically developing male and female cohorts. Here we describe a first-of-its-kind study designed to directly examine differences in neuroanatomy and cognitive-behavioral function between prepubertal, age-matched cohorts of girls with TS, boys with KS and typically developing male and female controls. The proposed project builds on striking observations from previous research conducted by our group and others suggesting that spatial patterns of neuroanatomical variation in TS and KS may be largely complementary relative to typical development. The cross-sectional investigation we propose would be the first to directly compare TS and KS in the same study with the goal of elucidating the early (prepubertal) effects of varying sex chromosome gene expression and associated sex hormone exposure on neuroanatomy. This research holds great promise for improving our understanding of sex chromosome gene expression and sex hormone effects on neurodevelopment in young children and correspondingly, and for providing new insights into neural processes underlying sex differences related to risk and resilience for mental illness.

Public Health Relevance

There are significant sex differences in neuropsychiatric diseases of childhood, such as attention-deficit hyperactivity disorder, autism and learning disorders. This includes differences in the number of boys vs. girls who are diagnosed, and the nature and course of their symptoms over time. A better understanding of mechanisms underlying these sex differences is critical for improving long-term clinical outcomes. The study proposed here will investigate differences in brain structure and cognition in children with an abnormal number of sex chromosomes, such as Turner and Klinefelter syndromes. Examining these populations will provide important insights into the role of sex chromosomes and sex hormones on cognition and brain structures, and potentially impact clinical treatment of individuals with these disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZMH1-ERB-L (07))
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Gilotty, Lisa
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Stanford University
Schools of Medicine
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Green, Tamar; Fierro, Kyle C; Raman, Mira M et al. (2016) Sex differences in amygdala shape: Insights from Turner syndrome. Hum Brain Mapp 37:1593-601
Green, Tamar; Bade Shrestha, Sharon; Chromik, Lindsay C et al. (2015) Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function. J Psychiatr Res 68:217-25
Green, Tamar; Chromik, Lindsay C; Mazaika, Paul K et al. (2014) Aberrant parietal cortex developmental trajectories in girls with Turner syndrome and related visual-spatial cognitive development: a preliminary study. Am J Med Genet B Neuropsychiatr Genet 165B:531-40
Lepage, J-F; Hong, D S; Raman, M et al. (2014) Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study. Genes Brain Behav 13:127-34
Hong, David S; Reiss, Allan L (2014) Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol 13:306-18