Structural and functional neuroimaging in Klinefelter (47,XXY) syndrome: A review of the literature and preliminary results from a functional magnetic resonance imaging study of language

Abstract

Klinefelter (47, XXY) syndrome (KS), the most common form of sex-chromosomal aneuploidy, is characterized by physical, endocrinologic, and reproductive abnormalities. Individuals with KS also exhibit a cognitive/behavioral phenotype characterized by language and language-based learning disabilities and executive and attentional dysfunction in the setting of normal general intelligence. The underlying neurobiologic mechanisms are just now beginning to be elucidated through structural and functional neuroimaging. Here, we review the literature of structural and functional neural findings in KS identified by neuroimaging and present preliminary results from a functional magnetic resonance imaging study examining brain activity during a verb generation task in KS. KeywordsKlinefelter syndrome; XXY; MRI; neuroimage; Magnetic Resonance Imaging; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-PhotonThe 47, XXY karyotype is the most common form of sex-chromosomal aneuploidy, with an estimated prevalence in the general population between one in 500 and one in 1000 [Lanfranco et al., 2004]. The clinical manifestations associated with this genotype are referred to as Klinefelter syndrome (KS). Characteristic physical and medical attributes of infertility, small testes, gynecomastia, and tall body habitus with long legs are thought to result from testosterone deficiency [Wattendorf and Muenke, 2005]. Individuals with KS also exhibit a characteristic pattern of cognitive and behavioral dysfunction [Geschwind et al., 2000], which is reviewed NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in depth in another article in this issue [Boada et al., 2009]. In brief, the cognitive/behavioral phenotype includes language and language-based learning disabilities (similar to that observed in cytogenetically-normal children with dyslexia) as well as executive and attentional dysfunction [Lanfranco et al., 2004]. General intelligence appears to be within the typical range in men with KS, though global developmental delays in childhood include delayed language and (gross and fine) motor development [Wattendorf and Muenke, 2005].Though a characteristic KS cognitive phenotype is now recognized, relatively little is known about the underlying neural mechanisms [Geschwind et al., 2000;Reiss et al., 2000;Geschwind and Dykens, 2004;Giedd et al., 2007;van Rijn et al., 2008]. In this article, we review the current literature of studies beyond case-report status that used structural and functional neuroimaging techniques to further understanding of the neurobiologic mechanisms underlying cognitive and behavioral differences in KS. We begin by presenting studies of volumetric differences in KS, organized by neuroanatomic level of the brain findings, including (1) widespread brain differences and differences in ventricular size; (2) cerebral lobar and cerebellar differences; (3) differences in intra-individual asymmetries; and (4) regional differences. This is followed by a section discussing f...

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies

“…Neuroanatomical alterations in XXY mice recapitulate some of the more robust findings in structural MRI studies of XXY humans: volume reductions relative to XY karyotype in the amygdala and hippocampus (Bryant et al 2011; Steinman et al 2009). However, several of the structures that we find to be volumetrically altered in XXY mice are technically difficult to assay using conventional structural neuroimaging methods humans including the BNST, substantia innominata, hypothalamus and PAG.…”

“…First, we chart neuroanatomical alterations in the XXY SCA mouse model for the first time. We were specifically interested in determining (1) if foci of sexually dimorphic murine brain volume that are detectible by sMRI, such as relative male volume excess in BNST and amygdala relative to females (Raznahan et al 2013), are preserved in XXY males, and (2) if XXY mice recapitulate any of the better-replicated anatomical alterations in studies of XXY humans [e.g., amygdala and hippocampal volume reductions relative to typically developing males (Bryant et al 2011; Steinman et al 2009)]. Second, we use reciprocal anatomical abnormalities in XXY and XO mice to detect replicable X-dosage effects on the brain that are independent of gonadal or Y chromosome status.…”

Mouse model systems to study sex chromosome genes and behavior: Relevance to humans

“…The aspect of the syndrome that has received the most attention is impaired verbal abilities, including lower verbal IQ scores, in Klinefelter boys (Geschwind et al , 2000), which correlate with differences in brain morphology and function. Specifically, the frontal and temporal lobes and the cerebellum are reduced in volume in Klinefelter males (Steinman et al , 2009), and Klinefelter men have less lateralized processing in language centers than controls (Aleman et al , 2008). One of the key features of autism spectrum disorders (ASD) is disrupted language skills, and in one study 27% of boys with Klinefelter syndrome (Bruining et al , 2009) met the criteria for ASD.…”

Variability in Cognitive Behavioral Phenotypes in Klinefelter Syndrome (KS) and Other Sex Chromosomal Aneuploidies (SCAs)

“…Neuroimaging studies have documented anomalies in the brain structures of boys and adults with KS, which correlated with the presence of psychosocial problems [41]. These psychopathological aspects may be partly explained by a psychoneurological phenotype that includes grey matter deficits in the superior temporal gyrus, the orbitofrontal cortex and the inferior frontal gyrus, white matter anomalies, impaired executive functions with severe deficits in the inhibitory component, abnormal structure of amygdala, caudate and putamen [37][38][39][40][41][42]. These alterations may be caused by excessive expression of genes that lie in the pseudoautosomal regions of the X-chromosome [41].…”