Gender Dsyphoria and Psychiatric Disorders in Children and Adolescents with Congenital Adrenal Hyperplasia

Abstract

Context

Gender identity, psychosexual function, psychiatric adjustment and quality of life have been investigated in congenital adrenal hyperplasia(CAH) patients.

Objective

We aimed to investigate gender identity problems and the psychiatric disorders and associated factors in children and adolescents with CAH patients.

Subjects and methods

Forty-five children and adolescents with CAH were included in the study. Psychiatric comorbidity was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children – Present and Lifetime Version. Gender identity problems were investigated using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria.

Results

The mean age of the sample was 11.02 years (SD: 3.25, range: 6–18). 51.1% of the patients had at least one lifetime comorbid psychiatric disorder. The most common diagnoses were anxiety disorders, attention deficit hyperactivity disorder(ADHD), tic disorders and enuresis nocturna. Tic disorders and ADHD were higher in males but they were not statistically significant. Two female patients were diagnosed with gender dysphoria and 18.5% of females showed variably masculinized behaviors. The girls with gender identity problems expressed lower satisfaction with their sex than other girls and boys.

Conclusions

Children and adolescents with CAH had many psychiatric disorders, especially neurodevelopmental disorders. ADHD and tic disorders should be kept in mind during assessment especially in male patients. Gender dysphoria and masculine behaviors seem to be common in female patients with CAH so they should be carefully investigated.

Introduction

Disorders of sexual development (DSDs) presenting with atypical genitalia are associated with complex psychological and surgical problems (1). Congenital adrenal hyperplasia (CAH), one of the DSDs, is an autosomal recessive disorder (1). Congenital adrenal hyperplasia is a syndrome of prenatal and/or postnatal androgen excess secondary to genetic deficits in the cortisol synthesis pathway. Classic CAH (C-CAH) encompasses salt-wasting (SW) or simple virilizing (SV) forms, depending on the degree of aldosterone deficiency. Classic CAH patients are exposed to excessive androgen in utero. 46XX CAH have varying degree of virilisation of external genitalia at birth and therefore may require feminizing genital surgery. A few of the genitally more masculinized newborns are initially assigned to the male gender (2). Hormonal treatment is based on cortisol and, when necessary, aldosterone substitution.

Several studies have revealed higher rates of psychiatric disorders in subjects with DSDs (3-5). However, only a minority of patients apply for psychiatric assessment. In a study although 71% of the female CAH patients had psychosexual problems, only 17% undertook routine psychiatric assessment (6). Gender identity, sexual orientation and sex-typed behavior, psychosexual function, psychiatric disorders, body images and quality of life have been examined (4, 7, 8).

We aimed to investigate the psychiatric disorders and gender identity problems and associated factors in children and adolescents with CAH. Congenital adrenal hyperplasia is a chronic illness with hormonal abnormalities that can have serious consequences, so we hypothesized that psychiatric disorders and gender identity problems will be common in CAH patients.

Materials and methods

Participants

Participants were 45 children and adolescents (aged 6–18 years) with CAH who were recruited from the Pediatric Endocrinology Clinic of Kanuni Sultan Suleyman Training and Research Hospital. The diagnosis of the patients was made by a pediatric endocrinologist with clinical and laboratory examinations. All of the patients had classical 21-Hydroxylase deficiency. Subjects with intellectual disabilities or chronic medical disorders other than CAH were excluded. Sociodemographic data forms were filled out by the authors. Psychiatric evaluation was done using the Schedule for Affective Disorders and Schizophrenia for School Age Children – Present and Lifetime Version – Turkish Version (K-SADS-PL-T). Gender identity problems were assessed using DSM-5 criteria. The Strengths and Difficulties Questionnaire (SDQ) and Child Depression Inventory (CDI) were used to screen emotional and behavioral symptoms and gender identity problems of the child. All of these clinical data were collected by the authors themselves. Two sessions were required to complete the entire clinical assessment.

General Clinical Data

A sociodemographic and clinical data form prepared by the authors was completed according to data obtained from the parent and the child. The sex of the children was specified according to karyotype analysis. This form covers the current age and education level of the child, monthly income level of the family, medical history, history of genital surgery, previous psychiatric history, family history of psychiatric disorders, gender identity problems and intersex disorders, gender role behaviors of the child before diagnosis of CAH and the satisfaction of the child with his or her current genitalia and sex characteristics.

Assessment of psychiatric disorders and gender identity problems

Schedule for Affective Disorders and Schizophrenia for School Age Children – Present and Lifetime Version – Turkish Version (K-SADS-PL-T)

Psychiatric disorders were assessed using the K-SADS-PL-T. The KSADS-PL is a semi-structured interview schedule designed to assess 32 psychiatric disorders in children and adolescents on the basis of DSM-IV criteria (9). The Turkish version of the K-SADS-PL was demonstrated to be a reliable and valid tool (10). All of the interviews were conducted by certified and experienced child and adolescent psychiatrists. Lifetime psychiatric diagnoses were examined and noted.

Strengths and Difficulties Questionnaire (SDQ)

The parents also filled out the Turkish version of the Strengths and Difficulties Questionnaire (SDQ) for emotional and behavioral problems of the children. SDQ is a brief scale consisting of 25 items. The SDQ focuses on both positive and negative attributes of child behavior. SDQ has five subscales to assess five areas of functioning: Prosocial Behavior, Hyperactivity/Inattention, Emotional Symptoms, Conduct Problems and Peer Relationship Problems. The scores for Hyperactivity/Inattention, Emotional Symptoms, Conduct Problems and Peer Relationship Problems are summed to obtain a “Total Difficulties” score. The total SDQ scores had a possible range of 0–40. The total difficulties score can be categorized into ‘normal,’ ‘borderline’ and ‘abnormal’ scores. The ‘borderline’ and ‘abnormal’ SDQ total difficulties scores predict that mental health disorders are possible or probable (11, 12).

Child Depression Inventory (CDI)

Additionally, children older than eight years old filled out the Child Depression Inventory (CDI). The CDI is a 27-item self-report measure of childhood depression. The total score ranges from 0 to 54. The reliability and validity of the CDI has been verified in participants between 7 and 17 years of age and 19 was recommended as the cut-off point for the screening of depression (13, 14).

Assessment of intellectual abilities

The Turkish version of the Wechsler Intelligence Scale for Children – Revised (WISC-R) was administered for the assessment of intellectual abilities. Wechsler Intelligence Scale for Children – Revised scores were categorized as full scale intelligence quotient (IQ), verbal IQ and performance IQ. Cases with full scale IQ scores lower than 70 were excluded.

Ethics

Approval was obtained from our hospital’s local ethics committee for our study (August-2015, Decision no: 476). Parents of all children signed informed consent forms prior to participation in the study. In addition, children older than 12 years signed the consent forms themselves. The study was conducted in accordance with the Helsinki Declaration.

Statistical analysis

Data were analyzed using the SPSS (Statistical Package for the Social Sciences), version 16.0 (SPSS, Inc., Chicago, IL, USA). The sample description was done with descriptive analyses: frequencies and percentages for discrete variables and means and standard errors for continuous variables. Categorical variables were compared using Pearson’s Chi-square test and Fischer Exact test. Because most data were not strictly normally distributed and some groups had unequal variances, nonparametric tests were used for the evaluation of most results: the Mann–Whitney test for comparisons of groups for continuous parameters. Continuous variables are presented as median [interquartile range (IQR)]. Correlations between continuous parameters were tested with Pearson or Spearman correlation analyses. A probability level of P<0.05 was used to indicate statistical significance.

Results

General data

A total of 45 children and adolescents with CAH were included in the study. Twenty-seven subjects (60%) were chromosomal wise and rearing wise female. The mean age of the sample was 11.02 years (SD: 3.25, range: 6–18). Twelve cases (26.7%) described problems in the perinatal period and five (11.6%) patients had delayed developmental milestones.

Age at diagnosis ranged from two weeks to 156 months. Median age of diagnosis was two months. Diagnosis in the neonatal period was established in 17 cases (37.8%). Clinical characteristics of the sample are shown in Table 1.

Table 1.

Demographic and clinical characteristics of the sample

Variables	N (%) or mean ± SD
Female	27 (60)
Male	18 (40)
Age (years)	11.02 ± 3.25
Child (6-12 years old)	24 (53.3)
Adolescent (>12 years old)	21 (46.7)
Age at diagnosis (months)	15.4 ± 31.4
Having at least one comorbid psychiatric disorder	23 (51.1)
Having at least two comorbid psychiatric disorders	11 (24.4)
Previous psychiatric referral	8 (17.8)
History of genital surgery	23 (51.1)

Salt-wasting phenotype was diagnosed in 25 patients (mean age 11.12±3.04 year; range, 6–18), SV phenotype in 15 patients (10.8±3.85 year; range 6–18) and NC phenotype in 5 patients (11.2±2.94 year; range 7–15). Twenty-three patients (51.1%) (21 female, 2 male patients) had undergone genital surgery; 13 patients (27.3%) had two or more operations. Three chromosomal female patients were assigned to the male sex at birth but they were later raised as females. All cases were raised in accordance with their chromosomal sex by their families.

Only eight patients (17.8%) had a history of psychiatric referral prior to the examination. Previous psychiatric symptoms included attention problems, anxiety symptoms and adjustment problems.

For treatment, 2 cases were using only prednisolone, 2 cases were using both dexamethasone and fludrocortisone, 18 cases were using only hydrocortisone and the remaining 23 cases were using both hydrocortisone and fludrocortisone.

Psychiatric comorbidity

Twenty-three subjects (51.1%) had at least one lifetime comorbid psychiatric disorder, and eleven subjects (24.4%) had two or more lifetime comorbid psychiatric disorders. The most common diagnoses were enuresis nocturna (EN) (24.4%), anxiety disorders (20%), attention deficit hyperactivity disorder (ADHD) (11.1%) and tic disorders (11.1%). Enuresis nocturna was not due to an organic and structural condition associated with adrenal hyperplasia. The distribution of diagnoses is presented in Table 2.

Table 2.

Distribution of psychiatric disorders and comparison according to sex

	Total (n=45)	Female (n=27)	Male (n=18)	p
Diagnosis	N(%)
Anxiety disorders	9(20)	7(25.9)	2(11.1)	0.22
Social phobia	5 (11.1)	4(14.8)	1(5.6)	0.33
Obsessive compulsive disorder	3(6.6)	2(7.4)	1(5.6)	0.80
Seperation anxiety disorder	2(4.4)	1(3.7)	1(5.6)	0.76
Specific phobia	2(4.4)	1(3.7)	1(5.6)	0.76
Generalized anxiety disorder	1(2.2)	1(3.7)	0(0)	0.40
Depressive disorders	3(6.6)	3(11.1)	0(0)	0.14
Tic disorders	5 (11.1)	1(3.7)	4(22.2)	0.05
Attention deficit/hyperactivity disorder	5 (11.1)	1(3.7)	4(22.2)	0.05
Conduct disorder	1 (2.2)	0(0)	1(5.6)	0.21
Oppositional defiant disorder	1(2.2)	0(0)	1(5.6)	0.21
Enuresis nocturna	11 (24.5)	6(22.2)	5(27.8)	0.67
Gender dysphoria	2(4.4)	2(7.4)	0(0)	0.23

Strengths and Difficulties Questionnaire-total scores [11.5 (7-15), 7 (4-8), p=0.017] and SDQ-hyperactivity scores [3 (2-5), 2 (1-3), p=0.023] were significantly associated with having lifetime comorbid psychiatric disorders. Although not statistically significant, CDI scores were associated with an increase in emotional disorders (p=0.06). Mean SDQ and CDI were shown in Table 3. Genital surgery history was not found to be with presence of lifetime psychiatric comorbidity. Distribution of lifetime psychiatric disorders according to clinical phenotypes of CAH is presented in Table 4.

Table 3.

Scores of Psychiatric Scales

	Mean±SD	Min-Max
CDI	8.9±5.7	0-20
SDQ-E	1.9±1.9	0-6
SDQ-C	1.5±0.6	0-6
SDQ-H	2.6±2.1	0-9
SDQ-P	2.5±1.4	0-7
SDQ-T	8.6±5.5	1-21

CDI: child depression inventory score, SDQ-C: strength and difficulties questionnaire-conduct score, SDQ-E: strength and difficulties questionnaire-emotional score, SDQ-H strength and difficulties questionnaire-hyperactivity score, SDQ-P: strength and difficulties questionnaire-peer problems score, SDQ-T: strength and difficulties questionnaire-total score.

Table 4.

Distribution of lifetime psychiatric disorders according to clinical phenotypes of congenital adrenal hyperplasia

	Salt-wasting (n=25)	Simply virilizing (n=15)	Nonclassical/ late onset (n=5)
Diagnosis	N (%)
Anxiety disorders	3 (12)	4 (26.7)	2 (40)
Social phobia	2 (8)	2 (13.3)	1 (20)
Obsessive compulsive disorder	1 (4)	1 (6.7)	1 (20)
Seperation anxiety disorder	0 (0)	2 (13.3)	0 (0)
Specific phobia	0 (0)	1 (6.7)	1 (20)
Generalized anxiety disorder	1 (4)	0 (0)	0 (0)
Depressive disorders	2 (8)	0 (0)	1 (20)
Tic disorders	4 (16)	1 (6.7)	0 (0)
Attention deficit/hyperactivity disorder	4 (16)	0 (0)	1 (20)
Conduct disorder	0 (0)	0 (0)	1 (20)
Oppositional defiant disorder	0 (0)	0 (0)	1 (20)
Enuresis nocturna	7 (28)	4 (26.7)	0 (0)
Gender dysphoria	1 (4)	1 (6.7)	0 (0)

Gender differences

The ADHD rate was found to be 3.7% in females and 22.2% in males. Tic disorder and ADHD were more common in boys compared to girls but it did not reach to statistically significance (p=0.056 and p=0.052, respectively). Conversely, there was a trend for higher rates of anxiety disorders in female patients (7 of 27 females had anxiety disorders, but 2 of 18 males had anxiety disorders) (Table 2). The median SDQ-conduct scores were significantly higher in male patients [female: 0.5 (0-1), male: 2 (0.25-4.75), p=0.012]. No significant difference was found between genders regarding other scale scores.

Twenty-four subjects were aged between 6 and 12 years (children), and twenty-one subjects were older than 12 years (adolescents). Adolescents had higher rates of psychiatric disorders compared to children they did not reach statistical significance (p=0.058). Eleven adolescents and five children had a current psychiatric disorder. Types of psychiatric diagnoses did not differ between age groups.

Gender dysphoria

Two female patients (7.4% of the females) were diagnosed with gender dysphoria. Five girls (18.5% of the females) showed variably masculinized behavior in regard to play, playmates, toys and activities, and they were named “tomboys” by their relatives. Gender dysphoria was not found in any of the males. Interestingly, both patients with gender dysphoria did not have any psychiatric comorbidity. Both cases were nine years old. One had SV subtype, and the other had SW subtype. Their ages at diagnosis were 24 months and one month, respectively.

Two of the five tomboy patients had SV subtype; the other three had SW subtype. Four were diagnosed with at least one psychiatric disorder. The diagnoses included social phobia (SP), depressive disorder not otherwise specified (Dep. NOS), ADHD, EN and tic disorder.

Discussion

Psychiatric disorders

In this study, we found that half of the CAH patients had accompanying psychiatric disorders, however only one-fifth of them had referred to a psychiatry clinic before. Childhood psychiatric disorder prevalence rates range from 10 to 20% (15). In Ercan et al.’s epidemiological study (16) at least one psychiatric disorder with a moderate impairment was found in 25.6% and with severe impairment in 14.1% of the Turkish children. Our psychiatric disorder rate in this study was higher than in both studies. The consequences of chronic illness and hormonal changes may have affected normal psychosocial development. Psychiatric disorders and gender identity problems have been investigated in CAH patients using a variety of instruments (17, 18). Some previous studies have reported increased rates of psychiatric symptoms among CAH patients (3, 5), whereas other studies did not show increased rates of psychiatric disorders compared to normal data (18, 19). Mueller et al. (3) have found that lifetime psychiatric comorbidity was 44.4% in CAH patients. This rate was similar to our result.

In this study, the most common diagnoses were EN, ADHD, social phobia and tic disorders. Enuresis nocturna was the most common psychiatric diagnosis in our patients. The prevalence of EN in Turkey was found to be 8.9–13.7% (20). Mueller et al. (3) found that 3% of their population had EN. Our higher rate may be associated with the lower mean age of the sample as the prevalence of EN decreases with age.

Our study revealed a slightly higher prevalence of anxiety disorders in female patients. The rate of anxiety disorders was 2.6% in the Turkish sample. Girls had slightly higher rates of mood and anxiety disorders, but these differences were not statistically significant in a community sample (16). Two of the tomboy girls had SP; social stigmatization because of their masculinized behaviors may have affected these girls. Having a chronic illness may also have precipitated social anxiety.

Attention deficit hyperactivity disorder comorbidity was 11.1% (3.7% in girls, 22.2% in males) in our population. The pooled prevalence of ADHD is 5.3% worldwide (21). Attention deficit hyperactivity disorder prevalence in the Turkish population is between 8.1–13.3% (16, 22). Attention deficit hyperactivity disorder is more commonly seen in boys than in girls (23). The ADHD rate was 2.8-fold higher in boys than in girls in a Turkish epidemiologic study (16). Although the ADHD rate was not higher in our female patients, it was two to four times more common in the male patients in our study. A similar pattern was also reported by Mueller et al. (7) ADHD is a neurodevelopmental disease, and early exposure to androgens may increase the risk for ADHD, especially in susceptible males. Alexander et al. (24) suggested that glucocorticoid levels may reflect disease severity and may be associated with behavioral outcome. However, we could not find any relationship between age at diagnosis of CAH and having ADHD. Prenatal androgen excess may be responsible for this condition, and the intrauterine period is very important for brain development. In a study, no significant differences in behavioral problems were found in children with CAH who were treated prenatally, compared with the controls (25). Therefore, prenatal diagnosis and treatment of CAH seems very important.

Four of our 18 male patients had tic disorders. Alexander et al. (26) reported that the androgen-dependent process of sexual differentiation during prenatal life may contribute to the development of tic-related disorders. Tic disorder is a neurodevelopmental disorder like ADHD. As with ADHD, exposure to excessive prenatal androgen may have facilitated the emergence of tics in our male CAH patients.

Conduct disorder and oppositional defiant disorder were found to be more common in the nonclassical/late onset type of CAH in our study. It is an unexpected finding because nonclassical/late onset type is a less severe form of CAH. The small sample size may have contributed to this result. Although SW subtype is the most severe form, we found no association with SW subtype and a more severe psychiatric condition in our study. Mueller and colleagues also found no difference in psychiatric morbidity between those with SW and SV phenotypes (3).

Gender identity problems

Gender dysphoria was detected in 7.4% of the females in our study sample which is a high rate. Five girls (close to one-fifth of the females) exhibited masculine behaviors, but they did not meet the diagnosis of gender dysphoria. The girls with gender dysphoria and tomboy-like behaviors reported lower satisfaction with their current gender than other girls and boys.

A recent study reported that 5.2% of female CAH patients have serious problems with their gender identity which is a similar finding with our study (27). Some studies showed that girls with CAH display more male-typical toy choices or interests. It has been shown that femininity increased through developmental stages; masculine behaviors were considered to be associated with both prenatal androgen exposure and socialization-affected gender role (28, 29). Oner et al. found that patients with CAH also reported engaging in male-typed play more frequently than patients with diabetes mellitus and controls (30).

Many children with CAH have a history of repeated genital exams, genital surgeries or atypical genital appearances. The traditional practice of early surgery in girls was based on the assumption that this would lead to better psychosocial and psychosexual adjustment. However, there is limited evidence available to support this practice. Our results revealed that genital surgery history and number of operations were not associated with psychiatric comorbidity; however genital surgery history and preoperative gender role behaviors of the child were associated with gender identity problems. Therefore, a child’s gender role behaviors should be evaluated carefully before making operational decisions.

The adolescence period is important for gender identity and emergence of psychiatric disorders (31, 32). Our study revealed that adolescent patients should be more carefully evaluated.

Strengths and Limitations

One of the strengths of our study is that we assessed lifetime comorbid psychiatric disorders with a semi-structured interview. Our study was important to explore gender-related differences in young CAH patients. Gender identity problems, psychiatric disorders and associated factors (such as age, gender, operation history) were examined in detail. The major limitation of our study is the relatively small sample size and lack of any control group.

In conclusion, children and adolescents with CAH have increased rates of psychiatric disorders, especially neurodevelopmental disorders. ADHD and tic disorders should be kept in mind in male CAH patients while making psychiatric assessment. Gender dysphoria should be carefully evaluated in children with preoperative gender role behavior problems or lower satisfaction with their gender. Consultation with a child and adolescent psychiatrist before sexual assignment surgery may be useful for preventing gender dysphoria in later years.

Future studies are needed with larger samples of boys and girls with CAH in the periods of childhood, adolescence and adulthood, and studies with examining of effecting by prenatal diagnosis and treatment.

Conflict of interest

The authors declare that they have no conflict of interest. The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.