A case of Klinefelter syndrome presenting with an acute psychotic episode after COVID‐19 infection

Abstract

Background

Klinefelter syndrome (KS) is a disease caused by a 47, XXY sex chromosome abnormality. It has been reported that KS not only causes physical problems but also confers the risk of developing psychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder.

Case Presentation

Here we present a case of an 18‐year‐old male with complete KS who developed an acute psychotic episode after COVID‐19 infection. The patient presented a catatonic state with stupor, rejection of others, and hallucinations that led him to self‐injury. Psychotic symptoms improved in about 2 months with an antipsychotic, aripiprazole.

Conclusion

To our knowledge, this is the first report of a KS patient who acutely developed a psychotic disorder after COVID‐19. Vulnerability to psychotic conditions of KS likely manifests as an acute psychotic episode facilitated by the neurotropic effects of COVID‐19.

BACKGROUND

Klinefelter syndrome (KS) is a sex chromosome disorder with a 47, XXY karyotype, initially described by Klinefelter et al. in 1942, ¹ affecting approximately 1 in 500 live births. ² Clinically, KS is characterized by gynecomastia, small testes, azoospermia, and hypergonadotropinemia. KS is associated not only with endocrinological abnormalities but also with psychiatric disorders. For example, a population‐based study in Sweden examining 860 KS patients and 86,000 controls reported an elevated risk of developing schizophrenia (odds ratio [OR] = 3.6), bipolar disorder (OR = 3.8), autism spectrum disorder (OR = 6.2), and attention‐deficit hyperactivity disorder (OR = 5.6). ³

Coronavirus disease 2019 (COVID‐19) was first reported in Wuhan, China, in 2019. ⁴ The pathogen, SARS‐CoV‐2, invades human bodies through the respiratory epithelium via the angiotensin‐converting enzyme 2 receptor, ⁵ , ⁶ causing symptoms such as fever, respiratory symptoms, and fatigue. ⁷ Furthermore, SARS‐CoV‐2 exhibits a neurotropic feature, allowing it to reach the central nervous system via the olfactory and vagus nerves, which can lead to neuropsychiatric comorbidities and consequences. ⁸ Here we report a case of KS who presented with an acute psychotic episode after COVID‐19 infection. We discuss the pathological relationship between psychiatric vulnerability in KS and psychiatric symptoms after SARS‐CoV‐2 infection. The patient gave verbal and written informed consent for the publication of this case report.

CASE PRESENTATION

The patient was an 18‐year‐old male, born to relatively elderly parents (both 48 years old). The family history of psychiatric illnesses was that his father had bipolar disorder, and the older brother had long been absent from junior high school without a particular psychiatric diagnosis. KS was diagnosed by prenatal amniocentesis and explained to the parents. However, the patient was fostered without being informed of the diagnosis. The patient had difficulty communicating with peers since childhood and often threw tantrums when frustrated. Low academic grades and bullying‐victim experiences led him to stop attending classes from the fourth grade of elementary school through junior high school. Meanwhile, he spent his days playing computer games and drawing pictures at home. He later enrolled in a part‐time high school, regained regular commuting, and achieved graduation. In April 2024, he entered an art vocational school.

He was having trouble communicating with his new classmates and felt isolated. Further, from mid‐May 2024, the patient was under psychological pressure while preparing for the vocational school recital of the student's artwork. On May X 2024, the patient developed cold‐like symptoms, including a sore throat and fever, and was diagnosed with COVID‐19 based on an antigen test.

Although these symptoms subsided within a week, he acutely developed neuropsychiatric signs: visual hallucination, auditory hallucinations that forced him to strangle himself, incoherent muttering, disorganized behavior such as shaking, tremor, and whole body stiffness, and strangling himself when instructed by someone. His communication also deteriorated. He had few conversations and responses, staring fixedly at one spot. He refused to eat meals, drink, or take medications. The patient was referred to our psychiatric clinic 11 days after contracting COVID‐19 and was admitted to the psychiatric ward.

On admission, his height was 155.8 cm, and his weight was 47.5 kg. Vital signs were as follows: body temperature 37.4°C, blood pressure 123/92 mmHg, heart rate 120 beats/min, respiratory rate 28 times/min, and oxygen saturation 97% on room air. He denied any history of smoking, alcohol consumption, or illegal drug use. He seemed polite and maintained his orientation to time and place. However, he appeared confused and was unable to answer complex questions. He was hypersensitive to sound and light. During the examination, his whole body became tense, and he repeatedly tried to strangle himself with his hands. It was impossible to assess the severity of schizophrenia related symptoms, using the Brief Psychiatric Rating Scale (BPRS). ⁹

Blood tests showed normal blood counts and no abnormal findings in immunological panels. Endocrine tests, however, showed markedly elevated luteinizing hormone and follicle‐stimulating hormone; while testosterone, estradiol, and prolactin remained within the normal range, listed in Table 1. A consulted urologist found bilateral dwarf testicles (6 cc/6 cc < adult average 22 cc) without gynecomastia. The patient was able to achieve erections and ejaculate. In a semen analysis, the semen was nearly transparent, and no sperm were found. An electrocardiogram, chest and abdominal x‐rays, and brain magnetic resonance imaging (MRI) revealed no abnormal findings. An electroencephalogram showed no signs of impaired consciousness or epileptiform activities. After the following course of hospitalization, when the psychotic symptoms had sufficiently disappeared, we administered the Wechsler Adult Intelligence Scale‐Fourth Edition (WAIS‐IV) ¹⁰ ; the score showed a borderline full‐scale intellectual quotient (IQ) of 71 (subscales: verbal comprehension 79, perceptual reasoning 78, working memory 74, and processing speed 75). Chromosome analysis revealed 47, XXY chromosomal abnormalities in all 20 cells analyzed, listed in Figure 1 (i.e., complete type of KS).

Table 1.

Endocrine tests.

Parameters	Patient values	Reference ranges
Luteinizing hormone	28.9 mIU/mL	2.2–8.4
Follicle‐stimulating hormone	46.4 mIU/mL	1.8–12.0
Testosterone	372.6 ng/dL	142.4–923.1
Estradiol	33.8 pg/mL	14.6–48.8
Prolactin	7.9 ng/mL	4.3–13.7

Figure 1.

Diagram of human chromosomes.

At the time of admission, olanzapine 5 mg was initially administered, followed by paliperidone 3 mg (both in daily oral doses), but both were discontinued due to elevation of liver enzymes and prolactin levels. On Day 14, aripiprazole was administered and gradually increased from 3 to 15 mg. Aripiprazole was effective, and the patient recovered from various symptoms; he outgrew catatonic states such as rejection and stupor, and self‐injurious behavior became compliant with taking medication. His appetite was restored, and he began to eat and drink enough water. Parallel to these clinical recoveries, there was improvement in objective measures of psychotic symptoms. The BPRS score on Day 21 was 70, in the severely ill range, while it decreased to 37 on Day 50, in the moderately ill range. The patient was discharged on Day 107. In admission, psychotic symptoms, including delusions, hallucinations, behavioral disintegration, catatonic behavior, and negative symptoms, had been observed for approximately 2 months. According to DSM‐5‐TR, from the perspective of the duration of symptoms, the diagnosis at admission was schizophreniform disorder; to be revised to schizophrenia after discharge. In the outpatient treatment period, his functioning gradually recovered. Although he dropped out of the vocational school, he started a part‐time job 6 months after his discharge. We obtained consent for the disclosure of diagnosis from the patient and informed them of the KS diagnosis. He accepted this calmly and did not experience a relapse into the psychiatric symptoms.

DISCUSSION

We described a young male with KS who developed an acute psychotic state soon after contracting COVID‐19. Physical examination revealed hypogonadism with dwarf testes and endocrine abnormalities such as high levels of follicle‐stimulating hormone. In addition to the patient's borderline intelligence and autistic spectrum traits, he experienced a sudden onset of hallucinations, delusions, conceptual disintegration, disorganized behaviors, and a catatonic state. Aripiprazole produced clinical recovery within 2 months, and social recovery after that. To our knowledge, there have been no reports of a patient with KS who developed a psychotic episode after contracting COVID‐19.

Because of the COVID‐19 neurotropic nature, cognitive and psychiatric symptoms can emerge not only during the acute illness phase but also in the recovery phase. Post‐COVID‐19 condition (“long COVID”) is defined as symptoms that persist or newly appear at least 3 months after the initial SARS‐CoV‐2 infection and continue for 2 months or longer without another explanation, and the World Health Organization estimates that about 10%–20% of infected individuals develop long COVID. ¹¹ A meta‐analysis (comprising 17 studies, N = 41,249 individuals with long COVID) reported a comorbidity rate of 20.4% for impaired cognition (commonly described as “brain fog”) and mental illness conditions. ¹² A retrospective cohort study of 236,379 COVID‐19 survivors found that 33% received a neuropsychiatric diagnosis within 6 months, although psychotic disorders occurred in only 1.4% of the patients, and the proportion of newly diagnosed cases was 0.42%. ¹³ Further, a meta‐analysis of 36 studies identified cognitive impairment, anxiety, and depression as the most frequent neuropsychiatric features of long COVID, while psychosis was rarely reported. ¹⁴ Together, the emergence of acute psychotic disorder after COVID‐19 is very rare. In this case, psychotic symptoms might have presented as an organic psychosis secondary to COVID‐19. However, the possibility was considered unlikely, since no abnormal findings were revealed on electroencephalography or MRI of the brain.

A recent Spanish cohort study reported that aripiprazole significantly decreased the risk of death from COVID‐19 (OR = 0.86). ¹⁵ Therefore, aripiprazole might have been a beneficial treatment option in this case, not only for managing psychotic symptoms as an atypical antipsychotic but also for its potential protective effects against COVID‐19. Another possible pharmacotherapy option could have been high‐dose benzodiazepine administration, which focuses on the patient's catatonic symptoms, and it carries the equivalent level of recommendation as an appropriate dosage of antipsychotics in the Guideline for Pharmacological Therapy of Schizophrenia, 2022.

In a Swedish cohort study comparing 860 KS patients with 86,000 controls, KS patients are at higher risk for schizophrenia (OR = 3.6), bipolar disorder (OR = 3.8), autism spectrum disorder (OR = 6.2), and attention‐deficit hyperactivity disorder (OR = 5.6). ³ On the other hand, Kunugi et al. reported that the incidence of KS in patients with schizophrenia was 1.6% (two individuals among 122 Japanese male schizophrenics), which demonstrated a possibly high rate of KS in schizophrenia patients, ¹⁶ compared to that in the general population, that is, approximately 1 in 500 males. ²

KS patients are characterized by smaller gray and white matter volumes throughout the whole brain compared to healthy individuals, particularly in the insular cortex, putamen, caudate nucleus, hippocampus, amygdala, right parahippocampal gyrus, cerebellum, temporal lobe, and inferior orbitofrontal cortex. ¹⁷ In contrast, they often have enlarged gray‐matter volumes in the right postcentral gyrus, precuneus, parietal lobe, sensorimotor cortex, occipital lobe, and enlarged lateral ventricles. ¹⁷ These neurostructural abnormalities are thought to contribute to the cognitive, emotional, and psychosocial difficulties, including comorbid psychiatric disorders. ¹⁷ Structured brain damage has also been reported after SARS‐CoV‐2 infection. A UK Biobank study of 785 participants (401 post‐COVID‐19, 384 controls) reported that individuals infected with COVID‐19 showed global brain volume reduction, including reduced gray matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus. ¹⁸ They also noted microstructural damage in regions functionally connected to the primary olfactory cortex. ¹⁸ Similarly, people with first‐episode of schizophrenia have an increased lateral ventricular volume and show a slight decrease in cortical volume (2%) with greater decrements (about 5%) in the hippocampus, amygdala, and thalamus. ¹⁹ Although the brain MRI revealed no overt abnormality in the present case, it is possible that there are subtle neurodevelopmental anomalies attributed to KS and additional changes due to COVID‐19.

Finally, it is of note that the patient was under a stressful condition (i.e., preparing for a vocational school recital), which also facilitated the development of the acute psychosis.

CONCLUSIONS

We report a case of KS who developed an acute psychotic episode after contracting COVID‐19. It is rare to develop a psychotic disorder after COVID‐19. It is thought that vulnerability for the psychotic episode can be attributable, at least in part, to KS and associated psychiatric impairments such as borderline IQ and autistic spectrum traits.

Since COVID‐19 has a neurotropic nature, it may also have contributed to the development of the psychotic episode. The combined effects of KS and COVID‐19 in the brain may have resulted in the acute psychotic episode observed in our case.

AUTHOR CONTRIBUTIONS

Ryosuke Fujii and Hiroshi Kunugi contributed to the concept and design of the study. Ryosuke Fujii drafted the manuscript. Sho Kanata, Yukako Watanabe, and Hiroshi Kunugi critically reviewed the manuscript for important intellectual content. Hiroshi Kunugi supervised the overall study. All authors contributed to the acquisition, analysis, and interpretation of data, reviewed the final version of the manuscript to be published, and agreed to be accountable for all aspects of the work.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS APPROVAL STATEMENT

N/A.

PATIENT CONSENT STATEMENT

Consent for open access publication was obtained for the present case.

CLINICAL TRIAL REGISTRATION

N/A.

Fujii R, Kanata S, Watanabe Y, Kunugi H. A case of Klinefelter syndrome presenting with an acute psychotic episode after COVID‐19 infection. Psychiatry Clin Neurosci Rep. 2025;4:e70262. 10.1002/pcn5.70262

DATA AVAILABILITY STATEMENT

N/A.