Klinefelter syndrome and risk of psychosis, autism and ADHD

doi:10.1016/j.jpsychires.2013.10.001

Journal of Psychiatric Research

Volume 48, Issue 1, January 2014, Pages 128-130

https://doi.org/10.1016/j.jpsychires.2013.10.001 Get rights and content

Abstract

Background

Schizophrenia, bipolar disorder, autism spectrum disorders and ADHD might be overrepresented in Klinefelter syndrome, but previous investigations have yielded inconclusive results.

Methods

We compared a national sample of 860 Klinefelter patients in Sweden with 86 000 matched population controls. To assess the risks of schizophrenia, bipolar disorder, autism spectrum disorder and ADHD in Klinefelter patients, we estimated odds ratios and 95% confidence intervals using conditional logistic regressions.

Results

Klinefelter patients had almost four times higher risks of schizophrenia, odds ratio (OR) = 3.6, 95% confidence interval (CI) 2.0–6.7 and bipolar disorder (OR = 3.8, CI 1.8–7.6) and about six times higher risk of autism spectrum disorder (OR = 6.2, CI 4.0–9.4) and ADHD (OR = 5.6, CI 4.0–7.8).

Conclusions

The risk of psychosis, autism and ADHD is increased in Klinefelter patients. These findings indicate an X chromosome-related factor in the etiology of the studied psychiatric disorders, and may also have implications for treatment of patients with Klinefelter syndrome.

Introduction

Klinefelter syndrome is characterized by an extra X chromosome, usually resulting in the 47, XXY karyotype. It is the most common sex chromosome aberration and affects about 1 in 670 men (Bojesen et al., 2003). Previous research suggests that psychiatric disorders might be overrepresented in Klinefelter patients; several case reports describe concurrence with schizophrenia and bipolar disorder (DeLisi et al., 1994). In the same vein, Van Rijn et al. (2006) reported a significantly higher mean level of schizotypal traits among 36 men compared with controls. Further, in 51 boys aged 6–19 years, 12% met diagnostic criteria for a psychotic disorder, 27% had an autism spectrum disorder and 63% had ADHD (Bruining et al., 2009). The risk of psychosis in Klinefelter patients has also been investigated in two studies based on Danish population registers, where the first found no evidence of an increased risk of schizophrenia or bipolar disorder (Mors et al., 2001), whereas the second found a five times higher risk of broadly defined psychosis (Bojesen et al., 2006). Taken together, prior findings suggest that X chromosomal abnormalities may be involved in increased liability to schizophrenia, bipolar disorder, autism spectrum disorders and ADHD, but the status of the associations remain somewhat unclear. We wanted to test the hypothesis that diagnoses of schizophrenia, bipolar disorder, autism spectrum disorders and ADHD are more common among Klinefelter patients in a Swedish population-based setting.

Section snippets

Method

We used the National Patient Register (Ludvigsson et al., 2011) to identify 860 Klinefelter patients coded according to the ICD-10 (1997 and onwards, inpatient or out-patient diagnoses of Q98.0-Q98.2, Q98.4). Individuals with schizophrenia (ICD-8: 295.0–295.6, 295.8, 295.9; ICD-9: 295A–295G, 295W, 295X; ICD-10: F20) and bipolar disorder, defined according to a validated algorithm by Sellgren et al. (2011), were also identified through the National Patient Register. Individuals with autism

Results

The number of individuals with Klinefelter syndrome, schizophrenia, bipolar disorder, autism spectrum disorder and ADHD identified from the Swedish registers are presented in Table 1.

The results from the conditional logistic regressions are shown in Table 2. Individuals with Klinefelter syndrome had 3.6–3.8 times higher risks of having a diagnosis of schizophrenia or bipolar disorder and 5.6–6.2 times higher risks of having autism spectrum disorder or ADHD, compared with controls.

Discussion

We found that Klinefelter patients had a nearly four times higher risk of being diagnosed with schizophrenia and bipolar disorder and an about six times higher risk of autism spectrum disorder and ADHD. These findings are consistent with most prior investigations (DeLisi et al., 1994, Van Rijn et al., 2006, Bojesen et al., 2006, Bruining et al., 2009). Given the relatively high prevalence of Klinefelter syndrome, clinicians should be aware of the possibility of the syndrome in a proportion of

Contributors

MC performed the analyses and wrote the first version of this manuscript. AOG contributed in the write-up of the manuscript. MB wrote the programs that the analyses are based on and HL contributed with issues pertaining to classifications of disorders. ES and NL contributed with valuable comments on the clinical significance of the results and were parts in the write-up of the final version of the manuscript. ML and PL contributed with advices regarding the study design and sampling procedure

Declaration of interest

None.

Funding

None.

References (9)

A. Bojesen et al.
Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study
Journal of Clinical Endocrinology & Metabolism
(2003)
A. Bojesen et al.
Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses
Journal of Clinical Endocrinology & Metabolism
(2006)
H. Bruining et al.
Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome
Pediatrics
(2009)
L.E. DeLisi et al.
Schizophrenia and sex chromosome abnormalities
Schizophrenia Bulletin
(1994)

There are more references available in the full text version of this article.

Cited by (63)

Mentalization and cognitive skills in men with Klinefelter syndrome versus non-clinical controls
2023, Psychiatry Research Communications
We investigated cognition and mentalization skills, defined as the ability to understand one's own and others' intentions and emotions, in men with Klinefelter Syndrome (KS). The sample was 26 men with KS and 26 non-clinical male controls aged 19–65 years. We measured mentalization with the Reading the Mind in the Eyes Test (RMET) and cognition with neuropsychological tests. The results showed that men with KS had significantly lower scores on the RMET compared to controls. However, the group difference was not significant when controlling for IQ. There were more significant correlations between cognitive domains and mentalization skills in the KS group than for controls. In regression models, cognitive domains explained up to 54% of the variance in mentalization skills for men with KS, compared to 15% for controls. The men with KS struggled particularly with interpreting neutral and negative emotional states relative to the control group. We conclude that men with KS exhibit mentalization difficulties, which are strongly linked to their cognitive abilities, and especially their deficits in verbal learning. Interventions aimed at enhancing language and other neuropsychological functions, as well as mentalization skills, are warranted.
Associations of psychiatric disorders with sex chromosome aneuploidies in the Danish iPSYCH2015 dataset: a case-cohort study
2023, The Lancet Psychiatry
Increased prevalence of mental illness has been reported in clinical studies of sex chromosome aneuploidies, but accurate population-based estimates of the prevalence and clinical detection rate of sex chromosome aneuploidies and the associated risks of psychiatric disorders are needed. In this study, we provide such estimates, valid for children and young adults of the contemporary Danish population.
We used the iPSYCH2015 case-cohort dataset, which is based on a source population of single-born individuals born in Denmark between May 1, 1981, and Dec 31, 2008. The case sample comprises all individuals from the source population with a diagnosis of any index psychiatric disorder (schizophrenia spectrum disorder, bipolar disorder, major depressive disorder, autism spectrum disorder, or ADHD) by the end of follow-up (Dec 31, 2015), registered in the hospital-based Danish Psychiatric Central Research Register. The cohort consists of individuals randomly selected from the source population, and overlaps with the case sample. Biobanked blood samples for individuals in the case and cohort samples underwent genotyping and quality-control filtering, after which we analysed microarray data to detect sex chromosome aneuploidy karyotypes (45,X, 47,XXX, 47,XXY, and 47,XYY). We estimated the population-valid prevalence of these karyotypes from the cohort sample. Weighted Cox proportional hazards models were used to estimate the risks of each index psychiatric disorder associated with each sex chromosome aneuploidy karyotype, by use of date of first hospitalisation with the index disorder in the respective case group and the cohort as outcome. The clinical detection rate was determined by comparing records of clinical diagnoses of genetic conditions from the Danish National Patient Register with sex chromosome aneuploidy karyotype determined by our study.
The assessed sample comprised 119 481 individuals (78 726 in the case sample and 43 326 in the cohort) who had genotyped and quality-control-filtered blood samples, including 64 533 (54%) people of gonadal male sex and 54 948 (46%) of gonadal female sex. Age during follow-up ranged from 0 to 34·7 years (mean 10·9 years [SD 3·5 years]). Information on ethnicity was not available. We identified 387 (0·3%) individuals as carriers of sex chromosome aneuploidies. The overall prevalence of sex chromosome aneuploidies was 1·5 per 1000 individuals. Each sex chromosome aneuploidy karyotype was associated with an increased risk of at least one index psychiatric disorder, with hazard ratios (HRs) of 2·20 (95% CI 1·42–3·39) for 47,XXY; 2·73 (1·25–6·00) for 47,XXX; 3·56 (1·01–12·53) for 45,X; and 4·30 (2·48–7·55) for 47,XYY. All karyotypes were associated with an increased risk of ADHD (HRs ranging from 1·99 [1·24–3·19] to 6·15 [1·63–23·19]), autism spectrum disorder (2·72 [1·72–4·32] to 8·45 [2·49–28·61]), and schizophrenia spectrum disorder (1·80 [1·15–2·80] to 4·60 [1·57–13·51]). Increased risk of major depressive disorder was found for individuals with 47,XXY (1·88 [1·07–3·33]) and 47,XYY (2·65 [1·12–5·90]), and of bipolar disorder for those with 47,XXX (4·32 [1·12–16·62]). The proportion of sex chromosome aneuploidy carriers who had been clinically diagnosed was 93% for 45,X, but lower for 47,XXY (22%), 47,XXX (15%), and 47,XYY (15%). Among carriers, the risk of diagnosis of at least one index psychiatric disorder did not significantly differ between those who had and had not been clinically diagnosed with sex chromosome aneuploidies (p=0·65).
Increased risks of psychiatric disorders associated with sex chromosome aneuploidies, combined with low rates of clinical diagnosis of sex chromosome aneuploidies, compromise the adequate provision of necessary health care and counselling to affected individuals and their families, which might be helped by increased application of genetic testing in clinical settings.
Lundbeck Foundation and National Institutes of Health.
Testicular biopsy for fertility preservation in early-diagnosed Klinefelter patients: patient characteristics and long-term follow-up
2022, Reproductive BioMedicine Online
Citation Excerpt :
Most Klinefelter syndrome diagnoses are made during adulthood due to difficulties in conceiving naturally. Earlier diagnosis during childhood is usually made because of cognitive and/or behavioural problems, as these are known to be increased in Klinefelter syndrome patients compared with the general population (Boada et al., 2009; Cederlöf et al., 2014; Skakkebaek et al., 2020). Emotional and/or psychosocial problems like depression, social anxiety and withdrawal, timidity, inappropriate social behaviour and impulsivity are also common for Klinefelter syndrome patients (Bender et al., 1995; Skakkebaek et al., 2020; van Rijn et al., 2008).
Which early-diagnosed Klinefelter syndrome patients have been offered cryopreservation of testicular tissue as part of fertility preservation before spermatogonial stem cell (SSC) loss? Do these Klinefelter syndrome patients present with behavioural, cognitive and/or psychological problems? Does a testicular biopsy procedure have long-term effects on the gonadal development of Klinefelter syndrome patients?
Early-diagnosed Klinefelter syndrome patients followed between 2009 and 2020 and offered testicular tissue banking in an experimental context at the Universitair Ziekenhuis Brussel were included. The prevalence of behavioural, cognitive and/or psychological problems was determined. Changes in testicular volume and in gonadal function (LH, FSH, testosterone and inhibin B [INHB]) were studied.
Of the 48 Klinefelter syndrome patients included, 22 had testicular tissue removed (biopsy group) and 26 had no surgical intervention (control group). The need for specialized education was significantly higher in prenatally (P = 0.0159) and prepubertally (P = 0.0002) diagnosed Klinefelter syndrome patients. Psychological problems were significantly more prevalent in Klinefelter syndrome patients who did not opt for fertility preservation (P = 0.0447). In the first 4.2 (1.9–9.1) years after testicular biopsy, no difference in testicular volume was observed between the biopsied and the contralateral non-biopsied testes (P > 0.9999). After pubertal onset, no differences in LH, FSH, testosterone and INHB were found between the biopsy and the control groups (P = 0.1324 for LH, P > 0.9999 for FSH, P = 0.5433 for testosterone, P > 0.9999 for INHB).
Early-diagnosed Klinefelter syndrome patients presented with behavioural, cognitive and/or psychological problems. Only psychological problems seemed to influence the decision towards fertility preservation. Follow-up data confirm that harvesting testicular tissue does not have a long-term impact on the gonadal development of Klinefelter syndrome patients.
The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder
2021, Neuroscience and Biobehavioral Reviews
Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.
We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.
We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.
Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
Triple X syndrome: Psychiatric disorders and impaired social functioning as a risk factor
2023, European Psychiatry
Diversity and Classification of Genetic Variations in Autism Spectrum Disorder
2023, International Journal of Molecular Sciences

View all citing articles on Scopus

View full text

Klinefelter syndrome and risk of psychosis, autism and ADHD

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Method

Results

Discussion

Contributors

Declaration of interest

Funding

Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study

Journal of Clinical Endocrinology & Metabolism

Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses

Journal of Clinical Endocrinology & Metabolism

Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome

Pediatrics

Schizophrenia and sex chromosome abnormalities

Schizophrenia Bulletin