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Context: Reports on psychiatric morbidity in males with congenital adrenal hyperplasia (CAH) are
lacking.
Objective: The aim was to study psychiatric disorders in CAH males.
Design, Setting, and Participants: We studied males with CAH (21-hydroxylase deficiency, n 253;
CYP21A2 mutations known, n 185), and compared them with controls (n 25 300). Data were
derived through linkage of national population-based registers. We assessed the subgroups of
CYP21A2 genotype separately (null, I2splice, I172N, P30L, and NC), as well as outcomes before and
after the introduction of national neonatal screening in 1986.
Main Outcome Measures: Psychiatric disorders including attempted and completed suicide (suicidality) were reviewed.
Results: Psychiatric disorders (suicidality not included), suicidality, and alcohol misuse were increased in CAH males compared with controls (odds ratios, 1.5, 2.3, and 1.9; 95% confidence
intervals, 1.12.2, 1.15.0, and 1.0 3.5, respectively). In the null genotype group, no increased rates
were seen; in the I2splice group, psychiatric disorders, personality disorders, and alcohol misuse
were increased; in the I172N group, suicide attempt and drug misuse were increased; and in the
P30L and NC groups, psychotic disorders were increased. In CAH males born before the neonatal
screening, the rates of psychiatric disorders and suicidality were increased, but only psychotic
disorders increased in those born afterward. There was no increased risk for any neurodevelopmental disorder.
Conclusions: CAH males have an increased psychiatric morbidity. Psychiatric morbidity was not
raised in the most severe genotype group. Late diagnosis of CAH may explain some of the findings.
Those born before the introduction of neonatal screening were more affected, which may be
explained by the higher age. (J Clin Endocrinol Metab 99: E554 E560, 2014)
E554
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doi: 10.1210/jc.2013-3707
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doi: 10.1210/jc.2013-3707
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E555
Study protocol
We used a matched cohort design, with exposure defined as
having the diagnosis of CAH in the national CAH registry or in
the NPR. We identified 100 unexposed individuals per CAH
male, matched by birth year, sex, and place of birth in the Total
Population Register. Those who had immigrated to Sweden were
matched with unexposed males who had also immigrated.
All Swedish citizens have a unique personal identification
number that enables linkage of population-based registers. All
CAH males and their controls were coded by Statistics Sweden
before linkage with the registers. The NPR (held by the National
Board of Health and Welfare) contains the discharge diagnoses
according to ICD of inpatient care since 1964 and outpatient care
since 2001 (28). The outcomes were diagnosis of psychiatric
disorders, suicide attempts, and death by suicide. Data on deaths
were derived from the Cause of Death Register (National Board
of Health and Welfare) with all registered deaths since 1952.
Psychiatric disorder was defined as any diagnosis within ICD-8
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E556
Falhammar et al
codes 290 315, ICD-9 codes 290 319, and ICD-10 codes F00F99 in the NPR. Separate analyses were performed for: 1) psychotic disorders (ICD-8 codes 295, 297299; ICD-9 codes 295,
297, 298; and ICD-10 codes F20-F29); 2) mood disorders
(ICD-8 codes 296, 300.4; ICD-9 codes 296, 300E, 311; and
ICD-10 codes F30-F39); 3) anxiety, dissociative, stress-related,
somatoform, and other nonpsychotic mental disorders (ICD-8
code 300 except 300.4, code 307; ICD-9 code 300 except 300.E,
or 308 309; and ICD-10 codes F40-F45, F48); 4) personality
disorders (ICD-8/ICD-9 code 301 and ICD-10 codes F60 F62,
F69); 5) mental and behavioral disorders due to psychoactive
substance use (alcohol: ICD-8 code 303; ICD-9 codes 303, 305A;
and ICD-10 code F10; and other drugs: ICD-8 code 304; ICD-9
codes 304, 305X; ICD-10 codes F11-F19); 6) other behavioral
emotional disorders with onset usually occurring in childhood or
adolescence (ICD-9 codes 312313; ICD-10 codes F91-F98); 7)
intellectual disability (ICD-8 codes 310 315; ICD-9 codes 317
319; and ICD-10 codes F70-F79); 8) attention-deficit hyperactivity disorder (ADHD) (ICD-9 code 314; ICD-10 code F90); and
9) autism spectrum disorders (ICD-9 code 299; and ICD-10 code
F84). Suicidality was defined as completed suicide (obtained
from the Cause of Death Register) or an attempt (ICD-8/ICD-9
codes E950-E959; ICD-10 codes X60-X84 in the NPR) and was
not included in the any psychiatric disorders group. The Migration Register (Statistics Sweden) with all migrations since
1901 was used to control for migration.
Statistical analysis
The association between CAH and defined outcomes (psychiatric disorders and suicidality) was calculated by conditional
logistic regression. To assess the effect of introduction of nationwide screening for CAH, a sensitivity analysis was done by stratification by year of birth (1986 and 1986). Results were
reported as odds ratios (ORs) and 95% confidence intervals
(CIs). Analysis was done by SAS version 9.3 software package
(SAS Institute Inc).
Results
Characteristics of the patients and controls
The males diagnosed with 21-hydroxylase deficiency
had a median age of 23.2 (range, 0.5 80) years at the last
observation time. The clinical severity could be established
in 200 patients. The SW phenotype was diagnosed in 105
patients (20.8 y; range, 0.5 65.2), SV phenotype in 76
patients (23.3 y; range, 1.4 79), and NC phenotype in 19
patients (16.2 y; 1.8 49). In 185 patients, the CYP21A2
mutations were available. The number of individuals in
each genotype group was: null, n 41 (19.4 y; range,
0.757); I2splice, n 55 (19.6 y; range, 0.5 65.2);
I172N, n 58 (23.5 y; range, 1.4 79); P30L, n 12 (18
y; range, 1.4 38); V281L, n 17; and P453S, n 1.
Matched controls were included from the Total Population Registry (n 25 300). An equal proportion of exposed and unexposed subjects had emigrated (CAH,
4.0%; controls, 4.5%).
Controls
OR (95% CI)
253
25 300
36 (14.2) 2486 (9.8) 1.5 (1.12.2)
7 (2.8)
309 (1.2)
2.3 (1.15.0)
1 (0.4)
6 (2.4)
4 (1.6)
9 (3.6)
9 (3.6)
3 (1.2)
12 (4.7)
11 (4.3)
3 (1.2)
1 (0.4)
1 (0.4)
5 (2.0)
39 (0.2)
279 (1.1)
191 (0.8)
524 (2.2)
737 (2.9)
115 (0.5)
804 (3.2)
606 (2.4)
218 (1.3)
268 (1.1)
166 (0.7)
369 (1.5)
3 (1.2)
174 (0.7)
Psychiatric disorders
The rate of occurrence of any psychiatric disorders and
alcohol misuse was increased in CAH males compared to
controls (Table 1). In 36% (13 of 36) of CAH males and
in 43% (1067 of 2486) of controls, the first psychiatric
diagnosis was found before the age of 18 years. The rate
of personality disorders and alcohol misuse was significantly raised among SW males, whereas in SV males drug
misuse was increased (Table 2). In the null genotype
group, no increased risk of any of the measured diagnoses
was found, whereas in the I2splice group, the risk of any
psychiatric disorder, personality disorder, and alcohol
misuse was raised. In the I172N group, drug misuse was
elevated (Table 3). Both the NC group and the P30L group
had increased risk of psychosis (Tables 2 and 3). No CAH
males had been diagnosed with eating disorders compared
to 0.11% (n 28) of controls. Further dividing the anxiety
disorders into phobic anxiety disorders, other anxiety disorders, obsessive compulsive disorders, reaction to severe
stress and adjustment disorders, dissociative, conversion
and somatoform disorders revealed a significant increase
of other anxiety disorders in males with the I172N genotype (5.2 vs 1.3%; OR, 4.3; 95% CI, 1.314.3) and tendencies to increased risks of other anxiety disorders in all
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E557
Table 2. Psychiatric Disorders in CAH Males With 21-Hydroxylase Deficiency Divided Into the Three Phenotypes,
Compared With Age- and Sex-Matched Controls (100 Controls per Case)
n
Any psychiatric
disorder
Suicide attempt
Psychotic disorders
Mood disorders
Anxiety disordersb
Personality disorders
Substance misuse
Alcohol
Drugs
ADHD
ASD
Other behavioral
disorders
Intellectual
disabilities
SW
OR (95% CI)
SV
OR (95% CI)
NCa
OR (95% CI)
105
14 (13.3)
76
9 (11.8)
19
2 (10.5)
2 (1.9)
0 (0)
4 (3.8)
2 (1.9)
2 (1.9)
6 (5.7)
6 (5.7)
0 (0)
1 (1.0)
0 (0)
2 (1.9)
3 (3.9)
1 (1.3)
2 (2.6)
3 (3.9)
1 (1.3)
4 (5.3)
3 (4.0)
3 (4.0)
0 (0)
1 (1.3)
1 (1.3)
0 (0)
1 (5.3)
0 (0)
1 (5.3)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0 to 1000)
12.3 (1.4 to 109)
0 (0 to 1000)
1.9 (0.2 to 14.8)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
1 (0.95)
0 (0)
0 (0 to 1000)
1 (5.3)
Abbreviation: ASD, autism spectrum disorders. Data are expressed as number (percentage), unless described otherwise. Severity of the phenotype
ranges from greatest to least, left to right. The significant findings are highlighted with bold text.
a
Seventeen patients had the V281L genotype, one had the P453S genotype, and one had not been genotyped.
CAH males (2.8 vs 1.4%; OR, 2.0; 95% CI, 0.9 4.3) and
among SV males (4.0 vs 1.3%; OR, 3.1; 95% CI, 0.9 10).
Suicidality
Suicidality was almost doubled in the CAH males compared to controls (Table 2). One CAH male (0.4%) had
committed suicide (geno- and phenotype unknown, diagnosed with depression on two occasions before suicide)
compared to 39 controls (0.2%) (OR, 2.6; 95% CI, 0.4
18.9), and six CAH males (2.4%) had made a suicide
attempt compared to 279 controls (1.1%) (OR, 2.20;
95% CI, 1.0 5.0). In the I172N genotype group, the risk
was increased around four times, whereas in the other
Table 3. Psychiatric Disorders in Male Patients Representing the Three Most Common CYP21A2 Genotype Groups
and P30L Compared With Age- and Sex-Matched Controls (100 Controls per Case)
Null
n
Any psychiatric disorder
Suicide attempt
Psychotic disorders
Mood disorders
Anxiety disordersa
Personality disorders
Substance misuse
Alcohol
Drugs
ADHD
Autism spectrum disorders
Other behavioral disorders
Intellectual disabilities
41
2 (4.9)
0 (0)
0 (0)
1 (2.4)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (2.4)
0 (0)
OR (95% CI)
I2 splice
55
9 (16.4)
1 (1.8)
0 (0)
2 (3.6)
2 (3.6)
1 (1.8)
5 (9.1)
5 (9.1)
0 (0)
1 (1.8)
0 (0)
1 (1.8)
0 (0)
OR (95% CI)
I172N
58
7 (12.1)
3 (5.2)
0 (0)
1 (1.7)
3 (5.2)
1 (1.7)
3 (5.2)
2 (3.4)
3 (5.2)
0 (0)
1 (1.7)
1 (1.7)
0 (0)
OR (95% CI)
P30L
OR (95% CI)
12
2 (16.7)
0 (0)
1 (8.3)
1 (8.3)
0 (0)
0 (0)
1 (8.3)
1 (8.3)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Data are expressed as number (percentage) unless described otherwise. Severity of the genotype ranges from greatest to least, left to right. The
significant findings are highlighted with bold text.
a
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E558
Falhammar et al
Discussion
This is the first study investigating psychiatric morbidity in
CAH males. We identified a 50% increased risk for any
psychiatric disorder, specifically suicidality and alcohol
misuse. Stratifying by clinical phenotype resulted in significantly increased frequency of substance misuse and
personality disorder among patients with SW phenotype
(Table 2). Stratification by genotype showed an increased
risk for alcohol misuse in the I2splice genotype group (OR,
5.9) and for drug misuse in the I172N genotype group
(OR, 5.3). Clinically, these two groups belong to the SW
and SV clinical groups, respectively. Suicide attempts
among I172N was increased (OR, 4.0), and it could be
speculated that a late diagnosis before the introduction of
neonatal screening could be a reason. Surprisingly, males
with the most severe form of CAH, the null genotype, had
no increased risk of overall psychiatric morbidity (4.9%
compared to 9.8% among controls).
There was an almost double risk for alcohol misuse in
the entire CAH male group compared to controls, and the
reason for this can only be speculated upon. It may be
related to having a chronic disease per se, to impaired
psychosocial situation, or to disturbances in the hypothalamic-pituitary-adrenal-axis. Glucocorticoid treatment in
other conditions may lead to psychiatric complications
directly related to dosage (27). For example, long-term
low-dose prednisolone treatment has been reported to give
a 60% risk of mood and anxiety disorders (29). However,
the lifetime exposure of glucocorticoid oversubstitution is
probably not the reason for the increased rate of psychiatric morbidity found here because the null genotype
group had no increased risk compared to matched controls. This was an unexpected finding. Before the introduction of neonatal screening, the null males could only be
diagnosed upon clinical suspicion, ie, failure to thrive or
salt crisis in the newborn period. Death was inevitable if
they were not diagnosed and treated during the first weeks
of life (4). In contrast, the I2 splice, I172N, and P30L
groups, and especially the NC group were diagnosed laterthe milder the mutation, the higher the risk of a later
diagnosis. In CAH males born after the introduction of
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doi: 10.1210/jc.2013-3707
Acknowledgments
Address all correspondence and requests for reprints to:
Henrik Falhammar, MD, PhD, Department of Endocrinol-
jcem.endojournals.org
E559
ogy, Metabolism, and Diabetes, D02:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail:
henrik.falhammar@ki.se.
This work was supported by grants from the Swedish Research Council (no. 523-2011-3807), the Magnus Bergvalls
Foundation, the Swedish Endocrine Society, the Karolinska Institutet, and the Stockholm County Council. A.B. received financial support from the Mobilnosc Plus project financed by
the Polish Ministry of Science and Higher Education (no.
903/MOB/2012/0).
Disclosure Summary: The authors have nothing to disclose.
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