Neurodevelopmental and psychosocial aspects of Turner syndrome

Abstract

Turner syndrome (TS) is the complex phenotype of human females with complete or partial absence of the second sex chromosome, or monosomy X. A characteristic neurocognitive and psychosocial profile has also been described in TS females. Typically, specific deficits in visual‐spatial/perceptual abilities, nonverbal memory function, motor function, executive function, and attentional abilities occur in TS children and adults of varying races and socioeconomic status. TS‐associated psychosocial difficulties occur in the areas of maturity and social skills. We hypothesize that a subset of the neurocognitive deficits (visual‐spatial/perceptual abilities) are genetically determined and result from abnormal expression of one or more X chromosome genes. In addition, a different subset of these neurocognitive deficits (memory, reaction time, and speeded motor function) result from estrogen deficiency and are at least somewhat reversible with estrogen treatment. The TS‐associated psychosocial problems are most likely linked to these core neurocognitive deficits and do not reflect a separate and independent component of the syndrome. Turner syndrome research has progressed significantly over the last decade. The field has moved from descriptive reports based on single individuals or small clinical samples to the use of experimental designs with larger, more diverse and representative samples. This degree of variability among individuals with Turner syndrome in all domains (karyotype or genetic constitution, physical attributes, neurocognitive and social functioning) suggests the need to identify risk and protective factors contributing to the heterogeneity in the phenotype. Active education about TS and participation in patient advocacy groups such as the Turner Syndrome Society of the United States (http://www. turner‐syndrome‐us.org/) has provided new information for TS adults and families as well as a supportive peer group. MRDD Research Reviews 2000;6:135‐141. © 2000 Wiley‐Liss, Inc.

Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome

“…Therefore, our findings of increased parahippocampal CT between age cohorts in the TD group, compared with a relatively smaller increase in CT in the TS group across this same span, suggest that differences in estrogen status may significantly impact developmental changes in this region. Previous studies of hormone replacement in TS have demonstrated positive effects of estrogen on cognition, and memory in particular (Ross et al 1998;Ross, Zinn et al 2000). Taken together with the prominent role of the parahippocampus in memory processes (van Strien et al 2009), our findings suggest a functional link between this anatomical region, estrogen status, and cognitive differences.…”

“…We found that individuals with TS did not undergo expected neuroanatomical changes during adolescence, implying that activational effects of pubertal sex hormones during adolescence are either reduced or absent, and that neurodevelopment in TS occurs in a time-sensitive fashion similar to other genetic conditions (Hoeft et al 2010). However, our parahippocampal findings and previous data regarding hormone replacement effects on cognitive function in TS (Ross et al 1998;Ross, Zinn et al 2000), suggest the possibility that these changes may, at least in part, be 'normalized' with sex hormone therapy, particularly in regions that are sensitive to sex hormone influence. In order to explicitly address these issues, prospective, longitudinal studies are needed to examine the effects and interaction of neuroanatomy and hormone replacement before, during and after puberty.…”

Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome

“…Therefore, our findings of increased parahippocampal CT between age cohorts in the TD group, compared with a relatively smaller increase in CT in the TS group across this same span, suggest that differences in estrogen status may significantly impact developmental changes in this region. Previous studies of hormone replacement in TS have demonstrated positive effects of estrogen on cognition, and memory in particular (Ross et al 1998;Ross, Zinn et al 2000). Taken together with the prominent role of the parahippocampus in memory processes (van Strien et al 2009), our findings suggest a functional link between this anatomical region, estrogen status, and cognitive differences.…”

“…We found that individuals with TS did not undergo expected neuroanatomical changes during adolescence, implying that activational effects of pubertal sex hormones during adolescence are either reduced or absent, and that neurodevelopment in TS occurs in a time-sensitive fashion similar to other genetic conditions (Hoeft et al 2010). However, our parahippocampal findings and previous data regarding hormone replacement effects on cognitive function in TS (Ross et al 1998;Ross, Zinn et al 2000), suggest the possibility that these changes may, at least in part, be 'normalized' with sex hormone therapy, particularly in regions that are sensitive to sex hormone influence. In order to explicitly address these issues, prospective, longitudinal studies are needed to examine the effects and interaction of neuroanatomy and hormone replacement before, during and after puberty.…”

Epigenetics of autism spectrum disorders

“…Consistent with this model, karyotypically normal females performed better on these measures than normal males and autism and/or ASD have been reported in females with 45,X mat Turner syndrome (123) and Xp deletions (124). This model has been somewhat controversial, in part, because the parent of origin effect on behavior has not been observed by other investigators (125), but also because of difficulties in mapping the locus. Thus, the recent discovery of a cluster of imprinted genes on the mouse X chromosome has generated considerable interest (126,127).…”

Functional and Structural Alterations of the Intraparietal Sulcus in a Developmental Dyscalculia of Genetic Origin

“…In control subjects, there was no This suggests a tight intermingling within the parietal significant difference between exact and approximate lobe of numerical circuits and of spatial working memory calculation in response times (RTs) or in error rates. circuits needed for the letter tasks (see Grü ber et al There was, however, a significant main effect of number [1999] for a similar result). size [RTs: F(1,12) ϭ 16.9, p ϭ 0.001; errors: F(1,12) ϭ Number Size Effect 32.5, p Ͻ 0.0001], with larger numbers inducing re-As in our previous study, number size had an impact on brain activation in exact calculation, while no impact sponses that were 231 ms slower and that contained of number size was found during approximate calcula-as the cerebral basis of the behavioral number size effect.…”

Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome

“…Therefore, our findings of increased parahippocampal CT between age cohorts in the TD group, compared with a relatively smaller increase in CT in the TS group across this same span, suggest that differences in estrogen status may significantly impact developmental changes in this region. Previous studies of hormone replacement in TS have demonstrated positive effects of estrogen on cognition, and memory in particular (Ross et al 1998;Ross, Zinn et al 2000). Taken together with the prominent role of the parahippocampus in memory processes (van Strien et al 2009), our findings suggest a functional link between this anatomical region, estrogen status, and cognitive differences.…”

“…We found that individuals with TS did not undergo expected neuroanatomical changes during adolescence, implying that activational effects of pubertal sex hormones during adolescence are either reduced or absent, and that neurodevelopment in TS occurs in a time-sensitive fashion similar to other genetic conditions (Hoeft et al 2010). However, our parahippocampal findings and previous data regarding hormone replacement effects on cognitive function in TS (Ross et al 1998;Ross, Zinn et al 2000), suggest the possibility that these changes may, at least in part, be 'normalized' with sex hormone therapy, particularly in regions that are sensitive to sex hormone influence. In order to explicitly address these issues, prospective, longitudinal studies are needed to examine the effects and interaction of neuroanatomy and hormone replacement before, during and after puberty.…”

Epigenetics of autism spectrum disorders

“…Consistent with this model, karyotypically normal females performed better on these measures than normal males and autism and/or ASD have been reported in females with 45,X mat Turner syndrome (123) and Xp deletions (124). This model has been somewhat controversial, in part, because the parent of origin effect on behavior has not been observed by other investigators (125), but also because of difficulties in mapping the locus. Thus, the recent discovery of a cluster of imprinted genes on the mouse X chromosome has generated considerable interest (126,127).…”

Functional and Structural Alterations of the Intraparietal Sulcus in a Developmental Dyscalculia of Genetic Origin

“…In control subjects, there was no This suggests a tight intermingling within the parietal significant difference between exact and approximate lobe of numerical circuits and of spatial working memory calculation in response times (RTs) or in error rates. circuits needed for the letter tasks (see Grü ber et al There was, however, a significant main effect of number [1999] for a similar result). size [RTs: F(1,12) ϭ 16.9, p ϭ 0.001; errors: F(1,12) ϭ Number Size Effect 32.5, p Ͻ 0.0001], with larger numbers inducing re-As in our previous study, number size had an impact on brain activation in exact calculation, while no impact sponses that were 231 ms slower and that contained of number size was found during approximate calcula-as the cerebral basis of the behavioral number size effect.…”

Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome

“…Therefore, our findings of increased parahippocampal CT between age cohorts in the TD group, compared with a relatively smaller increase in CT in the TS group across this same span, suggest that differences in estrogen status may significantly impact developmental changes in this region. Previous studies of hormone replacement in TS have demonstrated positive effects of estrogen on cognition, and memory in particular (Ross et al 1998;Ross, Zinn et al 2000). Taken together with the prominent role of the parahippocampus in memory processes (van Strien et al 2009), our findings suggest a functional link between this anatomical region, estrogen status, and cognitive differences.…”

“…We found that individuals with TS did not undergo expected neuroanatomical changes during adolescence, implying that activational effects of pubertal sex hormones during adolescence are either reduced or absent, and that neurodevelopment in TS occurs in a time-sensitive fashion similar to other genetic conditions (Hoeft et al 2010). However, our parahippocampal findings and previous data regarding hormone replacement effects on cognitive function in TS (Ross et al 1998;Ross, Zinn et al 2000), suggest the possibility that these changes may, at least in part, be 'normalized' with sex hormone therapy, particularly in regions that are sensitive to sex hormone influence. In order to explicitly address these issues, prospective, longitudinal studies are needed to examine the effects and interaction of neuroanatomy and hormone replacement before, during and after puberty.…”

Epigenetics of autism spectrum disorders

“…Consistent with this model, karyotypically normal females performed better on these measures than normal males and autism and/or ASD have been reported in females with 45,X mat Turner syndrome (123) and Xp deletions (124). This model has been somewhat controversial, in part, because the parent of origin effect on behavior has not been observed by other investigators (125), but also because of difficulties in mapping the locus. Thus, the recent discovery of a cluster of imprinted genes on the mouse X chromosome has generated considerable interest (126,127).…”

Functional and Structural Alterations of the Intraparietal Sulcus in a Developmental Dyscalculia of Genetic Origin

“…In control subjects, there was no This suggests a tight intermingling within the parietal significant difference between exact and approximate lobe of numerical circuits and of spatial working memory calculation in response times (RTs) or in error rates. circuits needed for the letter tasks (see Grü ber et al There was, however, a significant main effect of number [1999] for a similar result). size [RTs: F(1,12) ϭ 16.9, p ϭ 0.001; errors: F(1,12) ϭ Number Size Effect 32.5, p Ͻ 0.0001], with larger numbers inducing re-As in our previous study, number size had an impact on brain activation in exact calculation, while no impact sponses that were 231 ms slower and that contained of number size was found during approximate calcula-as the cerebral basis of the behavioral number size effect.…”