Meta-analysis of magnetic resonance imaging studies in chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome)

https://doi.org/10.1016/j.schres.2009.09.010Get rights and content

Abstract

Objectives

22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome (VCFS) or DiGeorge Syndrome, is a genetic disorder due to a micro deletion on chromosome 22q11.2. VCFS is associated with abnormalities in brain structure and with an increased risk of psychiatric disorders, particularly schizophrenia. The aim of this review was to statistically summarize the structural imaging literature on VCFS which due to the relatively rarity of the disorder tends to consider small sample sizes.

Method

A systematic review and meta-analysis of region of interest (ROI) studies comparing VCFS with healthy controls was carried out. Significant heterogeneity was explored using meta-regression.

Results

Subjects with VCFS were characterised by global brain volumetric reduction including several cortical regions, cerebellum and hippocampus. The area of the corpus callosum was increased.

Conclusions

Many regions extensively studied in schizophrenia were not covered in the existing VCFS literature. However, the studies considered support volumetric abnormalities which may help explain why VCFS is associated with a greatly increased risk of psychosis and other psychiatric disorders.

Introduction

Chromosome 22q11.2 deletion syndrome (22q11.2DS), affects approximately 1 in 5000 live births (Tézenas Du Montcel et al., 1996) and refers to a group of previously distinct genetically determined disorders (velocardiofacial syndrome, Shprintzen syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, Cayler cardiofacial syndrome, and CATCH 22 syndrome) caused by a microdeletion on the long arm of chromosome 22 (Scambler et al., 1992). VCFS is characterised by a distinct phenotype including a typical facial appearance, cleft palate, velopharyngeal insufficiency, cardiac anomalies (McDonald-McGinn et al., 1999, Swillen et al., 1997), learning disabilities and by an increased risk for psychotic disorders (Henry et al., 2002, Gothelf et al., 2004a, Gothelf et al., 2004b, Baker and Skuse, 2005, Papolos et al., 1996, Niklasson et al., 2002) particularly schizophrenia (Murphy et al., 1999). More specifically, psychotic symptoms have been diagnosed in up to 30% of adolescents and adults with 22q11.2DS (Murphy et al., 1999). Moreover, the deletion has been found in 1–6% of people with schizophrenia (Murphy et al., 1998, Yan et al., 1998).

This association has led to considerable research to morphologically characterise 22q11.2DS brain abnormalities and potential similarities with schizophrenia. Magnetic resonance imaging (MRI) has allowed detailed in vivo examination of brain structures in people with 22q11.2DS but the evidence is inconclusive (Eliez et al., 2000, Kates et al., 2001, Simon et al., 2005, Eliez et al., 2002, Kates et al., 2006, Campbell et al., 2006, Gothelf et al., 2007, Deboer et al., 2007; Shashi et al., 2004). This is in part due to the relative rarity of the disorder and the tendency for studies to be small and potentially underpowered. Nevertheless, even taking this into account, the literature appears heterogeneous and published significant effect sizes differ in both direction and magnitude.

The aim of this meta-analysis was to apply quantitative methods to characterise morphometric differences in 22q11.2DS in comparison with healthy controls by 1) identifying region of interest (ROI) studies which offered measurements of brain regions in 22q11.2DS and 2) synthesizing findings using random effects meta-analysis. We also assessed heterogeneity to clarify the role of a number of variables including year of publication, age, sex, IQ, scanner strength and slice thickness.

Section snippets

Search strategy and inclusion/exclusion criteria

A comprehensive search from a range of electronic databases, including Medline, EMBASE, PsycINFO, and PubMED was conducted up to March 2008 that reported structural MRI data in people with 22q11.2DS and unaffected controls. Search terms used to identify the studies included ‘Velocardiofacial syndrome’, ‘DiGeorge syndrome’, ‘22q11.2 deletion syndrome’ and related terms combined using the AND operator with ‘Magnetic Resonance Imaging’. The search was also supplemented by a manual and

Systematic search

The literature search identified 156 publications of which 48 were retrieved in full text format. Fig. 1 summarises the study flow and reasons for exclusion. Twenty-two studies met inclusion criteria and were included in the final analysis which provided information on 35 regions of interest (Table 1). Images were manually traced reflecting similar anatomical borders and used different software programs to aid image processing. In some cases a semiautomated stereotactic based parcellation

Discussion

Findings from this meta-analysis show that 22q11.2DS is associated with global brain volumetric reduction affecting both gray and white matter, and with reductions of the prefrontal cortex and hippocampi, while the corpus callosum area was increased. These relatively large effect sizes were found in the absence of either heterogeneity or publication bias.

Diffuse global brain volumetric reduction is consistent with the common occurrence of a learning disability in the 22q11.2DS population and

Role of funding source

GMT is currently supported by the Baily Thomas Charitable Fund. DA is currently supported by the UK Medical Research Council. AM is currently supported by the Health Foundation.

Contributors

GMT and DA were involved in literature searches, data extraction and analyses, and in writing the first draft of the report. AM provided supervision, statistical expertise, offered guidance in the interpretation of the results and participated at all stages of development of the final report. KPE had a role in overall supervision and final drafting of the report. All the authors contributed to and have approved the final manuscript.

Conflict of interest

Nothing to declare.

Acknowledgements

GMT and DA would like to thank Drs. Amelsvoort, Bearden, DeBoer, Kates and Simon for supplementing their work with unpublished data to complete this meta-analysis. GMT would like to thank the Baily Thomas Charitable Fund for their support and Professor Declan Murphy for his guidance and encouragement.

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