J C E M

O N L I N E

A d v a n c e s

i n

G e n e t i c s E n d o c r i n e

R e s e a r c h

Increased Psychiatric Morbidity in Men With

Congenital Adrenal Hyperplasia due to 21Hydroxylase Deficiency
Henrik Falhammar, Agnieszka Butwicka, Mikael Landn, Paul Lichtenstein,
Agneta Nordenskjld, Anna Nordenstrm, and Louise Frisn
Department of Endocrinology, Metabolism, and Diabetes (H.F.), Karolinska University Hospital, SE-171
76 Stockholm, Sweden; Departments of Molecular Medicine and Surgery (H.F., An.N.), and Medical
Epidemiology and Biostatistics (A.B., M.L., P.L.), Karolinska Institutet, SE-171 77 Stockholm, Sweden;
Department of Child Psychiatry (A.B.), Medical University of Warsaw, 02-091 Warsaw, Poland; Institute of
Neuroscience and Physiology (M.L.), University of Gothenburg, SE-405 30 Gothenburg, Sweden; Department
of Womens and Childrens Health and Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171
77 Stockholm, Sweden; Departments of Pediatric Surgery (Ag.N.), and Pediatric Endocrinology (An.N.), Astrid
Lindgren Children Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of
Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; and Child and Adolescent
Psychiatry Research Center (L.F.), SE-11330 Stockholm, Sweden

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)

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.
Copyright 2014 by the Endocrine Society
Received October 5, 2013. Accepted November 22, 2013.
First Published Online December 3, 2013

E554

jcem.endojournals.org

Abbreviations: ADHD, attention-deficit hyperactivity disorder; CAH, congenital adrenal

hyperplasia; CI, confidence interval; NC, nonclassic; OR, odds ratio; QoL, quality of life; SV,
simple virilizing; SW, salt-wasting.

J Clin Endocrinol Metab, March 2014, 99(3):E554 E560

doi: 10.1210/jc.2013-3707

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doi: 10.1210/jc.2013-3707

ongenital adrenal hyperplasia (CAH) is an autosomal

recessive disorder that in more than 95% of cases is
caused by 21-hydroxylase deficiency. The enzyme deficiency is characterized by decreased cortisol and aldosterone levels and, at the same time, increased adrenal androgens and steroid precursors (13). If not recognized,
the condition is lethal in severe cases due to salt crisis and
hypoglycemia. Females with classic CAH, ie, the saltwasting (SW) and simple virilizing (SV) phenotype, are
born with virilized external genitalia, whereas male infants have no overt signs of CAH at birth. SV males usually
present with early androgen symptoms at age 2 4 years.
To improve early detection, national neonatal screening
for CAH has been established in many countries. Sweden
introduced CAH screening in 1986, with 1 in 9000 infants
found to be affected (4). Because the neonatal screening
does not accurately detect nonclassic (NC) CAH, data on
the frequency of the NC phenotype are lacking; however,
NC CAH is estimated to be considerably more common,
and some claim it to be one of the most common monogenic disorders (1, 5). Most individuals with NC CAH are
diagnosed, if they are diagnosed at all, due to symptoms
and signs of androgen excess, resulting in more females
being identified. Many NC males are discovered due to
family screening (5). Also, in Sweden most NC males were
not detected by neonatal screening but were diagnosed at
a later age (4).
Lifelong glucocorticoid supplementation is generally
needed for survival in classic CAH. Mineralocorticoids are
often used, especially in the more severe cases. Oral glucocorticoids cannot reproduce the physiological circadian
rhythm of cortisol, and awareness of the long-term risks
has increased during recent decades (13) with reports of
cardiometabolic risk factors (6 14), bone mineral density
(10, 12, 14 17), and fractures (15, 16). In addition, quality of life (QoL) has been shown to be impaired in CAH
(10, 18 21), although a few reports show equal (22, 23)
or better (24) QoL compared to the reference populations.
Mostly, CAH women have been studied. In CAH women,
it has been suggested that genital malformations and corrective surgery can negatively influence long-term QoL
(18, 20, 22, 23, 25, 26), suggesting that males and females
should be analyzed separately. Moreover, in contrast to
males, increased adrenal androgens markedly affect females not only during fetal development but also as adults
(2, 18). Glucocorticoids, when given as a pharmacological
treatment and not only as a substitute, may also result in
psychiatric symptoms or complications ranging from anxiety, insomnia, and behavior disturbances to severe mood
and psychotic disorders, delirium, and dementia, with a
clear relation to dosage (27). Altogether, psychiatric mor-

jcem.endojournals.org

E555

bidity has not been studied systematically in CAH

individuals.
The aims of this study were to investigate psychiatric
disorders in CAH males and to determine whether the
outcomes differed between the phenotypes or the different
CYP21A2 genotypes, as well as before and after the introduction of national neonatal screening.

Subjects and Methods

Subjects
The national registry of CAH individuals (4) was used to
identify 239 CAH males with 21-hydroxylase deficiency clinically, and in most cases they were also genetically verified. Fourteen additional males were identified who had the diagnosis of
CAH at least three times in the National Patient Register (NPR)
using the International Classification of Diseases ICD-8 (255.01,
255.08), ICD-9 (2552, 255C), and ICD-10 (E25.0) and who had
not subsequently been given other diagnoses (ie, Addisons disease, Cushings syndrome, acromegaly) or received glucocorticoid treatment due to malignancies. Thus, 253 males with CAH
were identified.
The cases were divided into subgroups according to the five
most prevalent CYP21A2 mutations: null, I2splice, I172N,
P30L, and V281L. In compound heterozygotes, the mildest mutation defined the genotype group. Null is associated with the SW
phenotype, I2splice is most often associated with the SW phenotype, and I172N typically leads to SV, whereas V281L and
P453S result in NC CAH. P30L results in a phenotype with
severity between SV and NC. CAH males with unknown
CYP21A2 mutations were given a clinical classification (SW, SV,
or NC) if clinical data were available that clearly could be used
for classification. Patients with genetically verified or clinically
diagnosed NC disease were combined and categorized as the NC
group. The data were also stratified between those born before
and after 1986, the year of the introduction of neonatal screening
for CAH in Sweden.
The study was approved by the Ethics Committee of the Karolinska Institutet, Stockholm, Sweden.

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

Psychiatric Morbidity in CAH

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%).

J Clin Endocrinol Metab, March 2014, 99(3):E554 E560

Table 1. Psychiatric Disorders and Suicide or Suicide

Attempt in CAH Males With 21-Hydroxylase Deficiency
Compared With Age- and Sex-Matched Controls (100
Controls per Case)
CAH
Males
n
Any psychiatric
disorders
Suicide or suicide
attempts
Completed suicide
Suicide attempt
Psychotic disorders
Mood disorders
Anxiety disordersa
Personality disorders
Substance misuse
Alcohol
Drugs
ADHD
ASD
Other behavioral
disorders
Intellectual disabilities

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)

2.6 (0.4 18.9)

2.2 (1.0 5.0)
2.1 (0.8 5.8)
1.6 (0.8 3.2)
1.2 (0.6 2.4)
2.7 (0.8 8.5)
1.5 (0.9 2.8)
1.9 (1.0 3.5)
0.9 (0.33.0)
0.4 (0.12.7)
0.6 (0.1 4.3)
1.4 (0.6 3.4)

3 (1.2)

174 (0.7)

1.7 (0.6 5.5)

Abbreviation: ASD, autism spectrum disorders. Data are expressed as

number (percentage) unless described otherwise. The significant
findings are highlighted with bold text.
a

Anxiety, dissociative, stress-related, somatoform, and other

nonpsychotic mental disorders.

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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doi: 10.1210/jc.2013-3707

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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)

1.6 (0.9 to 2.9)

76
9 (11.8)

1.2 (0.6 to 2.4)

19
2 (10.5)

1.1 (0.3 to 5.0)

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)

1.8 (0.4 to 7.3)

0 (0 to 1000)
2.0 (0.7 to 5.5)
0.7 (0.2 to 3.0)
5.1 (1.2 to 21.6)
2.3 (1.0 to 5.4)
3.2 (1.4 to 7.5)
0 (0 to 1000)
0.8 (0.1 to 6.0)
0 (0 to 1000)
1.3 (0.3 to 5.2)

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)

3.1 (0.9 to 10.1)

1.4 (0.2 to 10.5)
1.1 (0.3 to 4.6)
1.5 (0.5 to 4.8)
2.7 (0.4 to 20.4)
1.6 (0.6 to 4.5)
1.4 (0.4 to 4.7)
3.6 (1.1 to 11.9)
0 (0 to 1000)
2.2 (0.3 to 16.1)
0.8 (0.1 to 6.2)

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)

1.4 (0.2 to 10.4)

0 (0)

0 (0 to 1000)

1 (5.3)

5.3 (0.7 to 41.7)

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.

Anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders.

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

genotype groups there was no increase at all (Table 3). Six

of the seven patients (86%) had a psychiatric diagnosis
before the completed or attempted suicide (depression,
n 3; anxiety disorder, n 1; schizophrenia, n 1; other
behavioral disorder, n 1; alcohol misuse, n 2; drug
misuse, n 1; two different psychiatric diagnoses in the
same patient, n 3).
Before and after introduction of neonatal
screening
In CAH males born before the start of neonatal screening (n 127), suicidality (4.7 vs 2.0%; OR, 2.4; 95% CI,
1.15.5) and any psychiatric disorders (19.7 vs 11.7%;

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

0.5 (0.1 to 2.1)

0 (0 to 1000)
0 (0 to 1000)
1.3 (0.2 to 9.9)
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)
1.4 (0.2 to 10.6)
0 (0 to )

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

2.2 (1.1 to 4.6)

1.85 (0.3 to 13.8)
0 (0 to 1000)
2.1 (0.5 to 8.7)
1.6 (0.4 to 6.6)
8.7 (1.1 to 70.1)
4.3 (1.6 to 11.5)
5.9 (2.2 to 15.5)
0 (0 to 1000)
1.7 (0.2 to 12.4)
0 (0 to 1000)
1.2 (0.2 to 9.0)
0 (0 to 1000)

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)

1.2 (0.5 to 2.7)

4.0 (1.2 to 13.5)
0 (0 to 1000)
0.8 (0.1 to 5.9)
2.1 (0.6 to 7.0)
3.2 (0.4 to 23.9)
1.6 (0.5 to 5.3)
1.2 (0.3 to 5.0)
5.3 (1.6 to 17.8)
0 (0 to 1000)
2.9 (0.4 to 21.7)
1.2 (0.2 to 8.8)
0 (0 to 1000)

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)

1.7 (0.4 to 8.0)

0 (0 to 1000)
100 (6.3 to >1000)
5.7 (0.7 to 50.8)
0 (0 to 1000)
0 (0 to 1000)
3.3 (0.4 to 27.9)
4.34 (0.5 to 37.4)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)
0 (0 to 1000)

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

Anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders.

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E558

Falhammar et al

Psychiatric Morbidity in CAH

OR, 1.8; 95% CI, 1.22.9) were significantly increased

compared to controls, whereas personality disorders had
a tendency to be raised (2.4 vs 0.83%; OR, 2.9; 95% CI,
0.9 9.2). In those born after the introduction of screening
(n 126; maximum age, 24), only psychotic disorders
were significantly increased (1.6 vs 0.10%; OR, 17.0;
95% CI, 3.8 77.1), but substance misuse had a tendency
to be raised (4.5 vs 1.8%; OR, 2.6; 95% CI, 0.9 7.3).

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

J Clin Endocrinol Metab, March 2014, 99(3):E554 E560

neonatal screening, no increase in any psychiatric disorder

or suicidality was observed. Thus, the lack of early initiation of glucocorticoids with a prolonged period of increased adrenal androgens and ACTH may be a contributing cause of increased psychiatric morbidity in this
cohort. This could further strengthen the argument for
introducing national neonatal screening in those countries
that still have not implemented screening. However, the
groups before and after the launch of neonatal screening
differ in several aspects as health care has evolved, but
most importantly, patients identified through screening
are much younger.
The male NC group, almost all with the genotype
V281L, and the P30L group had a markedly increased
frequency of psychotic disorders. Even if there was only
one case in each group, they represented half of all CAH
males with psychotic disorders despite only corresponding
to 12% of the total CAH cohort. Most of the patients in
the NC group had probably been diagnosed late due to
clinical signs or due to family screening because the Swedish national neonatal screening is not designed to detect
these patients (4). NC CAH causes no or mild cortisol
insufficiency but increased adrenal androgens resulting in
growth acceleration and pseudopubertas precox in childhood or infertility or cystic acne in adults; however, many
patients are claimed to be asymptomatic (1, 3, 5). They
also have slightly raised ACTH if not treated with glucocorticoids, which are used only if the patients are symptomatic. Whether it is the increased adrenal androgens and
ACTH, the decreased adrenal androgens and ACTH ensuing treatment with glucocorticoids (6, 16), glucocorticoids per se, or some other factors that are responsible for
the increased prevalence of psychotic disorders is
unknown.
The risk for neurodevelopmental disorders such as
ADHD and autism spectrum disorders was decreased
(0.4% compared to 1.1 and 0.7%, respectively, among
controls). Although this did not reach significance, it does
not support the hypothesis that fetal T exposure is involved in the pathogenesis of ADHD and autism spectrum
disorders (30). However, increased adrenal androgens
may inhibit the secretion of gonadotropins, giving slightly
decreased T. This has been observed at least in adult CAH
males (31).
Much of what we know about androgen effects on
brain development and behavior has been derived from
studies of CAH females. Gender-related behaviors such as
toy play, activity level, career choices, and sexual orientation are associated with the severity of CAH, ie, the
degree of prenatal androgen exposure (18, 32, 33). However, this does not apply to males; hence, males and females should be analyzed separately, and other causes for

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doi: 10.1210/jc.2013-3707

the increased psychiatric morbidity have to be sought.

Having a congenital disorder could be one, but this would
not explain the differences between the genotypes and between patients diagnosed with or without neonatal
screening.
In CAH women, poor long-term QoL (18, 20, 22, 23,
25, 26) and increased rate of depressive symptoms (20)
have often been attributed to genital malformations and
corrective surgery. However, Arlt et al (10) reported that
adult CAH men and women both had decreased QoL and
more depressive symptoms. This study and the present
data lend themselves to an alternative interpretation: that
glucocorticoid supplementation, late diagnosis, and/or
the CYP21A2 mutations per se contribute to poor QoL
and depressive symptoms in CAH females, and not the
surgical treatment. However, this has to be investigated in
future studies.
The major limitations of this study are that all outcome
data were derived from national registries, and the number
of patients with a psychiatric diagnosis was limited. Moreover, the CAH males are subject to the attention of the
health care system to a greater extent than controls, which
may increase the probability of detecting a psychiatric
condition. However, a smaller proportion of CAH patients with a psychiatric diagnosis received it before 18
years of age compared to controls, which does not point in
this direction. A prerequisite to obtain approval by the
Ethics Committee was that all included individuals were
anonymized to protect the integrity of the included individuals. Therefore, analyzing results on an individual level
and comparing results with medical files is not possible.
Furthermore, the ICD coding may be inadequate. On the
other hand, psychiatric ICD codes have been validated in
Sweden, eg, in bipolar disorders (34). An additional
strength is the unique national registry of CAH individuals
covering almost all CAH patients diagnosed in Sweden,
with most registered patients being both geno- and
phenotyped.
In summary, increased psychiatric morbidity including
drug or alcohol abuse as well as suicidality was identified
among the 253 CAH males when compared to 25 300
age-matched controls. The psychiatric morbidities were
not elevated in the most severely affected CAH group (the
null genotype). Late diagnosis of CAH may explain some
of the findings. Patients born before the introduction of
neonatal screening seemed more affected, but this may be
explained by the higher age in that cohort.

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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