Neuroanatomical Phenotype of Klinefelter Syndrome in Childhood: A Voxel-Based Morphometry Study

Abstract

Klinefelter Syndrome (KS) is a genetic disorder characterized by a supernumerary X chromosome. As such, KS offers a naturally occurring human model for the study of both X-chromosome gene expression and androgen on brain development. Previous neuroimaging studies reveal neuroanatomical variations associated with KS, but differ widely with respect to subject inclusion criteria, including mosaicism, pubertal status, and history of testosterone replacement therapy (TRT), all factors likely to influence neurodevelopment. We conducted a voxel-based morphometry (VBM) study of regional grey and white matter volumes in 31 KS males (mean age: 9.69 years ± SD: 1.70) and 36 typically developing (TD) male controls (10.99 ± 1.72). None of the participants with KS had received TRT, and all were prepubertal and had non-mosaic 47, XXY karyotypes. After controlling for age, males with KS showed trends (0.05<p<0.10) for significantly reduced total grey matter volume (TGMV) and total white matter volume (TWMV), relative to TD males. After controlling for TGMV and age, the KS group had significantly increased sensorimotor and parietal-occipital GM and significantly reduced amygdalar, hippocampal, insular, temporal, and inferior frontal GM relative to TD controls. After controlling for TWMV and age, the KS group had significantly increased left parietal WM as well as significantly reduced frontal and temporal WM. These findings are indicative of a characteristic prepubertal neuroanatomical phenotype that may be associated with cognitive-behavioral features of KS. This work offers new insight into the relationships among X-chromosome gene expression, neuroanatomy, and cognitive-behavioral functions impaired in KS, including language and attention.

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.…”

“…Neuroimaging studies have identified widespread structural and functional brain alterations in humans SCAs suggesting that variations in sex chromosome gene dosage may have direct effects on mammalian brain development (Lenroot et al 2009; Raznahan et al 2010; Lepage et al 2012; Bryant et al 2011; Skakkebaek et al 2013; Itti et al 2006). However, a number of factors complicate the use of human SCA syndromes as a model for examination of sex chromosome gene-dosage effects, including background genetic and environmental diversity, karyotypic mosaicism (Wolff et al 2010; Garcia-Quevedo et al 2011), and X chromosome parent of origin (Lepage et al 2013).…”

“…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.…”

Brain Structure and Resting-State Functional Connectivity in University Professors with High Academic Achievement

“…ion.ucl.ac.uk/spm), using Matlab 7.8 (R2009a; Math Works, Natick, MA, USA) and the Diffeomorphic Anatomical Registration through Exponentiated Lie algebra toolbox (DARTEL; Abutalebi et al, 2012;Ashburner, 2007). SPM8 was used to convert the raw image data to NiFTI format; reorient the image to the anterior commissure manually for better registration (Frodl et al, 2008); and segment the data into gray matter, white matter, and cerebrospinal fluid using the ''New Segment'' toolbox (Ashburner & Friston, 2005;Bryant et al, 2011). DARTEL was subsequently used in SPM8 for registration, normalization, and modulation (Ashburner, 2007).…”

Is it all the X: Familial learning dysfunction and the impact of behavioral aspects of the phenotypic presentation of XXY?

“…This finding afforded the opportunity of prospective population studies through newborn screening as well as a variety of research investigations at different ages on boys with 47,XXY. Since the 1970s, several commonalities regarding the neurocognitive and neurodevelopmental profile were identified in individuals with XXY, including language-based learning disabilities, developmental dyspraxia with neuromotor dysfunction and speech and language abnormalities, reading disorders, and frontal dysfunction [Robinson et al, 1979[Robinson et al, , 1990Bender et al, 1986Bender et al, , 1995Bender et al, , 2001Simpson et al, 2003;Giedd et al, 2007;Bryant et al, 2011;Samango-Sprouse et al, 2012a].…”