Hong Kong J Psychiatry 2006;16:117-20


Androgen Insensitivity Syndrome and Schizophrenia - a Case Report


KL Lee, SSM Chan


Dr KL Lee, MBChB, Department of Orthopaedics and Traumatology, Prince of Wales Hospital, New Territories, Hong Kong, China.
Dr SSM Chan, MBChB, MRCPsych, FHKAM (Psychiatry), FHKCPsych, Department of Psychiatry, The Chinese University of Hong Kong, New Territories, Hong Kong, China.

Address for correspondence: Dr KL Lee, G/F, Department of Psychiatry, Multicentre, Tai Po Hospital, 9 Chuen On Road, Tai, Po, New Territories, Hong Kong, China.
Tel: (852) 2607 6025; Fax: (852) 2667 1255; E-mail: leekalok2009@yahoo.com.hk

Submitted: 15 November 2006; Accepted: 15 January 2007

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Schizophrenia is equally prevalent in males and females but presents with different clinical course. Gender or sex chromosomes may be aetiologically related to schizophrenia. Genetic studies of schizophrenia have neither excluded nor supported linkage with X chromosome markers. We report a case of a schizophrenic patient with concurrent androgen insensitivity syndrome, which is an X-linked recessive disease. Her biological sister also has both androgen insensitivity syndrome and a psychotic disorder. The possible role of an X chromosome linkage in the aetiology of schizophrenia is discussed.

Key words: Androgeninsensitivity syndrome; Feminization; Schizophrenia; Testosterone; X Chromosome





Schizophrenia is a complex disease with multiple contributing genes and a complex interaction with environmental factors. The genetic defects seen in schizophrenia are multiple, non-specific, and inconsistent across different studies.1-3 Studies of schizophrenia have neither excluded nor supported linkages with X chromosome markers. This paper gives the clinical history of a Chinese patient in Hong Kong who suffers from both schizophrenia and androgen insensitivity syndrome (AIS), the latter being an X-linked recessive disease.

Clinical History

History of Presenting Complaints

A 49-year-old, reclusive, unmarried woman first presented to the mental health service in Hong Kong in August 2006. She was referred by a social worker to the community psychiatric team for violent behaviour towards neighbours and a long-standing state of poor hygiene. Compulsory admission under the Mental Health Ordinance Section of the Hong Kong Special Administrative Region, Caption 136 was applied for her first admission to a regional psychiatric unit.

According to the patient’s siblings, she had become socially withdrawn at least 10 years earlier. She was self- absorbed, with frequent muttering and giggling when on her own. Apart from her anti-sociability, she always felt she was being spied on and believed that people had broken into her home and stolen her things. She locked her doors with 5 to 6 chains and locks. She also refused to renew her Hong Kong Identity Card as she was convinced there were hidden political motives behind the smart ID card campaign. After her mother died 2 years ago, she led a life of extreme squalor. For instance, she filled her two-bedroom apartment with hoarded garbage and refused to take showers for months. The electricity supply to her house was suspended as she had refused to pay the bills and from then on she simply survived in the dark. To her neighbours, she was a quiet woman who wandered alone in the neighbourhood collecting stuff, not attracting much attention with any disinhibited behaviour. Shortly before her index admission, the patient was frustrated by noise caused by her neighbours’ renovation work. She confronted those neighbours she blamed for the nuisance with a wooden log. A regional community psychiatric team was notified of her situation and, after an initial assessment, a psychiatric admission was arranged.

Medical History

The patient consulted a gynaecologist for primary amenorrhoea when she was 18 years old and was found to have absent ovaries and fallopian tubes and intra-abdominal testes. She was diagnosed with testicular feminisation, or AIS, and both testes were removed to prevent testicular malignancy. She was initially given hormone replacement therapy but failed to attend medical follow-up and ceased hormonal treatment altogether in her 20s. Neither the patient nor her family received any genetic counselling.

Personal History

The patient was born in Hong Kong and reached all the normal developmental milestones. She had a happy childhood but had to leave school after Primary 2 because her family had financial difficulties. She did not have a marked change of personality after being diagnosed with testicular feminisation. She worked in factories and later as a waitress in a Chinese restaurant until she lost her job 10 years ago. She had several relationships but she refused to elaborate on whether there had been any sexual difficulties and how her ex-boyfriends reacted to her hormonal illness. After losing her job she became socially isolated and lived with her mother until the latter died 2 years ago. Financially, she subsisted on the government social security scheme. She had no forensic record.

Family History (Refer to Genogram)

The patient’s mother died 2 years earlier from a pulmonary embolism. Her father died of carcinoma of the colon when she was 18 years old. Both parents had no mental illnesses. There were 8 children in the family (including the patient). An elder, married sister also has AIS. This sister was also diagnosed with paranoid schizophrenia 2 years ago and has been receiving treatment from a private psychiatrist. One of the patient’s maternal aunts developed late-onset psychotic illness after the death of her son. There was no information on the prevalence of AIS in second-degree relatives on the maternal side.

Premorbid Personality

The patient was a sociable person who made friends easily. There was no evidence suggestive of paranoid or obsessional personality traits. She had no religious affiliations.

Mental State Examination on Admission

The patient was a medium-built woman in a pink dress with grey, dry, uncombed, long hair. Although she had refined facial features and a fair complexion, she looked much older than her chronological age. Since she had not washed for quite a while, she had an unpleasant body smell and a thick layer of sludge on her skin. She exhibited no psychomotor abnormalities. She was guarded but cooperative in general. Her speech was grossly relevant and coherent with a normal tempo and volume. She argued against her compulsory admission logically and fluently. Her mood was neutral and affect was congruent and reactive. There was no perceptual disturbance and she was evasive about her other psychotic symptoms. She had poor insight into her mental disturbance and self-neglect. She kept asking for discharge during the interview as she claimed that she did not have any health problems. She acknowledged her hormonal problem and superficially endorsed the genetic basis of her problem. She did not volunteer any thoughts about her ‘gender identity’ and was unconcerned about her hormonal problem.

Cognitive Profile

The patient scored 25 out of 30 on the Cantonese version of the Mini-Mental State Examination4 with scores taken off for the serial-7 test. Her autobiographical memory and recent long-term memory were well preserved. She scored 15 on the Chinese version of the Executive Interview (EXIT25),5 which hit the cut-off score of 15 recommended by the English version of EXIT25 as a screen for dementia. In the Modified Wisconsin Card Sorting Test, she could achieve 3 categories promptly and 17% of her total errors were perseverative errors.6 An intelligence quotient (IQ) test showed that the patient was intellectually normal.

Results of Physical Examination and Investigations

Systemic examinations were all normal. There was no sign of dehydration or malnutrition. All female secondary sexual characteristics were present except that she had sparse body hair. A baseline full blood count, renal, liver and thyroid function tests were all normal. Her serum oestrogen was on the low side of a normal postmenopausal level. Testosterone, dehydroepiandrosterone sulphate and 17-hydroxylase were on the low side of normal (possibly due to the removal of both testes, leaving only the adrenal cortex as the major site of hormonal production). Computed tomography of the brain and an electroencephalography were normal. The patient and her family refused to have genetic counselling and no genetic linkage studies were performed.

Progress since Admission

The patient was noted to be quiet, asocial, muttering while wandering on her own. She spoke coherently and relevantly on casual encounters. She complied with all nursing managements and displayed no hoarding behaviour, social disinhibition or forced utilisation behaviour. She was essentially independent in all areas of basic physical self-maintenance with minimal prompting by nursing staff. She had no fluctuating consciousness or episodes of disorientation. Little change to her mental state occurred after she was put on low-dose oral sulpiride and oestrogen. Her engagement with occupational and domestic skill training sessions was minimal initially but this gradually improved.

Clinical Summary

The patient, a 49-year-old, single, reclusive, unemployed ‘woman in phenotype’ with a history of AIS, presented with hoarding behaviours and self-neglect on a background of long-standing untreated non-bizarre paranoid delusions. She had good premorbid functioning, an intact premorbid personality, a strong family history of both psychotic disorders and testicular feminisation. Her global social function had been declining over the past 10 years but there were no definite clinical features suggestive of dementia.


This patient suffers from male pseudohermaphroditism, a condition in which affected individuals have a 46,XY karyotype, normal testes, and abnormal genitalia, ranging from completely female to slightly feminised external genitalia with hypospadias and cryptorchidism. In view of her total absence of body hair, completely female external genitalia and hormonal profile, the most likely form of male pseudohermaphroditism in this patient is AIS, formerly known as testicular feminisation. The incidence of AIS in Chinese populations is not known but the best available data, from a Danish registry, give an estimated incidence of about 1 case per 20,400 live births. Androgen insensitivity syndrome is associated with gender identity disorder, depression, anxiety, mental retardation, and even anorexia nervosa but has rarely been linked to schizophrenia.

The absence of any organic disorder and her normal IQ make paranoid schizophrenia the most likely diagnosis in this patient. Her presentation could have been explained by mental retardation, which is commonly associated with AIS, but her normal IQ score ruled this out. For these reasons she was treated with antipsychotics for the schizophrenia but was also given hormone replacement therapy because hormones like oestrogen and testosterone have an effect on behaviour, mood, and cognition.7-11 We expected that this patient, having a deficiency of both male and female hormones, would suffer from marked cognitive impairment; however, the mental state assessment did not bear this out. Nevertheless, it was reasoned that hormonal replacement therapy should have a positive effect on the patient’s mood and behaviour.

In this case, it is possible that this patient’s AIS is linked to her schizophrenia. At a pathological level, patients with AIS usually have a complete absence of androgenic response and limited oestrogen (converted from androgen), especially after removal of the testes. Currently, there is no literature on the possible schizophrenia-enhancing or protecting role of androgen.12 Androgen predisposes to motor activity, impulsivity and risk taking, which in turn provoke a series of biological or psychosocial sequelae, resulting in males having earlier onset and relatively more severe schizophrenia. The deficiency of sex hormones in this AIS patient may not be the aetiological cause of her schizophrenia. From a psychosocial perspective, one may expect that a patient with AIS would suffer from immense psychological stress and gender identity problems because they are regarded as intersex. Androgen insensitivity syndrome patients are chromosomally and gonadally male. Studies show that gender identities are established and maintained in all individuals diagnosed with AIS.13 No one with AIS has been described as having gender dysphoria. This may be because prenatal androgens play a critical role in the masculinisation of the foetal brain and therefore influence behaviour and gender identity later in life. One study showed that most women with AIS were satisfied with their psychosexual development and sexual function.14 All of them were satisfied with having been raised as female. None of them desired gender reassignment. Another study showed that AIS patients did not differ from control subjects in terms of quality of life (self-esteem and psychological general well- being), gender-related psychological characteristics (gender identity, sexual orientation, and gender role behaviour in childhood and adulthood), marital status and personality traits that showed sex differences and hand preferences.15,16

Most of them did not regard infertility as a great problem. These studies suggest that AIS does not cause a severe level of psychological stress likely to precipitate schizophrenia in people with this condition. Nonetheless, these conclusions have arisen from studies in Caucasian populations and little is known about the psychological impact of AIS on Chinese patients. Chinese culture puts great value on the ability to reproduce as a means of venerating one’s ancestors, a teaching inherited from Confucius (551-479 BC). Infertility is probably a much greater taboo for Chinese patients with AIS than it is for Caucasians.

Our patient has one sister and one maternal aunt suffering from schizophrenia, so probably inherited the genetic defect predisposing to schizophrenia from her mother. Androgen insensitivity syndrome is an X-linked recessive disease so the abnormal X gene in this XY patient must have come from the maternal X chromosome. The genetic defect in AIS is monogenic and located on the long arm of the X chromosome (Xq11-13) while schizophrenia is a complex disease with multiple contributing genes. A review has found that the genetic defects of schizophrenia are multiple, non-specific, and inconsistent between different studies. They are primarily on 2q but also on 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q and 14p (neuregulin-1 gene, dysbindin gene, G72/G30 gene, COMT gene)1,2 while another study showed that 22q11.2 microdeletions detected by fluorescence in-situ hybridisation are significantly associated with schizophrenia.3 The same study also suggested that sex chromosome abnormalities seem to be more common among people with schizophrenia. One study found that 47,XXY and 47,XXX are about 4 to 6 times more common in people with schizophrenia than in the general population17 but there are insufficient data to determine whether there is a higher incidence of schizophrenia among people with sex chromosome abnormalities. Studies of schizophrenia have neither excluded nor suggested linkage with X chromosome markers. The significance of associations between schizophrenia and sex chromosome aneuploidies is therefore uncertain. Although the current level of evidence does not suggest that schizophrenia and AIS share common genetic defects on the sex chromosome, an increasing number of gene defects are being discovered as techniques for genetic analysis to improve. Thus occurrence of AIS and schizophrenia in the same patient may or may not be genetically related.

To conclude, there are possible common X chromosome defects in this family explaining the occurrence of the two diseases in the two siblings. The effects of gender, sex hormones and the psychological impact of AIS on the development of schizophrenia should be explored further.


The authors would like to thank Dr Dicky WS Chung, Chief of Service, Department of Psychiatry of Tai Po Hospital and Dr Irene Kam, Associate Consultant, Department of Psychiatry of Tai Po Hospital for their advice and support.


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