Neurocognitive and psychosocial profiles of children with Turner syndrome

Article information

Ann Pediatr Endocrinol Metab. 2023;28(4):258-266

Publication date (electronic) : 2023 February 5

doi : https://doi.org/10.6065/apem.2244222.111

So Yeong Park¹, Su Jin Kim¹, Myeongseob Lee¹, Hae In Lee¹, Ahreum Kwon¹, Junghwan Suh¹, Kyungchul Song¹, Hyun Wook Chae¹, Bonglim Joo², Ho-Seong Kim^,1

¹Department of Pediatrics, Division of Pediatric Endocrinology, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea

²Department of Pediatric Neurology, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea

Address for correspondence: Ho-Seong Kim Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Email: kimho@yuhs.ac

Received 2022 September 14; Revised 2022 November 1; Accepted 2022 November 7.

Abstract

Highlights

· This article highlights the neurocognitive and psychosocial characteristics in Korean patients with Turner syndrome. Patients with Turner syndrome maintained their verbal function, but attention, visuospatial function, and social competence were lower compared with normal controls.

Introduction

Turner syndrome (TS) is a relatively common genetic disorder caused by partial or complete loss of the X chromosome. The clinical features of TS include short stature, gonadal dysgenesis, various renal and cardiovascular defects, and specific psychosocial and neurocognitive profiles [1,2]. Despite some individual variation in TS severity, patients with TS present unique neurocognitive and psychosocial characteristics according to developmental period. During early infancy, some patients with TS exhibit a high rate of developmental delay across all domains of development, including fine motor, gross motor, and language skills [3]. The risk of neurodevelopmental delay increases following medical or surgical interventions. However, most patients with TS display relatively typical psychosocial development [4]. In early childhood, patients with TS manifest attention deficits, hyperactivity, and low social competence with obvious short stature [4,5]. As they grow, their neurocognitive and psychosocial development continues to diverge from that of their typically developing counterparts. Most children with TS manifest Full-Scale Intelligence Quotient (FSIQ) scores in the normal range, but they display relative strength in the verbal domains and weaknesses in domains such as arithmetic, visuospatial processing, and executive functioning [6]. In addition, patients with TS are at high risk for anxiety, depression, and attention-deficit hyperactivity disorder (ADHD) [7]. Young adult patients with TS generally have normal self-perceived physical and mental health; however, some patients report social anxiety and reduced self-esteem and often complain of difficulties in relationships with colleagues [8-10]. In contrast with those findings, a population-based cohort study of 1,392 TS patients reported a relatively high risk of neurodevelopmental or psychiatric disorders, including intellectual disability, autism-spectrum disorder, eating disorders, behavioral and emotional disorders, and schizophrenia [11].

Despite those previous findings, little research has examined the neurocognitive and psychosocial characteristics of children and adolescents with TS in Korea. Therefore, we evaluated the neurocognitive and psychosocial functions and quality of life (QoL) of pediatric Korean patients with TS.

Materials and methods

3. Neurocognitive and psychosocial evaluation

Patients with TS and the controls under went several neuropsychological tests to assess their intelligence, memory, attention, executive function, emotion, behavior, and adaptive function (Table 1).

Table 1.

Neuropsychological tests and assessment tools

1) Korean Wechsler Intelligence Scale for Children-IV and Korean Wechsler Primary and Preschool Scale Intelligence

For the intelligence evaluations, we used the Korean Wechsler Intelligence Scale for Children-IV (K-WISC-IV) and Korean Wechsler Primary and Preschool Scale Intelligence (K-WPPSI). Participants younger than 6 years were assessed for intelligence using the K-WPPSI, which consists of the FSIQ, Verbal Scale IQ, and Performance Scale IQ scales, with a mean of 100 and standard deviation (SD) of 15 [12]. Participants 6 years and older were assessed for intelligence using the K-WISC-IV, which comprises 5 scales: FSIQ, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI), with a mean of 100 and SD of 15 [13].

The VCI of the K-WISC-IV was used as a measure of verbal ability, such as understanding, learning, retaining verbal information, and using language to solve novel problems. The PRI of the K-WISC-IV was used as a measure of visuoperceptual ability, such as understanding visual information and solving novel abstract visual problems. The WMI of the K-WISC-IV was used as a measure of a participant's ability to maintain verbal information in short-term memory and to manipulate that information, assessing attention, concentration, and working memory. The PSI of the K-WISC-IV was used to measure the speed of mental and graphomotor processing.

2) Comprehensive Attention Test

We administered the Comprehensive Attention Test (CAT) to measure comprehensive attention, including visual and auditory attention. The attention quotient (AQ) was determined using the CAT. AQ scores ≤69, 70–84, and ≥85 indicate defect, borderline defect, and average, respectively [14].

3) Rey-Kim Memory Test

We administered the Rey-Kim Memory Test (RKMT) to evaluate verbal and nonverbal memory performance. The participants learned 15 unrelated words and pictures over 5 trials and were requested to recall them immediately and 20 minutes later. The mean score of the memory quotient (MQ) was 100±15. The MQ comprises 10 indices, and the subscales have a mean score of 10±3 [15].

4) Children's Color Trails Test

The Children's Color Trails Test (CCTT) evaluates visualmotor coordination, attention, and cognitive impairment. The CCTT part 1 requires the participants to identify numbers in ascending order (1–2–3) and to connect them rapidly. In the CCTT part 2, the participants sequentially connect numbers while alternately connecting colors (pink-yellow-pink). The CCTT score is determined by the time (seconds) from the beginning of inspection to completion and the number of errors. The mean CCTT score was 50±10 [16].

5) Korean-Child Behavior Checklist

The Korean-Child Behavior Checklist (K-CBCL) test, completed by parents, was used to measure sociality, behavior, and adaptability. To provide estimates of behavioral problems, we examined the individual subscales of the K-CBCL and the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. For the behavioral problems and DSM criteria subscales, a higher score indicates more severe problems. We also evaluated total competence, social competence, and school competence, with higher scores indicating better performance [17].

6) Social Maturity Scale

The Social Maturity Scale (SMS) was designed to measure the social competence of people 30 years of age or younger. The social age and social quotient were measured by conducting a test with 117 items. Higher social age and social quotient scores indicate greater social competence [18].

7) Pediatric QoL Inventory

We administered the Pediatric QoL Inventory (PedQL) test, which consists of self-reported questionnaires, to measure QoL. The PedQL test consists of 23 questions about functioning in the physical, emotional, social, and school domains. The parents of those in the experimental group evaluated the QoL of their child. The scores range from 0 to 100, with a higher score indicating better QoL in children and adolescents [19].

8) Children's Depression Inventory

The Children's Depression Inventory (CDI) is a self-reported test consisting of 27 items used to measure depressive thoughts and feelings. The scores range from 0 to 54, with higher scores indicating more depressive thoughts and feelings [20].

Results

1. Clinical characteristics of participants

Table 2 summarizes the clinical data of all participants, who were female. The mean ages of the TS and control groups were 9.4±3.3 and 9.1±3.2 years, respectively. The mean heights of the TS and control groups were 124±18.6 cm and 128.7±20.8 cm, respectively. The height SD scores were -2.09±0.77 and -0.81±0.90 in the TS and control groups, respectively, revealing a low height SDS in the TS group. The mean body weights were 30.3±11.7 and 29.8±12.0 kg in the TS and control groups, respectively, with mean weight SD scores of -1.06±1.20 and -0.67±0.90. Body mass index values were 18.9±3.6 and 17.2±2.0 kg/m² in the TS and control groups, respectively, which were within the normal range. The chromosomal type was 45,X in 25% of the participants, and mosaicism was confirmed in 75% of the participants. All patients with TS (100%) were currently under growth hormone treatment. Three patients with TS (15%) were currently under estrogen treatment. Among the patients with TS, 6 (30%) had comorbid diseases or a medical history of surgery (1 patient with atrial septal defect repair and partial anomalous pulmonary venous return repair, 1 patient with eccentric aortic valve regurgitation and bicuspid valve, 1 patient with atrial septal defect, 1 patient with horseshoe kidney, 1 patient with scoliosis, and 1 patient with hip dislocation surgery).

Table 2.

Demographic and clinical characteristics of the participants

2. K-WISC-IV and K-WPPSI

The TS group exhibited significantly lower FSIQ, PRI, WMI, and PSI scores than the control group (P<0.005, P<0.05, P<0.001, and P<0.005, respectively). The TS group presented an FSIQ score of 90.75±17.30, whereas the control group presented a score of 109.43±12.33. Within the TS group, 3 patients had borderline FSIQ (15%) and 2 patients had deficit FSIQ (10%). The TS group presented a WMI score of 83.31±17.27 and a PSI score of 89.75±12.78, which are within the low average range. In contrast, the VCI score did not differ significantly between the groups (Table 3). Among the subtests, the TS group displayed significantly lower scores for Block Design (P<0.05), Matrix Reasoning (P<0.05), and Picture Completion (P<0.05) in PRI; Digit Span (P<0.001), Letter-Number Sequencing (P<0.001), and arithmetic (P<0.05) in WMI; and Symbol Search (P<0.01) in PSI compared with the control group. Of the K-WISC-IV subtests in the TS group, the Picture Completion score was the lowest at 6.69±2.89, which indicated a borderline deficit.

Table 3.

Korean Wechsler Intelligence Scale scores in children with TS compared with age-matched controls

We performed within-group post hoc analyses among the indices to compare index-level discrepancies. The TS group had higher a VCI score than PRI, WMI, and PSI scores (P<0.05, P<0.005, and P<0.05, respectively). No index-level discrepancies were observed in the control group.

Next, we compared clinical characteristics (chromosome type, age, treatment history, and comorbidity) between patients with deficit and borderline scores and patients with normal scores on the K-WISC-IV. We found no differences between the groups (Supplementary Table 1).

In the K-WPPSI test performed on participants aged 3–5 years, the groups did not differ significantly (TS patients, n=4; control, n=4) (data not shown).

3. Comprehensive Attention Test

The omission error, commission error, response time, and response time variability scores for visual selective responses were significantly lower in the TS group than the control group (P<0.005, P<0.001, P<0.05, and P<0.001, respectively) (Table 4). The auditory selective CAT scores did not differ significantly between the groups. The forward correct response and memory span scores were significantly lower in the TS group than the control group (P<0.005 and P<0.001, respectively). The average scores in the TS group were borderline for visual selective response time variability, visual selective response time, forward correct response, and forward memory span.

Table 4.

Comprehensive Attention Test scores in children with TS compared with age-matched controls

6. Korean-Child Behavior Checklist

The mean CBCL scores in the TS group were within the normal range, but the total behavioral problem, withdrawn/depressed, and social problem scores were significantly higher in the TS group than the control group (P<0.05, P<0.005, and P<0.005, respectively) (Table 5). According to the DSM criteria, somatic problems scored significantly higher in the TS group than the control group (P<0.05). The ADHD scores did not differ significantly between the groups. In the TS group, the total competence and social competence scores were significantly lower than in the control group (P<0.05 and P<0.005, respectively). The proportion of the social competence scores in the clinical range was significantly higher in the TS group than the control group (TS, 31.25%; control, 0%, P<0.05, Fisher's exact test).

Table 5.

The Korean-Child Behavior Checklist score in children with TS compared with age-matched controls

Discussion

This study confirms the distinctive neurocognitive and psychosocial characteristics of Korean children with TS. In the K-WISC-IV test, the TS group displayed lower FSIQ scores than the control group, though the mean FSIQ score of the TS group was within the normal range. The pattern of global intellectual function was consistent with that reported in previous studies, suggesting that patients with TS do not commonly have global intellectual disabilities. However, patients with TS do maintain or display a slight decrease in FSIQ score compared with healthy controls [21].

The between-group differences in individual indices of the K-WISC-IV reveal lower scores on all indices except the VCI score in the TS group compared with the control group. In addition, an analysis of within-group differences in the K-WISC-IV indices shows that the VCI score was highest among the subtests. In other words, nonverbal abilities are diminished in patients with TS, whereas verbal abilities are spared, consistent with the literature. The VCI scores of patients with TS remain within the normal range, demonstrating better maintained verbal abilities than nonverbal abilities [5]. Despite the maintenance of verbal function, verbal tasks requiring the substantial use of visuospatial function or executive function, such as sequence and temporal relationships, appear to be impaired in TS [5].

Upon a closer examination of the individual K-WISC-IV indices, the PRI score was significantly lower in the TS group than in the control group, though it was within the normal range. All 4 PRI subtests displayed lower scores in the TS group than the control group, but all the results were within the normal range except the borderline Picture Completion score. The relatively low PRI score, which measures the ability to analyze and synthesize abstract visual problems and the ability to reason about nonverbal tasks, suggests that the TS group exhibits reduced ability to process visuospatial information. The impaired visuospatial function in patients with TS and the discrepancy between verbal and visuospatial abilities are consistent with previous findings [5]. Some neuroimaging studies have suggested that visuospatial deficits are related to gray matter volume loss, including that in the right intra-parietal sulcus and superior parietal and postcentral gyri, in patients with TS [22,23]. Functional magnetic resonance imaging studies have demonstrated activation deficits in the parietal cortex [24,25].

In our study, the TS group displayed a lower average WMI score than the control, and within-group post hoc analyses revealed that the WMI score was lower than the VCI score (P=0.002 by post hoc analysis). The lower WMI score, which measures attention, visual-motor coordination, concentration, and working memory, suggests that attention and working memory were impaired in the TS group. A previous study showed that patients with TS have low working memory and WMI scores [6]. In addition, the TS group demonstrated significantly lower arithmetic subtest scores than the control group. Poor math performance in the TS group is associated with poor visual tracking, visual-motor coordination, and figure-ground processing [26].

In this study, the PSI score of the K-WISC-IV, used as a measure of mental and graphomotor processing speed, was lower in the TS group than in the controls. In other words, decreased cognitive functions such as visual-motor coordination, attention, and concentration in patients with TS could affect their PSI scores. In our study, chromosome type, growth hormone or estrogen treatment, and comorbid diseases did not affect the K-WISC-IV scores.

Together with the results of the K-WISC-IV, we speculate that children with TS have a normal range of global intellectual function but decreased visuospatial function that results in diminished attention, poor working memory, and decreased cognitive functions affecting execution. The verbal function was maintained in patients with TS; however, they displayed low attention, working memory, arithmetic skills, and visuospatial problem-solving ability, similar to the pattern seen in patients with nonverbal learning disability (NLD) [27,28].

Decreased visuospatial function in children with TS was also confirmed by CAT score, which revealed that visual selective attention, but not auditory selective attention, was lower in patients with TS. This finding suggests that a decrease in visuospatial function in TS might lead to the diminished attention observed in our and previous studies [3,5,8]. Attention is closely related to executive function [29]. Previous studies have reported low attention and impaired executive ability because of visuospatial difficulties in patients with TS [5,7,30]. Executive function in our patients with TS, as assessed by the CCTT, was not impaired. However, this finding cannot exclude the possibility of impaired executive function in TS. No definitive tests for executive function are available because it involves complex processes such as cognitive conversion, control, and inhibition.

Even though the K-CBCL scores assessing sociality, behavior, and adaptability were within the normal range in the TS group, problems were prominent. The mean social competence score in patients with TS was within the normal range; nonetheless, 31.25% of the patients experienced difficulty in social relationships. According to the DSM diagnostic criteria, only the scores for somatic problems were significantly higher in the TS group than the control group, and even those were within the normal range. Unlike previous studies, we did not observe an association between TS and a high risk of ADHD [3]. However, we performed the K-CBCL test using a parental self-report about the possibility of ADHD. Additionally, no significant depression was observed in the TS group in our study. Children with TS have been reported to have high levels of depression and anxiety [11,31,32], though other studies found no difference in depression [33]. In our study, children with TS might not have reported emotional problems because we included several patients who had not yet reached puberty. Patients with TS might recognize their emotional problems as they age; this possibility requires additional research and interpretation.

The SQ score on the SMS test was lower in the TS group than the control group. In this study, children with TS displayed lower social competence and social adaptation, consistent with earlier findings [4,5]. Impaired social competence is related to impaired facial cognition, poor performance in recognizing the expressions of anger and fear, and impaired eye gaze processing [5].

Parental assessments of social and academic QoL were lower in the TS group than the control group. However, the QoL reported by participants did not differ between the groups.

The neurocognitive profiles of patients with TS were similar to those with NLD [27]. Similar to NLD treatment, education programs for children with TS should include social training and learning therapy to improve their neurocognitive function. Learning therapy requires a curriculum to improve visuospatial, attention, planning, and organizational skills. Moreover, additional math instruction and extended education time (to accommodate slower processing speed and attentional deficits) could help these children. Interpersonal and self-esteem training are also necessary social skills. Low social competence is related to impaired cognitive function; thus, education to improve cognitive and visuospatial functions should be combined to improve social competence. Furthermore, training for facial emotion recognition and interpretation of social cues might be helpful. An individualized education program specific to TS is required so patients can improve their psychosocial functioning, QoL, and neurocognitive function.

This study was conducted at a single center with an insufficient number of participants. Because of our small sample size, our results have limited generalizability. We intend to address this limitation in the future by increasing the number of patients. We did not collect or analyze data about socioeconomic status. The control group was selected from among healthy participants who visited a university hospital to evaluate their growth patterns. Therefore, selection bias, such as selecting a control group with a high socioeconomic level, might have affected our results.

In summary, children with TS displayed normal global intellectual function and maintained good verbal function, but they exhibited reduced visuospatial function, attention, and social competence. Reduced attention, concentration, and social competence might result from attenuated visuospatial function. Our findings will allow physicians to focus on neurocognitive and psychosocial functioning when treating children with TS.

Supplementary material

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