Outline

• ABSTRACT
  
• METHOD
  
• RESULTS
  
• Case 1: 47,XYY and MDI
  
• Case 2: 45,XO Mosaicism and COS
  
• DISCUSSION
  
• Clinical Implications
  
• REFERENCES
  

Objective: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DSM-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI).

Method: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine.

Results: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi squared = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed.

Conclusions: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine. J. Am. Acad. Child Adolesc. Psychiatry, 1998, 37(3):292-296.

Since 1990, a clinical and neurobiological study of childhood-onset schizophrenia (COS) has been ongoing at the National Institute of Mental Health (NIMH) (McKenna et al., 1994) [12]. Approximately 20% of children and adolescents referred to our study who were then excluded because they did not meet criteria for DSM-III-R-defined schizophrenia had developmental disorders particularly in language, prominent attention and impulse control difficulties, and transient psychotic symptoms (Kumra et al., 1998; McKenna et al., 1994) [11,12]. Although DSM-IV would classify these children as having psychotic disorder not otherwise specified, we provisionally labeled this subgroup "multidimensionally impaired" (MDI) and developed criteria that reliably identified these patients (McKenna et al., 1994) [12].

In previous studies we reported that both the MDI and COS patients shared a similar pattern of transient autistic symptoms, expressive and receptive language deficits, brain magnetic resonance imaging (MRI) abnormalities, neuropsychological impairments, and increased rates of schizophrenia spectrum disorders in first-degree relatives (Kumra et al., 1998) [11].

Because chromosomal aberrations may suggest regions in which to focus a search for genes predisposing to psychosis, cytogenetic screening was carried out for both the COS (n = 38) and MDI (n = 28) groups. Previous cytogenetic screenings have found increased rates of sex chromosome aneuploidies (XXX, XXY, and possibly XYY) in adults and children with schizophrenia and unspecified psychoses (DeLisi et al., 1994; Nielsen and Wohlert, 1991) [6,14]. The rate of sex chromosome anomalies in the general population has been reported to be 1 per 426 live births, or 2.34 per 1,000 (Nielsen end Wohlert, 1991) [14].

Abnormalities of cerebral organization, neuropsychological impairments, an increased susceptibility to stress, and behavioral problems have been reported in population-based samples of patients with sex chromosome anomalies (Bender et al., 1989, 1996; Money and Alexander, 1966) [3,4,13]. Boys with 47,XXY frequently demonstrate a selective disadvantage in verbal ability, or left hemisphere deficits, manifested as delayed acquisition of language skills, impairments in expressive language, poor reading and spelling skills, a relative reduction in Verbal IQ, and psychiatric disturbances (Rovet et al., 1995; Walzer et al., 1991) [15,20]. Boys with 47,XYY were also noted to have communication deficits, attentional and impulse control difficulties which interfered with their academic performance, and a selective reduction in performance IQ (Walter et al., 1978, 1991) [21,20].

In contrast, nonverbal skills (e.g., visuospatial deficits, arithmetic learning disabilities) appear to be more affected in girls with 45,XO, and disruptive behavior problems and poor "social cognitive" skills have been noted (Bender et al., 1989, 1996; Money and Alexander, 1966; Skuse et al., 1997) [3,4,13,17].

On the basis of these data, we hypothesized that there might also be an increased rate of sex chromosome abnormalities in our group with very early-onset psychotic disorders. This is the first survey, to our knowledge, of screening for sex chromosome abnormalities in a sizable and carefully diagnosed group of children and adolescents with psychotic disorders. Previous case reports from our group have described a boy with 1:7 translocation and a boy with a deletion of chromosome 22 q11.2 (velocardiofacial syndrome) from the COS cohort (Gordon et al., 1994; Yan et al., in press) [8,22].

METHOD^
This protocol was approved by the institutional review board at the NIMH, and each parent and child gave informed consent or assent before the child was entered into the study.

Neuroleptic-nonresponsive children and adolescents who had received a diagnosis of schizophrenia were sought by national recruitment through professional and patient advocacy organizations for participation in an inpatient trial of clozapine. As of June 1997, sixty-six patients have received a diagnosis of MDI syndrome (n = 28) or COS (n = 38) from at least two child psychiatrists (S.K., L.K.J., J.L.R.), independent of cytogenetic test results.

The MDI group (23 males, 5 females) ranged in age from 6 through 18 years (mean: 11.5 +/- 3.0) and had a mean age of onset of psychotic symptoms at 7.7 +/- 2.2 years (range, 3 to 12). The COS group (21 males, 17 females) ranged in age from 9 through 18 years (mean: 14.7 +/- 2.2) and had a mean age of onset of psychotic symptoms at 10.4 +/- 1.7 years (range, 5 to 12).

The details of this study have been described elsewhere (Kumra et al., 1998; McKenna et al., 1994) [11,12]. In brief, all patients were evaluated using structured psychiatric interviews, neuropsychological tests, and anatomic brain MRI scans. Chromosomal analyses were performed from a peripheral blood culture, and in each case, at least 20 well-spaced Giemsa-trypsin banded metaphases were screened to search for mosaicism (J.M, A.C.M.S.).

RESULTS^
The total incidence of sex chromosome abnormalities among consecutively born infants in the general population has been reported to be 1 per 426 children or 2.34 per 1,000 (Nielsen and Wohlert, 1991) [14]. Analysis of our sample detected 4 (6.1%) of 66 patients (3 MDI boys, 1 COS girl) to have a sex chromosome abnormality (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is 26 times the rate reported in the general population (4/66 versus 1/426, chi squared = 19.2, df = 1, p = .00001).

By diagnostic group, the rate of sex chromosome abnormality would be higher only in the MDI group compared with the general population rate (3/28 versus 1/426, chi squared = 33.0, df = 1, p <.00001) and with a population-based sample of children, excluding cases of fragile X, with mild mental retardation (3/28 versus 2/171, chi squared = 8.9, df = 1, p = .003) (Gustavson et al., 1987) [9].

All four children had been referred to our study without knowledge of their cytogenetic abnormalities. No other chromosomal aberrations were seen. Two cases of sex chromosome anomalies that were otherwise clinically representative of the rest of our MDI and COS cohort are described in detail.

Case 1: 47,XYY and MDI^
A 13-year-old boy was evaluated at the NIMH for attentional and impulse control difficulties, difficulty separating reality from fantasy, brief auditory hallucinations, and exaggerated mood swings.

The patient's obstetrical history was notable for a nuchal cord and mild asphyxia. Delays in both language and motor development were reported: he began walking at age 2 and he combined words in sentences by age 4. Upon entry into primary school, he was placed in special education classes for learning disabilities and language delay; motor tics were also noted. These developmental and emotional difficulties were complicated by parental divorce and alleged physical abuse.

Physical examination was unremarkable. Significant laboratory findings during the patient's stay at the NIMH were an MRI of the cerebrum which was read clinically as "enlarged lateral ventricles with an asymmetry (left > right)."

The WISC-R IQ test showed a mild discrepancy between verbal and nonverbal abilities, favoring nonverbal skills: Full Scale IQ, 69; Verbal IQ, 65; Performance IQ, 77. These results were believed to reflect accurately the patient's abilities at the time of testing. Previous testing at age 10, however, had shown a Full Scale IQ of 83, a Verbal IQ of 69, and a Performance IQ of 101.

After leaving the NIMH study, the patient continued to do poorly, requiring multiple psychiatric hospitalizations and residential treatment. Trials of various typical neuroleptics and mood stabilizers, from age 13 to 17, were not helpful. The patient's symptoms of depressed and irritable mood became more prominent, as did his explosive outbursts, delusions of reference and persecution, and auditory hallucinations. When the patient returned to the NIMH for a 2-year follow-up at age 17, his diagnosis was schizoaffective disorder, depressed type.

Case 2: 45,XO Mosaicism and COS^
A 16-year-old girl was admitted to the NIMH for an inpatient trial of clozapine for treatment-refractory COS. Her obstetrical and family history was unremarkable. At age 2 years and 8 months, she was evaluated at a developmental disorders clinic and was found to have balance and coordination problems, as well as possible speech and language delay. At age 11, she gradually developed unusual fixations such as believing that there was a Nazi general living under her bed and that there were scud missiles located in the apartment nearby. In addition, her family noted that she was responding to auditory and visual hallucinations, had inappropriate affect, and had increased attentional impairments and distractibility. These symptoms were associated with a marked deterioration in her social skills and overall level of functioning and were only partially responsive to both typical and atypical neuroleptics. Thus, she was referred to the NIMH for participation in an inpatient clozapine trial.

Physical examination revealed a fully pubescent female of normal stature with a high, arched palate but no other stigmata of Turner's syndrome. During her stay at the NIMH, which included a 2-week, drug-free observation period, the patient continuously experienced psychotic symptoms, and because of her level of disorganization, accurate testing of her intellectual ability was not possible. However, previous prepsychotic testing from fourth grade showed performance in the high end of the average range on standardized achievement tests.

Cytogenetic testing revealed that 47 cells (94%) had a deletion of the long arm of one X chromosome (partial monosomy for distal Xq), and 3 (6%) of 50 cells were monosomic for the entire X chromosome (mos46,X,del(X)(q24)[47]/45,X[3]). A separate cytogenetic analysis from a skin biopsy revealed only the cell line with partial monosomy Xq in all 100 cells examined.

Karyotype of the patient's mother showed low-grade mosaicism for a monosomy X cell line. Forty-two (84%) of 50 cells were karyotypically normal. Seven cells (14%) were monosomy X (mos46,XX[42]/45,X[7]). One additional cell (2%) had a deletion of the long arm of X at band q21, which was not the same breakpoint observed in the patient. This latter finding is believed to be a random event with no clinical significance. Chromosomal analysis on the mother's cultured skin fibroblasts was completely normal and did not show a monosomy X cell line.

The karyotype of the patient's father and siblings was reported as normal, with the exception that one sister, 46,XX, was noted to have 1 cell (2%) of 50 with the same deletion as the proband.

DISCUSSION^
We observed a rate of 4/66 (6.1%) for sex chromosome abnormalities in children with childhood-onset psychotic disorder. As reviewed by DeLisi et al. (1994) [6], the association of sex chromosome anomalies with psychosis does not appear to be specific to schizophrenia; the majority of reported cytogenetic studies were conducted before the introduction of standardized diagnostic criteria and may have included a broad spectrum of ill individuals (e.g., Sperber et al., 1972 [18]). The cases of sex chromosome anomalies reported by DeLisi et al. (1994) [6], however, did not have early onset of psychotic illness.

The clinical pictures of the four patients with sex chromosome abnormalities resembled those of the rest of the MDI and COS subjects in our cohort. With the exception of the boy with 47,XXY, the brain MRIs for the other three cases (and the great majority of the COS and MDI cohorts) were read as clinically normal. Similar to the rest of our cohort, the three MDI patients demonstrated low average to average intellectual abilities, expressive and receptive language deficits, and attentional impairments (Kumra et al., 1998) [11]. The COS patient who was a mosaic 45,XO also showed a pattern of prepsychotic abnormalities similar to those of the other female disorganized schizophrenics within our group (Alaghband-Rad et al., 1995) [2].

Clinical Implications^
If valid, these findings suggest that the loss of gene product balance of the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and (pre- and postnatal) environmental insults that result in childhood psychotic disorders (Shapiro, 1997) [16]. Such a pattern has been observed in hereditary forms of neuropathy, wherein a variety of genetic alterations such as an increase in the dosage of myelin proteins, as well as deletions and point mutations, can result in the disorder (Hodes and Dlouhy, 1996) [10].

Other findings also suggest a link between childhood-onset psychosis and sex chromosome abnormalities. One of the schizophrenic probands (a normal karyotype female) has a sister with an extra X chromosome (47,XXX) and moderate mental retardation. Another schizophrenic proband (normal karyotype male) has a sister with fragile X syndrome and mild mental retardation (Alaghband-Rad et al., in press). A similar finding of an excess of psychotic disorders (17.1%) has been reported in relatives of female fragile X carriers (Franke et al., 1996) [7]. In addition, an increasing number of genes coding for the development of higher intelligence (e.g., abstract thought, planning, and complex verbal communication) have been localized to the sex chromosomes, and allelic variants may have evolved which result in lower intellectual performance, smaller total cerebral volume, and psychosis (Crow, 1993; Skuse et al., 1997; Turner, 1996) [5,17,19].

There are several limitations to this study. To date, prospective studies of population-based samples of children with sex chromosome abnormalities identified at birth suggest that psychotic disorders are rare, although many of the individuals included in these studies are only now entering the age of risk for schizophrenia (Bender et al., 1996; DeLisi et al., 1994; S. Walzer, personal communication, December 1996) [4,6]. Other limitations include the small sample tested, the severity of this cohort's illness, and the low average IQ that characterize this sample. Because of the rarity of childhood psychotic disorders, population screening is not possible, and there is no evidence to suggest that patients with sex chromosome abnormalities and psychotic disorders have earlier onset or are less treatment-responsive (DeLisi et al., 1994) [6]. To pursue the question of the influence of the sex chromosomes on the development of childhood psychosis, molecular studies are in progress.

REFERENCES^
1. Alaghband-Rad J, Kumra S, Lenane MC et al. (1998), Early-onset schizophrenia: mental retardation in siblings (letter). J Am Acad Child Adolesc Psychiatry 37:137-138. [Fulltext Link] [Medline Link]

2. Alaghband-Rad J, McKenna K, Gordon C et al. (1995), Childhood-onset schizophrenia: the severity of premorbid course. J Am Acad Child Adolesc Psychiatry 34:1273-1283. [Fulltext Link] [Medline Link] [BIOSIS Previews Link] [Context Link]

3. Bender BG, Linden MG, Robinson A (1989), Verbal and spatial processing efficiency in 32 children with sex chromosome abnormalities. Pediatr Res 25:577-579. [Medline Link] [Context Link]

4. Bender BG, Linden MG, Robinson A (1996), Environment and developmental risk in children with sex chromosome abnormalities. J Am Acad Child Adolesc Psychiatry 26:499-503. [Medline Link] [Context Link]

5. Crow TJ (1993), Sexual selection, Machiavellian intelligence, and the origins of psychosis. Lancet 342:594-598. [Medline Link] [BIOSIS Previews Link] [Context Link]

6. DeLisi LE, Friedrich U, Wahlstrom J et al. (1994), Schizophrenia and sex chromosome anomalies. Schizophr Bull 20:495-505. [Medline Link] [BIOSIS Previews Link] [Context Link]

7. Franke P, Maier W, Halutzinger M, Weiffenbach O (1996), Fragile-X carrier females: evidence for a distinct psychopathological phenotype? Am J Med Genet 64:334-339. [Medline Link] [BIOSIS Previews Link] [Context Link]

8. Gordon CT, Krasnewich D, White B, Lenane M, Rapoport JL (1994), Brief report: translocation involving chromosomes 1 and 7 in a boy with childhood-onset schizophrenia. J Autism Dev Disord 24:537-545. [Medline Link] [BIOSIS Previews Link] [Context Link]

9. Gustavson KH, Holmgren G, Blomquist K (1987), Chromosomal aberrations in mildly mentally retarded children in a northern Swedish county. Ups J Med Sci Suppl 44:165-168. [Medline Link] [Context Link]

10. Hodes ME, Dlouhy SR (1996), The proteolipid protein gene: double, double ... and trouble. Am J Hum Genet 59:12-15. [Medline Link] [BIOSIS Previews Link] [Context Link]

11. Kumra S, Jacobsen LK, Lenane M et al. (1998), "Multidimensionally impaired disorder": is it a variant of very early-onset schizophrenia? J Am Acad Child Adolesc Psychiatry 37:91-99. [Context Link]

12. McKenna K, Gordon C, Lenane M, Kaysen D, Fahey K, Rapoport J (1994), Looking for childhood-onset schizophrenia: the first 71 cases screened. J Am Acad Child Adolesc Psychiatry 33:636-644. [Medline Link] [BIOSIS Previews Link] [Context Link]

13. Money J, Alexander D (1966), Turner's syndrome: further demonstration of the presence of specific congenital deficiencies. J Med Genet 3:47-48. [Medline Link] [Context Link]

14. Nielsen J, Wohlert M (1991), Chromosome abnormalities found among 34,910 newborn children: results from a 13 year incidence study in Aarhus, Denmark. Hum Genet 87:81-83. [Medline Link] [Context Link]

15. Rovet J, Netley C, Bailey J, Keenan M, Stewart D (1995), Intelligence and achievement in children with extra X aneuploidy: a longitudinal perspective. Am J Med Genet 60:356-363. [Medline Link] [BIOSIS Previews Link] [Context Link]

16. Shapiro BA (1997), Whither Down syndrome critical regions? Hum Genet 99:421-423. [Medline Link] [BIOSIS Previews Link] [Context Link]

17. Skuse DH, James RS, Bishop DVM et al. (1997), Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature 39:705-708. [Medline Link] [Context Link]

18. Sperber MA, Salomon L, Collins MH, Stambler M (1972), Childhood schizophrenia and 47,XXY Klinefelter's syndrome. Am J Psychiatry 128:84-92. [Medline Link] [Context Link]

19. Turner G (1996), Intelligence and the X chromosome Lancet 347:1814-1815. [Context Link]

20. Walzer S, Bashir AS, Silbert AR (1991), Cognitive and behavioral factors in the learning disabilities of 47,XYY and 47,XYY boys. In: Birth Defects: Original Article Series. New York: March of Dimes Birth Defects Foundation, pp 45-58. [Context Link]

21. Walzer S, Wollf PH, Bowen D et al. (1978), A method for the longitudinal study of behavioral development in infants and children: the early development of XXY children. J Child Psychol Psychiatry 19:213-229. [Medline Link] [Context Link]

22. Yan W, Jacobsen LK, Krasnewich DM et al. (in press), Chromosome 22 q 11.2 interstitial deletions among childhood-onset schizophrenics and "multidimensionally impaired." Neuropsychiatr Genet. [Context Link]