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 finding 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 finding 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 first 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 first 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 questioned and has become more restrictive after the reports on postoperative loss of sensitivity of the clitoris and vaginal strictures requiring reoperation [63-65]. Long-term outcome data from this reported genital operated cohort is therefore of great importance. The Council of Europe’s resolution of 2017(Assembly, 2017), as well as the European Parliaments resolution of 2019 on the rights of intersex people (Parliament, 2019) states that all surgical procedures involving correction of ambiguous genitalia in young children should be postponed until the patient is able to participate in the decision-making process. Also, surgery should only be considered in cases of severe virilization for patients with CAH (Gardner & Sandberg, 2018; Hughes, Houk, Ahmed, & Lee, 2006). However, surgeries are still performed (Michala, Liao, Wood, Conway, & Creighton, 2014), and data in this study will still be relevant for future generations, and are important for further discussion on childhood surgery practice.
The total cohort of children and adolescents had a significant 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 findings (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 finding 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. Specifically, 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 significantly 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, Metwalley, & Farghaly, 2018). As so, some studies have highlighted the need to assess cognitive functions in children and adolescents with CAH (Amr, Baioumi, Serour, Khalifa, & Shaker, 2019; Hamed et al., 2018). However, a newly published study of children and adolescents diagnosed through the neonatal screening program for CAH in Sweden showed normal cognitive abilities (Valeria Messina 2020). Nevertheless, early intervention in children with cognitive deficits is crucial to prevent learning deficits later in childhood, and especially when combined with attention problems, which also was found in this cohort.
About half of the participants, when assessed as adults, scored high on self-reported psychological distress. Also other studies have found psychological problems to be apparent in adults with different DSD diagnoses, and inferior to children (Kleinemeier, Jurgensen, Lux, Widenka, & Thyen, 2010). As in adolescence, the symptoms published are internalizing emotional problems, especially anxiety and depression (Ediati et al., 2015; Migeon et al., 2002). A large study of adults with DSD in six European countries revealed that scores for anxiety were significantly higher in female individuals with XY-DSD with PAIS, and scores for depression were higher for female groups with CAH (de Vries et al., 2019). In male and female participants with various XY-DSD conditions, clinically significant psychological distress is reported in 42% to 68% of participants (Bennecke et al., 2017; Johannsen et al., 2006; Schützmann, Brinkmann, Schacht, & Richter-Appelt, 2009). However, other studies do not find any psychological or psychosocial struggles (Migeon et al., 2002; Stikkelbroeck et al., 2003; G. Warne et al., 2005). 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 find no psychiatric comorbidities in CAH (Kung et al., 2018; Reisch et al., 2011).
The QoL measures from the current cohort are in line with (name of the country anonymized for peer review) norms (Wahl et al., 2004). However, the scores were scattered between 49-111, with half of the patients having scores below the norm, and half above. These mixed results may warrant clinicians that within the DSD population, some individuals may show resilience against developing difficulties and other might have more challenges. Studies have earlier suggested a lot of different possible risk factors for reduced QoL and increased psychological distress among the DSD patient group: having a chronic illness, trauma from stressful diagnostic procedures, severity of condition, issues related to psychosexual identity, psychological distress and anxiety towards sexual contact and relationships (Johannsen et al., 2006; Kuhnle, Bullinger, & Schwarz, 1995; Nordenskjold et al., 2008; G. Warne et al., 2005), sex reassignment procedures, genital surgery, hospital admissions, hormonal substitution and infertility (Slijper et al., 1998), being isolated from peer groups because of hospitalization and surgeries for long periods of time (Diseth, Tangeraas, Reinfjell, & Bjerre, 2011), societal and peer pressure on the child and the family, and the patient’s own personality (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 find it difficult 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.
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 difficult 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).