Cognition and behavior in Turner syndrome: A brief review

Turner syndrome (TS) is a common genetic disorder occurring in approximately 1/2500 live births (Gravholt CH, 2005; Baena N, De Vigan C, Cariati E, et al. 2004). The physical phenotype is often characterized by short stature, cardiac, renal and endocrine abnormalities, including loss of ovarian function and estrogen deficiency (Dhooge IJ, De Vel E, Verhoye C, Lemmerling M, Vinck B, 2004; Sybert VP, McCauley E, 2004; Bondy CA, Bakalov VK, 2006). There is also extensive evidence for a characteristic neurocognitive phenotype in TS, which is comprised of normal full-scale IQ, accompanied by selective deficits in visuospatial reasoning skills, executive function, and social cognition. Difficulties in these domains have a significant impact on long-term academic and adaptive functioning in affected individuals. As an example, girls with TS lag behind peers in math achievement (Rovet J, Szekely C, Hockenberry MN, 1994), and are more likely to be diagnosed with attention-deficit disorder and nonverbal learning disorders (Mazzocco MM, 2006, Russell HF, Wallis D, Mazzocco MM, et al. 2006). Social competence and adaptive living skills are similarly impacted relative to typically developing peers, particularly in childhood. Parents of young girls with TS report that their daughters have significantly more difficulty in social interactions compared to peers (Hong DS, Dunkin B, Reiss AL, 2011). Studies also suggest that impaired social competence continues into adulthood (Lagrou K, Froidecoeur C, Verlinde F, et al, 2006; Downey J, Ehrhardt AA, Gruen R, Bell JJ, Morishima A, 1989). Importantly, these differences cannot be attributed to physical sequelae of TS alone but instead are posited to occur in conjunction with and/or as a result of neurocognitive deficits (McCauley E, Ito J, Kay T, 1986; Lepage JF, Dunkin B, Hong DS, Reiss AL, 2011).

Recent advances in magnetic resonance imaging (MRI) research techniques have begun to elucidate brain differences that may explain this neurocognitive phenotype. This includes a range of findings including volumetric differences in cortical gray matter, aberrant structure of white matter tracts connecting these cortical regions, and differences in brain activation patterns during cognitive tasks related to visuospatial, executive and social cognitive functions. As an example, regions implicated in visuospatial reasoning, such as the superior parietal lobule and the postcentral gyrus (Brown WE, Kesler SR, Eliez S, Warsofsky IS, Haberecht M, Reiss AL, 2004) demonstrate decreased gray matter volume in individuals with TS compared to peers. Similarly, both structural and functional brain differences have been identified in prefrontal regions responsible for executive functions, such as attention, problem solving, planning and impulse control (Kesler SR, Haberecht MF, Menon V, et al., 2004; Hart SJ, Davenport ML, Hooper SR, Belger A, 2006; Bray S, Dunkin B, Hong DS, Reiss AL, 2011) (see Fig. 1), and in limbic brain regions related to social cognitive processes, such as emotional face processing (Hong DS, Bray S, Haas B, Hoeft F, Reiss AL, 2011; Skuse DH, Morris JS, Dolan RJ, 2005). Evidence that these neurobiological deficits correlate directly to behavioral phenotype (Bray S, Dunkin B, Hong DS, Reiss AL, 2011; Skuse DH, Morris JS, Dolan RJ, 2005) provides further evidence for a comprehensive model linking brain differences to neurocognitive phenotype in X-monosomy.

Figure 1.

Parietal regions show significant volumetric reductions (red) and working memory functional activation reductions (yellow) in TS relative to TD controls, which correlate to impaired working memory performance. (Bray et al. 2011)

While the neurocognitive phenotype is thought to arise from haploinsufficiency of gene products in the pseudoautosomal region (PAR) of the X chromosome and/or sex steroid effects on the brain throughout development, there is still limited evidence to support these hypotheses. Neuroanatomical differences in young prepubertal girls with TS who have not received estrogen replacement therapy suggest that sex hormone effects are not solely responsible for structural brain variation in TS (Bray S, Dunkin B, Hong DS, Reiss AL, 2011; Marzelli MJ, Hoeft F, Hong DS, Reiss AL, 2011). Furthermore, gene mapping studies have identified potential regions within the X chromosome that may contribute to the neurocognitive phenotype in TS (Zinn AR, Tonk VS, Chen Z, et al., 1998; Weiss LA, Purcell S, Waggoner S, et al., 2007). Undoubtedly, the fundamental genetic influence of X-monosomy is complex and likely interacts with other genetic liabilities, epigenetic and environmental factors and warrants ongoing examination in future research.

The neurocognitive domains discussed here are highly interdependent and work in an interconnected manner allowing individuals to respond adaptively to the changing demands of everyday life. Therefore, clinicians working with individuals with TS should be highly attuned to the identification of impairments related to the neurocognitive phenotype in TS, which may be significantly impacting their patients’ ability to successfully navigate school, personal or work environments. Unfortunately there is still a relative scarcity of effective interventions for cognitive-behavioral issues in TS, however, clinicians may play an important role in family counseling and guidance, and may assist in obtaining referrals to appropriate services. This includes a range of therapies for behavioral and social issues, and possibly pharmacotherapy when clinically indicated. Organizational and visuospatial strategies are also useful for school and work environments, as well as advocacy for services in the classroom when needed. Recent evidence has also demonstrated that focused cognitive interventions, such as structured math training programs, may significantly improve behavioral performance and functional brain activation in girls with TS (Kesler SR, Sheau K, Koovakkattu D, Reiss AL, 2011). This provides direction for the development of neurocognitive treatments that are more TS-specific in the future.

In conclusion, there is a compelling model for brain and behavioral differences in individuals with TS that affects a variety of neurocognitive domains. Future research studies should continue to focus on elucidating genetic and hormonal influences of X-monosomy on neurocognitive phenotype in order to improve clinical treatment strategies in TS.