Velocardiofacial Syndrome: Is There a Neuropsychiatric Phenotype? Edith M. Jolin, MD, MPH, Elizabeth B. Weller, MD, and Ronald A. Weller, MD

Corresponding author Elizabeth B. Weller, MD Children’s Hospital of Philadelphia, Department of Child and Adolescent Psychiatry, 3440 Market Street, Suite 200, Philadelphia, PA 19104 E-mail: [email protected]

the constellation of observable cognitive, developmental, and psychiatric symptoms associated with this genetic syndrome [5••].

Current Psychiatry Reports 2006, 8:96 –101 Current Science Inc. ISSN 1523-3812 Copyright © 2006 by Current Science Inc.

Early History

A neuropsychiatric phenotype specific to the velocardiofacial syndrome (VCFS) has not yet been identified. Neuropsychological research suggests that children with VCFS have problems in the domains of cognition, attention, and social interaction. Preliminary psychiatric studies of children and adolescents with VCFS suggest that they may be at higher risk than their nonaffected peers to develop mood disorders (including bipolar disorder), anxiety disorders, and attention deficit disorders. An unresolved question remains whether adults are at higher risk to develop psychotic mood disorders or schizophrenia in early adulthood. A research paradigm developed by Robins and Guze for the validation of psychiatric disorders may be helpful. Systematic studies in the areas of phenomenology, neurobiology, heredity, and the natural course of VCFS may clarify its psychiatric manifestations. Better understanding of the neuropsychiatric phenotype associated with VCFS will better inform ongoing genetic research. The study of VCFS holds the potential to give important insight into the pathogenesis of psychiatric disorders.

Introduction Velocardiofacial syndrome (VCFS) is one of the most common congenital malformation syndromes [1]. Most cases occur sporadically and are associated with a twoto three-million–nucleotide base deletion, encompassing up to 30 genes, on one copy of chromosome 22 [2••]. VCFS has been associated with an increased susceptibility to psychiatric disorders, particularly schizophrenia, in early adulthood [3,4]. The purpose of this paper is to systematically review the literature on the neurocognitive, neuroanatomic, and psychiatric findings of VCFS and assess the status of the neuropsychiatric phenotype,

Velocardiofacial syndrome was first described in 1978 by Shprintzen et al. (Montefiore group) [6] in 12 children referred to a craniofacial disorders clinic for evaluation of cleft palates, velopharyngeal insufficiency, and hypernasal speech. Upon examination, most of these children had overt or submucous clefts of the secondary palate, conotruncal cardiac defects (most often ventricular septal defects) and facial anomalies such as long facies, flat malar regions, and broad nasal bridges. Two children had mental retardation and 11 had nonverbal learning disabilities. Nonspecific findings included hypotonia in infancy, poor fine motor coordination, slender hands and digits, and small stature. It was suspected these malformations had occurred at 6 to 8 weeks of gestation but a familial link was established for only two patients, who had a family member with similar clinical findings. Golding-Kushner et al. (Montefiore group) [7] reported the first psychological data on 26 children and adolescents with VCFS. Psychometric testing found that mean verbal and performance intelligence scores fell in the borderline to low-average range and several patients tested in the mildly mentally retarded range. Personality observations included a bland affect with minimal facial expression and an impaired social interaction style characterized as “disinhibited and impulsive or serious and shy.” In 1992, Shprintzen et al. [3] reported severe psychiatric symptoms, often diagnosed as schizophrenia, in 12 of 90 patients with VCFS (13%). The mean age of onset of psychiatric symptoms was 14 years. Pulver et al. [4] conducted systematic psychiatric assessments at the Montefiore Center of 14 patients over age 15 with VCFS. Psychiatric histories of relatives were gathered through telephone interviews. A consensus diagnosis was reached by a psychologist and a psychiatrist, who independently reviewed the results of a semistructured clinical interview and medical records. Of the 14 patients, 11 (79%) received a DSM-III-R [8] psychiatric diagnosis. Schizophrenia or schizoaffective disorder was diagnosed in four

Velocardiofacial Syndrome: Is There a Neuropsychiatric Phenotype?

patients (29%). Three of these four patients had comorbid anxiety disorders, which included phobias and obsessivecompulsive disorder. Other diagnoses included alcohol abuse and adjustment disorders with depressed mood. Psychotic disorders in second- and third-degree relatives were reported by 25% of the families in the study. The authors suggested a genetic association between VCFS and schizophrenia. Advances in molecular genetics in the early 1990s established that in over 90% of cases, VCFS is associated with a submicroscopic deletion on the long arm (designated q) of chromosome 22 [2••,9]. Most VCFS cases occur de novo; about 10% are familial and inherited in an autosomal dominant manner [9]. Cytogenetic techniques facilitated confirmation of chromosome 22q11 deletions in patients with suspected VCFS. The fluorescent in situ hybridization (FISH) technique uses fluorescent markers to identify missing pieces of DNA [5••]. VCFS became diagnosable with a degree of certainty not previously possible with clinical examination alone [10]. The remainder of this report focuses on studies of patients with VCFS with confirmed chromosome 22q11 deletions.

Neurocognitive and Behavioral Profile of Children and Adults with VCFS Swillen et al. [11] reported on the development, intelligence, and behavior of 37 children and adolescents between the ages of 8 months and 20 years who had VCFS with FISH-confirmed chromosome 22q11 deletions. Most children had histories of delayed motor and language development. Twenty children and adolescents (54%) had borderline or normal intelligence and 17 (46%) had mild mental retardation. Verbal intelligence scores were significantly higher than performance intelligence scores. Of 12 patients with a familial deletion, 10 (83%) had intelligence in the mental retardation range, compared with 7 (28%) of the 25 patients with a de novo deletion. Child behavior checklists completed by parents of children aged 4 to 18 years (n = 19) revealed problems in the areas of social functioning and attention. In a later study, Swillen et al. [12] made cross-sectional observations on the behavioral phenotype of 60 children and adolescents with chromosome 22q11 deletions. Teachers, parents, and adolescents filled out questionnaires that spanned 112 behaviors. From preschool through adolescence, problem behaviors consistently emerged in the four domains of social relations, shyness, attention deficits, and thought patterns. Thought problems such as “seeing and hearing things” were significantly associated with degree of intellectual impairment. Overall, the informants reported more internalizing problems (depression and anxiety) than externalizing problems (aggression and delinquency). Gerdes et al. [13] reported on the cognitive and neurodevelopmental outcomes of 40 preschool children aged

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13 to 63 months with FISH-confirmed chromosome 22q11 deletions. Mental development in the toddler group (n = 28) ranged from average (21%) or mildly delayed (32%) to significantly delayed (46%). Hypotonia was present in over 54% of the toddlers, and 79% had motor development in the significantly delayed range. The IQ scores of the preschoolers (n = 12) were average to borderline in 67%; mild mental retardation was present in 33%. A statistically significant difference of 9 points was noted between verbal and performance IQ scores in 44% of the preschoolers. Language skills were delayed in all children and 50% experienced voice dysfunction. Of the children over 2 years old, 62.5% did not speak by age 2. Whereas toddlers were within normal limits on behavioral measures, 75% of the preschoolers exhibited impulsive, disorganized, and highly emotional behavior. Overall, children with de novo deletions (87.5%) had significantly higher cognitive-measure scores than children with familial deletions. Moss et al. [14] examined the psychoeducational profile of 33 patients aged 6 to 27 years with VCFS and FISH-confirmed chromosome 22q11 deletions. Full scale intelligence scores ranged from average to moderate mental retardation. Their cohort demonstrated significantly higher mean verbal IQ scores than mean performance IQ scores. To better isolate verbal and nonverbal skills, composite verbal comprehension and perceptual organization factor scores were derived from IQ subtests. Comparison of the factor scores revealed an even greater, significant difference between verbal and performance IQs. Mathematics achievement scores were significantly lower than reading and spelling scores. The authors concluded that their findings were consistent with a pattern suggesting a nonverbal learning disability in patients with VCFS. Wang et al. [15] conducted developmental pediatric evaluations in 36 school-aged children with FISH-confirmed deletions. The children demonstrated a significant difference between verbal and performance IQ scores and significantly lower achievement scores in mathematics than in reading and spelling. These researchers tested the hypothesis that mathematics deficits are associated with impairments in visuospatial short-term memory. Subtests from the Kaufman Assessment Battery for Children (KABC) [16] were administered to assess short-term memory. The children scored one standard deviation below the normal population on the spatial short-term memory subtest, supporting the authors’ hypothesis. There are relatively few studies on the neuropsychological profiles of adults with VCFS. Henry et al. [17] compared 19 adults with VCFS confirmed by FISH testing with 19 control subjects matched by IQ, age, and sex. Similar to children and adolescents with VCFS, 58% of the adults with VCFS had borderline or normal intelligence and 42% fell in the mild mental retardation range. In contrast to children and adolescents with VCFS, however, less than half (32%) of the adults with VCFS

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demonstrated a significant difference between verbal and performance IQ scores. Compared with the control group, adults with VCFS demonstrated deficits in visuoperceptual and executive functioning. The VCFS group planned less and performed significantly worse on problem-solving tasks than the controls. No differences between the two groups were noted on attention and memory tests. In a recent study, the same research group compared 13 subjects with VCFS and schizophrenia (mean age 33 years) with a matched group of 15 subjects with VCFS without schizophrenia (mean age 34 years) [18]. No significant differences between verbal and performance intelligence scores were noted between the two groups. Compared with controls, the VCFS group with schizophrenia performed worse on cognitive tests measuring spatial working memory and strategy formation, visual recognition, and attention. The authors concluded that cognitive deficits associated with schizophrenia in adults with VCFS most likely involve the frontal lobe.

Structural Brain Abnormalities Brain imaging may be a useful tool to study the neurobiologic consequences of chromosome 22q11 deletion in VCFS. Quantitative MRI analyses have found white-matter volume abnormalities in the brains of children and adolescents with VCFS. Eliez et al. [19] compared 15 children and adolescents with FISH-confirmed chromosome 22q11 deletions with 15 controls. They reported an 11% total reduction in brain volume in subjects with VCFS. Whitematter volume reduction was greater than gray-matter volume reduction (16.3% vs 7.5%). There was loss of parietal symmetry due to loss of gray matter in the left parietal lobe of children with VCFS, compared with controls. Subsequent studies have also supported the finding of white-matter volume changes in children and adolescents with VCFS. Kates et al. [20] reported that 10 children with VCFS had greater non–frontal lobe whitematter volume reductions than age- and gender-matched controls. Barnea-Goraly et al. [21] examined white-matter structure in 19 subjects with VCFS who ranged in age from 7 to 22 years (mean 12.2 years), compared with controls. The authors employed diffusion tensor imaging technology to assess the integrity of water-molecule movement within axons. Compared with controls, patients with VCFS had evidence of white-matter structural alterations throughout the frontal, temporal, and parietal lobes bilaterally, as well as in tracts connecting the frontal and temporal lobes. A recent high-resolution MRI study by Bearden et al. [22] found a 4.3% decrease in total brain volume, more pronounced (9.1% reduction) for cortical white matter, in 13 children with VCFS who were compared with nine control subjects. Temporal gray-matter volume correlated positively with full scale IQ scores and negatively with thought problem scores on a behavioral checklist.

Quantitative neuroimaging studies have revealed reductions of white-matter volume in adults with VCFS. van Amelsvoort et al. [23] compared MRI studies of 10 patients with VCFS (mean age 32 years) and 10 control subjects (mean age 37 years) matched for IQ, sex, and socioeconomic status. The patients with VCFS had a significantly smaller cerebellum and reduced white-matter volume bilaterally in several regions, including the frontal lobes and tracts extending to temporoparietal and occipital regions.

Psychiatric Disorders in Adults with VCFS The early cautionary reports of Shprintzen and colleagues [3,4] that VCFS might be associated with psychosis prompted further psychiatric investigation. Karayiorgou et al. [24] conducted a study to determine the prevalence of chromosome 22q11 deletions in schizophrenic patients. They evaluated a randomly chosen subset of 100 patients from a sample of 695 adults hospitalized with schizophrenia or schizoaffective and schizophreniform disorders. Chromosome 22q11 deletions were detected in two patients, suggesting a 2% prevalence of VCFS in schizophrenic patients. In a subsequent study of 207 schizophrenic patients, Karayiorgou et al. [25] found chromosome 22 deletions in three patients (1.5% prevalence). The elevated rate of chromosome 22q11 deletions in adults with schizophrenia, compared with the 1 in 6000 (0.017%) rate in the general population [26] spurred further investigation. Arinami et al. [27] screened for chromosome 22q11 deletions in 300 Japanese patients who met DSM-III-R [8] criteria for schizophrenia and 300 unrelated healthy volunteer controls. Only one patient with schizophrenia (0.3%) had a chromosome 22 deletion confirmed by FISH. She had no palatal, cardiac, or facial abnormalities but did have mild mental retardation. The authors concluded that their results did not support the premise that a high proportion of patients with VCFS develop schizophrenia. Ivanov et al. [28] analyzed whether there was an increased rate of VCFS in patients with early-onset psychosis, defined as onset before age 18. They checked for chromosome 22q11 deletions (with genotyping rather than FISH technique) in 192 patients with early-onset psychosis and 329 patients with adult-onset schizophrenia. No chromosome 22q11 deletions were detected in patients with early-onset psychosis and only one chromosome 22q11 deletion was found in the adult-onset group. Their study excluded patients with IQ scores less than 70, which may account for the lower prevalence of chromosome 22q11 deletions. Bassett et al. [29] predicted that there would be a high rate of chromosome 22q11 deletions in patients with a major psychiatric disorder who also had two or more VCFS phenotypic features such as cleft palate,

Velocardiofacial Syndrome: Is There a Neuropsychiatric Phenotype?

cardiac anomalies, craniofacial defects, or history of learning difficulties. They were referred 17 patients with schizophrenia or schizoaffective disorders and two or more VCFS features. Psychiatric diagnoses were based on clinical interviews and review of medical records by two psychiatrists. Of the 17 patients, 10 (59%) had chromosome 22q11 deletions confirmed by FISH. Of the 10 patients with deletions, nine had cognitive impairment and attended special education classes. Five patients had the onset of psychosis by age 18. They also displayed more aggression and temper outbursts. Murphy et al. [30] evaluated 50 patients with VCFS who were recruited mostly from genetics clinics. Psychiatric diagnoses were based on semistructured interviews and medical records. Of the 50 patients, 48 had FISH-confirmed chromosome 22q11 deletions. Overall, 21 patients (42%) had a major psychiatric disorder; 15 (30%) had a psychotic disorder and 12 (24%) met DSM-IV [31] criteria for schizophrenia. One patient had schizoaffective disorder (bipolar type), one patient had bipolar disorder with psychotic features, and one had psychotic disorder not otherwise specified. Six (12%) had major depression without psychosis. The schizophrenic patients with VCFS had fewer negative symptoms and a significantly later age of onset (26 years vs 19 years) than schizophrenic controls without VCFS. Schizotypy scores were significantly higher in patients with VCFS with psychosis than in patients with VCFS without psychosis. The authors cautioned that small sample size and ascertainment bias could have affected their findings.

Psychiatric Disorders in Children and Adolescents Psychiatric studies of patients with VCFS have often included combined groups of children, adolescents, and adults. Relatively few studies have focused exclusively on children. Papolos et al. [32] (Montefiore group) conducted a systematic study of psychiatric disorders in a group of 25 patients with clinically diagnosed VCFS. The study group included 19 children and adolescents aged 5 to 18 years (mean 12.6) and six adults. All were screened with psychiatric diagnostic instruments and were clinically interviewed. Consensus diagnoses were reached by two psychiatrists after review of available medical and psychiatric records. In children and adolescents, bipolar disorder (primarily bipolar II) was the most prevalent diagnosis (53%), followed by attention-deficit/hyperactivity disorder (ADHD, 47%), anxiety disorders (21%), depressive disorders (16%), and oppositional defiant disorder (ODD) (11%). All six adults had a diagnosis of bipolar spectrum disorder and four had psychotic symptoms. The authors proposed a possible association between VCFS and early-onset bipolar disorder. Carlson et al. [33] performed chromosome deletion evaluations in the patients with VCFS from the previ-

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ous study [32]. One of the children from the original group was not included and two additional children were recruited for testing. FISH and DNA marker analysis, using 14 different probes, revealed that 24 of the 26 patients had a chromosome 22q11 deletion. The authors could not rule out a very small deletion in the remaining two patients. Usiskin et al. [34] investigated whether VCFS was associated with a more severe, neurodevelopmental subtype of schizophrenia with early onset. Over an 8-year period, they reviewed more than 1000 medical records at the National Institute of Mental Health and recruited 47 patients with childhood-onset schizophrenia, defined as onset by age 12. MRI scanning and genetic testing were completed for all patients. Chromosome 22q11 deletions were detected in three patients (6.4%), a rate higher than the previously reported 2% chromosome 22q11 deletion rate in adult-onset schizophrenia. Brain imaging found increased corpus callosum and ventricular volumes, compared with controls. All three patients with chromosome 22q11 deletions had neurodevelopmental delays and special-education placement. Arnold et al. [35] assessed a group of 20 children and adolescents (mean age 11.0 years) with VCFS and chromosome 22q11 deletions confirmed by FISH and compared them with non-VCFS sibling controls. All subjects were screened for psychiatric disorders with a semistructured interview and a symptom checklist. The parents served as informants. Two clinicians, one of whom was a child psychiatrist, reached consensus diagnoses. Depressive disorders (four cases of major depression and four cases of dysthymia) were significantly more common among patients with VCFS than among sibling controls (40% versus 0%, P < 0.02). On follow-up, two of three patients with VCFS and schizotypal traits developed frank psychotic symptoms during adolescence and were diagnosed with schizophrenia at ages 16 and 22 years. Three of the children with VCFS had a parent with a chromosome 22q11 deletion. These three parents had past histories of mood disorders, which included bipolar disorder, major depression with comorbid anxiety, and depression associated with Parkinson’s disease. Feinstein et al. [36] investigated whether children with VCFS and cognitive impairments had higher rates of psychiatric disorders than children with similar developmental delays without VCFS. They compared 28 children and adolescents (mean age 12.3 years) with VCFS confirmed by FISH with a control group matched for age, sex, mean full scale IQ, and language skills. The parents of both groups completed a number of diagnostic instruments and a brief unstructured interview by a child psychiatrist. High rates of anxiety disorders (phobias 61%, generalized anxiety disorder 29%, and separation anxiety disorder 21%), ADHD (46%), and ODD (43%) were found in the group with VCFS. Similar rates of these disorders were also found in the control group, however. Of note, the control group

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had higher rates of lifetime major depression (41% vs 18%), a difference that nearly reached statistical significance. The authors discussed the possibility that ascertainment bias and small sample size could have obscured true differences between the two groups. Gothelf et al. [37] assessed the rate of psychiatric disorders in 43 consecutive patients aged 6 to 40 years (mean 18.3) who had VCFS with confirmed chromosome 22q11 deletions. Subjects and their parents were evaluated with semistructured interviews. The Yale-Brown ObsessiveCompulsive Scale [38] was administered to all patients. A child and adolescent psychiatrist interviewed all subjects. ADHD was the most prevalent diagnosis (37%), followed by obsessive-compulsive disorder (33%), phobias (33%), and dysthymia (21%). Six (26%) of the 23 adult patients had a diagnosis of a psychotic disorder with a mean age of onset of 19 years. Niklasson et al. [39] conducted neuropsychological and neuropsychiatric assessments in a clinical sample of 17 children and adolescents aged 5 to 18 and three adults aged 20 to 34. Two of the adults were mothers of children in the study. All patients had FISH-confirmed deletions. Parents of the children completed semistructured interviews, conducted by a child and adolescent psychiatrist (14 patients) or a general psychiatrist (six patients). Ten patients had normal to borderline intelligence, eight patients had mild mental retardation, and two patients had moderate mental retardation. Wide discrepancies (≥ 13 points) between verbal and performance IQ scores were noted in three patients. Eleven patients met criteria for ADHD, primarily inattentive type. One child had autistic disorder; six met criteria for pervasive developmental disorder, not otherwise specified (PPD, NOS); and 10 other patients had one to three autistic traits. In addition to deficits in sustaining attention, many patients had difficulty initiating activity and many had noticeably reduced spontaneous facial expression. The authors tentatively concluded that VCFS may have a characteristic profile of cognitive, attentional, and social problems.

Conclusions A neuropsychiatric phenotype specific to VCFS has not yet been identified. There is considerable variability in the neurocognitive and psychiatric expression of VCFS, although familial occurrence appears associated with more severe cognitive deficits. Many children with VCFS, even those with normal intelligence, appear to have delayed milestones in motor and language development. Many children demonstrate a significant split between verbal and performance intelligence scores suggestive of a nonverbal learning disability. Abnormalities in brain white-matter tracts have been reported in patients with VCFS but their relationship to cognitive deficits and psychiatric symptoms remains to be determined. Although as many as 30% of patients with VCFS may develop a

psychiatric disorder in early adulthood, whether they are more at risk to develop a mood disorder with psychosis or schizophrenia remains an unresolved question. Psychiatric studies of children and adolescents with VCFS suggest that they may be at higher risk than their nonaffected peers to develop a mood disorder (including bipolar disorder), anxiety disorder, ADHD, or ODD, but results remain inconclusive. Available studies are hindered by several methodologic issues such as lack of control groups, small samples, and ascertainment bias. Further research to delineate the neuropsychiatric phenotype associated with VCFS is warranted. A paradigm for the validation of psychiatric diagnoses by Robins and Guze [40] recommends systematic study in the areas of phenomenology, neurobiology, natural course, and heredity. From a phenomenologic standpoint, many patients with VCFS have neurocognitive and social-skills deficits that may complicate the diagnostic interview process. Assessments by child and adolescent psychiatrists may help to discriminate communication and developmental issues from pathologic mood and thought processes. Future neurobiologic studies need to correlate their findings with neuropsychiatric symptomatology. Longitudinal psychiatric assessments of larger samples of patients with VCFS are needed to appreciate the natural course of the syndrome and ascertain the true prevalence rates of psychiatric symptoms. Detailed psychiatric family histories may help elucidate whether children with VCFS have an underlying diathesis for mood or psychotic disorders. Clarification of the neuropsychiatric phenotype associated with VCFS will better inform ongoing genetic research as it attempts to isolate the gene or genes in the deletion region etiologically related to neuropsychiatric symptoms. The study of VCFS holds the potential to give important insight into the pathogenesis of psychiatric disorders.

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