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. 2023 May 1;44(10):4028–4039. doi: 10.1002/hbm.26327

Adolescent brain development in girls with Turner syndrome

Vanessa Lozano Wun 1,2,✉, Lara C Foland‐Ross 1, Booil Jo 1, Tamar Green 1, David Hong 1, Judith L Ross 3,4, Allan L Reiss 1,5,6
PMCID: PMC10258525  PMID: 37126641

Abstract

Turner syndrome (TS) is a common sex chromosome aneuploidy in females associated with various physical, cognitive, and socio‐emotional phenotypes. However, few studies have examined TS‐associated alterations in the development of cortical gray matter volume and the two components that comprise this measure—surface area and thickness. Moreover, the longitudinal direct (i.e., genetic) and indirect (i.e., hormonal) effects of X‐monosomy on the brain are unclear. Brain structure was assessed in 61 girls with TS (11.3 ± 2.8 years) and 55 typically developing girls (10.8 ± 2.3 years) for up to 4 timepoints. Surface‐based analyses of cortical gray matter volume, thickness, and surface area were conducted to examine the direct effects of X‐monosomy present before pubertal onset and indirect hormonal effects of estrogen deficiency/X‐monosomy emerging after pubertal onset. Longitudinal analyses revealed that, whereas typically developing girls exhibited normative declines in gray matter structure during adolescence, this pattern was reduced or inverted in TS. Further, girls with TS demonstrated smaller total surface area and larger average cortical thickness overall. Regionally, the TS group exhibited decreased volume and surface area in the pericalcarine, postcentral, and parietal regions relative to typically developing girls, as well as larger volume in the caudate, amygdala, and temporal lobe regions and increased thickness in parietal and temporal regions. Surface area alterations were predominant by age 8, while maturational differences in thickness emerged by age 10 or later. Taken together, these results suggest the involvement of both direct and indirect effects of X‐chromosome haploinsufficiency on brain development in TS.

Keywords: brain, gray matter, neurodevelopment, puberty, sex chromosome, Turner syndrome

Surface‐based analyses of cortical gray matter volume, thickness, and surface area were conducted using an accelerated longitudinal design in girls ages 4–17 years with Turner syndrome (TS; 45, XO) and typical development (TD). Statistical analyses revealed that whereas TD girls exhibited normative declines in gray matter structure throughout adolescence, this pattern was reduced or inverted in girls with TS. Findings suggest the involvement of both direct and indirect effects of the X‐chromosome on brain development.

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1. INTRODUCTION

Research has shown that sex chromosomes affect the development of the brain in two critical ways: directly, via the relative “dosage” of X‐chromosome gene expression, and indirectly, via organizational/activational effects of gonadal hormones (Arnold, 2004). Sex chromosome aneuploidies, defined as the loss or gain of one or more X or Y chromosomes, provide researchers with the unique opportunity to study these effects on the brain. One relatively common aneuploidy, known as Turner syndrome (TS; 1:2500 live female births) (Bondy, 2007), is caused by the partial or complete deletion of an X‐chromosome (Gravholt, 2005; Stochholm et al., 2006). TS is characterized by several physical features, including short stature, heart malformations, and gonadal dysgenesis with ovarian failure and infertility. In addition, this condition is associated with increased risk for various behavioral alterations, including impairment in visuospatial reasoning, executive functioning, attention and memory, social cognition, and increased anxiety (Baker & Reiss, 2016; Green et al., 2015; Hong et al., 2009; Hong et al., 2011; McCauley et al., 2001; Messina et al., 2007; Ross et al., 2002). Moreover, TS is associated with a heightened risk for anxiety, depression, autism spectrum disorder, and attention‐deficit/hyperactivity disorder (Green et al., 2015; Hutaff‐Lee et al., 2019; Lesniak‐Karpiak et al., 2003; Morris et al., 2020).

Due to gonadal dysgenesis, TS is often accompanied by primary hypogonadism including reduced endogenous estrogen levels, absent pubertal development, and amenorrhea (Lippe, 1991). In non‐mosaic TS, spontaneous menarche is estimated to occur in only 5–10% of individuals and spontaneous breast development in 0–10% (Tanaka et al., 2015). As such, most individuals with TS require estrogen replacement therapy in order to induce puberty, maintain secondary sex characteristics (e.g., breasts, menstrual cycle, increased body fat), achieve peak bone mass, and normalize uterine growth for possible pregnancy later in life (Klein et al., 2018). Although the need for supplementation is common, there is no standardized approach for estrogen replacement therapy in TS. Indeed, the age of replacement therapy initiation, dose, and form of supplementation vary greatly depending on the patient and treating endocrinologist.

In addition to physical and reproductive effects, alterations in estrogen levels are likely to have consequences on brain development, cognition, and behavior in TS. Sex hormones have been shown to have significant “organizational” effects on the central nervous system during prenatal and perinatal development, leading to observable structural sexual dimorphisms. More recent animal and human investigations show that sex steroids have significant “activational” effects and continue to influence brain structure, function, and plasticity during pubertal development (Arnold, 2009; Phoenix et al., 1959). Specifically, estrogen is posited to play a role in pubertal decreases in gray matter volume via cortical pruning and increases in white matter volume via increased myelination (for a review of the effect of estrogen on females across the lifespan, please see Rehbein et al., 2021). Notably, within TS, the administration of low doses of estrogen intended to avoid precipitating puberty in adolescents with TS results in improved memory abilities, motor processing speed, self‐esteem, and self‐image (Ross et al., 1996, 1998, 2000). Whether estrogen supplementation in TS influences brain development, however, remains to be clarified.

Neuroimaging investigations have pointed to a possible neuroanatomic basis for the behavioral phenotype in TS. Consistent findings across studies include reduced volume of parieto‐occipital (Brown et al., 2002; Green et al., 2014; Hong et al., 2014; Marzelli et al., 2011; Raznahan et al., 2010), and postcentral cortical gray matter volume (Brown et al., 2004; Marzelli et al., 2011), as well as increased gray matter volume of the amygdala (Good et al., 2003; Green et al., 2016; Kesler et al., 2004; Lepage, Hong, et al., 2013), caudate (Cutter et al., 2006; Haberecht et al., 2001; Marzelli et al., 2011), and frontal and temporal lobe gyri (Cutter et al., 2006; Kesler et al., 2003; Lepage, Hong, et al., 2013; Marzelli et al., 2011).

However, fewer studies have examined longitudinal alterations in brain development of girls with TS. Understanding disorder‐specific neurodevelopmental trends represent an essential research goal, since dynamic waves in cortical remodeling occur during adolescence when girls with TS often exhibit delayed or incomplete endogenous pubertal development. To our knowledge, only two studies, both from our lab, have examined longitudinal trends in brain structure in TS adolescents. In the first, Green et al. (2014) used a region‐of‐interest‐based analysis and observed slower growth of surface area and white matter volume in the left parietal lobe among a separate sample of 16 young girls with TS and 13 age‐matched typically developing (TD) girls, scanned at a mean baseline age of 8 years old, and again 1 year later. In the second, O'Donoghue et al. (2020) examined neurodevelopment in an overlapping sample of 55 girls with TS and 53 TD girls using voxel‐based morphometry. Results of this study indicated X‐monosomy was associated with slower growth of gray matter volume in the parietal, occipital, postcentral, and temporal cortices and with faster growth of gray matter volume in the striatum, parahippocampal gyrus, and insula.

In the current investigation, we sought to build upon and extend extant findings by examining TS‐associated alterations in the development of cortical gray matter volume and the two components that comprise this measure—surface area and thickness. We focused on these metrics since they follow different neurodevelopmental trajectories (Fjell et al., 2015; Hogstrom et al., 2013), have distinct genetic influences (Panizzon et al., 2009; Winkler et al., 2010), and exhibit unique associations with various aspects of cognition and psychiatric conditions (Noble et al., 2015; Schnack et al., 2015; Vuoksimaa et al., 2016). Notably, whereas surface area expands during early childhood and gradually contracts during adolescence and adulthood, cortical thickness exhibits a mostly linear decrease over time (Bethlehem et al., 2022; Jernigan et al., 2016). Thus, examining individual components that make up cortical gray matter volume may yield more specific insights into the effects of X‐monosomy on the brain. Further, we focused our analyses on adolescent ages spanning the prepubertal (8 years old) and pubertal (14 years old) timeframe, allowing us to examine potential direct effects of X‐monosomy present before pubertal onset and indirect hormonal effects of estrogen deficiency/X‐monosomy emerging shortly after the expected typical onset of puberty.

We conducted these analyses on a sample of 116 girls aged 4–17 years. Total and regional gray matter metrics were examined to evaluate TS‐associated alterations in brain maturation. Additionally, within the TS group, we explored whether treatment with estrogen supplementation was associated with regional alterations in structure. Based on prior research from our lab and others (Brown et al., 2002, 2004; Cutter et al., 2006; Good et al., 2003; Green et al., 2014, 2016; Haberecht et al., 2001; Hong et al., 2014; Kesler et al., 2003, 2004; Lepage, Mazaika, et al., 2013; Marzelli et al., 2011; Raznahan et al., 2010), we expected global alterations in total brain volume, gray matter volume, cortical thickness, and surface area in TS. Further, we expected decreased volume in specific brain areas including the parieto‐occipital region and postcentral gyrus, as well as increased volume in the frontal and temporal lobe gyri, amygdala, and caudate in TS relative to TD girls. Finally, we hypothesized that there would be group differences in the developmental rate of the cerebral cortex across all morphologies (gray matter volume, surface area, and thickness) in association with pubertal development, with the TS group exhibiting both congenital (i.e., trait differences implying direct genetic effects), and maturational differences (implying indirect hormonal effects) relative to TD girls.

2. MATERIALS AND METHODS

2.1. Participants

The study was approved by Stanford University's Institutional Review Board. Girls over 7 years of age provided written assent, and a parent provided written informed consent. Participants with TS were recruited through the National Turner Syndrome Society and the Turner Syndrome Foundation, as well as through local physicians and advertisements on the Stanford University School of Medicine website. TD participants were recruited through local print media and parent networks. Exclusion criteria for both groups included premature birth (gestational age <34 weeks), low‐birth weight (<2000 g), and known diagnosis of a major psychiatric condition (i.e., psychotic or mood disorder) or current neurological disorder, including seizures. All participants in the TS group had non‐mosaic X‐monosomy, confirmed by karyotype reports supplied by families. Girls with TS exhibiting mosaic karyotypes, that is, X‐monosomy was only detected in some but not all cells, were excluded.

All participants completed structural MRI scanning annually for up to four timepoints. A total of 67 girls with TS and 62 TD girls were enrolled. Of these, 61 girls with TS (age range = 4.7–17.3, mean = 11.3 ± 2.8 years) and 55 TD girls (age range = 5.3–15.9, mean = 10.8 ± 2.3 years) had usable (low‐motion) scan data and were included in the final analyses. At each study visit, intellectual functioning and pubertal status were also assessed.

Of the 61 total girls with TS included in our analyses, 24 unique individuals received estrogen supplementation over the course of our investigation. Of the 137 total scans from girls with TS, 48 were acquired when participants were receiving estrogen supplementation. 15 of the 61 total girls with TS included in analyses had initiated estrogen treatment prior to study enrollment. Across all TS participants, the average initiation age of estrogen supplementation was 12.2 ± 1.6 years. Supplemental Table S1 presents the number of TS participants receiving estrogen treatment across all years of the study.

2.2. Cognitive assessment

Participants were administered the Wechsler Intelligence Scales for Children‐Fourth Edition (Wechsler, 2003) to assess intellectual functioning at each scan visit. This assessment results in a combined Full‐scale IQ (FSIQ) and separate index scores for Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed.

2.3. Tanner staging

A trained physician assessed breast and pubic hair Tanner stages at each study timepoint via physical exam (Tanner & Whitehouse, 1976). Parents and participants also provided Tanner ratings of breast and pubic hair development via questionnaire. Comparisons among self, parent, and physician ratings of pubertal development indicated a high degree of consistency (ICCTanner‐Breast = 0.957 and ICCTanner‐Pubic = 0.935). For this reason, self‐ and parent‐reported ratings were used in place of physician ratings when a physician's physical exam was unavailable (8% of all study visits). Breast and pubic hair ratings were averaged to produce mean Tanner scores.

2.4. Magnetic resonance imaging data acquisition

Magnetic resonance imaging data were collected at the Lucas Center for Imaging at Stanford University using a 3‐Tesla GE Discovery MR 750 scanner (GE Healthcare Systems). To decrease the likelihood of poor data quality due to excessive motion, behavioral training using a mock MRI scanner was conducted before scanning. A fast‐spoiled gradient recalled echo pulse sequence to obtain a high‐resolution T1 anatomical brain image for each participant (176 sagittal slices, TR = 8.2 ms, TE = 3.2 ms, inversion time = 450 ms, flip angle = 12°, number of excitations = 1, FOV = 240 × 192 mm; matrix = 256 × 256; voxel size = 1.0 × 1.0 × 1.0 mm thickness, acquisition time = 4 min 29 s).

2.5. Data processing

MRI scans were visually inspected for head motion and geometric distortions. Bias field correction was conducted using SPM8 (http://www.fil.ion.ucl.ac.uk/spm), following which scans were processed in FreeSurfer version 5.3 (http://surfer.nmr.mgh.harvard.edu). The technical details of the FreeSurfer procedures used are extensively described in prior publications (Dale et al., 1999; Fischl, 2004; Fischl et al., 2002; Fischl & Dale, 2000). Briefly, following standard preprocessing pipelines, placement of gray–white boundaries and pial surfaces was made at locations where the greatest shift in intensity defines the transition to another tissue class (Dale et al., 1999; Fischl & Dale, 2000). Gray–white and pial surfaces were visually inspected, and manual corrections were performed when needed. Resulting surfaces for each hemisphere were parcellated into 34 distinct regions based on gyral and sulcal landmarks (Desikan et al., 2006; Fischl, 2004), from a subset of which measures of volume, surface area, and thickness of cortical gray matter were computed.

In primary analyses, global measures of total gray matter volume, total white matter volume, total surface area, and average cortical thickness were used as dependent variables to evaluate TS‐associated alterations in brain maturation. Secondary analyses focused on between‐group differences in the maturation of 10 distinct subregions chosen a priori as areas of interest based on prior findings. These regions included the amygdala, caudate, inferior parietal lobule, superior parietal lobule, pericalcarine cortex, rostral and caudal middle frontal gyri, postcentral gyrus, and middle and superior temporal gyri. Past investigations from our lab and others have consistently demonstrated TS‐related differences in gray matter volume and rates of volume maturation in these regions (Brown et al., 2002, 2004; Cutter et al., 2006; Good et al., 2003; Green et al., 2014, 2016; Haberecht et al., 2001; Hong et al., 2014; Kesler et al., 2003, 2004; Lepage, Mazaika, et al., 2013; Marzelli et al., 2011; Raznahan et al., 2010). Moreover, differences in these regions are posited to play a role in the behavioral profile in TS. However, it remains unclear how the individual components that make up cortical gray matter volume (e.g., cortical thickness and surface area) in these regions differ developmentally in those with TS and as such these regions represented ideal targets for our analyses.

2.6. Statistical analyses

Statistical analyses of structural measures were conducted in line with our accelerated longitudinal design (ALD), where different age groups act as multiple cohorts, allowing for flexible modeling of longitudinal trends over a long period. This approach identifies growth parameters based on the assumption that individuals measured at different ages will follow the same longitudinal trend (Castellanos, 2002; Giedd et al., 1999). In our study, individuals were assessed up to four times with an approximate interval of 1 year. Among 116 participants, 13 completed 4 assessments, 33 completed 3, 26 completed 2, and 40 completed 1 assessment. Linear mixed effects modeling was used for analyses of ALD data. Data points missing by design (i.e., in ALD) or due to subject attrition were handled assuming that data were missing at random conditional on observed information (Little & Rubin, 2002). Treating individual age at four assessment points as time, we used maximum likelihood estimation. All subjects were included in the longitudinal analyses if they had at least one usable scan. A total of 243 scans from 116 unique participants were included in the final analyses, including 137 TS and 106 TD scans. A linear growth model was utilized for all metrics, except for those in which a nonlinear (quadratic) growth model yielded a better fit. Additionally, we allowed individual variation in the outcomes regarding where they started (random intercept) and how they changed (random slope). Linear modeling was implemented in R version 3.6.2 (R Core Team, 2019; https://www.R-project.org/) using the lme4 package (Bates et al., 2015), and nonlinear modeling was implemented in Mplus version 8.6 (https://www.statmodel.com/download/usersguide/MplusUserGuideVer_8.pdf). For more straightforward interpretation, mixed‐effects modeling results were converted to group differences (TD vs. TS) at ages 8, 10, 12, and 14 years. Group‐by‐age interaction effects analyses were examined to capture group differences in brain development during the typical transition to puberty, focusing on changes occurring between ages 10–12 and 12–14. Analyses of cortical gray matter volume and surface area were conducted conditional on total brain volume. A two‐tailed significance level of α = .05 was used in primary analyses. In secondary regional analyses of 10 bilateral regions, a two‐tailed significance level of α = .0025 (.05/20) was considered significant.

2.7. Effect of estrogen supplementation

Post hoc cross‐sectional analyses were conducted on a subset of girls with TS to explore the effects of estrogen supplementation on brain structure. This analysis included 20 untreated girls with TS (range = 10.46–14.78 years; mean age 11.9 ± 1.3 years old) and 20 age‐matched (t = −1.71, p = .09) girls with TS that were prescribed supplemental estrogen at the time of scan (range = 10.29–14.4 years; mean age 12.6 ± 1.0 years old). Linear regression models were used to test group differences in volume, thickness, and surface area. Given the small sample size and similar age at scan between the two groups, age was not included as a covariate in these analyses. An uncorrected two‐tailed significance level of α = .05 was applied to these exploratory analyses.

3. RESULTS

3.1. Participant characteristics

Participant characteristics are presented in Table 1. As expected, scores on baseline assessments of intellectual functioning were significantly lower in the TS group compared to the TD group (ps < .007).

TABLE 1.

Participant characteristics at baseline

Turner syndrome group
Age (years) N FSIQ VCI PRI WMI PSI Mean Tanner stage Number of estrogen‐treated girls
4.0–5.9 4 ‐ ‐ ‐ ‐ ‐ 1.0 ± 0.0 0
6.0–7.9 12 88.0 ± 16.0 97.9 ± 16.9 89.6 ± 18.3 87.5 ± 11.2 82.7 ± 16.6 1.0 ± 0.0 0
8.0–9.9 10 97.5 ± 16.9 112.9 ± 18.6 94.0 ± 16.1 92.8 ± 12.8 85.9 ± 17.5 1.1 ± 0.2 0
10.0–11.9 17 92.1 ± 11.3 105.2 ± 9.4 92.4 ± 15.4 89 ± 11.4 83 ± 16.8 1.3 ± 0.4 2
12.0–13.9 13 97.6 ± 13.4 108.5 ± 17.6 97.8 ± 10.1 95.1 ± 9.4 86 ± 16.1 2.3 ± 0.6 9
14.0–16.9 5 101.6 ± 10.5 112.6 ± 8.9 96.6 ± 18.1 100.2 ± 10.8 89.8 ± 8.8 3.4 ± 0.5 4
Total 61 94.3 ± 14.0 106.4 ± 15.4 93.7 ± 15.1 91.7 ± 11.4 84.7 ± 15.8 1.5 ± 0.8 15
Typically developing group
Age (years) N FSIQ VCI PRI WMI PSI Mean Tanner stage Number of estrogen‐treated girls
4.0–5.9 2 ‐ ‐ ‐ ‐ ‐ 1.0 ± 0.0 0
6.0–7.9 8 106.3 ± 14.9 103.8 ± 13.4 109.9 ± 15.7 97.5 ± 16.1 101.7 ± 8.6 1.2 ± 0.4 0
8.0–9.9 20 114.3 ± 10.1 115 ± 16.6 115.1 ± 9.9 110.3 ± 11.5 99.7 ± 11.7 1.2 ± 0.4 0
10.0–11.9 11 112.7 ± 10.8 116.8 ± 10.4 113.0 ± 10.8 101.0 ± 7.8 102.5 ± 14.7 2.0 ± 1.0 0
12.0–13.9 12 112.5 ± 9.8 115.6 ± 11.8 108.0 ± 11.8 109.3 ± 16.0 102.8 ± 15.8 3.1 ± 1.2 0
14.0–16.9 2 113.0 ± 8.5 127.0 ± 4.2 111.5 ± 13.4 103.5 ± 9.2 90.0 ± 9.9 4.0 ± 0.7 0
Total 55 112.4 ± 10.8 114.2 ± 14.2 112.1 ± 11.5 105.9 ± 13.3 100.9 ± 12.8 1.8 ± 1.1 0
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Note: Values represent n or mean ± SD at baseline/year 0 of study. WISC‐IV can only be administered to individuals beginning at age 6; therefore, the youngest age group does not have IQ information. Bold font denotes independent t‐test results with p < .05 comparing turner syndrome and typically developing IQ within each age group and across all ages.

Abbreviations: FSIQ, Full Scale IQ; PRI, Perceptual Reasoning Index; PSI, Processing Speed Index; VCI, Verbal Comprehension Index; WMI, Working Memory Index.

The two groups did not differ based on mean Tanner stage at baseline, X 2(7, N = 166) = 9.36, p = .23. Using a threshold mean Tanner stage of 1.5 to denote pubertal onset, participants were dichotomized into prepubertal or peripubertal. This threshold implies that a person has a Tanner stage of 2 for at least their breast or pubic hair ratings, a well‐accepted indication of pubertal onset (Berenbaum et al., 2015). When participants were dichotomized as such, significant differences in pubertal stage emerged by age 10, whereby girls with TS had significantly lower Tanner scores than TD girls (p = .039).

3.2. Analysis of global structure

Results of Freesurfer global analyses are presented in Table 2 and Figure 1. Significantly smaller total surface area was observed in the TS group at all ages in our analysis (8, 10, 12, and 14 years; ps < .008). Comparison of slopes indicated that the rates of change in total surface area from ages 10 to 12 and 12 to 14 were not significantly different between groups (ps > .115).

TABLE 2.

Differences in structural brain metrics between TD and TS groups estimated on the basis of longitudinal mixed‐effects modeling

Region Group difference at age 8 years Group difference at age 10 years Group difference at age 12 years Group difference at age 14 years
Estimate a ES b p‐Value Estimate a ES b p‐Value Estimate a ES b p‐Value Estimate a ES b p‐Value
TBV (mm3) 9505.78 0.091 .318 4184.31 0.043 .819 −1137.17 −0.011 .951 −6458.64 −0.060 .749
Total WMV (mm3) 5816.40 −0.232 .213 7149.00 −0.363 .052 7292.60 −0.333 .075 6247.40 −0.231 .215
Total GMV (mm3) 4867.70 0.220 .230 5451.30 0.310 .092 1565.50 0.100 .672 −6789.8 −0.270 .152
Total SA (mm2) 6313.50 0.810 <.001 6145.40 0.970 <.001 5415.00 0.800 <.001 4122.2 0.500 .008
Average CT (mm) −0.004 −0.033 .850 −0.025 −0.260 .164 −0.046 −0.460 .015 −0.066 −0.508 .006
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Abbreviations: CTh, cortical thickness; GMV, gray matter volume; SA, surface area; TBV, total brain volume; TD, typically developing; TS, Turner syndrome; WMV, white matter volume. Bold values denotes p < .05.

a

Estimates represent the difference between groups (TD‐TS).

b

Effect sizes (Cohen's d) were approximately calculated as two times t‐value divided by square root of sample size minus one, where t‐values were calculated as point estimates of group differences from mixed effects modeling divided by their robust maximum likelihood standard errors.

FIGURE 1.

FIGURE 1

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Developmental trajectories of global brain structure. Developmental trajectories for total brain volume, total gray matter volume, total surface area, and average thickness in girls with Turner syndrome (red) and typically developing control girls (blue). Shaded area represents 95% confidence intervals around estimated means (see Section 2 for details on statistical approach).

Thickness analyses indicated that the two groups did not differ with respect to this measure at ages 8 or 10 (ps > .163). However, group differences were present at ages 12 and 14, such that increased thickness was observed in the TS relative to the TD group (ps < .016). Analysis of linear slope differences indicated a significant difference between groups; a reduced thinning rate was observed in the TS relative to the TD group (TS slope = −0.025, TD slope = −0.045, p = .045 for the group differences).

At all ages analyzed, no differences were observed between the groups for total brain volume (ps > .317), total white matter volume (ps > .053), or total gray matter volume (ps > .110). However, analysis of slope differences indicated decreased reductions in total gray matter volume between ages 12 and 14 in the TS relative to the TD group (TS slope = −9488.8; TD slope = −17,844.1; p = .004 for the group differences). No slope differences were observed for total gray matter volume between ages 10 and 12, nor for total brain volume or total white matter volume at any ages analyzed (ps > .055).

3.3. Analysis of regional structure

Secondary analyses were conducted on specific brain areas to assess TS‐associated alterations in age‐related regional gray matter morphology changes. The results of these analyses are presented in Figure 2. Three major patterns emerged. First, the TS group showed variable differences in gray matter volume. Increased gray matter volume was observed in the TS group relative to the TD group in the left caudate (by age 14), amygdala (by age 10), and superior temporal gyrus (all ages), and the right rostral middle frontal gyrus (ages 10–12) (ps ≤ .001). In contrast, the TS group exhibited decreased gray matter volume in regions including the right postcentral and superior parietal gyri (ages 8–12), right caudal middle frontal gyrus (ages 10–12), bilateral pericalcarine, and left postcentral and superior parietal gyri (ps ≤ .002).

FIGURE 2.

FIGURE 2

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Regional brain structure development. Results of regional analysis comparing girls with Turner syndrome (TS) and typically developing (TD) girls at ages 8, 10, 12, and 14 years. Cool colors indicate regions of structural reductions in the TS group relative to the TD group; warm colors indicate regions of TS‐associated increases. p‐Values are corrected for multiple comparisons.

Second, the TS group exhibited overall reductions in surface area across widespread regions relative to the TD group, including in the right middle temporal gyrus (by age 10) and caudal middle frontal gyrus (by age 12), bilateral postcentral and superior parietal gyri, and bilateral pericalcarine cortex (ps ≤ .002).

Third, larger cortical thickness was observed in the TS group relative to the TD group in several areas, including the left inferior (by age 10) and superior (by age 12) parietal gyri, and right middle (by age 10) and superior (by age 12) temporal gyri (ps ≤ .002).

Regional differences in growth rates between groups were also observed. Whereas the TD group showed a reduction in regional thickness from ages 10 to 14, girls with TS did not show this pattern. This difference was significant in the right inferior parietal (TS slope = 0.064, TD slope = −0.116, p = .002 for the group difference) and superior temporal gyri (TS slope = −0.017, TD slope = −0.081, p = .001 for the group difference). Additionally, while the TD group demonstrated a reduction in cortical gray matter volume in the left caudate from ages 10 to 12, the TS group demonstrated a significantly increased growth rate of gray matter volume in this region (TS slope = 26.2, TD slope = −106.2, p < .001 for the group difference).

3.4. Exploratory analyses of the effects of estrogen supplementation

Exploratory cross‐sectional analyses were completed using scans from 20 girls with TS who received estrogen supplementation at the time of a scan, in addition to 20 age‐matched girls with TS who did not receive estrogen supplementation (ages 10.29–14.78 years). Results of these analyses are presented in Figure 3. Findings indicate estrogen supplementation within the TS group was associated with reduced surface area and gray matter volume of the left postcentral gyrus (ps < .047) and left caudal middle frontal gyrus (ps < .020). No differences were observed between subgroups for cortical thickness or other global measures of brain structure.

FIGURE 3.

FIGURE 3

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Effects of estrogen supplementation on regional brain structure. Regional analysis comparing girls with Turner syndrome (TS) on and off estrogen supplementation. Cool colors indicate regions of structural reductions in the TS subgroup currently receiving estrogen supplementation relative to the TS group not receiving this treatment.

4. DISCUSSION

This ALD study examined TS‐associated alterations in gray matter volume, thickness, and surface area during adolescence. Using surface‐based morphometry, girls with TS exhibited widespread differences in regional cortical and subcortical morphology relative to TD girls. Longitudinal analyses indicated that whereas TD girls showed normative reductions in gray matter volume and thickness over time, this pattern was significantly reduced or inverted in girls with TS. Both regional increases and decreases in cortical gray matter volume were observed in girls with TS. Closer inspection of the surface area and thickness areas that showed a significant group difference in volume shed light on the specific aspects of cortical morphology that likely drove volume differences. Girls with TS, for example, showed both reductions in volume and surface area across many areas relative to the TD group, including in the right middle temporal gyrus and caudal middle frontal gyri, bilateral postcentral and superior parietal gyri, and bilateral pericalcarine cortex. In contrast, in areas such as the superior temporal gyri, widespread increases in cortical thickness and volume were observed in girls with TS.

4.1. TS effect on brain morphology

Results of the present investigation indicated global effects of TS on brain morphology, including reduced total surface area irrespective of age at assessment. Moreover, increased average cortical thickness and a decreased rate of total gray matter volume reduction were observed in the TS relative to the TD group, but only at later ages (12 and older). No differences were observed between the two groups in total brain volume or total white matter volume. Investigation of regional morphology elucidated specific spatial patterns of gray matter volume, surface area, and cortical thickness alternation in TS. Our findings showing a stable, overall effect of TS on the brain are consistent with previous studies documenting alterations in the amygdala, and gray matter of the pericalcarine, parietal and postcentral cortices of females with TS (Good et al., 2003; Kesler et al., 2004; Lepage, Hong, et al., 2013; Molko, 2004). Alterations in the frontal cortex and amygdala may be associated with the high prevalence of anxiety (McCauley et al., 1987; Schmidt et al., 2006) and social dysfunction in this population (Hong et al., 2011; Lepage, Dunkin, et al., 2013; McCauley et al., 1987; Romans et al., 1998). Parietal and postcentral alterations, in turn, may be related to TS‐associated deficits in visuospatial and sensory processing, respectively (Jajor et al., 2019; McCauley et al., 1987; Murphy et al., 1994). Concerning longitudinal differences, our finding of a slower rate of decline in cortical gray matter over time in TS is consistent with that of previous work by Lepage, Dunkin, et al. (2013), Lepage, Hong, et al. (2013), and Lepage, Mazaika, et al. (2013) and, more recently, Li et al. (2019). Such a pattern implies disruptions in synaptic pruning that typically occurs during puberty. The absence of this neurodevelopmental process could contribute to behavioral and cognitive development disruptions in girls with TS.

Regional analyses demonstrated that alterations in gray matter volume in the TS group are primarily driven by significant surface area alterations, not cortical thickness. This was true for reduced volume in the left pericalcarine, bilateral postcentral and superior parietal gyri, and right caudal middle frontal gyrus and increased volume in the right rostral middle frontal gyrus. While the precise neurobiological factors that drive each metric of brain morphology in humans have yet to be fully understood, available evidence indicates that one determinant of surface area is the number of cortical columns (Rakic, 1988). This number does not change following birth, despite the significant surface area increases seen in childhood (Hill et al., 2010). However, surface area is also influenced by the spacing between columns and inter‐columnar neuropil (Buxhoeveden et al., 2001). Additional research is needed to test whether these or other factors directly underlie the alterations in cortical gray matter volume and surface area observed here in girls with TS. Nonetheless, the use of surface‐based analyses in the current study serves as a unique contribution to the literature as it points to spatially overlapping alterations in thickness and surface area—metrics that comprise cortical gray matter volume and that are genetically and phenotypically independent from one another (Panizzon et al., 2009; Winkler et al., 2010).

4.2. Direct versus indirect effects on brain morphology

To more fully elucidate the direct effects of sex chromosome genes on brain development from the indirect effects mediated by gonadal hormones secreted during puberty, a proposed strategy is to assess brain morphology prior to and subsequent to puberty onset (Arnold, 2004). For example, Johnson et al. (1993) used this approach to delineate “congenital” and “maturational” brain activity alterations in TS. Similarly, our analytical design allowed us to begin to distinguish between these direct genetic and indirect hormonal effects of X‐monosomy on brain development in TS. Within our sample, the TD group was more likely to have initiated puberty than the TS group by age 10, consistent with ovarian failure and estrogen deficiency in TS. Therefore, early onset alterations in TS brain morphology (i.e., congenital differences due to genetics) were defined as alterations observed by age 8. In contrast, later‐onset alterations (i.e., maturational differences due to delayed puberty and/or hormone deficiencies) were defined as changes occurring after age 10.

Our analyses revealed several congenital alterations in the TS group apparent by age 8, including globally reduced total surface area and regionally reduced bilateral pericalcarine, postcentral, and superior parietal gyri volume and surface area, and increased left superior temporal gyrus volume. These early onset, stable alterations in brain morphology, including several surface area aberrations, in TS relative to TD girls likely represent the direct effects of haploinsufficiency in X‐monosomy of X‐linked genes that escape inactivation. Indeed, these findings are well supported by the significant influence of X‐chromosome genes on brain surface area development, particularly in cortical systems supporting attention, decision‐making, and motor control (Mallard et al., 2021). The structural patterns observed here are likely to have long‐lasting functional consequences in girls with TS from childhood through adulthood.

Our analyses also revealed several maturational differences emerging at age 10 or later, including increased volume in the left caudate and increased cortical thickness in the left superior parietal gyrus and right temporal lobe. These later‐onset alterations occurring shortly after normative pubertal onset are likely driven by delayed puberty and estrogen deficiency in girls with TS. Importantly, adolescence is a period of prolonged cortical thinning that extends into adulthood (Mills et al., 2016; Tamnes et al., 2017; Zhou et al., 2015). Gonadal hormones secreted during puberty can influence brain structure and function through activational effects (Schulz & Sisk, 2016; Sisk & Foster, 2004) and have been linked to pubertal cortical maturation, including cortical pruning (Juraska & Willing, 2017; Vijayakumar et al., 2018, 2021). As such, the maturational differences observed here imply that indirect effects of X‐monosomy include aberrant pubertal cortical thinning. This hypothesis is supported by all significant group‐by‐age effects in our analyses; globally, the TS group demonstrated reduced mean cortical thinning, specifically in the right temporal lobe, at all ages analyzed and a diminished rate of total gray matter volume reduction by age 14. Further, from ages 10 to 12, the TS group demonstrated growth in the left caudate volume, while TD girls demonstrated normative volume reductions during this age frame (Goddings et al., 2014). Contrary to this pattern, however, the right caudal middle frontal gyrus demonstrated increased volume by age 10 and decreased surface area by age 12. Future studies that clarify the factors underlying longitudinal change in this region are of interest, as is additional research that more fully tests the role of puberty in TS‐associated alterations.

4.3. Exploratory analyses of the effects of estrogen supplementation

Exploratory cross‐sectional analyses, conducted in a subset of age‐matched girls with TS, showed significant associations between brain morphology and estrogen supplementation at the time of scans. While a pubertal framework would suggest that these associations would align with “maturational differences” identified in our primary analyses and that the effects would be in the direction of normative brain development (e.g., we hypothesized that estrogen supplementation in girls with TS would be associated with decreased caudate volume relative to age‐matched girls in the TS group without treatment), our findings did not support these predictions. In contrast, we found that estrogen supplementation was associated with alterations in regional metrics our primary analyses identified as genetically influenced and in directions that are contrary to normative development in our TD group (i.e., estrogen supplementation was associated with reduced surface area and volume in the left postcentral and caudal middle frontal gyri). The reason for these findings is unclear. However, one possibility is that girls receiving estrogen treatment in this sample were experiencing more severe estrogen deficiency or more significant behavioral or cognitive impairment, presumably caused by a greater magnitude of neural alterations. Future prospective, longitudinal studies that test these possibilities are needed.

4.4. Strengths and limitations

Unique strengths of the present study include surface‐based analyses of cortical gray matter volume, thickness, and surface area, as well as our ability to begin to disentangle direct and indirect effects of X‐monosomy on TS brain development. However, our findings should be interpreted considering certain limitations. First, while we speculated that regional alterations in thickness and surface area drove local volume differences between the two groups, additional research is needed to test this assumption. Second, although we limited our secondary analyses to specific regions affected in TS and corrected for multiple comparisons, we cannot exclude the possibility of Type II error. Third, the sample size decreased over time, with limited data available at the upper limits of the ages of interest. As such, robust longitudinal follow‐up studies are necessary to replicate and add to our findings. Fourth, we could not explore the potential effects of estrogen supplementation longitudinally due to the limited number of treatment‐naive TS participants around pubertal ages and the naturalistic design of our study. Finally, the dose, route of administration (e.g., oral vs. transdermal), and duration of estrogen replacement were highly variable in our cohort, and estrogen levels were not measured in our TS or TD cohorts. Therefore, more extensive longitudinal studies focused on recruiting treatment‐naive prepubertal girls with TS at baseline with in‐depth measurements of pubertal hormones are needed to help assess the effects of estrogen treatment on brain and behavioral development in adolescent girls with TS more directly.

5. CONCLUSION

In summary, we found widespread cortical and subcortical morphology alterations in an adolescent sample of girls with TS. Moreover, longitudinal analyses revealed that, in contrast to TD girls who showed normative reductions in gray matter volume and thickness reductions, this pattern was significantly reduced or altogether absent in girls with TS. Taken together, our results suggest the involvement of both direct (i.e., genetic) and indirect (i.e., hormonal) effects of X‐chromosome insufficiency on brain development in girls with TS. Future studies that replicate and build upon these findings in larger samples are warranted, as are investigations that tease apart the influence of X‐chromosome dosage and estrogen replacement therapy on the brain in girls with this genetic condition. Nonetheless, our findings likely generalize to elucidate brain morphological changes common to TD girls during adolescence and the unique effects of X‐monosomy on brain development.

CONFLICT OF INTEREST

The authors declare no competing conflict of interests.

Supporting information

TABLE S1. Number of Turner syndrome participants receiving estrogen treatment.

Click here for additional data file. (13.9KB, docx)

ACKNOWLEDGMENTS

The authors thank the participants and their families for contributing to this study and the Turner Syndrome Society and Turner Syndrome Foundation for assisting with participant recruitment. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. HD049653 [to ALR]), the National Institute of Mental Health (Grant No. MH099630 [to ALR]), the Sharon Levine Foundation and Niggeman Family Foundation, and the National Science Foundation Graduate Research Fellowship (Grant No. 2237827 [to VLW]).

Lozano Wun, V. , Foland‐Ross, L. C. , Jo, B. , Green, T. , Hong, D. , Ross, J. L. , & Reiss, A. L. (2023). Adolescent brain development in girls with Turner syndrome. Human Brain Mapping, 44(10), 4028–4039. 10.1002/hbm.26327

DATA AVAILABILITY STATEMENT

The data supporting this study's findings are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

TABLE S1. Number of Turner syndrome participants receiving estrogen treatment.

Click here for additional data file. (13.9KB, docx)

Data Availability Statement

The data supporting this study's findings are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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