Regional Cortical White Matter Reductions in Velocardiofacial Syndrome: A Volumetric MRI Analysis Wendy R. Kates, Courtney P. Burnette, Ethylin W. Jabs, Julie Rutberg, Anne M. Murphy, Marco Grados, Michael Geraghty, Walter E. Kaufmann, and Godfrey D. Pearlson Background: Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabil- ities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. Methods: Subjects were ten children with velocardiofa- cial syndrome and ten age- and gender-matched unaf- fected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue bound- aries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. Results: Analyses indicated that children with velocardio- facial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. Conclusions: The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocog- nitive and neuropsychiatric phenotype of velocardiofacial syndrome. Biol Psychiatry 2001;49:677– 684 © 2001 Society of Biological Psychiatry Key Words: Velocardiofacial syndrome, volumetric MRI, chromosome 22q11, cerebral lobes, white matter Introduction V elocardiofacial syndrome (VCFS) is a relatively com- mon genetic disorder that affects between 1:2000 and 1:5000 individuals (du Montcel et al 1996). Caused by a microdeletion on chromosome 22q.11 (Driscoll et al 1992; Edelmann et al 1999; Scambler et al 1992), the syndrome is associated with multiple anomalies, including cardiac defects, cleft palate, a characteristic facial appearance, pharyngeal structural abnormalities leading to hypernasal speech, language deficits, attentional deficits, executive domain dysfunction, and learning disabilities (Golding- Kushner et al 1985; Moss et al 1999; Shprintzen et al 1978; Swillen et al 1997). The behavioral and psychiatric phenotype associated with VCFS includes disinhibition, impulsivity, schizoid features, and flat affect (Papolos et al 1996). Between 10% and 30% of patients with VCFS develop severe psychiatric illness during late adolescence (Shprintzen et al 1992), including schizophrenia (Bassett and Chow 1999; Pulver et al 1994a, 1994b) and bipolar disorder (Papolos et al 1996). Murphy et al (1999), for example, evaluated a cohort of 50 adults with VCFS, and found that 30% had a psychotic disorder, with 24% of those individuals meeting the criteria for schizophrenia. In addition, 12% of the total cohort had symptoms that fulfilled the criteria for major depression without psychosis. Little is known about how the 22q.11 deletion affects brain development, ultimately producing the neurocogni- tive and neuropsychiatric phenotype that is characteristic of VCFS patients. Initial qualitative reports of MRI findings in these patients described the presence of smaller than normal cerebellar vermi, brainstem and posterior fossa, enlarged sylvian fissure, cysts adjacent to the anterior ventricular horns, and white matter hyperintensi- From the Kennedy Krieger Institute (WRK, CPB, MGr, WEK); the Division of Psychiatric Neuroimaging (WRK, GDP), and the Departments of Psychiatry and Behavioral Science (WRK, MGr, WEK, GDP), Pediatrics (EWJ, JR, AMM, MGe, WEK), Medicine (EWJ), Plastic Surgery (EWJ), Pathology (WEK), and Neurology (WEK), Johns Hopkins University School of Medicine; and the Department of Mental Hygiene, Johns Hopkins University School of Public Health (GDP), Baltimore, Maryland. Address reprint requests to Wendy R. Kates, Ph.D., Division of Psychiatric Neuroimaging, Johns Hopkins University School of Medicine, Meyer 3-166, 600 N. Wolfe Street, Baltimore, MD 21287. Received January 28, 2000; revised July 24, 2000; accepted July 31, 2000. © 2001 Society of Biological Psychiatry 0006-3223/01/$20.00 PII S0006-3223(01)01002-7