Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome

Abstract

Chromosome 22q11 deletion syndrome (22q11DS) is associated with elevated rates of schizophrenia and other psychoses in adulthood. Childhood morphologic brain abnormalities are frequently reported, but the significance of these and their relationship to the development of schizophrenia are unclear. We sought to delineate midline neuroanatomical abnormalities in nonpsychotic children with 22q11DS and their age- and sex-matched controls and compare these to those reported in individuals with schizophrenia. On qualitative analysis, we found a high incidence of midline developmental abnormalities (cavum septum pellucidum, or CSP). On quantitative analysis, the total corpus callosum (CC) area was significantly increased in the patient group and among the subregions, the patients had a significantly larger isthmus. These findings of an increased area of the corpus callosum, specifically the isthmus, have not been reported before in individuals with 22q11DS. We also found a relative lack of the age-related increase in the size of the corpus callosum in the children with 22q11DS. There were no differences in cerebellar vermis measurements between the patient and control groups. Our findings are indicative of frequent midline brain anomalies, including dysgenesis of the corpus callosum, in nonpsychotic children with 22q11DS. Although the increased size of the corpus callosum in our 22q11DS patients is in direct contrast to the decrease seen in schizophrenia, the high frequency of structural midline abnormalities in these nonpsychotic children with 22q11DS is similar to that seen in schizophrenia. Further longitudinal studies on these children will help determine which of these structural abnormalities is/are pertinent to the development of psychosis.

Introduction

Chromosome 22q11 deletion syndrome (22q11DS) is a common genetic condition, with a prevalence of 1/2000 to 1/4000 Shprintzen, 2000, Tezenas du Montcel et al., 1996, Wilson et al., 1994. Also known as DiGeorge or velocardiofacial syndrome, the deletion causes variable manifestations, mainly consisting of developmental delays and learning disabilities (80–100%), mental retardation (50%), congenital heart disease (70%) and palatal problems (70%) Gerdes et al., 2001, Moss et al., 1999, Shprintzen et al., 1981, Swillen et al., 1997. The diagnosis is made by chromosome analysis and fluorescence in situ hybridization (FISH), demonstrating the deletion at band q11.2 on chromosome 22. Most deletions occur sporadically—in 10–15% of patients, an affected parent is found on FISH analysis.

Recent retrospective studies have reported that children with 22q11DS have a markedly heightened risk (approximately 40%) of developing schizophrenia and mood psychoses in adulthood Murphy et al., 1999, Papolos et al., 1996, Pulver et al., 1994, Shprintzen et al., 1992. These preliminary findings provide the strongest known link between psychosis and an identified genetic abnormality. Conversely, about 1–6% of individuals with schizophrenia have been found to have a deletion of 22q11.2 Karayiogou et al., 1995, Murphy et al., 1998, Yan et al., 1998. Thus, 22q11DS represents a specific genetic subtype of schizophrenia, but the pathophysiology remains poorly understood.

In the last decade, qualitative MRI studies in children and adults with 22q11DS have shown structural brain abnormalities. In children, a small cerebellar vermis, white matter hyperdensities, cysts adjacent to the anterior horns, cerebellar and midline anomalies, and enlarged Sylvian fissures have been reported Bingham et al., 1997, Lynch et al., 1995, Mitnick et al., 1994, Papolos et al., 1996, Vataja and Elomaa, 1998.

With the application of quantitative (morphometric) MRI analyses, additional structural brain abnormalities have been described in nonpsychotic children with 22q11DS. These include reduced total brain volume, increased mid-corpus callosum area, white matter reductions in nonfrontal areas, gray matter reduction in the parietal lobe, relatively large frontal lobes, decreased right cerebellar tissue volume, small temporal lobe, superior temporal gyrus and hippocampus and increased basal ganglia volume Eliez et al., 2000, Eliez et al., 2001, Eliez et al., 2002, Kates et al., 2001, Usiskin et al., 1999.

In adults with 22q11DS who had developed schizophrenia, midline developmental abnormalities (45%), white matter hyperdensities (90%) and cerebellar atrophy (36%) were seen on a qualitative MRI analysis (Chow et al., 1999). On quantitative MRI studies, septum pellucidum abnormalities (40%), smaller cerebellum, gray matter deficits and large ventricles were reported Chow et al., 2002, van Amelswoort et al., 2001. Frontal lobe size was reduced in the second study, similar to the findings in schizophrenia in the general population (Lawrie and Abukmeil, 1998), but in contradiction to the studies in young nonpsychotic children with 22q11DS discussed above. Thus, while several abnormalities have been described in nonpsychotic and psychotic individuals with 22q11DS, there are differences from one study to another and the relationship between these and the development of schizophrenia is unclear.

The CC is a key midline white matter structure that carries fibers that connect cortical areas in a topographical manner. Changes in the CC provide a way of examining anatomical abnormalities in the corresponding cortical areas. Studies of the CC in schizophrenia have provided insights into various underlying neurodevelopmental abnormalities (reviewed by Keshavan et al., 2002, Shenton et al., 2001).

We performed a cross-sectional study in nonpsychotic preadolescent and adolescent children with 22q11DS to characterize neuroanatomical abnormalities by qualitative and quantitative methods, and to compare and contrast these changes to those found in individuals with schizophrenia. We hypothesized that we would see a high frequency of midline structural developmental abnormalities such as cavum septum pellucidum and decreased size of the corpus callosum (CC) based on the reports of decreased intracranial volume in 22q11DS children and the frequent reports of decreased CC area in individuals with schizophrenia. Based on previous reports of relatively large frontal lobes in children with 22q11DS, we expected to find differences in size between the subregions of the CC. We also expected to see cerebellar hypoplasia, a common feature in 22q11DS and in schizophrenia.