Klinefelter's syndrome (mosaic) with chromosome 9 inv and schizophrenia

Abstract

Klinefelter's syndrome is a sex chromosome abnormality with low androgen level. The varied manifestations of the mental symptoms in some of them, that are inexplicable based on their genotype alone, has fascinated the researchers. We present here a case of Klinefelter's syndrome having a karyotype of mos 47, XXY, and also inversion in 9^th chromosome, with schizophrenia. Despite the view that inv 9 is a normal variant, it is still worthwhile to explore whether it has any role in the etiology of schizophrenia especially when it occurs with other genotypic aberrations that are suspected to have relevance to psychiatric disorders including the Klinefelter's syndrome.

INTRODUCTION

The co-existence of an aberration in a different chromosome of a Klinefelter's syndrome is rare. Still rare is the co-occurrence of a psychiatric disorder in such cases. Several cases of double aneuploidy of XXY and trisomy 21 have been published since the first report.[1] But occurrence of XXY aneuploidy and 9^th chromosome inversion with co-existing schizophrenia has not been reported so far.

CASE REPORT

A 38-year-old unmarried male was brought to our psychiatric center, Sri Ramachandra Medical College and Research Institute, Chennai, for the complaints of withdrawn behavior, muttering to self, lacking self-care and having disturbed sleep for 2 years. He used to wander away from home on and off, but used to return home on his own within 2–3 days. But he went missing for about 1.5 years before he was traced in a temple and brought to our facility on 10 November 2008.

He was born of non-consanguineous parents and the delivery was a full-term normal one. The milestones were normal. He was reared only by his mother as his father had left their family 2 years after his birth. On discontinuation from school after his failure in 6^th standard, from the age of 17 years he undertook several jobs. He was unmarried.

Family history revealed that his paternal uncle had mental illness, but the details could not be obtained for want of suitable informant.

On mental status examination, his general appearance was found to be poor, with ill-kempt hair, unclipped nails, and untidy clothes. His psychomotor activity was retarded and rapport could be established only with difficulty. He replied to questions briefly in a hesitant muffled tone. He denied the identity of his mother and sister who had brought him, but called them as his relatives. Delusions of persecution and reference, and second person auditory hallucination were present. The orientation to place, persons, and time, and memory for immediate, recent, and remote events were intact. His abstract thinking was poor. His intellectual capacity seemed to be mildly backward as indicated by his verbal and performance [Intelligence quotient (IQ) of 71 and 56, respectively] with full scale IQ of 63 on assessment with Wechsler's adult intelligence scale[2] that was administered in regional language. However, the diagnosis of co-morbid mental retardation was shelved considering the possible decline in his cognitive and social spheres as a result of psychosis. Further, the IQ test performance could be attributed to Klinefelter's syndrome itself. DSM-IV[3] diagnosis of schizophrenia was established after performing the structured clinical interview using the Mini International Neuropsychiatric Interview schedule[4] for psychotic disorders.

On general examination, absence of hair in the axillary region and on the face and chest was observed. His height was 165 cm. The dimensions of the testes as measured by the ultrasound were 15 mm in length, 10 mm in breadth and 12 mm antero-posteriorly. The length of penis was 8 cm.

Hormonal assay showed his free testosterone as 4.70 pg/ml which was low (reference range 8.8–27 pg/ml). Additionally, the follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were detected to be high (41.04 and 28.21 mIU/ml, respectively) (respective reference ranges 9–15 and 2.4–5.9 mIU/ml). The chromosome analysis of 50 metaphases with GTG banding showed a numerical and a structural abnormality. The karyotype was mos 47,XXY, inv(9) (p12; q12) [90%] / 46,XY[10%], inv(9) (p12; q12) and that of Klinefelter's syndrome (Male Mosaic) [Figures 1 and 2]. Noteworthy was the absence of mosaic pattern in chromosome 9 inv.

Figure 1.

Karyotype XXY

Figure 2.

Chromosome 9 inv

DISCUSSION

A small pericentric inversion of chromosome 9 has been noted to be present in up to 1.98% of all individuals tested by cytogenetic laboratories and is seen mostly in African-Americans. It is said that inv(9)(p11q12) has no known deleterious effect on carriers and does not appear to be associated with a risk of miscarriage or unbalanced offspring. It is, therefore, generally considered as a normal variant.[5] Notwithstanding this, it is difficult to rule out at this stage the impact of inv(9) on the human behavior. Pericentric region of chrosomome 9 was suggested as one of the regions of interest for linkage analysis based on an examination of 120 patients with schizophrenia of whom 4 (3.3%) were found to have a pericentric inversion of chromosome 9.[6] A Turkish study noted pericentric inversion and enlargement of the heterochromatin region of chromosome 9(inv(9); 9qh+) in 7 out of their 134 schizophrenics (5.2%). This incidence was found to be higher than the general population.[7] More recently, a clonal pericentric inversion on chromosome 9 was detected in 1 male patient from a sample of 62 Brazilian schizophrenic patients.[8]

Higher rates of Klinefelter's syndrome among people with schizophrenia have been reported.[9] There has been no systematic report on the levels of schizophrenia psychopathology in a large sample of people with Klinefelter's syndrome unselected for psychiatric disorders. In a sample of 32 men with Klinefelter's syndrome, higher level of schizotypal traits and higher scores for positive and negative symptoms were noted.[10] But it has not been mentioned whether their sample fulfilled the criteria for schizophrenia. Case reports on Klinefelter's syndrome with schizophrenia fulfilling the diagnostic criteria have not so far observed the presence of inv(9) in their series.

Despite the absence of unequivocal evidences for any deleterious effect of inv(9), it is still worthwhile to explore whether it has any role in the etiology of schizophrenia, especially when it occurs along with other genotypic aberrations that are suspected to have relevance to psychiatric disorders including the Klinefelter's syndrome. These anomalies might increase the risk for schizophrenia in a relatively nonspecific way such as contributing to disruption of normal embryogenesis of the nervous system.