Psychosocial well-being and quality of life in women with Turner syndrome

Journal Pre-proof Psychosocial Well-Being and Quality of Life in Women with Turner Syndrome Ariane Liedmeier, David Jendryczko, Hedi Claahsen van der Grinten, Marion Rapp, Ute Thyen, Catherine Pienowski, Andreas Hinz, Nicole Reisch

PII:

S0306-4530(19)31289-2

DOI:

https://doi.org/10.1016/j.psyneuen.2019.104548

Reference:

PNEC 104548

To appear in:

Psychoneuroendocrinology

Received Date:

8 July 2019

Revised Date:

14 October 2019

Accepted Date:

13 December 2019

Please cite this article as: Liedmeier A, Jendryczko D, van der Grinten HC, Rapp M, Thyen U, Pienowski C, Hinz A, Reisch N, Psychosocial Well-Being and Quality of Life in Women with Turner Syndrome, Psychoneuroendocrinology (2019), doi: https://doi.org/10.1016/j.psyneuen.2019.104548

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Psychosocial Well-Being and Quality of Life in Women with Turner Syndrome Ariane Liedmeier1, David Jendryczko2, Hedi Claahsen van der Grinten3, Marion Rapp1, Ute Thyen1, Catherine Pienowski4, Andreas Hinz5, Nicole Reisch6

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Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany 2

Institute of Psychology, Westfälische Wilhelms-Universität Münster, Münster, Germany

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Department of Pediatric Endocrinology, Radboud University Nijmegen Medical Centre, the Netherlands Médecin Endocrinologie et métabolismes. Hôpital des Enfants, CHU, Toulouse, France

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Department of Psychology, University of Leipzig, Leipzig, Germany

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Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Germany

Prof. Nicole Reisch

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Medizinische Klinik IV

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Corresponding author:

Klinikum der Universität München

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Ziemssenstraße 1

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80336 München

Highlights  Adult women with Turner syndrome across Europe suffer from substantial impairment in all quality of life domains and experience multiple psychosocial challenges.  Depression and self-esteem seem to be the best predictors of quality of life in women with Turner syndrome.  Women with Turner syndrome are satisfied with their work life and income. Abstract

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Background: Turner syndrome (TS) affects approximately one out of 2,500 females. Previous research indicates that women with TS experience impairment in several psychosocial domains as well as in quality of life (QoL). Data, however, mainly focus on girls, whereas

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data on adult women is extremely scarce, inconsistent and mainly low in sample size. Separate analysis of adult women, however, is important since women face other challenges

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of TS than girls.

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Methods: We compared 301 women with TS aged 16-73 years (from 14 centres in six European countries) to healthy controls with regard to depression, anxiety, self-esteem,

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attention deficit/hyperactivity disorder (ADHD), autism, romantic relationships, social participation, amount of working hours and satisfaction with income as well as with regard to

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psychological, physical, environmental, social and global QoL. The influence of psychosocial well-being on the different QoL-domains was examined via multiple regression models.

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Results: Women with TS showed impairments in all psychosocial variables (anxiety, depression, ADHD, autism, self-esteem, social participation all p < 0.001) except for the amount of working hours (p = 0.062) and satisfaction with income (p = 0.369). They also showed lower social (p < 0.001), psychological (p < 0.001) and physical QoL (p < 0.001) compared to controls. Depression, satisfaction with income and self-esteem could be shown to be the best predictors for QoL.

Conclusion: In conclusion, quality of life in TS is impaired, in particular it seems to be negatively affected by depression and low self-esteem whereas satisfaction with income has a positive influence. These results implicate that medical staff needs to pay attention on possible psychosocial impairments when treating women with TS. Strengthening self-esteem and counteracting depression potentially raises their QoL.

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Key words: Turner syndrome, quality of life, psychosocial well-being

1. Introduction Most humans are born with 23 pairs of chromosomes with one of them determining the individual’s sex. Females have hereby usually two X chromosomes. Women with Turner syndrome (TS), however, are characterized by an only partly developed or completely missing X chromosome in some or all cells. This chromosomal abnormality affects approximately one out of 2,500 females. The most prominent medical conditions of TS are short stature and primary ovarian failure. Without estrogen replacement therapy, girls with TS generally do not experience pubertal development and about 95% of women with TS suffer from infertility. Other phenotypic characteristics in TS include impaired hearing and vision,

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cardiac and renal malformations, diabetes, thyroid dysfunction, hepatic dysfunction, hypertension and dysmorphic features of various severities (Gravholt & Backeljauw, 2017).

Besides those physical health concerns, previous research indicates that women with TS experience impairments in several psychosocial domains as well as in quality of life (QoL;

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Reis et al., 2018). It has been shown that women with TS experience social interaction challenges across the lifespan; in particular they have difficulties in developing and

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maintaining friendships and relationships. Already at a young age, parents describe their daughters with TS to be less socially competent, to have fewer friends and to spend less time

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with friends (Wolstencroft & Skuse, 2018). Women with TS seem to be less likely to have a partner and being married than controls (Rolstad et al., 2007). Moreover, females with TS are also reported to have a lower self-esteem (Carel et al., 2006). Several studies found an

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increased prevalence in depression and anxiety (Cardoso et al., 2004; Schmidt et al., 2006), while others could not confirm this (Lesniak-Karpiak, Mazzocco, & Ross, 2003; McCauley et al., 2001; Van Pareren et al., 2005). Several studies also found substantially increased

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prevalence of ADHD in girls with TS (McCauley et al., 2001; Green, Flash, & Reiss, 2018). Those attention problems can be associated with distractibility, hyperactivity, clumsiness and

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problems in school, although most girls with TS were found to have normal intelligence levels (McCauley et al., 2001). Contrary to this, other researchers reported women with TS to have a comparable or slightly better educational achievement and occupational status than controls (Boman et al., 2001; Fjermestad et al., 2016; Gould et al., 2013; Næss, Bahr, & Gravholt, 2010). In addition to these specific determinants of psychosocial well-being, QoL also includes satisfaction with physical and environmental conditions. Hence, QoL is a measure for the overall well-being. Only nine studies in mainly small cohorts have examined QoL in

women with TS compared to a general female population, mostly indicating compromised health-related QoL (Amundson et al., 2010; Boman et al., 2001; Fjermestad et al., 2016; Lasaite, Lašiene, & Lašas, 2010; Nadeem, & Roche, 2014; Næss, Bahr, & Gravholt, 2010). Three studies stated that women with TS had a normal overall QoL compared with that of the general female population (Bannink et al., 2006; Carel et al., 2005; Taback, & Van Vliet, 2011). Only two studies included over 100 patients with TS (Amundson et al., 2010; Carel et al., 2005) and only four of these studies included patients above the age of 25 (Amundson et al., 2010; Fjermestad et al., 2016; Næss, Bahr, & Gravholt, 2010; Boman et al., 2001). The largest cohort examining 568 French women with TS who were treated with growth hormone

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in childhood, interestingly showed similar scores in health-related QoL using the MOS SF-36 compared to the general French female population (Carel et al., 2005).

Thus, data on psychosocial well-being and QoL in TS mainly focuses on girls, whereas data on adult women is scarce, inconsistent and mainly low in sample size. Separate analysis of adult women, however, is important since women face other challenges of TS than

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girls, such as partnership, infertility and work life impacting on psychosocial well-being and QoL. Moreover, the quality of life was most commonly measured by the SF-36 (Bannink et

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al., 2006; Carel et al., 2005; Næss, Bahr, & Gravholt, 2010; Nadeem, & Roche, 2014; Taback, & Van Vliet, 2011) which focuses mainly on health-related functioning and perception rather

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than on subjective well-being (Huang, Wu, & Frangakis, 2006). This has the disadvantage that individuals who are severely impaired in their physical functioning cannot reach high

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quality of life scores in the SF-36.

In this study we investigated psychosocial well-being and overall QoL in a comprehensive manner, not only focusing on health-related QoL but including psychological,

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environmental and social QoL in adult women with TS and compared it with existing data from a general female population. The aim of this study was to determine how and to which

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extent psychosocial challenges in TS adversely affect overall QoL in these women. 2. Methods

2.1. Subjects

The study cohort was recruited and examined within the collaborative international European study “dsd-LIFE”, funded by the European Commission (7th Framework Programme, FP7). This study recruited participants with disorders/differences of sexual development (DSD) ≥ 16 years from 14 study centres in six European countries (France (n = 4), Germany (n = 4),

United Kingdom (n = 1), Poland (n = 2), Sweden (n = 1), and the Netherlands (n = 2)) during February 2014 and September 2015. All participants gave written informed consent. Ethical approvals were obtained for each participating centre. Study participation implied filling out digital patient reported outcome (PRO) questionnaires and answering medical questionnaires, while medical examination was optional. Participants were examined at their local DSD centre. All medical data were pseudonymised and reviewed on data quality for accuracy of statements. Theoretical and methodological details of the study have been described elsewhere (Röhle et al., 2017). In total, 1.161 individuals with DSD of whom 301 had a diagnosis of TS participated

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in the dsd-LIFE study. A large proportion of the TS sample was recruited in France (n = 116, 38.54%), followed by the Netherlands (n = 82, 27.24%), Sweden (n = 46, 15.28%), Germany (n = 43, 14.29%), the United Kingdom (UK; n = 11, 3.65%) and Poland (n = 3, 3.1%). More details of the study population are presented in Table 1.

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2.2. Design

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Participants filled out a web-based questionnaire including standardized instruments and selfconstructed items. Sociodemographic data for comparison was gathered according to the European Social Survey (ESS Round 7, 2015). This paper includes information regarding the

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relationship and working status of the participant, her satisfaction with her income and her subjective social participation. Each participant with TS was matched by age, gender and

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nationality to one participant of the ESS-sample.

For the assessment of “quality of life”, the WHOQOL-BREF was used (WHOQOL Group, 1998). Reference data was taken from two different samples. As the largest proportion

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of participants with TS was French, reference data from Baumann et al. (2010) was used. However, as only the means and standard errors of the means were given for the

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psychological, physical and social dimensions but not for environmental and global QoL, the clinical sample depicted in this paper was also compared with means and standard deviations of the German sample of Angermeyer, Kilian and Matschinger (2000). To screen for anxiety and depression, the Hospital Anxiety and Depression Scale (HADS) was chosen (Zigmond & Snaith, 1983). Data from Hinz and Brähler (2011) that was collected via the random-route-technique in Germany in two elicitations 1998 and 2009 served as reference. Each participant with TS was matched with one participant of the HADSsample by age and gender.

To evaluate ADHD, the Adult ADHD Self-Report Screener (ASRS-v1.1) was used (Kessler et al., 2005). As a reference, mean and standard deviation of a sample from Switzerland by Mörstedt, Corbisiero and Stieglitz (2016) were taken. To screen for signs of autism, the Autism Spectrum Quotient (AQ10) was used (Allison, Auyeung, & Baron-Cohen, 2012). The mean and standard deviation of the female subgroup of the original publication which Carrie Allison provided via email were used as reference data for the AQ10. To assess self-esteem, the Rosenberg Self-Esteem Scale (RSES) was used (Rosenberg, 1965). For the RSES, reference data from two independent studies were utilized. The first one

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was carried out by Schmitt and Allik (2005) in 53 countries. The means and standard deviations of the corresponding French and German sample were used as reference data since most participants with Turner syndrome were recruited in France and the sample size for Germany was the largest in the study by Schmitt and Allik. Since the comparison with these

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samples has its weaknesses because no mean and standard deviation are given for female subgroups and since the mean age is probably a lot lower than in the sample of women with

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TS, a Dutch reference sample from Franck et al. (2008) was also used for comparison. The mean and standard deviation of the corresponding female subgroup (N= 293) were provided

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by Erick Franck. 2.3. Analysis

For comparing psychosocial well-being and QoL in women with TS to that in the general

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population, t-tests and one binomial test for the dichotomous variable “having a partner” were carried out. For all variables that were not homoscedastic, Welch-tests were conducted in

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addition to student’s t-test. As this study used the same sample for the verification of multiple hypotheses, the likelihood of rejecting certain null hypotheses although they should be

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maintained (type 1 error) increases (multiple comparison problem). To neutralize the increased risk of type I errors, the conservative Bonferroni correction was applied. Since 18 ttests with a desired significance level of α = 0.05 were run in the framework of this study, the Bonferroni correction lead to testing each variable at a significance level of α = 0.05/18 = 0.0027. In order to investigate the strength of the relationship between factors measuring psychosocial well-being and QoL in women with TS, a Pearson correlation coefficient matrix

was conducted. Since 91 comparisons with a desired significance level of α = 0.05 were carried out, a Bonferroni correction set the alpha level at α = 0.05/91 = 0.00055. For assessing the influence of the various psychosocial variables on the quality of life domains, a multiple regression model was built for each of the QoL dimensions that had significant correlations with at least one variable of psychosocial well-being. To do that, stepwise p-value criterion based selection with both inclusion and exclusion of variables in every step was used. Since age and country are known to be typical confounding variables and previous research on TS discussed height to have an effect on psychosocial well-being and QoL (Reis et al., 2018), the conducted multiple regression models controlled for age,

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country and participant’s height. No Bonferroni correction was used for the multiple regression models as those were only exploratively built and have to be cross-validated on a new sample nonetheless. Therefore, it is more important to avoid type II errors (erroneously maintaining the null hypothesis) so that no possibly influential variable is lost at this point in

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3. Results

3.1. Psychosocial well-being in women with and without TS

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To compare psychosocial well-being in women with and without TS, ten separate one-sided ttests for independent samples and one binomial test for the dichotomous variable “having a partner” were conducted. For all metric variables, qq-plots showed that the assumption of

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normal distribution was fulfilled. The results of the t-tests can be seen in Table 2. Significant differences between women with and without Turner syndrome could be

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found for all measurements except for self-esteem when compared with the French data of healthy controls collected by Schmitt & Allik (2005), amount of working hours and

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satisfaction with income. A one-sided exact binomial test indicated that the proportion of having a partner of 0.32 was significantly lower in women with TS than the expected 0.43 in women without TS, p < 0.001. As the assumption of homoscedasticity was not met for the variables on ADHD and self-esteem, additional Welch-tests were calculated to compare these two constructs in women with and without TS. A significant difference could be found for ADHD; t(283) = 11.05, p < 0.001. For self-esteem, significant differences could be found for the sample of Frank (2008); t(532) = 3.75, p < 0.001 and for the German sample of Schmitt & Allik (2005);

t(427) = 7.39, p < 0.001. However, no significant differences could be found with regard to self-esteem for the French sample of Schmitt & Allik (2005) when using the Bonferroni correction; t(330) = 1.83, p = 0.034. 3.2. Quality of life in women with and without TS To compare overall QoL in women with and without TS, eight separate t-tests for independent samples were conducted. For all quality of life domains, qq-plots showed that the assumption of normal distribution was met. The results of the t-tests can be seen in Table 3.

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3.3. Correlations between QoL dimensions The Pearson correlation coefficient matrix that depicts the correlations between the various psychological well-being variables and the QoL domains can be seen in Figure 1. The scores on anxiety, depression, ADHD, autism and self-esteem were all significantly correlated with each other (all p < 0.0001). Moreover, social participation was significantly correlated

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with depression, autism, and self-esteem and satisfaction with income was correlated with ADHD (all p < 0.0001). The scores on the quality of life dimensions were all significantly

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intercorrelated and showed correlations with anxiety, depression, ADHD, self-esteem and social participation (all p < 0.0001). All scores on the QoL dimensions were significantly

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correlated with autism and satisfaction with income scores except for the social dimension (all p < 0.0001).

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3.4. Influence of psychosocial well-being on QoL

The results for the multiple regression analyses for the QoL domains are depicted in Table 4. In summary, depression (β = -0.45, p < 0.001), satisfaction with income (β = 0.22, p

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< 0.001), age (β = -0.2, p < 0.001), self-esteem (β = 0.18, p = 0.001) and having a partner (β = 0.09, p = 0.037) were important predictors of global QoL. For social QoL, self-esteem (β =

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0.24, p < 0.001), depression (β = -0.15, p = 0.008), social participation (β = 0.18, p < 0.001), age (β = -0.27, p < 0.001), having a partner (β = 0.2, p < 0.001) and anxiety (β = -0.15, p = 0.005) were significant predictors. Depression (β = -0.22, p < 0.001), satisfaction with income (β = 0.25, p < 0.001), self-esteem (β = 0.14, p = 0.015), ADHD (β = -0.2, p < 0.001), age (β = -0.12, p = 0.016), social participation (β = 0.13, p = 0.01) and country were significant predictors for environmental QoL. Participants in Germany reported the highest environmental QoL, followed by participants in Sweden, Poland, France, the United Kingdom, and the Netherlands (see Table 4). For physical QoL, two participants were shown

to be influential subjects in the residual vs. leverage plot and were removed from the sample for the multiple regression model. Depression (β = -0.34, p < 0.001), ADHD (β = -0.32, p < 0.001), age (β = -0.28, p < 0.001), satisfaction with income (β = 0.18, p < 0.001), height (β = 0.15, p = 0.003) and social participation (β = 0.11, p = 0.002) were included as predictors into the multiple regression model. For psychological QoL, self-esteem (β = 0.5, p < 0.001), depression (β = -0.33, p < 0.001), country, satisfaction with income (β = 0.07, p = 0.046), anxiety (β = -0.12, p = 0.007) and amount of working hours (β = 0.07, p = 0.046) were predictors for psychological QoL. Participants from the United Kingdom reported the highest environmental QoL, followed by participants from Poland, France, Germany, Sweden, and

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the Netherlands. 3.5 Post-hoc analyses

Post-hoc analyses correlating the severity of Turner stigmata (measured on a four point scale ranging from “no stigmata” to “typical stigmata”), the age at puberty induction,

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the age at menarche and the body mass index with self-esteem and the five dimensions of

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QoL were all insignificant (all p > 0.05). 4. Discussion

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Improving QoL is one of the main aims for medical care in all patients. For TS the influence of height, puberty and treatment with growth hormone on health-related QoL in individuals with TS has been investigated. However, multiple other factors may influence overall QoL.

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To the best of our knowledge this is the first study to address the relation between psychosocial factors and overall QoL in TS.

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In our study both psychosocial well-being and QoL appear to be decreased in individuals with TS. Women with TS were found to have higher levels of depression, anxiety,

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autism and ADHD. Moreover, they appear to have less often a partner and participate less often in social activities. Compared to two out of three control samples, women with TS reported lower levels of self-esteem. This is in line with the majority of previous research that found women with TS to be less socially competent (Wolstencroft & Skuse, 2018), to have a lower self-esteem (Carel, et al., 2006), to be more anxious and depressed (Cardoso et al., 2004; Schmidt et al., 2006) and to have more often ADHD (Green, Flash, & Reiss, 2018; Reis et al., 2018). Post-hoc analyses correlating the severity of Turner stigmata, the body height, the age at menarche, the age at puberty induction and the body mass index were all

insignificant. This indicates that the impaired psychosocial well-being and QoL might rather be an independent symptom of TS than secondary to the physical phenotype. In line with the results of Gould et al. (2013) our study showed no subjective impairment in work life in women with TS. Individuals with TS do not work fewer hours and are equally satisfied with their income as individuals without TS. It should be noted, however, that satisfaction with income is a very subjective variable and similar means between groups do not necessarily indicate that the actual income of women with and without TS resemble each other. Underlying reasons for that might be lower expectations or a positive response bias in individuals with TS (Otero et al., 2013) or the recruitment of predominantly upper and

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middle-class subjects (Röhle et al., 2017). Women with TS in our study reported impairment with regard to the physical, the psychological and the social, but not the environmental or global dimensions of QoL compared to two control samples (Angermeyer et al., 2000; Bauman et al, 2010). Previous

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studies with smaller samples which used the SF-36 to examine the QoL have found females with TS to be solely impaired in their physical functioning and the role physical functioning

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domain, but not in their social functioning and mental health (Nadeem & Roche, 2014; Ros et al., 2013). In this study we used the WHOQOL-BREF questionnaire as it allows a more comprehensive exploration of all facets of QoL including physical, psychological, social and

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environmental dimensions. This is the first study on QoL in TS using the WHOQOL-BREF and comparing it to a control population. A study on QoL in Klinefelter syndrome applying

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the WHOQOL-BREF similarly showed impaired physical and mental QoL (Skakkebæk et al., 2018).

The fact that women with TS report to be less satisfied with their physical health

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compared to controls could easily be explained by objective physical problems such as abnormalities of their organs and consequences from gonadal failure. We found a correlation

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of height outcome and physical QoL as did Nadeem and Roche (2014) and Næss, Bahr, & Gravholt, (2010). The here-reported reduced psychological well-being and social participation might partially account for overall low levels of psychological and social QoL. On the other hand, the high satisfaction with employment in our cohort of TS might contribute to the normal environmental QoL as employment rates are known to correlate positively with environmental QoL (Reis et al., 2018). Interestingly, women with TS did not report lower global QoL rates. These findings might again be indicative for a positive response bias:

Global questions rather tend to show a positive answering pattern, whereas answers to more specific questions usually are not that strongly biased. The correlation matrix shows interrelations within most of the psychosocial variables as well as between psychosocial well-being and the QoL domains, however, does not give any information on which combination of variables can explain QoL best. For that, the multiple regressions with QoL as outcome were built. They show that in women with TS psychosocial well-being strongly influences the quality of life: it explains between 35% (of social QoL) and 73% (of psychological QoL) of the domain’s variances with depression and self-esteem being the most important predictors. In addition, age influenced all dimensions of QoL except the

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psychological one in this study, meaning that the older the participants were, the lower their quality of life was generally. This is congruent with the normative data of Angermeyer, Kilian, and Matschinger (2000) that showed QoL-scores decreasing with age in every domain. Self-esteem on the other hand positively influences psychological QoL. It was found

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to help adjusting to various life hassles (Friedlander et al., 2007) and therefore serves as a protective factor against psychiatric disorders. The positive influence of self-esteem on social

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QoL might be explained by the sociometer-theory (Leary et al., 1995). According to this theory, individuals with higher self-esteem experience more satisfying social interactions.

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Depression and self-esteem are strongly connected: Two contrary theories, the vulnerability and scar-model, explain their mutual influences. According to the vulnerability model low self-esteem causes depression whereas the scar-model suggests that depression

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erodes self-esteem (Orth & Robins, 2013). The results of a meta-analysis with 77 studies support the vulnerability-model (Sowislo & Orth, 2013). We therefore conclude that

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optimization of self-esteem is a key factor to achieve good QoL in TS. Overweight is known to be associated with lower self-esteem in the general population

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(Tiggemann, 2005) but was not in our TS cohort. Height and dysmorphic features were not associated with self-esteem in our study, consistent with the French population based data (Carel et al., 2005). To the best of our knowledge, this study is the most comprehensive investigation of

psychosocial well-being and QoL in a large cohort of adult women with TS compared to control data from the general female population. It is the first study in TS that examines QoL using the WHOQOL-BREF and the first that investigates the influence of various psychosocial well-being variables on QoL. The study however also faces some limitations:

First, no matched control group was recruited and therefore some variables could only be compared to means and standard deviations of reference samples. This emphasizes once again that more longitudinal studies and case control studies on QoL in TS are necessary to analyze these issues in more detail. Second, items were solely answered by women with TS themselves who were mostly asked for subjective criteria; relatives or partners have not been included. This bears the risk of an undetected desirability response bias as opposed to an “actual” performance in the investigated domains in these women. Assuming a desirability response bias in our study, the observed differences between women with and without TS would be even more striking.

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In conclusion, this study suggests that women with TS have an impaired psychosocial well-being and QoL but show no differences in their work life. QoL seems to be in particular negatively affected by depression and low self-esteem whereas satisfaction with income has a positive influence. Therefore, mental health should be examined with as much caution as the

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physical condition when caring for patients with TS. Psychological support and counseling should be offered to patients. Future intervention studies could evaluate the effect of self-

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esteem training and depression treatment programs on psychosocial well-being and QoL of

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women with Turner syndrome.

Credit

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Ariane Liedmeier: formal analysis, visualization, Roles/Writing – original draft

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David Jendryczko: formal analysis, methodology, supervision, software, validation, Writing – review & editing Hedi Claahsen van der Grinten: conceptualization, data curation, funding acquisition, investigation, Writing – review & editing

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Marion Rapp: data curation, investigation, methodology, project administration, validation, Writing – review & editing Ute Thyen: conceptualization, data curation, methodology, funding acquisition, investigation, supervision, Writing – review & editing Catherine Pienowski: conceptualization, data curation, funding acquisition, investigation, Writing – review & editing Andreas Hinz: data curation, methodology, software, validation, Writing – review & editing

Nicole Reisch: conceptualization, data curation, funding acquisition, investigation, supervision, validation, visualization, Roles/Writing – original draft Funding:
The work leading to the results of the study dsd-LIFE has received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement n° 305373. More information on: http://www.dsd-life.eu/ Disclosure

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None of the authors has anything to disclose.

Conflicts of interest:

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None to declare.

Acknowledgements: The dsd-LIFE group are: Birgit Kohler, Berlin; Peggy Cohen-Kettenis

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and Annelou de Vries, Amsterdam; Wiebke Arlt, Birmingham; Claudia Wiesemann, Gottingen; Jolanta Slowikowska-Hilczer, Lodz; Aude Brac de la Perriere, Lyon; Charles

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Sultan and Francoise Paris, Montpellier; Claire Bouvattier, Paris; Ute Thyen, Lubeck; Nicole Reisch, Munich; Annette Richter-Unruh, Munster; Hedi Claahsen-van der Grinten, Nijmegen;

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Anna Nordenstrom, Stockholm; Catherine Pienkowski, Toulouse; and Maria Szarras-Czapnik, Warsaw. The authors would like to thank all participants as well as the members of the dsd-

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LIFE consortium who enabled this study.

References

Allison, C., Auyeung, B., Baron-Cohen, S., 2012. Toward "red flags" for autism screening: the short autism spectrum quotient and the short quantitative checklist in 1,000 cases and 3,000 controls. J. Am. Acad. Child. Adolesc. Psychiatry. 51(2), 202-212. Angermeyer, M. C., Kilian, R., Matschinger, H., 2000. Handbuch für die deutschsprachigen Versionen der WHO-Instrumente zur internationalen Erfassung von Lebensqualität (WHOQOL). Göttingen: Hogrefe.

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Amundson, E., Boman, U. W., Barrenas, M. L., Bryman, I., Landin-Wilhelmsen, K., 2010. Impact of growth hormone therapy on quality of life in adults with Turner syndrome. J. Clin. Endocinol. Metab. 95, 1355-1359. Armstrong, R. A., 2014. When to use the Bonferroni correction. Ophthalmic Physiol. Opt. 34(5), 502-508.

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Bannink, E. M., Raat, H., Mulder, P. G., Keizer-schrama, S., 2006. Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome. J. Pediatr. 148, 678-684.

lP

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Baumann, C., Erpelding, M. L., Regat, S., Collin, J. F., Briancon, S., 2010. The WHOQOLBREF questionnaire: French adult population norms for the physical health, psychological health and social relationship dimensions. Rev. Epidemiol. Sante. 58(1), 33-39.

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Boman, U. W., Bryman, I., Hailing, K., Möller, A., 2001. Women with Turner syndrome: psychological well-being, self-rated health and social life. J. Psychosom. Obstet. Gynecol. 22(2), 113-122.

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Cardoso, G., Daly, R. J., Haq, N. A., Hanton, L., Rubinow, D. R., Bondy, C. A., et al., 2004. Current and lifetime psychiatric illness in women with Turner syndrome. Gynecol. Endocrinol. 19(6), 313-319.

Jo

Carel, J. C., Ecosse, E., Bastie-Sigeac, I., Cabrol, S., Tauber, M., Léger, J., et al., 2005. Quality of life determinants in young women with Turner’s syndrome after growth hormone treatment: results of the StaTur population-based cohort study. J. Clin. Endocinol. Metab. 90(4), 1992-1997. Carel, J. C., Elie, C., Ecosse, E., Tauber, M., Léger, J., Cabrol, S., et al., 2006. Self-esteem and social adjustment in young women with Turner syndrome—influence of pubertal management and sexuality: population-based cohort study. J. Clin. Endocinol. Metab. 91(8), 2972-2979. Downey, J., Elkin, E. J., Ehrhardt, A. A., Meyer-Bahlburg, H. F., Bell, J. J., Morishima, A., 1991. Cognitive ability and everyday functioning in women with Turner syndrome. J. Learn. Disabil. 32-39.

ESS, 2015. European Social Survey Round 7 (2014/2015) Data. Technical Report. London: ESS ERIC. Fjermestad, K. W., Naess, E. E., Bahr, D., Gravholt, C. H., 2016. A 6‐year Follow‐up survey of health status in middle‐aged women with Turner syndrome. Clin. Endocrinol. 85(3), 423-429. Franck, E., De Raedt, R., Barbez, C., Rosseel, Y., 2008. Psychometric propertes of the Dutch Rosenberg self-esteem scale. Psychol. Belg. 48(1), 25-35. Friedlander, L. J., Reid, G. J., Shupak, N., Cribbie, R., 2007. Social support, self-esteem, and stress as predictors of adjustment to university among first-year undergraduates. J. Coll. Stud. Dev. 48(3), 259-274.

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Gould, H. N., Bakalov, V. K., Tankersley, C., Bondy, C. A., 2013. High levels of education and employment among women with Turner syndrome. J. Womens Health. 22(3), 230-235.

-p

Gravholt, C. H., Backeljauw, P., 2017. New international Turner syndrome guideline: a multisociety feat. Eur. J. Endocrinol. 177(3), E1-E2.

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Green, T., Flash, S., Reiss, A. L., 2018. Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacology. 1. Hinz, A., Brähler, E., 2011. Normative values for the Hospital Anxiety and Depression Scale (HADS) in the general German population. J. Psychosom. Res. 71(2), 74-78.

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Huang, I. C., Wu, A. W., Frangakis, C., 2006. Do the SF-36 and WHOQOL-BREF measure the same constructs? Evidence from the Taiwan population. Qual. Life Res. 15(1), 1524.

na

Kessler, R. C., Adler, L., Ames, M., Demler, O., Faraone, S., Hiripi, E. V., et al., 2005. The World Health Organization adult ADHD self-report scale (ASRS): a short screening scale for use in the general population. Psychol. Med. 35(2), 245-256.

Jo

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Lasaite, L., Lašiene, D., Lašas, L., 2010. Cognition, emotions and quality of life in Lithuanian girls with Turner syndrome after growth hormone therapy discontinuation. J. Pediatr. Endocrinol. Metab. 23(5), 443-450. Leary, M. R., Tambor, E. S., Terdal, S. K., Downs, D. L., 1995. Self-esteem as an interpersonal monitor: The sociometer hypothesis. J. Pers. Soc. Psychol. 68(3), 518. Lesniak-Karpiak, K., Mazzocco, M. M., Ross, J. L., 2003. Behavioral assessment of social anxiety in females with Turner or fragile X syndrome. J. Autism Dev. Disord. 33(1), 55-67. McCauley, E., Feuillan, P., Kushner, H., Ross, J. L., 2001. Psychosocial development in adolescents with Turner syndrome. J. Dev. Behav. Pediatr. 22(6), 360-365.

Mörstedt, B., Corbisiero, S., Stieglitz, R. D., 2016. Normierung der Adult ADHD SelfReport-Scale-V1. 1 und der ADHS Selbstbeurteilungsskala an einer repräsentativen deutschsprachigen Stichprobe. Diagnostica. Nadeem, M., Roche, E. F., 2014. Health-related quality of life in Turner syndrome and the influence of key features. J. Pediatr. Endocrinol. Metab. 27(3-4), 283-289. Næss, E. E., Bahr, D., Gravholt, C. H., 2010. Health status in women with Turner syndrome: a questionnaire study on health status, education, work participation and aspects of sexual functioning. Clin. Endocrinol. 72(5), 678-684. Orth, U., Robins, R. W., 2013. Understanding the link between low self-esteem and depression. Curr. Dir. Psychol. Sci. 22(6), 455-460.

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Reis, C. T., de Assumpção, M. S., Guerra-Junior, G., de Lemos-Marini, S. H., 2018. Systematic review of quality of life in Turner syndrome. Qual. Life Res. 27(8), 19852006.

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Röhle, R., Gehrmann, K., Szarras-Czapnik, M., Claahsen-van der Grinten, H., Pienkowski, C., Bouvattier, C., et al., 2017. Participation of adults with disorders/differences of sex development (DSD) in the clinical study dsd-LIFE: design, methodology, recruitment, data quality and study population. BMC Endocr. Disord. 17(1), 52.

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re

Rolstad, S. G., Möller, A. B., Boman, U. W., 2007. Sexual functioning and partner relationships in women with Turner syndrome: some empirical data and theoretical considerations regarding sexual desire. J. Sex Marital Ther. 33(3), 231-247.

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Ros, C., Alobid, I., Balasch, J., Mullol, J., Castelo-Branco, C., 2013. Turner's syndrome and other forms of congenital hypogonadism impair quality of life and sexual function. Am. J. Obstet. Gynecol. 208(6), 484-491. Rosenberg, M., 1965. Rosenberg self-esteem scale (RSE). Acceptance and commitment therapy. Measures package. 52.

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Schmidt, P. J., Rubinow, D. R., Bondy, C. A., 2006. Adult women with Turner Syndrome: A systematic evaluation of current and past psychiatric illness, social functioning, and self-esteem. Int. Congr. Ser. 100-107.

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Schmitt, D., Allik, J., 2005. Simultaneous administration of the Rosenberg Self-Esteem Scale in 53 nations: exploring the universal and culture-specific features of global selfesteem. J. Pers. Soc. Psychol. 89(4), 623-642. Skakkebæk, A., Moore, P. J., Chang, S., Fedder, J., Gravholt, C. H., 2018. Quality of life in men with Klinefelter syndrome: the impact of genotype, health, socioeconomics, and sexual function. Genet. Med. 20(2), 214. Sowislo, J. F., Orth, U., 2013. Does low self-esteem predict depression and anxiety? A metaanalysis of longitudinal studies. Psychol. Bull. 139(1), 213.

Van Pareren, Y. K., Duivenvoorden, H. J., Slijper, F. M., Koot, H. M., Drop, S. L., de Muinck Keizer-Schrama, S. M., 2005. Psychosocial functioning after discontinuation of longterm growth hormone treatment in girls with Turner syndrome. Horm. Res. Paediatr. 63(5), 238-244. WHOQoL Group, 1998. Development of the World Health Organization WHOQOL-BREF quality of life. Psychol. Med. 28(3), 551-558. Wolstencroft, J., Skuse, D., 2018. Social skills and relationships in Turner syndrome. Curr. Opin. Psychiatry. 32(2), 85-91.

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Zigmond, A., Snaith, R., 1983. The hospital anxiety and depression scale. Acta Psychiatr. 67, 361-370.

N

Total N

%

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Figure 1: Pearson correlation coefficient matrix of the measured variables (N = 301).

Table 1: Description of karyotype and baseline characteristics of patients with Turner syndrome

Number of patients

301

Karyotype

301 150

49.83

Mosaics

31

10.29

Isochromosomes

59

19.51

Deletions

19

6.31

Polyploidy

16

5.32

Ring material

12

3.99

Not classified

4

1.33

Unknown

10

3.32

Median age at assessment (min-max) in

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Monosomy

32.23 (16-73)

301

Median age at diagnosis (min-max) in years

10.49 (0-61)

262

Median height in cm

152.66 (132-172)

Turner stigmata (dysmorphic features) 43

Minimal stigmata

56

Moderate stigmata

Puberty induction

na

Median age at puberty induction (min-max) in years

16.93 22.05 31.50

75

29.53

78

281

27.76

217

281

77.22

14.81 (10-27)

253

31.98 (0.2-138.9)

100

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Median FSH at diagnosis (min-max) in girls in U/L

254

80

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Typical stigmata Spontaneous puberty

290

re

No stigmata

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years

Table 2: Comparison of anxiety, depression, ADHD, autism, self-esteem, social participation, hours of work and satisfaction with income in women with Turner syndrome and reference groups. The control group of self-esteem1) is taken from the Dutch sample examined by Frank et al. (2008), control group of self-esteem2) is taken from the French sample examined by Schmitt & Allik (2005) and control group of self-esteem3) is taken from the German sample examined by Schmitt & Allik (2005).

Turner group Questionnaire

Reference group

M

SD

M

SD

df

t

p

Anxiety

6.89

3.69

4.01

3.08

580

-10.23

< 0.001

Depression

3.67

2.87

2.73

2.90

581

- 3.92

< 0.001

ADHD

9.01

4.25

6.15

0.91

912

-16.21

< 0.001

Autism

3.23

2.02

2.54

1.95

787

- 4.66

< 0.001

Self-esteem1)

18.95

5.62

20.55

4.47

571

3.77

< 0.001

Self-esteem2)

18.95

5.62

19.86

4.16

408

1.64

0.051

Self-esteem3)

18.95

5.62

21.73

4.71

1060

8.03

< 0.001

2.61

0.82

2.87

0.82

30.21

12.11

32.26

16.05

32.14

7.78

32.38

7.7

Participation Working Hours Satisfaction with

575

3.85

< 0.001

470

1.53

0.062

544

0.37

0.369

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Income

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Social

Note. Control group of self-esteem1) is taken from the Dutch sample examined by Frank et al. (2008), control group of self-esteem2) is taken from the French sample examined by Schmitt & Allik (2005) and control group of

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self-esteem3) is taken from the German sample examined by Schmitt & Allik (2005).

Table 3: Comparison of global, physical, psychological, environmental and social quality of

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life in women with Turner syndrome and reference groups. The control group of QoL1) is taken from the German sample of Angermeyer (2000) and control group of QoL2) is taken from the French sample of Baumann (2010). Psych. QoL describes psychological QoL and

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Envir. QoL describes environmental QoL. As the assumption of homoscedasticity was not met for the comparisons with the French sample by Bauman et al. (2009), additional Welch-

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tests were calculated for these. Significant differences could be found for physical QoL; t(305) = 3.74, p < 0.001, for psychological QoL; t(289) = 3.39, p < 0.001 as well as for social QoL; t(286) = 7.73, p < 0.001.

Turner group M

SD

M

SD

df

t

p

Global QOL

67.61

17.40

66.49

18.26

1410

- 0.93

0.823

Physical QOL1)

71.49

16.81

75.35

18.13

1408

3.25

<0.001

Physical QOL2)

71.49

16.81

75.30

19.58

9865

3.24

<0.001

Psych. QOL1)

63.74

16.11

72.49

16.28

1410

8.11

<0.001

Psych. QoL2)

63.74

16.11

67

9.79

9866

5.39

<0.001

Envir. QoL

73.87

12.92

69.73

14.05

1409

- 4.51

Social QoL1)

65.9

18.63

71.41

18.78

1404

4.42

<0001

Social QoL2)

65.9

18.63

74.5

9.79

9865

14.05

<0.001

1

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Questionnaire

Reference group

Note. Control group of QoL1) is taken from the German sample of Angermeyer (2000) and control group of

QoL2) is taken from the French sample of Baumann (2010). Psych. QoL describes psychological QoL and Envir.

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QoL describes environmental QoL.

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Table 4: Multiple regression analysis predicting global, social, environmental, physical and psychological QoL. Regression models were constructed by stepwise p-value criterion based selection with both inclusion and exclusion of variables in every step. Predictors are listed in

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order of their incremental contribution to criterion prediction. Adj. R² and R² refer to a model in which the predictor of the current table row and all previous predictors are included (N =

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301).

Dependent

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variable

Predictor variable

β

t

p

Adj. R²

R²

- 0.45

- 7.92

< 0.001

0.32

0.32

0.22

4.54

< 0.001

0.41

0.42

- 3.9

< 0.001

0.44

0.44

Global QoL

Depression Satisfaction with income Age

- 0.2

Self-esteem

0.18

3.17

0.001

0.46

0.47

Having a partner

0.09

1.79

0.037

0.46

0.48

Social QoL Self-esteem

0.24

3.9

< 0.001

0.2

0.2

Depression

- 0.15

- 2.4

0.008

0.24

0.25

0.18

3.3

< 0.001

0.27

0.27

- 0.27

- 4.9

< 0.001

0.29

0.30

0.20

3.7

< 0.001

0.32

0.33

Anxiety

- 0.15

- 2.5

0.005

0.34

0.35

Depression

- 0.22

- 3.53

< 0.001

0.21

0.22

0.25

4.8

0.14

2.18

Social participation Age Having a partner

Environmental

Satisfaction with income Self-esteem

- 0.2

- 3.35

Age

- 0.12

- 2.16

Country France

0.015

0.36

0.37

< 0.001

0.39

0.4

0.016

0.4

0.41

2.35

0.01

0.41

0.42

0.055

- 0.16

- 2.22

0.014

- 0.08

- 1.45

0.074

- 0.04

- 0.6

0.274

- 0.13

- 2.24

0.013

Depression

- 0.34

- 5.98

< 0.001

0.24

0.24

ADHD

- 0.32

- 6.12

< 0.001

0.35

0.38

Age

- 0.28

- 5.49

< 0.001

0.42

0.44

0.18

3.66

< 0.001

0.46

0.5

- 0.15

- 2.83

0.003

0.49

0.52

Social participation

0.11

2.19

0.002

0.5

0.53

Self-esteem

0.5

10.16

< 0.001

0.55

0.55

Depression

- 0.33

- 6.82

< 0.001

0.65

0.65

0.68

0.67

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UK

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Sweden

Satisfaction with

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0.32

- 1.61

Poland

Psychological

0.31

0.11

Netherlands

Physical QoL

0.13

re

Social participation

< 0.001

-p

ADHD

ro of

QoL

income Height

QoL

Country France

0.01

0.22

0.414

Netherlands

- 0.18

- 3.28

< 0.001

Poland

0.01

0.25

0.402

Sweden

- 0.08

- 1.61

0.055

0.08

1.89

0.03

0.07

1.7

0.046

0.7

0.71

- 0.12

- 2.52

0.007

0.7

0.72

0.07

1.7

0.046

0.71

0.73

UK Satisfaction with income Anxiety

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na

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Working hours

ro of

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na

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