Downloaded from http://journals.lww.com/jonmd by BhDMf5ePHKbH4TTImqenVDiEotxSR1UH0aQm8ky4rg7zREmh/lFuUzSuerJlWhamIWs0uyNW0Jo= on 01/28/2019 Sexual Identity Disorder and Psychosis in Klinefelter Syndrome A Synthesis of Literature and a Case Report Aude Maillefer, MD,* Michel Sabe, MD,* Christophe Coste, MD,* Javier Bartolomei, MD,* Jaafar Jaafar, MD,† and Othman Sentissi, MD, PhD* Abstract: Klinefelter syndrome (KS) 47, XXY is the most frequent chromo- somal abnormality causing hypogonadism in humans. This chromosomal abnor- mality of number in its classical form called homogeneous (supernumerary X) is generally the result of a meiosis accident. Several studies have suggested that in- dividuals with KS are at greater risk of developing various psychiatric disorders, including depression and schizophrenia. The diagnosis is made based on subnor- mal testosterone with high pituitary gonadotropins and confirmed by determining the karyotype on a blood simple. We did a literature review using an electronic search in three databases: Pubmed/MEDLINE, Google Scholar, and PsychInfo. We found that since 1989, seven case reports with KS and mental disorders with similar and different characteristics of our case illustration of a patient with KS and psychosis were published. Key Words: Klinefelter syndrome, psychosis, sexual identity (J Nerv Ment Dis 2019;207: 121–125) K linefelter syndrome (KS) is the most frequent abnormality in sex chromosome in males (47, XXYor other mosaic karyotypes) with a frequency of 1 of 500–1000 and affects 1 in 600 male newborns (Lanfranco et al., 2004). This chromosomal abnormality of number in its classical form called homogeneous (supernumerary X) is generally the result of a meiosis accident. Its incidence increases with maternal age and has several clinical variants (Young Joo et al., 2013). Individuals with the XXY karyotype can present hypergonadotropic hypogonadism from puberty. They show a singular clinical picture, described in 1942 by Klinefelter et al. (1942), with pubertal delay, hypogonadism, small tes- tes, infertility, great stature, gynecomastia, taurodontism, and learning difficulties without systematic intellectual deficit (Groth et al. 2013). When KS is suspected clinically, diagnosis is made based on low or low normal testosterone with invariably high luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and it is confirmed by performing a karyotype on a blood simple. As early as puberty, with increased fre- quency compared with the general population, there are social, psycho- logical, and even psychiatric manifestations (Cederlöf et al., 2014). In addition, hypogonadal men tend to experience depression, anxiety, and decreased quality of life (Wang et al., 2004). Several studies have sug- gested that individuals with KS are at greater risk of developing various psychiatric disorders, including depression and schizophrenia (Bojesen et al., 2006) and, to a lesser extent, bipolar disorder, attention deficit hy- peractivity disorder, and autism (Boks et al., 2007, Bruining et al., 2009). The clinical features depend on both the supernumerary X chro- mosome and hypogonadism effects (Bonomi et al., 2017; Visootsak and Graham, 2006), but still the etiopathogenic mechanism is not known and the current state of research does not allow concluding the influence of the X chromosome, or hypogonadism, in the development of psychiatric disorders. Some authors described a classical clinical phenotype of men with KS, but still other clinical features that consist of a poor clinical picture exist (Simpson et al., 2003). Authors suggest that the phenotype is linked to the severity of the expression of the ge- netic defect, affecting androgen receptor sensitivity (Samplaski et al., 2014; Zitzmann et al., 2004). In addition, intelligence quotient seems to decrease with each extra X chromosome (Linden et al., 1995). However, Barlow in 1973 suggests that the supernumerary X slightly prolongs the time of cellular mitosis and reduces its rate of di- vision. This could eventually disrupt neurogenesis of XXY patients who have magnetic resonance imaging (MRI)–visible brain abnormal- ities (lower total cerebral volume than the general population, enlarged lateral ventricles, reduced volume of the upper temporal gyrus, hippo- campus, amygdala, insula, and cingulate gyrus) (Shen et al., 2004). Anomalies of the gray and white matter with neuropsychological reper- cussions are also found (Skakkebæk et al., 2014). Supernumerary X is hypothesized to be involved in the process of developing schizophrenic disorders as a cognitive and neuroanatomic expression of a genetic pre- disposition (Van Rijn et al., 2006). However, more research is needed to unravel symptoms due to androgen deficiency versus chromosomal ab- normalities to clarify benefits of testosterone replacement therapy (Groth et al., 2013). As for the genotype features, supernumerary X chromosome origin has been associated with phenotypic differences, although actual findings are not conclusive (Chang et al., 2015b). Whereas cases of the association of KS and psychosis have been published in the literature (see flowchart in Fig. 1), this is the first study to highlight and to discuss the pathogenesis of the sexual identity of these patients. METHODS We searched three electronic databases: Pubmed/MEDLINE Google Scholar and PsychInfo; we investigated the relationship be- tween psychosis and KS in the Pubmed/MEDLINE database, from in- ception to June 2017. We used the terms “Psychosis” [All Fields] AND “Klinefelter syndrome, OR 47XXY” [All Fields] AND “Sexual iden- tity. ” Articles published in English were reviewed. We found that since 1989 (review of case reports; Mizukami et al., 1989), there were seven new case reports with KS and mental disorders that examine the re- lationship between schizophrenia, psychosis, and KS (Fig. 1 and Table 1). In this paper, we aimed to point the disturbance of sexual identity in this association. CASE ILLUSTRATION We describe the clinical case of a patient with KS and psychotic decompensation: a 45-year-old Caucasian, single, and childless patient. The patient is the eldest of three siblings, including a 41-year-old brother and a 44-year-old sister. Their parents, retired, have settled in the same city for a long time. On the affective level, he is currently sin- gle and he reports a sentimental relationship with a woman between the ages of 23 and 33 years. He also mentions some ephemeral relation- ships with men. On the professional side, the patient trained and worked in mar- keting, and then stopped 3 years ago. Since then, he has been unem- ployed and is currently working independently. *Clinique Belle Idée, Department of Mental Health and Psychiatry, and †Endocrinology Unit, Medicine Department, University Hospital of Geneva, Geneva, Switzerland. Send reprint requests to Othman Sentissi, MD, PhD, Department of Mental Health and Psychiatry, University Hospital of Geneva, Cappi Jonction, 35 Rue des Bains, 1205 Geneva, Switzerland. E‐mail: o.sentissi@hcuge.ch. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0022-3018/19/20702–0121 DOI: 10.1097/NMD.0000000000000930 BRIEF REPORT The Journal of Nervous and Mental Disease • Volume 207, Number 2, February 2019 www.jonmd.com 121 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.