J C E M
O N L I N E
A d v a n c e s
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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 Landén, Paul Lichtenstein, Agneta Nordenskjöld, Anna Nordenström, and Louise Frisén 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 Women’s and Children’s 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, 1.1–2.2, 1.1–5.0, 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
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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 (1–3). 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 (1–3) 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-
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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, Addison’s disease, Cushing’s 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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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, 297–299; 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 312–313; 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 ⱖ1986). 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, 0.7–57); 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 (1.1–2.2) 7 (2.8)
309 (1.2)
2.3 (1.1–5.0)
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 (0.3–3.0) 0.4 (0.1–2.7) 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, 1.3–14.3) 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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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.
b
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, 1.1–5.5) 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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OR, 1.8; 95% CI, 1.2–2.9) 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 later—the milder the mutation, the higher the risk of a later diagnosis. In CAH males born after the introduction of
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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-
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ogy, Metabolism, and Diabetes, D02:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: [email protected]. 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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O N L I N E
A d v a n c e s
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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 Landén, Paul Lichtenstein, Agneta Nordenskjöld, Anna Nordenström, and Louise Frisén 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 Women’s and Children’s 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, 1.1–2.2, 1.1–5.0, 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
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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.
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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 (1–3). 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 (1–3) 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-
C
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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, Addison’s disease, Cushing’s 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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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, 297–299; 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 312–313; 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 ⱖ1986). 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, 0.7–57); 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%).
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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 (1.1–2.2) 7 (2.8)
309 (1.2)
2.3 (1.1–5.0)
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 (0.3–3.0) 0.4 (0.1–2.7) 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, 1.3–14.3) and tendencies to increased risks of other anxiety disorders in all
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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.
b
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, 1.1–5.5) 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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OR, 1.8; 95% CI, 1.2–2.9) 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 later—the 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
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ogy, Metabolism, and Diabetes, D02:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: [email protected]. 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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