Longitudinal Study of Individuals with Differences in Sex Development: A 15-20-year Follow-Up of Mental Health, Psychosocial Functioning and Quality of Life in a Cohort of Norwegian Patients.

Our main aim was to explore any associations in mental health, psychosocial functioning and quality of life (QoL) between childhood, adolescence, and adulthood in the same cohort of patients with a difference in sex development (DSD) born from four decades ago up until early 2000. The rst part of the study took place in 2002-2004 in a mixed cohort of children and adolescents born with a DSD in 1982 to 2002, compared to a control group. This part involved semi structured interviews and self-reported and proxy reported questionnaires. The second part of the study is a longitudinal study of the same participants 15-20 years later (2018-2020). The participants in part 1 of the study consisted of 33 patients; 24 assigned females (congenital adrenal hyperplasia, androgen insensitivity syndrome, gonadal dysgenesis and ovotesticular DSD) and nine assigned males; all with a hypospadias diagnosis. A key nding was more psychopathology in the adolescents with a DSD, and females with a 46, XX karyotype had more psychosocial problems compared to the 46, XY females. Two of the 16 patients in the follow-up had performed gender reassignment. Less than half of the female participants reported a heterosexual orientation. Another important nding was a correlation between psychosocial function in childhood with later adult QoL. As we do nd a correlation with psychosocial problems in adolescence and later adult QoL, it is of great importance to respond to these behaviors in early life and to have a psychological aspect in the follow up.


Introduction
Differences in sex development/disorders of sex development (DSD), formerly described as intersex conditions, are congenital conditions in which development of the chromosomal, gonadal, or anatomic sex is atypical (Diseth, 2008;. DSDs with genital abnormalities occur in approximately one in 4500 to 5500 live births ( & Hiort, 2006). DSD is classi ed into three subgroups, sex chromosome DSD, 46, XX DSD, and 46, XY DSD. In 2006, a consensus statement was produced concerning the management of DSD . A recommendation of this consensus was that evaluation and long-term care for people affected by DSD should be performed at medical centers with multi-disciplinary teams experienced in such conditions. In this country (name of the country anonymized for peer review) there are two such medical centers. These provide care for children up to the age of 18 years.
Several aspects of DSD management are surrounded by controversy and have led to a thorough revision of clinical practice in recent years (Lee et al., 2016). For example, genital surgery in young children is more often avoided nowadays in order to protect children's human rights (Gorduza, Quigley, Caldamone, & Mouriquand, 2018). Multidisciplinary DSD teams are supposed to provide psychological support to affected families as a standard component of care, children are informed early about their condition, and gender issues are openly discussed (Hiort et al., 2014). However, historically, health professionals did not openly and fully communicate with patients and families about their DSDs, which today might contribute to the patients with reduced possibility to have an optimal medical and psychological follow-up or frequently being "lost to follow-up" (Lee et al., 2016).
Even though the treatment of DSD has changed over the past two decades, there is still inadequate data to allow major concerns, such as the assignment of male or female sex, predictors of gender identity development and surgical issues to be addressed (Lee et al., 2016). Genital surgery still raises questions and criticism regarding its indication, timing, and the technical aspects ( Quality of life (QoL) was rarely measured as an outcome in patients with DSD in the past. However, in the last decades many publications have reported the distress of adult individuals with DSD (Diamond & Sigmundson, 1997;Hughes et al., 2007;Meyer-Bahlburg, 1999; "Timing of elective surgery on the genitalia of male children with particular reference to the risks, bene ts, and psychological effects of surgery and anesthesia. American Academy of Pediatrics," 1996). Current knowledge concerning the psychosocial situation and health related QoL (HRQoL) is limited and shows controversial results (Jääskeläinen & Voutilainen, 2000;Kanhere et al., 2015;Reisch et al., 2011). One large Swedish epidemiological study showed a suboptimal psychosocial situation for one of the DSD diagnoses, congenital adrenal hyperplasia (CAH) (Strandqvist et al., 2014). A European multicenter evaluation study about quality of life in adults with DSD showed that except for social relationships, most people with DSD adapt well to their life circumstances and report good QoL (Rapp et al., 2018). Not diagnosis, but the individual's health status is much more important than previously thought.
Overall, individuals with a DSD do report good QoL, but studies are often contradictory, possibly due to differences in local treatment and care, age and cultural context and differences in methodology (Bennecke, Thyen, Gruters, Lux, & Kohler, 2017). As for today, no studies on medical and psychological outcomes have been published in this country (name of the country anonymized for peer review).
Our main aim was to explore any associations in mental health, psychosocial functioning and QoL between childhood, adolescence, and adulthood in the same cohort of patients with a DSD diagnosis born from four decades ago up until early 2000.

Methods
The rst part of the study took place in 2002-2004 and had a cross-sectional design exploring the differences in mental health, psychosocial functioning and QoL in a mixed cohort of children and adolescents born with a DSD condition in 1982 to 2002, compared to a control group matched for age, gender and socioeconomic status (SES). We recruited individuals in two age-groups; small children aged 1-9 years and older children and adolescents aged 10-18 years, with a DSD diagnosis. The sample consisted of patients admitted to the hospital because of ambiguous genitalia or a later presentation of a DSD condition. This part involved semi structured interviews as well as self-reported and proxy reported questionnaires. The second part of the study is a longitudinal study of the same participants 15-20 years later (2018-2020). The patients were asked to participate in a second follow-up on mental health, psychosocial functioning and QoL. The longitudinal design aims to understand what factors are important in the management of the children and adolescents, in order to enhance mental health and QoL in adulthood. See Figure 1 for a ow diagram of patients in Part 1 and Part 2.

Setting
The rst recruitment took place at the Department of Pediatrics at (name of the clinic anonymized for peer review), one of the two hospitals in (name of the country anonymized for peer review) with a DSD team, year 2000-2002. The sample consisted of all patients admitted to the hospital in this period of time because of ambiguous genitalia or a later presentation of a DSD condition, and patients already enrolled in the multi-disciplinary DSD team. In total 52 DSD patients under the age of 18 met the inclusion criteria and were invited to participate in the rst study. All participants were given a study number which guaranteed their anonymity. The follow-up recruitment took place in 2018-2020. The same participants with a DSD diagnosis who took part in the rst study were invited to the follow up via invitations by post. They were asked to ll out questionnaires. Part 1; the cross-sectional study.

Measurements and questionnaires
The assessments of data collected in 2002-2004, were based on mental health, psychosocial functioning and QoL, and were done by the child psychiatrist in the DSD team. Participants 6 years and older ful lled validated standardized questionnaires on their mental health, psychosocial functioning and QoL, and their parents answered parent proxy reports that assesses parents' perceptions of their child's mental health, psychosocial functioning and QoL.

Medical history children and adolescents
Medical details were assessed by the pediatric surgeon or the pediatric endocrinologist in the DSD team using questions in a self-constructed questionnaire for children over 6 years old and parents, covering a broad assessment. 1982) covering aspects of the patient's life such as school, family, friends, activities, affect-life and behavior. The CAS provides a total problem score; higher score means more mental health problems.
Another set of scores consists of symptom complexes scores analogous to psychiatric diagnoses in the DSM.

Behavioral and emotional problems and capabilities
For assessing behavioral and emotional problems, and capabilitiesin children and adolescents, the Child Behavior Checklist (CBCL) and the Youth Self-Report (YSR) were used ( Nøvik, 1999). The CBCL were completed by the parents for children aged 1,5-18 years, and the YSR was completed by children and adolescents between 11-18 years old. The CBCL and YSR provide a combined total behavior and emotional score with internalizing and externalizing subscales. Also, eight syndrome scales are calculated, ve of these are included in the internalizing and externalizing behavior subscales. The internalizing subscale includes withdrawal, somatic complaints and anxiety/depression. The externalizing subscale includes delinquent and aggressive behavior. Higher scores imply either more symptoms or problems, or better academic or social abilities in other subscales. Raw scores were used in the statistical analyses.

Psychosocial functioning
Overall psychosocial functioning was assessed with Children`s Global Assessment Scale (CGAS) (Schorre & Vandvik, 2004;Shaffer et al., 1983). The score was determined from the total information after the patient and parent interviews. The scores range from 100 (excellent function) to 0 (severe malfunction). A score less than 71 re ect psychosocial problems of clinical signi cance. considered to re ect distress and psychopathology in ve dimensions corresponding to anxiety, feelings of incompetence, depression, di culty in coping, and social dysfunction. The questions are answered on a 4-point scale. The answers to each item have been treated as both Likert scores (0-1-2-3) and "case" score (0-0-1-1) (Malt, 1989). A higher Likert score indicates more psychological distress, and reduced wellbeing. Clinically important psychopathology is de ned as case total scores ≥6.

QoL
Overall satisfaction with life in parents was measured with The Quality of Life Scale (QOLS-N) (Wahl, Rustøen, Hanestad, Lerdal, & Moum, 2004) which is a 16-item self-report questionnaire and contains additional information on areas not usually included in HRQoL measures, such as materialistic properties, health, relationships, social activities, education, work, personal development, hobbies, physical activity and independence. The parents are asked to rate their present level of satisfaction with the above-mentioned factors on a seven-point scale. The scale is scored by adding up the items to obtain a total score with possible range 16-112. A higher score depicts a better QoL. Norwegian norms have been established (Wahl et al., 2004).

The control group
The control group for the psychiatric and psychosocial assessments of the children and adolescents in this study was a sub-sample drawn randomly from a (name of the country anonymized for peer review) epidemiological study of mental health (name of the reference anonymized for peer review). The study employed strati ed, random sampling and two-stage design. In the rst stage, screening was carried out by means of the CBCL. In the second stage, a random sample drawn as a control group, were invited to participate in a more detailed assessment based on the CAS and CGAS. Of the 49 adolescents, 35 and their parents participated. The control group for the preschool children were recruited randomly from a day care center in the south -eastern part of (name of the country anonymized for peer review). Of 33 families invited, 32 children and their parent participated. Part 2; the follow-up study.

Medical history adults
The assessment of medical data collected in 2018-2020 was based both on the DSD patient's medical records, and was also covered in an additional self-constructed questionnaire.
Mental health, psychosocial functioning and QoL as adults

Both part 1 and 2: Additional information
The interviews in both part 1 and part 2 were supplemented with speci c self-constructed questions covering the individuals view of the present and early situation regarding their DSD condition, medical history, gender role and identity, relationships and everyday lives, together with a questionnaire mapping socioeconomic status (SES), assessed in the interview with the parents. The adults in the follow-up also received an additional questionnaire with questions about SES, relationships, sexual functioning, and experiences with hospital appointments and surgical results.

Statistical analyses
Continuous variables are presented as the median and range. Categorical variables are presented as quantities and percentages. Data with normal distribution was analyzed using parametric tests and data not normally distributed -with non-parametric tests. The strength of associations between continuous variables was measured using Pearson and Spearman's correlation coe cients depending on the normality of data distributions. Statistical signi cance was assumed when p < 0.05. All analyses were performed using IBM SPSS Statistics 23 and 24.

Participant characteristics Part 1; rst inclusion in 2000-2002
The patients in part 1 of the study consisted of 33 patients, 24 assigned female and 9 assigned male, aged 2-18 years during the assessment period. The patients were; based on developmental issues, divided in age groups; small children, 1-9 years old (born 1993-2002) (n=17), and older children and adolescents, 10-18 years old (born 1982-1994) (n=16). Important to notice is that only one of the patients assigned male was in the adolescent group, therefore the statistical analyses of older children in this study were performed on females only. Diagnosis classi cations are presented in Table 1. The control group consisted of 34 females and 33 males divided in two groups: small children, 1-6 years old (n=32), and adolescents between 14-16 years old (n=35). There were no signi cant differences in age or sociodemographic variables between the DSD group and the control group (Supplementary Table 1).
Part 2: The follow-up in 2020.
All 33 patients were invited to take part in the follow-up study in 2018-2020. Sixteen out of 33 individuals consented to participate, but only 13 submitted the questionnaires (Table 1). Five patients responded that they were not interested in participating, one patient was not alive (suicide), and 11 patients we were not able to reach or they did not respond. Nine were assigned girls, eight of those had a CAH diagnosis (46, XX DSD), and one gonadal dysgenesis (46, XY DSD). Three of these participants were from the original small children group, aged 21-23 years today, and four from the older children and adolescents' group, aged 26 to 34 years at second inclusion. Four assigned males with hypospadias (46, XY) gave consent to participate, three from the small children group initially, aged 21-22 years today, and the one adolescent at rst inclusion, aged 34 years today.

Surgical history
Participants at rst inclusion as children and adolescents Surgery of inner or outer genitalia was performed on 31 of 33 participants before rst inclusion. Fifteen (88%) of the patients with a diagnosis of CAH had undergone clitoris reduction; ten (59%) before the age of 12 months and ve (29%) between the age of 2-9 years. The same patients went through a vaginoplasty at the same time as the clitoris reduction plasty, and one patient had a vaginoplasty only at the age of 4 years. Eight (47%) of the same patients with CAH had two or more genital operations before inclusion due to a new clitoris reduction plasty and/or a vaginoplasty. Of the patients assigned female at birth with 46, XY DSD (n=7), four had a diagnosis of gonadal dysgenesis, two an androgen insensitivity diagnosis and one a diagnosis of ovotestis. Four (57%) of the 46, XY females had a clitoris reduction and vaginoplasty before the age of 12 months, and all but one had removed the gonads before the age of 4 years. All the nine males had undergone a hypospadias operation before the age of 4 years.
Participants at follow-up as adults Only two of the 16 patients whom consented to access to medical records had new surgery after rst inclusion. A third clitoris reduction plasty and vaginoplasty for one patient with CAH, and one patient with 46,XY gonadal dysgenesis had removed the gonads in early 20s.

Experiences from clinical concerns and care
Parent-reported medical details and own experiences from rst inclusion in 2002-2004: Only about half of the parents were happy with the results of surgery on outer genitalia of their children, both parents of assigned females and males. When the parents were asked if it was di cult for the child to talk about the diagnosis, 34.7% of the assigned females and only 11.1% of the assigned males were in such situation.
Patients-reported health-related data and the patient's own experiences as adults: Self-reports from the 13 patients that completed the questionnaires shows a great variation in satisfaction with external genitalia in the group, ranging from 0-4 for the male participants, and 0-8 for the female participants, where 0 is not satis ed and 10 is very satis ed (Supplementary Table 2). Ten of 12 participants had mainly positive experiences with post-surgery follow-ups, but only 7/11 had mainly positive experiences with the information given before surgery. 9/13 stated that follow-up after the age of 18 is needed, and 4/13 thought that psychological care should be offered after 18 years of age. In addition, 4/13 had sought mental health care services outside of the hospital on their own.
Sexual orientation and gender identity as adults: Sexual orientation as adults: Less than half of the nine (4/9) female participants in the follow-up reported a heterosexual orientation, as did three out of four of the assigned males.
Gender identity as adult: When asked as adults, all nine female participants reported that their identity today corresponds with assigned gender. One of the female patients reported that she had a feeling that her gender identity in childhood did not correspond with assigned gender. One of four male participants reported a gender identity that did not correspond with assigned gender.
Gender reassignment: Of the 16 patients that consented to participate in the follow-up, two patients had performed gender reassignment. One patient with a CAH diagnosis of the salt-wasting form of 21hydroxylase de ciency, assigned female gender and operated with clitoris reduction plastic and vaginoplasty at the age of 6 months, is today living as a male. In the medical records it is reported that the patient had poor compliance concerning hydrocortisone treatment and in early childhood had a feeling of being a boy. The patient started testosterone treatment at the age of 16 years and performed mastectomy at the age of 18 years. Another patient diagnosed with 46, XY gonadal dysgenesis and assigned female at birth, had performed gender reassignment to male. The patient stopped estrogen treatment at the age of 17 years after changing social sex at 16 and at 19 years old started testosterone treatment and in his 20s performed a modi ed metaidoioplasty.
Mental health, psychosocial functioning and QoL in childhood and adolescence As shown in Table 2, DSD patients had a signi cantly higher total problem score according to the CAS interview (Mdn=28) than the control group (Mdn=16), which indicates more psychiatric problems in the DSD group than in the control group. Also, the DSD group (Mdn=2) scored signi cally higher than the control group (Mdn=1) on the anxious/depressed subscale on the CBCL. Furthermore, the DSD group as a whole, including small children to adolescents, had signi cantly lower overall psychosocial function (CGAS) scores (Mdn=77.5) than the control group (Mdn=85) ( Table 2).
No signi cant differences were found in parent-reported HRQoL between DSD patients compared with controls, or between age and diagnosis groups ( Table 2).
Age group 1-9 years: Differences in children in age groups 1-9 years old were investigated using the CAS, CGAS, CBCL and PedsQL both children and parent reported validated questionnaires. No signi cant differences were found between controls, neither different genders nor diagnoses on any scales or measures in this sample.
Assigned females with DSD compared with control group, and 46, XX females vs. 46, XY females, 10-18 years old (Table3 and 4) The CGAS total score, the total raw scores of CBCL and YSR, externalizing, and internalizing scores and CAS total score appear in Table 3 and 4 of both 46, XX and 46, XY females and the female control group. The scores for 46, XX females (69.25+11.92, p=.011) and the 46, XY females (67.29+16.73, p=.006) were statistically signi cantly lower inoverall psychosocial function (CGAS) than the control group (84.59+8.54, p=.002). There was no statistically signi cant difference between the 46, XX and 46, XY females on the CGAS score. However, signi cant differences were found for behavioral and emotional problems between groups, where 46, XX females total scores on YSR (49.43+24.17, p =0.047) were signi cantly higher than in the 46, XY females (21.00+12.04, p =0.032). Signi cantly higher scores were found on internalizing problems (YSR) in 46, XX females (16.57+9.74), compared with the 46, XY females (5.60+5.32, p=0.047). The 46, XX females also had signi cantly higher scores on different subscales of the YSR compared with XY females; both withdrawn behavior (p=0.024), social problems (p=0.026) and attention problems (p=0.003).
In the older children/adolescent group the self-assessment HRQL using PedsQL, showed a clear tendency of lower score in the female group with 46, XX compared to the females with 46, XY, however not signi cant. The physical health dimension had the highest score. The lowest scores were in emotional and school function.

Part 2: The follow-up
Mental health and QoL in adulthood, Table 5 and Supplementary Table 3.
Mental health in adulthood.
About half (7/13) of the participants in the follow-up reported clinically important psychological distress or mental health problems as de ned as case total scores ≥6 on GHQ 30.

QoL in adulthood.
The scores of the QOLS by the 13 participants were equally distributed above and below the (name of the country anonymized for peer review) average, and the mean of the participants (83.46+19.13) was not signi cantly different from the (name of the country anonymized for peer review) population (84.10+12.5) (Wahl et al., 2004), however, the variation among patients was large between a score of 49-111. Two of the patients from the initial small children group, and four from the adolescent group had QOLS total score below the QOLS norms or reference values from the general (name of the country anonymized for peer review) population.
No difference in QOLS total score were found between the males and females in the current sample.

Childhood predictors for QoL in adulthood
Positive associations between QoL of the participants in adulthood and PedsQL' social function (r=.657, p=0.020) and psychosocial function in childhood (r=.596, p=0.041) were found.
Associations between mental health, QoL and other variables such as satisfaction with genitalia All 6 patients with a QOLS total score below the normative data did have a score de ned as «cases» at the GHQ 30. Higher QoL (QOLS) correlated negatively with lower psychological distress (GHQ-30) (r=-.88, p=0.000). There were positive associations between QoL and satisfaction with outer genitalia (r=.77, p=0.004). Negative associations were found between psychological distress (GHQ-30) and satisfaction with outer genitalia (r=-.85, p=0.000).

Mental health, QoL and patient-reported health care management
Signi cantly lower psychological distress (GHQ-30) were discovered in the group who had mainly positive experiences with the information given before surgery (25.00+8.06), than the ones with mainly negative experiences (58.00+7.48). Also, higher QoL were found in the group who had mainly positive experiences with the information given before surgery (97.00+9.71), compared to the ones with mainly negative experiences (60.25+10.05).

Discussion
This study represents a unique longitudinal follow-up of mental health, psychosocial functioning and quality of life from childhood to adulthood in a single center sample of patients with different DSD diagnoses. A key nding was that we found more psychopathology in the adolescents with a DSD diagnosis compared to controls in general, and females with a 46, XX karyotype had more psychosocial problems compared to the females with 46, XY in particular. Another important nding was a correlation between self-reported social and psychosocial function in childhood with later adult QoL. Although several studies retrospectively have tried to explore if variables in childhood and adolescence can predict adult outcomes (Schweizer, Brunner, Gedrose, Handford, & Richter-Appelt, 2017), to our knowledge our study is the rst to track QoL of young people with different DSD diagnoses from childhood or adolescence to adulthood in a longitudinal study. Importantly we found an association between satisfaction with information given before surgery and good QoL and less psychological distress in adulthood.
In this study, all patients had one or more genital surgeries. All patients with a CAH diagnosis, except one, underwent a rst surgery at a young age that consisted of clitoris reduction and vaginoplasty between the years 1982-2002. In addition, the two patients included in the study with a partial androgen insensitivity syndrome (PAIS) were assigned girls, and had clitoris reduction and vaginoplasty early and a new reduction and vaginoplasty in late adolescents. Early clitoral and vaginal surgery has in later years been The total cohort of children and adolescents had a signi cant higher score on the CAS interview than the control group, indicating more psychiatric problems; most of the problems were internalizing in nature due to higher levels of anxiousness and depression. When looking at the DSD group of patients as a whole, the present study found a lower psychosocial functioning compared to controls. However, we found no increased risk of psychological problems, psychosocial problems or poor QoL in younger children (1-9 years old) with DSD compared to controls, both in the self-reports and the parent-reports. There are studies supporting such ndings (Jürgensen, Hiort, Holterhus, & Thyen, 2007), while others report the opposite (Slijper, Drop, Molenaar, & de Muinck Keizer-Schrama, 1998). One study found that age was negatively associated with QoL, indicating that there is a deteriorating effect as the child gets older (Mahesh, 2019). Supporting this nding is a study identifying more psychological symptoms in older children, (D'Alberton et al., 2015). One possible explanation for this is that people with DSD might struggle more with age, getting increasingly aware of their condition, especially when seeking out relationships (Johannsen, Ripa, Mortensen, & Main, 2006). The present study found lower self-reported overall psychosocial functioning in teenage females with DSD compared to the female control group. In particular, the 46, XX assigned females in this cohort, exclusively patients with a CAH diagnosis, self-reported more emotional and behavioral problems than the 46, XY assigned females. Speci cally, internalizing problems with withdrawn behavior and social problems, and attention problems were reported. This susceptibility to psychological distress in girls with a CAH diagnosis may be further increased by exposure to gender-related stigma by showing increased traditionally male-typical gender role behavior, gender identity, and sexual orientation (Hines, 2011;Kung et al., 2018;Strandqvist et al., 2014). Also, in line with the results in this study teenage girls with CAH have been found to more likely isolate themselves socially (Ediati et al., 2015), which, together with stigmatization are discussed to increase psychological distress (Kuhnle & Krahl, 2002; G. L. Warne & Raza, 2008). These results underline the importance of identifying young individuals with a CAH diagnosis and reduced psychosocial functioning and to provide psychological and social support. Interestingly, the 46, XY females showed better psychological health than both the 46, XX females and the control group, although not signi cantly so. However, comparing 46, XX females and 46, XY, females might not be of much relevance. Some of the 46, XY females got their diagnosis late in adulthood with less hospital contact from early age, different follow-up and with or without androgenization prenatal.
When it comes to self-assessment of HRQOL, in the teenage group there was a clear tendency of lower score in the assigned female group with 46, XX compared to the assigned females with 46, XY. The lowest scores were in emotional and school function. The reduced school functioning in adolescents 46, XX females, might be in due to increased risk of cognitive impairment. Children and adolescents with CAH are at risk of adrenal crisis with salt loss and hypoglycemia that may negatively impact cognitive performance (Hamed,  . Two quite recent studies in Sweden employed nation-wide population-based registers of CAH and psychiatric diagnoses to investigate if mental health outcomes differed between individuals with CAH and age-and sex-matched controls (Engberg et al., 2015). Elevated rates of alcohol misuse, substance use disorders, and stress-related and adjustment disorders were found in females with CAH (Engberg et al., 2015). However, other studies nd no psychiatric comorbidities in CAH (Kung et (Houk & Lee, 2012). But also health status and management have been found to be an important link. In the current cohort there was no association between number of surgeries or hospital admissions with QoL or psychological distress in adulthood. However, there was found an association between satisfactions with the information given before surgery with good QoL and less psychological distress in adulthood. Furthermore, although the consensus today is to recommend early disclosure to patients, earlier days it was not uncommon that medical doctors did not inform the patients about previous surgeries. Still many parents nd it di cult to divulge the diagnosis to their children. Good information about the diagnosis has been found to improve coping skills and adjustment to diagnosis (Cohen-Kettenis, 2010). Psychological support, both social and professional, has been positively connected to symptoms of QoL and psychological distress in both childhood and adulthood (Kanhere et al., 2015;Schweizer et al., 2017). One study found a connection between general psychopathology occurring twice as often in children not having psychological counseling at the diagnosis time (Slijper et al., 1998). Another study found that patients with CAH with regular follow-up after going into adult care had better psychological health and QoL than the group who did not have regular follow-up (Bachelot et al., 2015).
Interestingly, less than half of the nine female participants in the follow-up reported a heterosexual orientation. This is in line with a quite resent published review that indicates that females with CAH had a greater likelihood to not have an exclusively heterosexual orientation than females from the general population (Daae, Feragen, Waehre, Nermoen, & Falhammar, 2020). As so, clinicians also need to be open for a variation in non-heterosexual orientation in young and adults with CAH and address sexual orientation when indicated and if relevant. The dsd-LIFE study reported a gender variance in 4 % of the 1,040 participants (Kreukels et al., 2018). In this study, when asked as adults, all nine female participants reported that their identity today corresponds with assigned gender. One of the female patients reported that she had a feeling that her gender identity in childhood did not correspond with assigned gender, and one of four male participants reported a gender identity that did not correspond with assigned gender. Besides, two of the 16 patients that consented to participate in the follow-up had performed gender reassignment. Importantly, as this study also shows, clinicians should be aware of the gender identity variance and be open minded to the increasing knowledge of non-binary identity in general.

Limitations
Overall, this study was hampered by a low sample size in general, which was expected because of the rarity of the conditions, combined with response numbers. Because of missing participants in the male teenager group in part 1 of the study; partly due to the gender assignment practice at that time, it was not possible to compare across genders. Another limitation is the small sample in the follow up study, which might bias any statistical analyses, and made it di cult to analyze across groups of diagnoses or assigned genders. Many refused to take part in the follow-up study, which could mean that the mental health and QoL of patients are further compromised, since in general the no responders tend to have poorer health, may be depressed or socially isolated (Zainuddin, Grover, Shamsuddin, & Mahdy, 2013).

Conclusion
The most important nding from this study might be the possibility to predict adult QoL from the psychosocial functioning in adolescence. In summary, this study demonstrated that adolescents assigned females with DSD have more psychiatric problems and a poorer degree of psychosocial functioning compared to controls. The female adolescents with a CAH diagnosis do report more internalizing emotional and behavioral problems, including social problems, withdrawn behavior, and attention problems. As we do nd a correlation with these problems in adolescence and later adult QoL, it is of great importance to respond to these behaviors in early life. The study demonstrates that emotional and behavioral adjustment in adolescents with CAH may be particularly important because it sheds light on how early any CAH-related adjustment differences emerge. Another important nding was that higher satisfaction with information before surgery is associated with better QoL and lower psychological distress. This means that it might be important to have a psychological aspect in the follow up of children and adolescent patients, and also make sure that the information before surgery are understood by the patients, and not only by their parents. Median (min-max). * = p < 0.05, 1 : Either based on child interviews, or else parent interviews.