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The neuropsychological phenotype of velocardiofacial syndrome (VCFS): Relationship to psychopathology
Archives of Clinical Neuropsychology 21 (2006) 175–184
The neuropsychological phenotype of velocardiofacial syndrome (VCFS): Relationship to psychopathology Ren´ee Lajiness-O’Neill a,∗ , Isabelle Beaulieu b , Alexander Asamoah c , Jeffrey B. Titus b , Erawati Bawle d , Saadia Ahmad e , John W. Kirk f , Rebecca Pollack c b
a Eastern Michigan University, Ypsilanti, MI, USA Department of Behavioral Health, Division of Neuropsychology, Henry Ford Health System, Detroit, MI, USA c Department of Genetics, Henry Ford Health System, Detroit, MI, USA d Department of Genetics, Children’s Hospital of Michigan, Detroit, MI, USA e University of Winsdor, Ozad Institute, Windsor Regional Children’s Center, Windsor, Ont., Canada f The Johns Hopkins School of Medicine and Kennedy Krieger Institute, Baltimore, MD, USA
Accepted 6 September 2005
Abstract Children with velocardiofacial syndrome (VCFS; N = 14) and a comparison group of siblings (N = 8) underwent comprehensive neuropsychological assessment to examine the relationship between cognitive functioning and psychopathology. Significant group differences were obtained on tests of full scale and verbal intellectual functioning and perceptual–motor skills. With the exception of performance on tests of attention and executive functioning, children with VCFS displayed a profile consistent with nonverbal learning disability (NLD). However, within group comparisons revealed significantly poorer visuospatial intellectual and nonverbal memory functioning in sibling controls as well. No significant group differences were obtained on tests of motor speed, academic, language, attention, memory, or executive functioning, with significant variability in children with VCFS frequently accounting for the lack of robust differences. Parent-report measures revealed profiles consistent with ADHD. No clinically significant symptoms of psychosis, depression or anxiety were noted on either self- or parent-report measures. Wisconsin Card Sorting Test performance was found to be highly and negatively correlated with the Thought Problems subscale of the Child Behavior Checklist (CBCL) for VCFS children only, suggesting a possible at-risk indicator for later onset psychopathology. © 2005 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. Keywords: Neuropsychology; Genetics; Velocardiofacial syndrome; 22q11 deletion syndrome; Psychopathology
Velocardiofacial syndrome (VCFS) is one of the most prevalent genetic disorders and has been found to be one of the most common causes of learning disability and mild mental retardation, with an estimated prevalence of 1 in 4000 (Gothelf & Lombroso, 2001). It is caused by a microdeletion in the long arm of chromosome 22, and its clinical characteristics include congenital heart disease, palatal abnormalities, hypocalcemia and T-cell immunodeficiency, and abnormal facies that include a bulbous nasal tip and prominent nasal root, narrow and with flat cheeks, narrow palpebral fissures, small mouth, receding chin, and small cupped ears (Gothelf & Lombroso, 2001; Sphritzen et al., 1978).
∗
Corresponding author. Tel.: +1 313 876 2526; fax: +1 313 876 2279. E-mail address: [email protected] (R. Lajiness-O’Neill).
0887-6177/$ – see front matter © 2005 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.acn.2005.09.001
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Children with VCFS have been found to have a substantially greater risk for the development of schizophrenia and bipolar disorder with approximately 25–30% developing psychotic symptoms in adolescence, and the prevalence of schizophrenia 25 times that of the general population (Eliez, Antonarakis, Morris, Dahoun, & Reiss 2001; Gothelf & Lombroso, 2001). This makes a diagnosis of VCFS the highest known risk factor for the development of schizophrenia. While the gene or genes that cause the 22q11 microdeletion are unknown, the gene for encoding catechol-O-methyltransferase (COMT), an enzyme responsible for the degradation of dopamine, is located within this region. It has been suggested that the genes deleted in VCFS may assume a similar role in the pathophysiology of schizophrenia (Gothelf & Lombroso, 2001). Children with VCFS have also been purported to exhibit a nonverbal learning disability (NLD) (Rourke, 1989), primarily based on their intellectual and achievement profile. Children with VCFS typically function within the Borderline range of intellectual ability (Moss et al., 1999), and higher Verbal relative to Performance intellectual quotients have consistently been reported (Gothelf & Lombroso, 2001; Moss et al., 1999). Moreover, as noted, children with VCFS typically display weaknesses in mathematics, often reaching the level of a learning disability. Investigations have suggested relative strengths in reading and spelling; although, studies have not specifically addressed reading comprehension, an often noted area of weakness in NLD. As stated by Wang, Woodin, KrepsFalk, & Moss (2000), while the psychoeducational profile may assist in the diagnostic process, what is more critical is an “elucidation of the fundamental cognitive abilities associated with each syndrome (such as VCFS), and an understanding of how psychoeducational abilities and disabilities derive from the underlying cognitive phenotype” (p. 423). While Rourke (1989) acknowledges that individuals with NLD frequently possess language impairment, the deficits are most often in the area of pragmatics, and not necessarily consistent with the significant mixed receptive and expressive language delays reported in VCFS, lending debate to the NLD distinction and suggesting the need for more comprehensive assessment (Scherer, D’Antonio, & Kalbfleisch, 1999). The literature is equivocal with respect to the quality of language impairments (Moss et al., 1999; Scherer et al., 1999). Gerdes et al. (1999) identified significant delays in motor milestones; although, no studies to date have specifically examined fine motor functioning in these children. Only a few studies examining the neuropsychological phenotype have been reported in the literature, and the domains examined have been limited (Bearden et al., 2001; Woodin et al., 2001), especially with regard to visual attention or complex visual memory. For example, in a study by Wang et al. (2000) examining short-term recall, approximately two-thirds of the children scored higher on Number Recall relative to Spatial Memory. In addition, although attention-deficit hyperactivity disorder is a frequently reported comorbid feature (Gerdes et al., 1999; Moss et al., 1999), no studies have comprehensively examined attentional or executive functioning in children with VCFS. Despite the extremely high prevalence of psychopathology in VCFS, to date, no studies have examined the relationship between the behavioral and cognitive phenotype. That is, which cognitive weaknesses may serve as markers and suggest a risk for the onset of schizophrenia or bipolar disorder? Moreover, research on VCFS has been primarily descriptive in nature, without consideration of the need for control populations. The first aim of this study was to expand on previous research by more accurately characterizing the neurocognitive phenotype in velocardiofacial syndrome relative to sibling controls. It was hypothesized that children with VCFS would demonstrate evidence of impaired neurocognitive performance, with significant deficits noted on measures of frontotemporal functioning consistent with their psychiatric risk relative to a comparison group of siblings. We hypothesized that NLD would only partially characterize this heterogeneous disorder, and that the neurocognitive and neurobehavioral phenotype in children with VCFS would likely assume an intermediate position between profiles reported in the literature on children with autistic disorder and William’s syndrome. The second aim of the present study was to obtain standardized neurobehavioral measures on children with both VCFS and control children in order to identify patterns of psychopathology. It was hypothesized that children with VCFS would demonstrate elevations on scales of the Child Behavior Checklist (CBCL) that are sensitive to mood disorders and psychoses (i.e., Anxious/Depressed and Thought Problems), relative to control children. The third aim of the study was to identify potential cognitive predictors of neurobehavioral functioning in children with VCFS, relative to sibling controls. It was hypothesized that performance on measures of memory and executive functioning would correlate with current pathology as measured on behavioral indices, and as an indirect measure of those at risk for later onset schizophrenia or bipolar disorder.
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1. Method 1.1. Participants Participants included 14 children and adolescents with a diagnosis of a 22q11.2 deletion (9 males, 5 females) and 8 siblings of individuals diagnosed with this deletion (5 males, 3 females), recruited through the Department of Genetics at Henry Ford Health System, Children’s Hospital of Michigan or through local advertisement. Mean age of the children diagnosed with 22q11.2 deletion syndrome was 12.6 (S.D. = 6.4; range 7–17) and mean education level was 6.1 years (S.D. = 4.6; range 6–13). Thirteen (93%) of the children with 22q11.2 deletion syndrome were Caucasian and one (7%) was African American. Mean age of the siblings was 11.4 (S.D. = 5.6) and mean education level was 5.8 (S.D. = 4.9). Seven (87%) of the siblings were Caucasian and one (13%) was African American. The diagnosis of VCFS was confirmed by fluorescent in situ hybridization (FISH) conducted by the Cytogenetics Laboratory at Henry Ford Health System. There were no significant group differences with respect to age, t(22) = .44, P = .66, or years of education, t(22) = .19, P = .85. Of the 14 children with 22q11.2 deletion syndrome, 5 (36%) had a 22q11.2 deletion that was de novo in origin and 2 (14%) had a maternal deletion ruled out, though the fathers had not been tested. Exclusion criteria included pre- or perinatal pathology, head injury or previous neurological compromise, or history of substance abuse. 1.2. Neuropsychological procedures/protocol Each participant underwent comprehensive neuropsychological testing that included assessments of intellectual, academic, motor and perceptual–motor functioning, visuospatial processing, speech/language, verbal and visual memory, attention, executive functioning, and neurobehavioral and emotional functioning. Relevant constructs were assessed based upon tasks standardized to be appropriate for given ages. Neurobehavioral functioning was examined through behavioral indices completed by age appropriate participants and parents. Screening measures of depression and anxiety were administered to all children capable of completing self-report questionnaires. 1.2.1. Test administration and scoring Participants were scheduled for individual appointments and tested in the Division of Neuropsychology in the Department of Behavioral Health at Henry Ford Health System. All ethical guidelines as outlined by the American Psychological Association were followed. Participants were individually administered the neuropsychological battery of tests by a trained psychometrician or Ph.D. level graduate student in psychology who was blind to the study’s specific hypotheses. The following measures were included in the battery to examine the respective domains: Intellectual: Wechsler Intelligence Scale for Children—Third Edition (WISC-III, 1991) or Wechsler Adult Intelligence Scale; Academic Achievement: Wide Range Achievement Test-3 (Wilkinson, 1993), Gray Oral Reading Test-3 (Wiederholt & Bryant, 1992); Motor Functioning: Grooved Pegboard Test (Klove, 1963); Perceptual–Motor/Visuospatial: Developmental Test of Visual–Motor Integration (Beery, 1997), Motor Free Visual Perception Test (Colarusso & Hammill, 1995), Judgment of Line Orientation (Benton, Sivan, Hamsher, Varney, & Spreen, 1994); Speech and Language: Controlled Oral Word Association (Goodglass & Kaplan, 1983; Spreen & Benton, 1969, 1977), Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983), Tokens Test (Spreen & Benton, 1969, 1977); Learning and Memory: Test of Memory and Learning (Reynolds & Bigler, 1994); Attention/Executive Functioning: Test of Variables of Attention (Leark, Dupuy, Greenberg, Corman & Kindschi, 2000), Wisconsin Card Sorting Test (Heaton, 1981), Stroop Test (Golden, 1978), Behavior Rating Inventory of Executive Function (BRIEF) (Gioia, Isquith, Guy & Kenworthy, 1996); Behavioral Questionnaires: Child Behavior Checklist (Achenbach, 1991), Conners’ Parent Rating Scale (Conners, 1997); Affective Measures: Children’s Depression Inventory (Kovacs, 1992), Revised Children’ Manifest Anxiety Scale (Reynolds & Richmond, 1997). 1.3. Data analysis Group differences on cognitive and behavioral indices between children with VCFS and their siblings was examined with the t statistic. Standard scores (SS) were used in the analyses of intellectual, academic, visuospatial (with the
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exception of the JOLO in which raw scores were used), memory functioning, and the behavioral indices. Standard Z scores were derived for the analyses of the motor and speech and language variables using norms for the mean age of the cohort. This analysis was conducted to examine whether significant differences existed between the groups, thus allowing for a robust examination of the relationship between cognitive and neurobehavioral variables. Eta squared (ε2 ) was conducted to examine effect sizes. Pearson-product or Spearman correlation coefficients were completed to examine the relationships between cognitive and neurobehavioral variables. Subscales III (Anxiety/Depression) and IV (Thought Problems) of the CBCL were used as the primary criterion variables. A Bonferonni correction was used and the P-value established at .001 when making between group comparisons and when examining the relationships between cognitive and behavioral variables to decrease the likelihood of Type I error given the number of comparisons made. Within-group comparisons were examined by paired sample t statistics and for these comparisons a .05 P-value was retained. 2. Results 2.1. Neuropsychological phenotype 2.1.1. Intellectual/achievement Consistent with the existing literature, the groups differed significantly on Verbal IQ and Full Scale IQ and approached significance with respect to Performance IQ, with the VCFS group scoring approximately 2 S.D. below their siblings. The children with VCFS displayed significantly lower Performance relative to Verbal IQs, t(13) = 4.1, P = .001; however, a similar pattern was noted in the siblings, t(7) = 2.4, P = .05. There were no significant group differences noted with respect to sight reading, spelling, reading comprehension, or math performance. However, a trend was noted between the groups on math performance and the effect size was large. Examination of within group differences revealed that the VCFS group displayed significantly poorer performance on tests of math relative to reading, t(14) = 4.2, P = .001, and spelling, t(14) = 3.9, P = .002. 2.1.2. Motor/visuospatial/perceptual–motor There were no significant group differences noted on tests of fine motor speed and dexterity, bilaterally. However, children with VCFS displayed significantly poorer performance on tests of perceptual–motor functioning. In contrast, there were no significant group differences noted on visual–spatial tests for which motor demands were eliminated, specifically performance on the Judgment of Line Orientation test and Motor Free Visual Perception Test—Third Edition (MVPT-III). 2.1.3. Speech and language functioning There were no significant differences noted between the groups on tests of speech and language functioning. Specifically, group differences in phonemic fluency, semantic fluency, confrontational naming, and receptive language (i.e., Tokens Test), all fell below significance. Differences between groups on semantic fluency approached significance and the effect size was large. Table 1 presents the means, standard deviations, t scores, P values, and effect sizes for children with VCFS and sibling controls on tests of intellect, achievement, motor, visual–spatial/perceptual–motor, and speech/language functioning. 2.1.4. Memory and learning There were no significant group differences noted between children with VCFS and their siblings on all core memory indices. However, trends were noted, particularly with respect to the Composite Memory Index, and large effect sizes were evident on all indices. Overall, children with VCFS performed more poorly on the Verbal Memory Index, Nonverbal Memory Index, and Composite Memory Index than their siblings. Within group comparisons revealed significantly lower performance on measures of nonverbal relative to verbal memory for the VCFS group, t(8) = 4.3, P = .003. However, of note, within group comparisons also revealed a similar significant discrepancy in the sibling group, t(7) = 4.7, P = .003. Table 2 presents the means, standard deviations, t scores, P values, and effect sizes for each group on the Test of Memory and Learning.
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Table 1 Mean standard scores, standard deviations, t scores, P values, and effect sizes for the intellectual, academic, motor, perceptual–motor, visuospatial, and speech/language variables VCFS participants, M (S.D.)
Sibling controls, M (S.D.)
t-score
P
ε2
Intellect VIQ PIQ FSIQ
76.7 (11.4) 67.9 (10.3) 70.0 (11.2)
107.5 (16.8) 96.4 (17.9) 102.4 (17.5)
5.1* 4.1 5.3*
.001 .002 .001
.57 .53 .59
Academic WRAT Reading Spelling Arithmetic GORT RQ
86.4 (18.4) 83.4 (16.9) 69.8 (20.5) 73.1 (19.5)
100.3 (10.5) 100.8 (11.4) 94.3 (8.8) 94.0 (22.5)
2.3 2.6 3.2 1.8
.04 .02 .005 .26
.16 .25 .34 .23
Motor Pegs-D Pegs-ND
−6.2 (8.7) −8.5 (10.3)
0.41 (3.6) 0.70 (3.7)
1.8 2.5
.09 .02
.14 .18
Visuospatial/perceptual–motor VMI 77.0 (7.6) MVPT-R 69.9 (22.0) JOLO 11.1 (6.5)
95.4 (8.8) 91.5 (29.2) 20.3 (7.0)
4.6* 1.7 2.8
.001 .11 .01
.59 .17 .34
Speech/language Phonemic fluency Semantic fluency Boston naming Tokens
−1.3 (1.3) −0.15 (0.83) −1.5 (2.1) −1.4 (2.2)
.21 3.7 1.6 1.9
.83 .002 .13 .08
.003 .48 .11 .17
*
−1.5 (1.5) −1.4 (0.57) −3.4 (2.7) −4.0 (3.6)
P < .001.
2.1.5. Attention and executive functioning Unexpectedly, there were no significant differences noted on the Test of Variables of Attention (TOVA) with respect to either errors of inattention (% Omission) or impulsivity (% Commission). There were no significant group differences noted on the Wisconsin Card Sorting Test (WCST) with respect to nonverbal problem solving (conceptual level), flexibility in their approach (perseverative responses), ability to maintain conceptual set, or overall categories achieved, though children with VCFS performed more poorly on all measures and moderate to large effect sizes were evident on most indices. Likewise, there was no significant group difference noted on the Stroop Color and Word Test, with respect to interference effects. Parent report of perceived executive deficits revealed statistically significant group differences and large effect sizes for the Behavior Rating Inventory of Executive Function, with the VCFS group obtaining more elevated scores overall. Table 3 presents the means, standard deviations, t scores, P values, and effect sizes for children with VCFS and siblings controls on tests of attention and executive functioning. 2.1.6. Social and emotional functioning On all scales of the Child Behavior Checklist, scores were more elevated for the VCFS group. While there were no statistically significant differences noted between the groups, trends were noted with perceived attentional difficulties, Table 2 Means, standard deviations, t scores, P values, and effect sizes for the TOMAL Composite Indices
Verbal Memory Index Nonverbal Memory Index Composite Memory Index P < .001.
VCFS participants, M (S.D.)
Sibling controls, M (S.D.)
t-score
P
ε2
88.4 (12.9) 74.8 (12.0) 80.9 (11.9)
105.9 (4.4) 92.4 (8.5) 99.4 (6.1)
3.4 3.3 3.7
.004 .005 .002
.45 .44 .50
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Table 3 Means, standard deviations, t scores, P values, and effect sizes for the Attention and Executive variables VCFS participants, M (S.D.) Attention TOVA (% Omission)
16.6 (24.2)
Mental flexibility/inhibition/problems solving TOVA (% Commission) 8.2 (73.) Stroop interference 49.6 (3.8) WCST—perseveration 85.4 (12.1) WCST—conceptual 85.5 (13.7) WCST—categories 3.6 (1.9) WCST—set failure 1.3 (1.5) Parent report BRIEF BRI BRIEF MI BRIEF GEC *
65.9 (13.6) 68.1 (8.9) 68.3 (9.9)
t-score
P
ε2
8.8 (8.2)
0.8
.42
.04
6.0 (5.4) 51.4 (2.8) 102.4 (14.3) 101.4 (18.0) 5.6 (0.52) 0.75 (1.0)
0.7 1.1 2.9 2.2 3.6 0.8
.48 .28 .01 .04 .003 .42
.03 .07 .31 .22 .33 .04
47.0 (8.1) 51.6 (10.9) 49.7 (9.9)
3.3 3.5 3.9*
.005 .003 .001
.41 .48 .48
Sibling controls, M (S.D.)
P < .001.
t(15) = 3.6, P = .003, and more atypical and repetitive behaviors (i.e., thought problems), t(15) = 3.2, P = .006 in children with VCFS. Interestingly, and inconsistent with the literature, significant group differences were not obtained on scales sensitive to features of childhood depression and anxiety. Nonetheless, as noted, large effect sizes were evident on all scales except those sensitive to somatization, depression/anxiety, and defiant behaviors. Similar results were obtained on the Connors Parent Rating Scale in which children with VCFS were ranked as displaying a significantly greater degree of features of attention-deficit/hyperactivity disorder, relative to siblings, and above average correspondence with DSM-IV criteria for ADHD, Inattentive type and Combined type. Table 4 presents the means, standard deviations, t scores, P values, and effects sizes for children with VCFS and siblings controls on tests of social and emotional functioning. Interestingly, there were no statistically significant differences between the groups on self-report measures of depression (Child Depression Inventory), t(13) = .25, P = .80, and anxiety (Revised Children’s Manifest Anxiety Scale), t(15) = .07, P = .94. 2.2. Relationship to psychopathology There were no statistically significant relationships noted between the cognitive variables and the CBCL III—Anxiety/Depression subscale. The WCST conceptual level was the only variable that was highly and negatively correlated with the CBCL V—Thought Problems subscale, r(8) = −.93, P = .001, suggesting that as CBCL Thought Table 4 Means, standard deviations, t scores, P values, and effect sizes for the Child Behavior Checklist and Connors Parent Rating Scale VCFS participants, M (S.D.)
Sibling controls, M (S.D.)
t-score
(I) Withdrawn (II) Somatic (III) Anxiety/Depression (IV) Social Concerns (V) Thought Problems (VI) Attention (VII) Defiant (VIII) Aggressive
61.4 (13.1) 60.0 (11.5) 58.2 (7.6) 69.0 (12.9) 64.8 (11.0) 72.3 (11.1) 58.4 (7.8) 62.9 (13.1)
51.7 (3.1) 57.0 (4.9) 53.1 (5.6) 55.8 (8.0) 51.0 (2.7) 55.7 (6.1) 55.6 (6.1) 52.9 (3.8)
2.3 0.7 1.5 2.4 3.2 3.6 0.8 2.3
.05 .48 .16 .03 .006 .003 .43 .43
.26 .05 .12 .25 .40 .46 .06 .26
Connors’ Inattention Hyperactive-impulsive Combined
72.0 (8.6) 71.6 (11.6) 73.8 (7.9)
53.4 (8.8) 55.7 (12.3) 54.7 (9.2)
4.4* 2.7 4.6*
.001 .02 <.001
.54 .30 .57
*
P < .001.
P
ε2
CBCL scales
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Fig. 1. Significant relationship between CBCL V standard scores and WCST Conceptual Level Response for VCFS subjects.
Problems scores increased their scores on the WCST decreased (Fig. 1). A trend was also noted suggesting a possible negative relationship between math performance and higher scores on the CBCL V subscale, r(10) = −.78, P = .008. None of the intellectual, additional academic, motor, visual-spatial/perceptual–motor, speech and language, or memory variables were correlated with this subscale. In contrast, there were no significant correlations found between any of the cognitive variables and CBCL subscales in the sibling controls. 3. Discussion In the present study, children with VCFS generally performed within the Borderline to Mildly Mentally Deficient range of intellectual functioning, and their profile revealed the often noted Verbal greater than Performance IQ discrepancy, consistent with previous reports. However, a similar and clinically statistically significant discrepancy was also noted in the siblings of children with VCFS. This implies that the presence of the 22q11 deletion in VCFS may not fully account for the etiology of the VIQ/PIQ discrepancy, and an alternate genetic explanation may explain this pattern of cognitive performance in both groups. Equally plausible, is an interaction with another genetic factor for which both children with VCFS and their siblings are at risk, and having a 22q11 deletion allows for a more significant expression of this cognitive discrepancy. While it is tempting to implicate intellectual discrepancies between the groups as the sole etiology for any differences obtained in additional domains of cognition, it is important to recognize that significant group differences did not exist for many of the domains sampled despite the clear intellectual discrepancies. A significant risk is incurred when using IQ as a covariate in genetic studies as it significantly reduces the power of the group comparisons because it accounts for an inordinate degree of the variance. The perspective that IQ test performance reflects past learning and “genetic endowment” precludes the justification of equating groups of normal children with groups of children with genetic disorders based upon IQ (Taylor, Fletcher, & Satz, 1984). The VCFS group displayed a learning profile that revealed a relative weakness in the area of mathematics, also consistent with previous research. However, their performance was not significantly below that of their siblings with respect to oral reading and reading comprehension, as would be expected in NLD. An area that has not been comprehensively examined in prior research is that of motor, visuospatial, and perceptual–motor skills, despite the fact that it is the assessment of these skills that allows one to more validly characterize their phenotype as being consistent with NLD. The lack of significance between children with VCFS and their siblings is partially accounted for by the substantial variability in their performance, consistent with the reported heterogeneity of the disorder. The relatively impaired perceptual–motor compared to fine motor and motor-free visu-
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ospatial functioning noted in children with VCFS may also suggest somewhat better visuospatial skills than is often reported on intellectual testing, and further imply that the deficit is actually at the level of integration of motor and perceptual skills, possibly an expression of an executive deficit in planning and organization. The relative preservation of phonemic and semantic fluency, confrontational naming, and receptive language in children with VCFS may reflect a resolution of their language deficits with advancing age, although speech deficits such as poor articulation often persist. The lack of group differences also appeared to be partially accounted for by lower than average performance on language tests by the siblings. The current study revealed a pattern of verbal greater than nonverbal memory performance in children with VCFS, consistent with their intellectual profiles and preliminary research by other investigations. Interestingly, the sibling controls revealed the same clinically significant discrepancy with relatively better verbal as compared to nonverbal memory abilities. Again, this begs the question as to whether the verbal/nonverbal discrepancy is unrelated to the deletion, and whether an alternative explanation might account for their NLD profile. A third and independent factor may place children at risk for a deletion at the 22q11 break-point while it merely manifests in a similar pattern of cognitive strengths and weaknesses in unaffected children. Despite obvious attentional problems noted while examining children with VCFS and reported by parents, children with VCFS did not differ significantly from their siblings on tests of sustained attention, inhibition or set maintenance. However, a trend was noted suggesting that children with VCFS do tend to have more difficulty with nonverbal problem solving and display a propensity toward rigidity and inflexibility in their problem solving. Certainly additional aspects of executive functioning such as working memory, processing speed and selective attention need to be more thoroughly investigated. Our findings are generally consistent with our hypothesis that the cognitive phenotype of children with VCFS would assume an intermediate position between the profiles reported in the literature on children with autistic disorder and William’s syndrome. More specifically, children with VCFS present with perceptual–motor and visuospatial deficits, but not to the degree reported in William’s syndrome, in which profound visual-spatial dysfunction is evident. Likewise, language functioning is a clear and relative strength in these two populations. Interestingly, and in contrast to children with William’s syndrome who demonstrate increased sociability, children with VCFS tend to socially withdrawal. Children with autism, on the other hand, exhibit receptive and expressive language delays and often display relatively better-developed visuospatial skills. In fact, many individuals are able to recognize visual symbols such as letters very early in development. In contrast, language is marked by excessive nonfunctional and nonproductive verbalizations such as echolalia and idiosyncratic speech, as well as lack of communication through nonverbal methods. In general, these investigators have found better-developed reading than math abilities in developmental disorders, despite general patterns of cognitive functioning. Children with VCFS were ranked by their parents as exhibiting a significantly greater degree of inattention, impulsivity, and hyperactivity, clearly meeting criteria for ADHD, combined type. However, parent and self-report behavioral indices did not reveal that children with VCFS were significantly different from their siblings on subscales sensitive to thought disorder or childhood anxiety and depression. The literature examining the relationship between developmental psychosocial functioning and NLD provides a plausible explanation for this finding, as psychosocial deficits appear to follow a unique developmental course. Specifically, according to the NLD model, externalizing disorders would be more evident in early childhood and internalizing disorders would not be expected to arise until adolescence, and would likely worsen into teenage years and adulthood (Rourke et al., 2002). Thus, the age of the participants in the current investigation (i.e., neither well into their teenage years nor reaching adult years) would suggest that these participants would show some externalizing symptoms (e.g., ADHD, aggression) and early stages of internalized psychopathology (e.g., withdrawal); however, not yet display signs consistent with clear and impacting depression until later years. Partially consistent with our hypothesis, a significant and negative relationship between executive functioning (e.g., nonverbal problem solving) and the Thought Problems (V) subscale of the CBCL was found only for children with VCFS. This finding is consistent with what has been reported in the adult literature on schizophrenia, suggesting a common pathogenesis. It is further consistent with recent diffusion tensor imaging studies in schizophrenia which have reported reduced white matter tract integrity in the left uncinate and arcuate fasciculi, suggesting frontotemporal and frontoparietal disconnectivity (Barnea-Goraly et al., 2003). This is also an extremely intriguing finding when one considers that the age of the present sample was positively skewed and relatively young suggesting that executive tasks may be useful for identifying children at risk for future psychopathology as noted by their scores on the CBCL.
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In fact, in a recent retrospective study using cluster analysis, the CBCL has been found to distinguish two preschizophrenia subgroups of children (Rossi, Pollice, Daneluzzo, Marinangeli, & Stratte, 2000). In Cluster I, preschizophrenia profiles resulted in elevations on scales more closely linked to positive symptoms (i.e., thought problems and aggressive behaviors), similar to some children in our sample. In contrast, in Cluster II, preschizophrenia profiles resulted in higher ratings on scales more closely linked to negative symptoms (i.e., withdrawal and anxiousdepressed behavior). Overall, while the results of the present study suggest that a NLD profile provides a general explanation of cognitive functioning in children with VCFS, there are a few caveats. These children do not appear to exhibit global deficits in visual attention or executive functioning. Certainly our sample size may have limited our ability to detect these differences. In addition, consistent with previous reports, the relationship between performance based and parent report measures of executive functioning was inconsistent, suggesting that these two routes of measurement may be assessing separate functions (Anderson, 2002). To improve generalizability, future research on predicting psychopathology in VCFS will need to utilize larger sample sizes with more variability in age. Indeed, a more robust method for determining predictors of psychopathology would be to conduct a regression analysis, a limit of this study due to sample size. Moreover, risk for psychopathology would be best examined in those individuals with VCFS who have been diagnosed with schizophrenia or bipolar disorder. A focus of future research should include longitudinal investigation of VCFS to more fully understand changes in cognitive and neurobehavioral abilities throughout development. As the cognitive phenotype becomes more fully illuminated, structural and functional neuroimaging studies exploring the brain–behavior relationships and putative genes implicated in this phenotype will allow for a more extensive understanding of VCFS at all levels of analysis (i.e., etiology, brain development, neuropsychology, and behavior) (Pennington, 2002). References Achenbach, T. M. (1991). Manual for the Child Behavior Checklist/4–18 and 1991 profile. Burlington, VT: University of Vermont, Department of Psychiatry. Anderson, P. (2002). Assessment and development of executive function (EF) during childhood. Child Neuropsychology, 8, 71–82. Barnea-Goraly, N., Menon, V., Krasnow, B., Ko, A., Reiss, A., & Eliez, S. (2003). Investigation of white matter structures in velocardiofacial syndrome: A diffusion tensor imaging study. American Journal of Psychiatry, 160, 1863–1869. Bearden, C. E., Woodin, M. F., Wang, P. P., Moss, E., McDonald-McGinn, D., Zackai, E., et al. (2001). The neurocognitive phenotype of the 22q11.2 deletion syndrome: selective deficit in visual–spatial memory. Journal of Clinical and Experimental Neuropsychology, 23, 447–464. Beery, K. E. (1997). The Visual–Motor Integration Test. Administration, scoring, and teaching manual (4th ed.). Austin, TX: Pro-Ed. Benton, A. L., Sivan, A. B., Hamsher, K. D., Varney, N. R., & Spreen, O. (1994). Contributions to neuropsychological assessment. A clinical manual (2nd ed.). New York: Oxford University Press. Colarusso, R. P., & Hammill, D. D. (1995). Motor-Free Visual Perception Test—Revised. Novato, CA: Academic Therapy Publications. Conners, C. K. (1997). Conners’ Rating Scales—Revised. User’s manual. Multi-Health Systems, Inc. Eliez, S., Antonarakis, S. E., Morris, M. A., Dahoun, S. P., & Reiss, A. L. (2001). Prenatal origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome. Archives of General Psychiatry, 58, 64–68. Fernoff, P. M. (2000). The 22q11.2 deletion syndrome: More answers but more questions. The Journal of Pediatrics, 137, 145–147. Gerdes, M., Solot, C., Wang, P. P., Moss, E., LaRossa, D., Randall, P., et al. (1999). Cognitive and behavioral profiles of preschool children with chromosome 22q11.2 deletion. American Journal Medical Genetics, 85, 127–133. Gioia, G. A., Isquith, P. K., Guy, S. C., & Kenworthy, L. (1996). Behavior Rating Inventory of Executive Function. Professional manual. Odessa, FL: Psychological Assessment Resources, Inc. Golden, J. C. (1978). Stroop Color and Word Test. Chicago, IL: Stoelting Co. Goodglass, H., & Kaplan, E. (1983). The assessment of aphasia and related disorders (2nd ed.). Philadelphia: Lea & Febiger. Gothelf, D., & Lombroso, P. J. (2001). Genetics of childhood disorders: XXV. Velocardiofacial Syndrome, 40, 489–491. Heaton, R. K. (1981). Wisconsin Card Sorting Test Manual. Odessa, FL: Psychological Assessment Resources Inc. Kaplan, E. F., Goodglass, H., & Weintraub, S. (1978, 1983). The Boston Naming Test. Experimental Edition (1978). Boston: Kaplan & Goodglass (2nd ed.). Philadelphia: Lea & Febiger. Klove, H. (1963). Clinical neuropsychology. In F. M. Forster (Ed.). The medical clinics of North America. New York: Saunders (in Lezak, M. D. (1995). Neuropsychological assessment (3rd ed.). New York: Oxford University Press). Kovacs, M. (1992). Children’s Depression Inventory manual. Multi-Health Systems, Inc. Leark, R. A., Dupuy, T. R., Greenberg, L. M., Corman, C. M., & Kindshi, C. L. (2000). Test of Variables of Attention (TOVA)—professional guide. California: Universal Attention Disorders, Inc. Moss, E. M., Batshaw, M. L., Solot, C. B., Gerdes, M., McDonald-McGinn, D. M., Driscoll, D. A., et al. (1999). Psychoeducational profile of the 22q11.2 microdeletion: A complex pattern. The Journal of Pediatrics, 134, 193–198. Pennington, B. F. (2002). The development of psychopathology: Nature and nurture. New York: Guilford. Reynolds, C. R., & Bigler, E. D. (1994). Test of Memory and Learning (TOMAL). Austin, TX: Pro-Ed.
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Reynolds, C. R., & Richmond, B. O. (1997). Revised Children’s Manifest Anxiety Scale. Manual. Los Angeles, CA: Western Psychological Services. Rossi, A., Pollice, R., Daneluzzo, E., Marinangeli, M. G., & Stratta, P. (2000). Behavioral neurodevelopmental abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL). Schizophrenia Research, 44, 121–128. Rourke, B. P. (1989). Nonverbal learning disabilities: The syndrome and the model. New York: Guilford Press. Rourke, B. P., Ahmad, S. A., Collins, D. W., Hayman-abello, B. A., Hayman-Abello, S. E., & Warriner, E. M. (2002). Child clinical/pediatric neuropsychology: Some recent advances. Annual Reviews of Psychology, 53, 309–339. Scherer, N. J., D’Antonio, L. L., & Kalbfleisch, J. H. (1999). Early speech and language development in children with velocardiofacial syndrome. American Journal of Medical Genetics, 88, 714–723. Sphritzen, R., Goldber, R., Lewin, M., Sidoti, E., Berkman, M., Argamaso, R., et al. (1978). A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: Velo-cardio-facial syndrome. Cleft Palate, 15, 56–62. Spreen, O. & Benton, A. L. (1969, 1977). The Neurosensory Center Comprehensive Examination for Aphasia (NCCEA). Victoria: University of Vistoria Neuropsychology Laboratory. Taylor, H. G., Fletcher, J. M., & Satz, P. (1984). Neuropsychological assessment of children. In G. Goldstein & M. Hersen (Eds.), Handbook of psychological assessment. New York: Pergamon. Wang, P. P., Woodin, M. F., Kreps-Falk, R., & Moss, E. M. (2000). Research on behavioural phenotypes: velocardiofacial syndrome (deletion 22q11.2). Developmental Medicine & Child Neurology, 42, 422–427. Wechsler Intelligence Scale for Children—Third edition (WISC-III). (1991). The Psychological Corporation. Harcourt Brace & Company. Wiederholt, J. L., & Bryant, B. R. (1992). Gray Oral Reading Test (3rd ed.). Circle Pines, MN: AGS Publishing. Wilkinson, G. S. (1993). Wide Range Achievement Test—Third Edition (WRAT-3). Delaware: Wide Range Inc. Woodin, M., Wang, P. P., Aleman, D., McDonald-McGinn, D., Zackai, E., & Moss, E. (2001). Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genetics in Medicine, 3, 34–39.
The neuropsychological phenotype of velocardiofacial syndrome (VCFS): Relationship to psychopathology Ren´ee Lajiness-O’Neill a,∗ , Isabelle Beaulieu b , Alexander Asamoah c , Jeffrey B. Titus b , Erawati Bawle d , Saadia Ahmad e , John W. Kirk f , Rebecca Pollack c b
a Eastern Michigan University, Ypsilanti, MI, USA Department of Behavioral Health, Division of Neuropsychology, Henry Ford Health System, Detroit, MI, USA c Department of Genetics, Henry Ford Health System, Detroit, MI, USA d Department of Genetics, Children’s Hospital of Michigan, Detroit, MI, USA e University of Winsdor, Ozad Institute, Windsor Regional Children’s Center, Windsor, Ont., Canada f The Johns Hopkins School of Medicine and Kennedy Krieger Institute, Baltimore, MD, USA
Accepted 6 September 2005
Abstract Children with velocardiofacial syndrome (VCFS; N = 14) and a comparison group of siblings (N = 8) underwent comprehensive neuropsychological assessment to examine the relationship between cognitive functioning and psychopathology. Significant group differences were obtained on tests of full scale and verbal intellectual functioning and perceptual–motor skills. With the exception of performance on tests of attention and executive functioning, children with VCFS displayed a profile consistent with nonverbal learning disability (NLD). However, within group comparisons revealed significantly poorer visuospatial intellectual and nonverbal memory functioning in sibling controls as well. No significant group differences were obtained on tests of motor speed, academic, language, attention, memory, or executive functioning, with significant variability in children with VCFS frequently accounting for the lack of robust differences. Parent-report measures revealed profiles consistent with ADHD. No clinically significant symptoms of psychosis, depression or anxiety were noted on either self- or parent-report measures. Wisconsin Card Sorting Test performance was found to be highly and negatively correlated with the Thought Problems subscale of the Child Behavior Checklist (CBCL) for VCFS children only, suggesting a possible at-risk indicator for later onset psychopathology. © 2005 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. Keywords: Neuropsychology; Genetics; Velocardiofacial syndrome; 22q11 deletion syndrome; Psychopathology
Velocardiofacial syndrome (VCFS) is one of the most prevalent genetic disorders and has been found to be one of the most common causes of learning disability and mild mental retardation, with an estimated prevalence of 1 in 4000 (Gothelf & Lombroso, 2001). It is caused by a microdeletion in the long arm of chromosome 22, and its clinical characteristics include congenital heart disease, palatal abnormalities, hypocalcemia and T-cell immunodeficiency, and abnormal facies that include a bulbous nasal tip and prominent nasal root, narrow and with flat cheeks, narrow palpebral fissures, small mouth, receding chin, and small cupped ears (Gothelf & Lombroso, 2001; Sphritzen et al., 1978).
∗
Corresponding author. Tel.: +1 313 876 2526; fax: +1 313 876 2279. E-mail address: [email protected] (R. Lajiness-O’Neill).
0887-6177/$ – see front matter © 2005 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.acn.2005.09.001
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Children with VCFS have been found to have a substantially greater risk for the development of schizophrenia and bipolar disorder with approximately 25–30% developing psychotic symptoms in adolescence, and the prevalence of schizophrenia 25 times that of the general population (Eliez, Antonarakis, Morris, Dahoun, & Reiss 2001; Gothelf & Lombroso, 2001). This makes a diagnosis of VCFS the highest known risk factor for the development of schizophrenia. While the gene or genes that cause the 22q11 microdeletion are unknown, the gene for encoding catechol-O-methyltransferase (COMT), an enzyme responsible for the degradation of dopamine, is located within this region. It has been suggested that the genes deleted in VCFS may assume a similar role in the pathophysiology of schizophrenia (Gothelf & Lombroso, 2001). Children with VCFS have also been purported to exhibit a nonverbal learning disability (NLD) (Rourke, 1989), primarily based on their intellectual and achievement profile. Children with VCFS typically function within the Borderline range of intellectual ability (Moss et al., 1999), and higher Verbal relative to Performance intellectual quotients have consistently been reported (Gothelf & Lombroso, 2001; Moss et al., 1999). Moreover, as noted, children with VCFS typically display weaknesses in mathematics, often reaching the level of a learning disability. Investigations have suggested relative strengths in reading and spelling; although, studies have not specifically addressed reading comprehension, an often noted area of weakness in NLD. As stated by Wang, Woodin, KrepsFalk, & Moss (2000), while the psychoeducational profile may assist in the diagnostic process, what is more critical is an “elucidation of the fundamental cognitive abilities associated with each syndrome (such as VCFS), and an understanding of how psychoeducational abilities and disabilities derive from the underlying cognitive phenotype” (p. 423). While Rourke (1989) acknowledges that individuals with NLD frequently possess language impairment, the deficits are most often in the area of pragmatics, and not necessarily consistent with the significant mixed receptive and expressive language delays reported in VCFS, lending debate to the NLD distinction and suggesting the need for more comprehensive assessment (Scherer, D’Antonio, & Kalbfleisch, 1999). The literature is equivocal with respect to the quality of language impairments (Moss et al., 1999; Scherer et al., 1999). Gerdes et al. (1999) identified significant delays in motor milestones; although, no studies to date have specifically examined fine motor functioning in these children. Only a few studies examining the neuropsychological phenotype have been reported in the literature, and the domains examined have been limited (Bearden et al., 2001; Woodin et al., 2001), especially with regard to visual attention or complex visual memory. For example, in a study by Wang et al. (2000) examining short-term recall, approximately two-thirds of the children scored higher on Number Recall relative to Spatial Memory. In addition, although attention-deficit hyperactivity disorder is a frequently reported comorbid feature (Gerdes et al., 1999; Moss et al., 1999), no studies have comprehensively examined attentional or executive functioning in children with VCFS. Despite the extremely high prevalence of psychopathology in VCFS, to date, no studies have examined the relationship between the behavioral and cognitive phenotype. That is, which cognitive weaknesses may serve as markers and suggest a risk for the onset of schizophrenia or bipolar disorder? Moreover, research on VCFS has been primarily descriptive in nature, without consideration of the need for control populations. The first aim of this study was to expand on previous research by more accurately characterizing the neurocognitive phenotype in velocardiofacial syndrome relative to sibling controls. It was hypothesized that children with VCFS would demonstrate evidence of impaired neurocognitive performance, with significant deficits noted on measures of frontotemporal functioning consistent with their psychiatric risk relative to a comparison group of siblings. We hypothesized that NLD would only partially characterize this heterogeneous disorder, and that the neurocognitive and neurobehavioral phenotype in children with VCFS would likely assume an intermediate position between profiles reported in the literature on children with autistic disorder and William’s syndrome. The second aim of the present study was to obtain standardized neurobehavioral measures on children with both VCFS and control children in order to identify patterns of psychopathology. It was hypothesized that children with VCFS would demonstrate elevations on scales of the Child Behavior Checklist (CBCL) that are sensitive to mood disorders and psychoses (i.e., Anxious/Depressed and Thought Problems), relative to control children. The third aim of the study was to identify potential cognitive predictors of neurobehavioral functioning in children with VCFS, relative to sibling controls. It was hypothesized that performance on measures of memory and executive functioning would correlate with current pathology as measured on behavioral indices, and as an indirect measure of those at risk for later onset schizophrenia or bipolar disorder.
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1. Method 1.1. Participants Participants included 14 children and adolescents with a diagnosis of a 22q11.2 deletion (9 males, 5 females) and 8 siblings of individuals diagnosed with this deletion (5 males, 3 females), recruited through the Department of Genetics at Henry Ford Health System, Children’s Hospital of Michigan or through local advertisement. Mean age of the children diagnosed with 22q11.2 deletion syndrome was 12.6 (S.D. = 6.4; range 7–17) and mean education level was 6.1 years (S.D. = 4.6; range 6–13). Thirteen (93%) of the children with 22q11.2 deletion syndrome were Caucasian and one (7%) was African American. Mean age of the siblings was 11.4 (S.D. = 5.6) and mean education level was 5.8 (S.D. = 4.9). Seven (87%) of the siblings were Caucasian and one (13%) was African American. The diagnosis of VCFS was confirmed by fluorescent in situ hybridization (FISH) conducted by the Cytogenetics Laboratory at Henry Ford Health System. There were no significant group differences with respect to age, t(22) = .44, P = .66, or years of education, t(22) = .19, P = .85. Of the 14 children with 22q11.2 deletion syndrome, 5 (36%) had a 22q11.2 deletion that was de novo in origin and 2 (14%) had a maternal deletion ruled out, though the fathers had not been tested. Exclusion criteria included pre- or perinatal pathology, head injury or previous neurological compromise, or history of substance abuse. 1.2. Neuropsychological procedures/protocol Each participant underwent comprehensive neuropsychological testing that included assessments of intellectual, academic, motor and perceptual–motor functioning, visuospatial processing, speech/language, verbal and visual memory, attention, executive functioning, and neurobehavioral and emotional functioning. Relevant constructs were assessed based upon tasks standardized to be appropriate for given ages. Neurobehavioral functioning was examined through behavioral indices completed by age appropriate participants and parents. Screening measures of depression and anxiety were administered to all children capable of completing self-report questionnaires. 1.2.1. Test administration and scoring Participants were scheduled for individual appointments and tested in the Division of Neuropsychology in the Department of Behavioral Health at Henry Ford Health System. All ethical guidelines as outlined by the American Psychological Association were followed. Participants were individually administered the neuropsychological battery of tests by a trained psychometrician or Ph.D. level graduate student in psychology who was blind to the study’s specific hypotheses. The following measures were included in the battery to examine the respective domains: Intellectual: Wechsler Intelligence Scale for Children—Third Edition (WISC-III, 1991) or Wechsler Adult Intelligence Scale; Academic Achievement: Wide Range Achievement Test-3 (Wilkinson, 1993), Gray Oral Reading Test-3 (Wiederholt & Bryant, 1992); Motor Functioning: Grooved Pegboard Test (Klove, 1963); Perceptual–Motor/Visuospatial: Developmental Test of Visual–Motor Integration (Beery, 1997), Motor Free Visual Perception Test (Colarusso & Hammill, 1995), Judgment of Line Orientation (Benton, Sivan, Hamsher, Varney, & Spreen, 1994); Speech and Language: Controlled Oral Word Association (Goodglass & Kaplan, 1983; Spreen & Benton, 1969, 1977), Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983), Tokens Test (Spreen & Benton, 1969, 1977); Learning and Memory: Test of Memory and Learning (Reynolds & Bigler, 1994); Attention/Executive Functioning: Test of Variables of Attention (Leark, Dupuy, Greenberg, Corman & Kindschi, 2000), Wisconsin Card Sorting Test (Heaton, 1981), Stroop Test (Golden, 1978), Behavior Rating Inventory of Executive Function (BRIEF) (Gioia, Isquith, Guy & Kenworthy, 1996); Behavioral Questionnaires: Child Behavior Checklist (Achenbach, 1991), Conners’ Parent Rating Scale (Conners, 1997); Affective Measures: Children’s Depression Inventory (Kovacs, 1992), Revised Children’ Manifest Anxiety Scale (Reynolds & Richmond, 1997). 1.3. Data analysis Group differences on cognitive and behavioral indices between children with VCFS and their siblings was examined with the t statistic. Standard scores (SS) were used in the analyses of intellectual, academic, visuospatial (with the
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exception of the JOLO in which raw scores were used), memory functioning, and the behavioral indices. Standard Z scores were derived for the analyses of the motor and speech and language variables using norms for the mean age of the cohort. This analysis was conducted to examine whether significant differences existed between the groups, thus allowing for a robust examination of the relationship between cognitive and neurobehavioral variables. Eta squared (ε2 ) was conducted to examine effect sizes. Pearson-product or Spearman correlation coefficients were completed to examine the relationships between cognitive and neurobehavioral variables. Subscales III (Anxiety/Depression) and IV (Thought Problems) of the CBCL were used as the primary criterion variables. A Bonferonni correction was used and the P-value established at .001 when making between group comparisons and when examining the relationships between cognitive and behavioral variables to decrease the likelihood of Type I error given the number of comparisons made. Within-group comparisons were examined by paired sample t statistics and for these comparisons a .05 P-value was retained. 2. Results 2.1. Neuropsychological phenotype 2.1.1. Intellectual/achievement Consistent with the existing literature, the groups differed significantly on Verbal IQ and Full Scale IQ and approached significance with respect to Performance IQ, with the VCFS group scoring approximately 2 S.D. below their siblings. The children with VCFS displayed significantly lower Performance relative to Verbal IQs, t(13) = 4.1, P = .001; however, a similar pattern was noted in the siblings, t(7) = 2.4, P = .05. There were no significant group differences noted with respect to sight reading, spelling, reading comprehension, or math performance. However, a trend was noted between the groups on math performance and the effect size was large. Examination of within group differences revealed that the VCFS group displayed significantly poorer performance on tests of math relative to reading, t(14) = 4.2, P = .001, and spelling, t(14) = 3.9, P = .002. 2.1.2. Motor/visuospatial/perceptual–motor There were no significant group differences noted on tests of fine motor speed and dexterity, bilaterally. However, children with VCFS displayed significantly poorer performance on tests of perceptual–motor functioning. In contrast, there were no significant group differences noted on visual–spatial tests for which motor demands were eliminated, specifically performance on the Judgment of Line Orientation test and Motor Free Visual Perception Test—Third Edition (MVPT-III). 2.1.3. Speech and language functioning There were no significant differences noted between the groups on tests of speech and language functioning. Specifically, group differences in phonemic fluency, semantic fluency, confrontational naming, and receptive language (i.e., Tokens Test), all fell below significance. Differences between groups on semantic fluency approached significance and the effect size was large. Table 1 presents the means, standard deviations, t scores, P values, and effect sizes for children with VCFS and sibling controls on tests of intellect, achievement, motor, visual–spatial/perceptual–motor, and speech/language functioning. 2.1.4. Memory and learning There were no significant group differences noted between children with VCFS and their siblings on all core memory indices. However, trends were noted, particularly with respect to the Composite Memory Index, and large effect sizes were evident on all indices. Overall, children with VCFS performed more poorly on the Verbal Memory Index, Nonverbal Memory Index, and Composite Memory Index than their siblings. Within group comparisons revealed significantly lower performance on measures of nonverbal relative to verbal memory for the VCFS group, t(8) = 4.3, P = .003. However, of note, within group comparisons also revealed a similar significant discrepancy in the sibling group, t(7) = 4.7, P = .003. Table 2 presents the means, standard deviations, t scores, P values, and effect sizes for each group on the Test of Memory and Learning.
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Table 1 Mean standard scores, standard deviations, t scores, P values, and effect sizes for the intellectual, academic, motor, perceptual–motor, visuospatial, and speech/language variables VCFS participants, M (S.D.)
Sibling controls, M (S.D.)
t-score
P
ε2
Intellect VIQ PIQ FSIQ
76.7 (11.4) 67.9 (10.3) 70.0 (11.2)
107.5 (16.8) 96.4 (17.9) 102.4 (17.5)
5.1* 4.1 5.3*
.001 .002 .001
.57 .53 .59
Academic WRAT Reading Spelling Arithmetic GORT RQ
86.4 (18.4) 83.4 (16.9) 69.8 (20.5) 73.1 (19.5)
100.3 (10.5) 100.8 (11.4) 94.3 (8.8) 94.0 (22.5)
2.3 2.6 3.2 1.8
.04 .02 .005 .26
.16 .25 .34 .23
Motor Pegs-D Pegs-ND
−6.2 (8.7) −8.5 (10.3)
0.41 (3.6) 0.70 (3.7)
1.8 2.5
.09 .02
.14 .18
Visuospatial/perceptual–motor VMI 77.0 (7.6) MVPT-R 69.9 (22.0) JOLO 11.1 (6.5)
95.4 (8.8) 91.5 (29.2) 20.3 (7.0)
4.6* 1.7 2.8
.001 .11 .01
.59 .17 .34
Speech/language Phonemic fluency Semantic fluency Boston naming Tokens
−1.3 (1.3) −0.15 (0.83) −1.5 (2.1) −1.4 (2.2)
.21 3.7 1.6 1.9
.83 .002 .13 .08
.003 .48 .11 .17
*
−1.5 (1.5) −1.4 (0.57) −3.4 (2.7) −4.0 (3.6)
P < .001.
2.1.5. Attention and executive functioning Unexpectedly, there were no significant differences noted on the Test of Variables of Attention (TOVA) with respect to either errors of inattention (% Omission) or impulsivity (% Commission). There were no significant group differences noted on the Wisconsin Card Sorting Test (WCST) with respect to nonverbal problem solving (conceptual level), flexibility in their approach (perseverative responses), ability to maintain conceptual set, or overall categories achieved, though children with VCFS performed more poorly on all measures and moderate to large effect sizes were evident on most indices. Likewise, there was no significant group difference noted on the Stroop Color and Word Test, with respect to interference effects. Parent report of perceived executive deficits revealed statistically significant group differences and large effect sizes for the Behavior Rating Inventory of Executive Function, with the VCFS group obtaining more elevated scores overall. Table 3 presents the means, standard deviations, t scores, P values, and effect sizes for children with VCFS and siblings controls on tests of attention and executive functioning. 2.1.6. Social and emotional functioning On all scales of the Child Behavior Checklist, scores were more elevated for the VCFS group. While there were no statistically significant differences noted between the groups, trends were noted with perceived attentional difficulties, Table 2 Means, standard deviations, t scores, P values, and effect sizes for the TOMAL Composite Indices
Verbal Memory Index Nonverbal Memory Index Composite Memory Index P < .001.
VCFS participants, M (S.D.)
Sibling controls, M (S.D.)
t-score
P
ε2
88.4 (12.9) 74.8 (12.0) 80.9 (11.9)
105.9 (4.4) 92.4 (8.5) 99.4 (6.1)
3.4 3.3 3.7
.004 .005 .002
.45 .44 .50
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Table 3 Means, standard deviations, t scores, P values, and effect sizes for the Attention and Executive variables VCFS participants, M (S.D.) Attention TOVA (% Omission)
16.6 (24.2)
Mental flexibility/inhibition/problems solving TOVA (% Commission) 8.2 (73.) Stroop interference 49.6 (3.8) WCST—perseveration 85.4 (12.1) WCST—conceptual 85.5 (13.7) WCST—categories 3.6 (1.9) WCST—set failure 1.3 (1.5) Parent report BRIEF BRI BRIEF MI BRIEF GEC *
65.9 (13.6) 68.1 (8.9) 68.3 (9.9)
t-score
P
ε2
8.8 (8.2)
0.8
.42
.04
6.0 (5.4) 51.4 (2.8) 102.4 (14.3) 101.4 (18.0) 5.6 (0.52) 0.75 (1.0)
0.7 1.1 2.9 2.2 3.6 0.8
.48 .28 .01 .04 .003 .42
.03 .07 .31 .22 .33 .04
47.0 (8.1) 51.6 (10.9) 49.7 (9.9)
3.3 3.5 3.9*
.005 .003 .001
.41 .48 .48
Sibling controls, M (S.D.)
P < .001.
t(15) = 3.6, P = .003, and more atypical and repetitive behaviors (i.e., thought problems), t(15) = 3.2, P = .006 in children with VCFS. Interestingly, and inconsistent with the literature, significant group differences were not obtained on scales sensitive to features of childhood depression and anxiety. Nonetheless, as noted, large effect sizes were evident on all scales except those sensitive to somatization, depression/anxiety, and defiant behaviors. Similar results were obtained on the Connors Parent Rating Scale in which children with VCFS were ranked as displaying a significantly greater degree of features of attention-deficit/hyperactivity disorder, relative to siblings, and above average correspondence with DSM-IV criteria for ADHD, Inattentive type and Combined type. Table 4 presents the means, standard deviations, t scores, P values, and effects sizes for children with VCFS and siblings controls on tests of social and emotional functioning. Interestingly, there were no statistically significant differences between the groups on self-report measures of depression (Child Depression Inventory), t(13) = .25, P = .80, and anxiety (Revised Children’s Manifest Anxiety Scale), t(15) = .07, P = .94. 2.2. Relationship to psychopathology There were no statistically significant relationships noted between the cognitive variables and the CBCL III—Anxiety/Depression subscale. The WCST conceptual level was the only variable that was highly and negatively correlated with the CBCL V—Thought Problems subscale, r(8) = −.93, P = .001, suggesting that as CBCL Thought Table 4 Means, standard deviations, t scores, P values, and effect sizes for the Child Behavior Checklist and Connors Parent Rating Scale VCFS participants, M (S.D.)
Sibling controls, M (S.D.)
t-score
(I) Withdrawn (II) Somatic (III) Anxiety/Depression (IV) Social Concerns (V) Thought Problems (VI) Attention (VII) Defiant (VIII) Aggressive
61.4 (13.1) 60.0 (11.5) 58.2 (7.6) 69.0 (12.9) 64.8 (11.0) 72.3 (11.1) 58.4 (7.8) 62.9 (13.1)
51.7 (3.1) 57.0 (4.9) 53.1 (5.6) 55.8 (8.0) 51.0 (2.7) 55.7 (6.1) 55.6 (6.1) 52.9 (3.8)
2.3 0.7 1.5 2.4 3.2 3.6 0.8 2.3
.05 .48 .16 .03 .006 .003 .43 .43
.26 .05 .12 .25 .40 .46 .06 .26
Connors’ Inattention Hyperactive-impulsive Combined
72.0 (8.6) 71.6 (11.6) 73.8 (7.9)
53.4 (8.8) 55.7 (12.3) 54.7 (9.2)
4.4* 2.7 4.6*
.001 .02 <.001
.54 .30 .57
*
P < .001.
P
ε2
CBCL scales
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Fig. 1. Significant relationship between CBCL V standard scores and WCST Conceptual Level Response for VCFS subjects.
Problems scores increased their scores on the WCST decreased (Fig. 1). A trend was also noted suggesting a possible negative relationship between math performance and higher scores on the CBCL V subscale, r(10) = −.78, P = .008. None of the intellectual, additional academic, motor, visual-spatial/perceptual–motor, speech and language, or memory variables were correlated with this subscale. In contrast, there were no significant correlations found between any of the cognitive variables and CBCL subscales in the sibling controls. 3. Discussion In the present study, children with VCFS generally performed within the Borderline to Mildly Mentally Deficient range of intellectual functioning, and their profile revealed the often noted Verbal greater than Performance IQ discrepancy, consistent with previous reports. However, a similar and clinically statistically significant discrepancy was also noted in the siblings of children with VCFS. This implies that the presence of the 22q11 deletion in VCFS may not fully account for the etiology of the VIQ/PIQ discrepancy, and an alternate genetic explanation may explain this pattern of cognitive performance in both groups. Equally plausible, is an interaction with another genetic factor for which both children with VCFS and their siblings are at risk, and having a 22q11 deletion allows for a more significant expression of this cognitive discrepancy. While it is tempting to implicate intellectual discrepancies between the groups as the sole etiology for any differences obtained in additional domains of cognition, it is important to recognize that significant group differences did not exist for many of the domains sampled despite the clear intellectual discrepancies. A significant risk is incurred when using IQ as a covariate in genetic studies as it significantly reduces the power of the group comparisons because it accounts for an inordinate degree of the variance. The perspective that IQ test performance reflects past learning and “genetic endowment” precludes the justification of equating groups of normal children with groups of children with genetic disorders based upon IQ (Taylor, Fletcher, & Satz, 1984). The VCFS group displayed a learning profile that revealed a relative weakness in the area of mathematics, also consistent with previous research. However, their performance was not significantly below that of their siblings with respect to oral reading and reading comprehension, as would be expected in NLD. An area that has not been comprehensively examined in prior research is that of motor, visuospatial, and perceptual–motor skills, despite the fact that it is the assessment of these skills that allows one to more validly characterize their phenotype as being consistent with NLD. The lack of significance between children with VCFS and their siblings is partially accounted for by the substantial variability in their performance, consistent with the reported heterogeneity of the disorder. The relatively impaired perceptual–motor compared to fine motor and motor-free visu-
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ospatial functioning noted in children with VCFS may also suggest somewhat better visuospatial skills than is often reported on intellectual testing, and further imply that the deficit is actually at the level of integration of motor and perceptual skills, possibly an expression of an executive deficit in planning and organization. The relative preservation of phonemic and semantic fluency, confrontational naming, and receptive language in children with VCFS may reflect a resolution of their language deficits with advancing age, although speech deficits such as poor articulation often persist. The lack of group differences also appeared to be partially accounted for by lower than average performance on language tests by the siblings. The current study revealed a pattern of verbal greater than nonverbal memory performance in children with VCFS, consistent with their intellectual profiles and preliminary research by other investigations. Interestingly, the sibling controls revealed the same clinically significant discrepancy with relatively better verbal as compared to nonverbal memory abilities. Again, this begs the question as to whether the verbal/nonverbal discrepancy is unrelated to the deletion, and whether an alternative explanation might account for their NLD profile. A third and independent factor may place children at risk for a deletion at the 22q11 break-point while it merely manifests in a similar pattern of cognitive strengths and weaknesses in unaffected children. Despite obvious attentional problems noted while examining children with VCFS and reported by parents, children with VCFS did not differ significantly from their siblings on tests of sustained attention, inhibition or set maintenance. However, a trend was noted suggesting that children with VCFS do tend to have more difficulty with nonverbal problem solving and display a propensity toward rigidity and inflexibility in their problem solving. Certainly additional aspects of executive functioning such as working memory, processing speed and selective attention need to be more thoroughly investigated. Our findings are generally consistent with our hypothesis that the cognitive phenotype of children with VCFS would assume an intermediate position between the profiles reported in the literature on children with autistic disorder and William’s syndrome. More specifically, children with VCFS present with perceptual–motor and visuospatial deficits, but not to the degree reported in William’s syndrome, in which profound visual-spatial dysfunction is evident. Likewise, language functioning is a clear and relative strength in these two populations. Interestingly, and in contrast to children with William’s syndrome who demonstrate increased sociability, children with VCFS tend to socially withdrawal. Children with autism, on the other hand, exhibit receptive and expressive language delays and often display relatively better-developed visuospatial skills. In fact, many individuals are able to recognize visual symbols such as letters very early in development. In contrast, language is marked by excessive nonfunctional and nonproductive verbalizations such as echolalia and idiosyncratic speech, as well as lack of communication through nonverbal methods. In general, these investigators have found better-developed reading than math abilities in developmental disorders, despite general patterns of cognitive functioning. Children with VCFS were ranked by their parents as exhibiting a significantly greater degree of inattention, impulsivity, and hyperactivity, clearly meeting criteria for ADHD, combined type. However, parent and self-report behavioral indices did not reveal that children with VCFS were significantly different from their siblings on subscales sensitive to thought disorder or childhood anxiety and depression. The literature examining the relationship between developmental psychosocial functioning and NLD provides a plausible explanation for this finding, as psychosocial deficits appear to follow a unique developmental course. Specifically, according to the NLD model, externalizing disorders would be more evident in early childhood and internalizing disorders would not be expected to arise until adolescence, and would likely worsen into teenage years and adulthood (Rourke et al., 2002). Thus, the age of the participants in the current investigation (i.e., neither well into their teenage years nor reaching adult years) would suggest that these participants would show some externalizing symptoms (e.g., ADHD, aggression) and early stages of internalized psychopathology (e.g., withdrawal); however, not yet display signs consistent with clear and impacting depression until later years. Partially consistent with our hypothesis, a significant and negative relationship between executive functioning (e.g., nonverbal problem solving) and the Thought Problems (V) subscale of the CBCL was found only for children with VCFS. This finding is consistent with what has been reported in the adult literature on schizophrenia, suggesting a common pathogenesis. It is further consistent with recent diffusion tensor imaging studies in schizophrenia which have reported reduced white matter tract integrity in the left uncinate and arcuate fasciculi, suggesting frontotemporal and frontoparietal disconnectivity (Barnea-Goraly et al., 2003). This is also an extremely intriguing finding when one considers that the age of the present sample was positively skewed and relatively young suggesting that executive tasks may be useful for identifying children at risk for future psychopathology as noted by their scores on the CBCL.
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In fact, in a recent retrospective study using cluster analysis, the CBCL has been found to distinguish two preschizophrenia subgroups of children (Rossi, Pollice, Daneluzzo, Marinangeli, & Stratte, 2000). In Cluster I, preschizophrenia profiles resulted in elevations on scales more closely linked to positive symptoms (i.e., thought problems and aggressive behaviors), similar to some children in our sample. In contrast, in Cluster II, preschizophrenia profiles resulted in higher ratings on scales more closely linked to negative symptoms (i.e., withdrawal and anxiousdepressed behavior). Overall, while the results of the present study suggest that a NLD profile provides a general explanation of cognitive functioning in children with VCFS, there are a few caveats. These children do not appear to exhibit global deficits in visual attention or executive functioning. Certainly our sample size may have limited our ability to detect these differences. In addition, consistent with previous reports, the relationship between performance based and parent report measures of executive functioning was inconsistent, suggesting that these two routes of measurement may be assessing separate functions (Anderson, 2002). To improve generalizability, future research on predicting psychopathology in VCFS will need to utilize larger sample sizes with more variability in age. Indeed, a more robust method for determining predictors of psychopathology would be to conduct a regression analysis, a limit of this study due to sample size. Moreover, risk for psychopathology would be best examined in those individuals with VCFS who have been diagnosed with schizophrenia or bipolar disorder. A focus of future research should include longitudinal investigation of VCFS to more fully understand changes in cognitive and neurobehavioral abilities throughout development. 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