Progress in Pediatric Cardiology 15 (2002) 109–117
Cognitive development in VCFS
Tony J. Simona,b,*, Carrie E. Beardenb, Edward M. Mossb, Donna McDonald-McGinnb,
Elaine Zackaia,b, Paul P. Wanga,b
a
University of Pennsylvania School of Medicine, Philadelphia, PA, USA
b
Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Abstract
The 22q11.2 microdeletion (velocardiofacial syndrome, VCFS) results in a complex pattern of psychoeducational and
neurocognitive deficits. Mean full-scale IQ scores are in the range of borderline intellectual function, but academic achievement
scores are generally in the low–normal range. A dichotomy is often found between higher Verbal IQ scores and lower Performance
IQ, paralleled by relative strength in Reading and Spelling, but weakness in Math. Language skills are also typically delayed and
remain impaired later in life, and psychiatric disorders can be found in both children and adults with the syndrome. On-going
neurocognitive research suggests that the impairment in mathematical ability may be associated with poor visual–spatial skills.
This would be consistent with theoretical models that link arithmetic skills with visual attention and spatially referenced
representations of magnitude. Neuroimaging investigations indicate that these skills may all depend critically on the inferior
parietal lobes, and lead to our hypothesis that these may be dysfunctional in the 22q11.2 syndrome. Early reports find no
association between cognitive ability in the syndrome and the presence of cardiac malformations.
䊚 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Cognition; Neuropsychology; Numeracy; Visuospatial; Brain; Magnetic resonance imaging (MRI)
1. Introduction
The purpose of this review is to address issues relating
to the cognitive development of children with velocardiofacial syndrome (VCFS). Compared with work
focusing on the medical implications of the syndrome,
this is an area of relative novelty. Many questions have
yet to be asked concerning the intellectual outcomes of
affected children. These questions can be addressed at
different levels and each requires its own set of methodologies. In this review, we focus on two levels of
analysis where some progress has been made. The first
is the area of standardized testing of intelligence, academic achievement and neuropsychological function. At
present, this represents the largest body of knowledge
regarding intellectual function in children with VCFS.
Despite considerable variation in the phenotype, there is
general consensus in the picture that has emerged. The
second area, just getting underway, focuses on functional
*Corresponding author. Children’s Seashore House, Rm. 207, 3405
Civic Center Boulevard, Philadelphia, PA 19104, USA. Tel.: q1215-590-7198; fax: q1-215-590-6804.
E-mail address: tjsimon@mail.med.upenn.edu (T.J. Simon).
neurocognitive analysis. Taking the neuropsychological
testing data as its starting point, these studies are now
examining specific cognitive processes and the neural
substrates involved in their implementation in order to
provide mechanistic and integrative explanations as to
why certain clusters of cognitive dysfunction are
observed. This work also will also lay the groundwork
for subsequent cognitive interventions that may be able
to reduce, or even remove, some deficits by ‘retraining’
the brains of children with VCFS early in development
to process certain kinds of information in ways that are
more suited to their areas of strength. Although some
brain and cognition findings have been published about
adults with VCFS, we focus this review on children.
2. Psycho-educational
findings
and
neuropsychological
What is known so far about the cognitive implications
of VCFS? The broad psychoeducational picture is, in
fact, fairly clear. Children with VCFS show mean fullscale IQ scores (FSIQ) in the range of borderline
intellectual abilities, with verbal IQ (VIQ) significantly
1058-9813/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 1 0 5 8 - 9 8 1 3 Ž 0 2 . 0 0 0 3 5 - 8
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T.J. Simon et al. / Progress in Pediatric Cardiology 15 (2002) 109–117
Fig. 1. Psychoeducational and language profiles in VCF. Verbal IQ (VIQ) is typically higher than both Performance IQ (PIQ) and language
(CELF) scores. Reading scores are typically higher than Math scores. Lines connect data from individual subjects; dashed lines indicate atypical
profiles.
higher than performance IQ scores (PIQ) w1–3x (Fig.
1). In the largest study to date, Moss et al. w1x reported
a FSIQ of 71.2"12.8 (mean"standard deviation), VIQ
77.5"14.9, and PIQ 69.1"12.0, in a group of 33
subjects. Moss et al. w1x also reported a typical pattern
of results on academic achievement tests (e.g. w2,3x).
Math composite scores (80.1"15.2) were significantly
lower than Reading composite (86.7"18.2) and composite Spelling scores (88.3"16.4). Thus, while many
children with the 22q deletion often show IQ scores that
are in the borderline or mild range of mental retardation,
their academic achievement scores are typically in the
low–average range or higher. A majority of children
have IQ scores above the range of mental retardation,
and moderate or severe retardation is rare w1,4x.
Moss et al. pointed out that the profile of weakness
in math, with a PIQ score lower than VIQ, resembles
the profile known as a ‘Non-Verbal Learning Disorder’
(NVLD), because of the concentration of deficits in
areas of visual–spatial cognition, which we discuss in
more detail later. However, NVLD is probably something of a misnomer, since children with VCFS do show
early deficits in verbal skills as well, some starting at
an early age and typically persisting into later life w1,5x.
In a study of early language development in children
with VCFS below the age of 5 years 3 months, Gerdes
and colleagues w6x found delays in the emergence of
language skills in all 32 children assessed by a speech
pathologist. A total of 20 from 32 children were not yet
speaking when they reached 2 years of age. In addition,
14 of these children scored 2 or more standard deviations
(S.D.) below the mean and 13 scored 1–2 S.D. below,
on the Clinical Evaluation of Language Fundamentals
test (CELF-R), a comprehensive assessment of language
functions. Five had caught up and scored in the average
range. Expressive language lagged behind receptive
language with mean scores of 71.2"16.0 and 78.2"12,
respectively.
In the study by Moss et al. w1x of 33 VCFS patients
from 6 to 27 years, it is clearly evident that language
problems persist into the school years. A total of 20
children with similar FSIQ, VIQ and PIQ profiles to the
whole group were tested on the CELF-R, and showed
moderately impaired mean total scores (66.9"14.9). By
this age, receptive and expressive scores no longer
differed, but the total and expressive language scores
were significantly lower than VIQ for this group (Fig.
1). In an overlapping group, full clinical evaluation
revealed that 50% were diagnosed with specific language impairments involving receptive and expressive
deficits. Clearly, there is not an absence of language
problems in the NVLD-like profile, and these undoubtedly have a negative effect on developing cognition and
educational outcomes. However, as we shall see, the
T.J. Simon et al. / Progress in Pediatric Cardiology 15 (2002) 109–117
greatest deficits are to be found in other areas of
cognitive function.
In a larger group of patients (including those studied
by Moss et al.), Woodin et al. w3x examined the more
detailed neuropsychological profiles of 50 children with
VCFS whose mean age was 10 years 3 months. Within
neuropsychological domains, some interesting distinctions emerged. For example, in the domain of ‘executive
function,’ subjects scored higher on tests requiring simple, focused attention than on tests that requiring more
planning and cognitive flexibility. More detailed testing
of reading comprehension also suggested that this was
an area of weakness relative to the decoding of single
words. Woodin et al. also reported that rote verbal
memory skills were in the average to above-average
range, while memory for stories was in the borderline
range, as was memory for geometric objects. Therefore,
these findings further support the picture of relative
strength for simple verbal memory and simple reading
skills compared to deficits in complex verbal memory,
visual–spatial memory and math achievement.
This final pair of weaknesses may be more than
coincidental. Wang et al. w7x pointed out the link that
has been established between deficits in visuospatial and
arithmetical ability, but not reading or spelling difficulties. One of the most direct links comes from the work
of Dehaene w8x, who makes the claim that some of the
simpler numerical operations that are carried out, such
as judging the relative magnitude of two values, are
done on the basis of spatial representations that resemble
an analog ‘number line’. Using the Kaufman Assessment
Battery for Children, Wang et al. showed that almost
two-thirds of the 36 school aged children with VCFS
that they tested scored higher on the Number Recall
subtest (verbal repetition of numbers) than the Spatial
Memory subtest (remembering locations). The former
scores were in the normal range, while the latter were 1
S.D. below it. This suggests that the problem is not
some global numerical processing weakness, but can
indeed be traced to spatial representations. Further evidence linking visuospatial and numerical deficits in these
children comes from the study by Bearden et al. w9x,
which employed specific tests of visual and language
learning and memory functions on a population overlapping those studied by Moss et al. and Woodin et al.
There were 29 children with VCFS between the ages of
5 and 17 years (mean 10.34 years). As expected, scores
on visual–spatial memory were significantly lower than
those for verbal learning. Furthermore, these children
scored significantly higher on a test of memory for
object designs than on a test of memory for spatial
location.
This distinction fits quite well with the distinct visual
processing pathways in the human brain which process
identity information about visual inputs (the so-called
‘what’ pathway) and location or information (the so-
111
called ‘where’ pathway) within separate neural substrates w10x. The patients of Bearden et al., it seems,
had most trouble in processing location information in
visual stimuli that would be primarily handled in the
‘where’ pathway, which runs from the primary visual
cortex into the posterior parietal lobes. They had less
trouble with featural information, processing of which
would be primarily implemented by the ‘what’ pathway,
running from the primary visual cortex into the inferior
temporal cortex.
3. Cognitive process findings
Therefore, everything we have reviewed so far, from
IQ subscores to specific neuropsychological function
tests, suggests that a common pathway between visuospatial and numerical deficits in VCFS may lie in the
dysfunction of brain areas primarily responsible for
representing spatial information and for supporting the
cognitive functions common to visuospatial and numerical competence. A good deal of evidence points to the
inferior parietal lobes (IPL) as that substrate. Clinical
findings and cognitive experimentation have consistently
reported that patients who suffer IPL damage due to
stroke and other insults present with deficits in perception of peripersonal space w11x, visual attentional control
w12x, and numerical competence w13x. Cognitive process
studies have directly linked mechanisms involved in
visual attention and enumeration w14,15x, and these
mechanisms have been shown to rely on common neural
substrates, a major component of which is IPL w16x.
Finally, Dehaene’s w17x ‘triple code’ theory associates
three kinds of numerical representations with specific
brain areas or pathways. The mature store of numerical
facts on which adults rely for exact calculation w18x are
in left frontal language areas. Interpretation of visual
forms, such as numerals or number words, takes place
in the occipito-temporal ‘what’ pathway. Finally, analog
magnitude representations are represented spatially in
IPL, which is also the source of magnitude comparison
and approximate calculation processing w18,19x.
To investigate whether the reported numerical and
visuospatial deficits in VCFS are indeed due to dysfunction in areas of IPL that are involved in visuospatial
and numerical cognitive processes, we have recently
embarked on a study employing cognitive tests and
neuroimaging analysis specifically designed to evaluate
that hypothesis. A group of 7–13-year-old children with
VCFS is being compared to a group of their siblings.
All children complete an ‘endogenous cueing’ task, an
‘enumeration’ task, and a ‘distance effect’ task in our
lab. They also carry out a functional MRI (fMRI)
version of distance effect task and undergo three structural MRI scans in order to measure the volume of brain
tissue and the amount of and patterns of connectivity in
white matter.
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T.J. Simon et al. / Progress in Pediatric Cardiology 15 (2002) 109–117
Fig. 2. Example stimuli from Enumeration Task for (a) small (subitizing range) and (b) large (counting range) set sizes. (a) For small quantities,
typical observers can quickly determine the number of objects without resorting to counting individual items. This process is known as ‘subitizing.’
(b) Larger quantities cannot be subitized, but must be counted to determine the number of objects.
We use a Cueing experiment to evaluate visual orienting abilities. The task involves responding to a single
target object flashed on the screen to the right or left of
a central fixation point. The target’s appearance is
preceded either by a ‘valid’ cue (pointing briefly to the
side of the target’s appearance, and hence drawing
attention there) or an ‘invalid’ cue (where the cue points
to the opposite side and draws attention away from
where the target will appear). The child’s task is to
press one key for a target on the left and another for a
target on the right. We predicted that children with
VCFS would show increased difficulty in orienting
attention in the absence of facilitatory information if
there was parietal dysfunction involving directing and
engagement processes. Our preliminary results show that
patients perform no worse than their siblings when their
attention is directed to the target location by a valid cue
400 ms before its appearance. However, if the target is
preceded by a neutral cue, which does not direct attention to the target location, or an invalid cue, which
directs attention to the wrong location and which
requires IPL function to disengage that location and
reorient to the correct location, reactions times are much
longer and more errors are evident in the performance
of the patients. This suggests that if children with VCFS
need to search for and extract information within a
complex scene (e.g. a map), they should be provided
with strong cues to the critical information, such as the
use of arrows or distinct colors.
Problems with managing visual attentional orienting
are likely to have contributed to the worse performance
we predicted and observed for quantities larger than
three on the part of children with VCFS in our enumeration experiment. Enumeration of just a few objects is
known as ‘subitizing’ (Fig. 2a). This ability is largely
captured by the experience of instantly ‘knowing’ how
many entities comprise collections of up to three or
four. It is thought to be implemented by widely focused,
low-resolution attentional mechanisms that rely on
extrastriate occipital cortex. In contrast, counting larger
sets takes place through serial visual search (Fig. 2b) in
which IPL plays an important role w16,20x, and for this
reason we expected worse performance in that range.
The task requires each child to sit in front of a computer
screen and complete trials in which one to eight objects
are displayed on the screen. The child’s task is to
respond by speaking into a microphone, as quickly as
possible, the number of objects that were presented. Our
results showed no differences between patients and
siblings in their ability to enumerate one or two objects.
However, children with VCFS took increasingly longer
and made increasing errors in their efforts to count sets
as they increased in size. This suggests that children
with VCFS might be able to count more accurately if
objects can be grouped together in sets of no more than
two objects.
Based on Dehaene’s triple code theory, we also
predicted that our VCFS patients might not show the
standard ‘distance effect’. This is evident when individuals are asked to judge whether a given quantity is
larger or smaller than some other reference quantity, e.g.
five. Since judgments are thought to take place on
spatially represented ‘number lines’ (constructed in
IPL), quantities near the reference (e.g. four) are more
confusable than those further away (e.g. one) and the
judgment takes longer and produces more errors. However, we predicted that if there is some dysfunction in
IPL that disturbs the association between space and
quantity in the representations that are created, then this
distance effect might not be seen. Our Distance Effect
task is a replication of the one that Temple and Posner
w21x successfully used with young children. The task
involves making a judgment about whether the value of
a stimulus is ‘greater than’ or ‘less than’ five. The
T.J. Simon et al. / Progress in Pediatric Cardiology 15 (2002) 109–117
stimuli have the values one, four, six and nine. Each of
the four stimuli is presented five times in both Arabic
numeral and dot pattern form. As predicted, our preliminary data indicate that the siblings produced the normal
distance effect of longer reaction times to four and six
than one and nine for both stimulus types. However, the
children with VCFS did not. For dot patterns, the
patients took approximately the same time to judge the
relative magnitude of one, four and six to five, with
nine being the fastest. This stimulus type engages IPL
for both stimulus interpretation (how many spatially
arranged dots) and for the magnitude comparison itself.
However, when the stimuli were in numeral form, which
neuroimaging data (e.g. w19x) indicate would move some
task processing to take place in the inferior temporal
lobes, the patients’ performance came closer to exhibiting the actual distance effect. One implication of this
finding is that children with VCFS may benefit from
much earlier than usual mapping of quantities to some
form of notation (either numerals or number words) to
help them to represent more accurately the quantity they
need to think about.
We need to collect much more data to see if this
pattern holds up, but, at present, it does appear that
dysfunction in IPL, as detected by tasks which are
heavily dependent on processes implemented by that
neural substrate, may explain why children with VCFS
have problems in the areas of visuospatial and numerical
cognition. This also suggests that there may be cognitive
interventions that can designed, so that, instead of
waiting for these children to be diagnosed with numerical learning problems in early grade school, the problem
can be intercepted early in life and children might be
helped to form functional spatio-numerical representations in ways that their brains can handle. In order to
do this, we must know whether there are brain regions
that may be able to handle these reformatted tasks. To
this end, we have recently begun fMRI experiments
using the distance effect task with VCFS patients. A
single child studied so far exhibited two interesting
patterns. One is that there was little of the appropriate
IPL activity that we would expect to see based on fMRI
studies of normal adults or of ERP studies with children.
The other is that quite diverse and perhaps unusual
patterns of activation are evident. How unusual these
really are can only be determined when we have imaged
sufficient numbers of patients and unaffected control
subjects to determine what the normal pattern of immature brain activity is. Eliez et al. w22x reported a related
result from a study that required children with VCFS
and control subjects to carry out simple arithmetic in an
fMRI task. On the more difficult problems, patients
showed higher levels of activation in the left supramarginal gyrus (SMG) within IPL than did the control
subjects, which also suggested a relocation of processing
in this higher-order task. There were also higher levels
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of activation in patients on the difficult tasks in two
large clusters of voxels, one extending from the left
precentral gyrus to the left SMG, and the other from
right insular areas to the right SMG. These unusually
activated areas can be considered candidates for alternative processing sites if it can be established that their
recruitment can be used to improve performance. Once
we have established if there is a consistent pattern, we
will need to go about the task of creating alternative
processing trajectories to numerical competence that can
exploit these functional and apparently ‘willing’ alternate regions.
4. Cognitive development and cardiac status
An important question regarding the findings discussed above, particularly for this review, concerns the
role of cardiac anomalies in these deficits. While the
actual prevalence of cardiac defects associated with the
deletion is not definitively known, such a diagnosis was
made in 74% of the 250 patients observed by the
Children’s Hospital of Philadelphia clinic w23x. The
most common anomalies reported in an earlier survey
of this sample were tetralogy of Fallot (TOF), interrupted aortic arch (IAA), ventricular septal disorder
(VSD), and truncus arteriosus (TA) w23x. Clearly, cardiac problems cannot be the sole cause of cognitive
deficits, as individuals with VCFS but without heart
defects also show the intellectual profile described above
w9 x .
So far, no direct link between cardiac status and
cognitive outcome has been established in the VCFS
population, although it should be noted that no study
focusing specifically on this question has yet taken
place. Gerdes et al. w6x reported finding no association
between cardiac diagnosis and outcome scores in their
study of preschool children, in which 29 of 40 children
involved had a cardiac anomaly. Swillen at al. w4x
reported that FSIQ scores were actually higher in their
child and adolescent subjects who had a heart defect
than in those who did not. However, the difference was
not statistically significant.
Given the possibility that congenital heart defects
(CHD) could affect cognitive skills, it is helpful to
evaluate the mechanisms through which such effects
could be transmitted. The two most obvious, which may
not be independent of each other, are the effects of
surgicalyanesthetic interventions, and the direct effects
of abnormal cardiovascular physiology. In both cases,
the damage would likely take place via the hypoxic–
ischemic effects on brain tissue.
With respect to surgical intervention, Bellinger et al.
w24x evaluated developmental outcomes at 4 years of
age in 158 children who had undergone arterial-switch
operations for transposition of the great arteries (TGA).
Although this malformation is not typically found in
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T.J. Simon et al. / Progress in Pediatric Cardiology 15 (2002) 109–117
VCF, the profile of IQ scores in these subjects is
reminiscent of the profile observed in VCF. These
children showed a mean Verbal IQ score of 95.1, which
was significantly higher than their mean Performance
IQ score of 91.6. The authors state that ‘‘the subtests
on which scores tended to the lowest were those that
assessed visual-spatial and visual-motor integration
skills (p. 527).’’ The subjects also showed below average scores on almost every measure of language skill
that was administered. A diagnosis of VSD was an
independent risk factor for lower IQ scores and speech
apraxia. A separate study of 13-year-old children who
had undergone repairs for hypoplastic left heart syndrome (HLHS) w25x also showed VIQ scores higher
than PIQ scores, with weaknesses in language skills as
well.
Thus, by the age of four it appears that an effect of
some heart defects or their repair on intellectual function
can be measured, and that this effect resembles the
profile of VCFS. However, the mean IQ scores of
children with VCFS are notably lower than for children
with either TGA or HLHS. Furthermore, the pathogenesis of these cognitive deficits remains unclear, bringing
us to the second mechanism, the neurocognitive effects
of pre- and post-natal hypoxia–ischemia. There appears
to be some evidence that hypoxia–ischemia has a
particularly negative impact on neural white matter,
particularly in the periventricular regions w26x, and these
effects can be well detected using diffusion-weighted
MRI methods w27x. This is important, because quantitative MRI studies of the brains of children with VCFS
have shown that there are considerable reductions in
non-frontal lobar volumes and that the preponderance
of that loss is in white matter w28,29x.
Currently, the etiology of the specific cognitive and
neuroanatomic profile in VCFS remains unknown. However, other physical anomalies that result from the
22q11.2 gene deletion, including the cardiac abnormalities and facial malformations, are thought to result from
anomalous migration of the neural crest during early
embryogenesis w30x. During this time, anomalies in
events that are reliant on neural induction may produce
secondary effects in proliferation or migration, thereby
leading to cerebral white matter pathology w31x. The
reports of focal white matter hyperintensities in VCFS
patients offer tentative support for hypotheses of defective white matter. Also referred to as ‘leuko-araiosis’ or
‘lesions’, these white matter abnormalities are usually
not present in healthy persons under age 45. Although
of unknown etiology, the presence of these abnormalities
is known to increase with age and with the existence of
co-morbid medical conditions, and may indicate an
underlying ischemia process w32–34x. Given the high
prevalence of cardiac defects and cardiac repair in VCFS
patients, these hyperintensities may represent effects of
cardiac status, rather than an expression of the genetic
deletion itself.
Although the functional significance of white matter
hyperintensities is not entirely clear at present, their
presence has been associated with poorer cognitive
function on neuropsychological tests in a number of
studies w35,36x, suggesting that these structural brain
abnormalities may mediate the cognitive impairments
observed in VCFS. Recently, modern neuroimaging
techniques have been brought together with cognitive
studies to show that specific disruptions in white matter
connectivity might account for deficits in reading ability
w37x. These recent developments provide novel ways to
determine the precise nature of cognitive deficits in
VCFS, while at the same time providing another tool in
the task of evaluating the role played by cardiac anomalies. They also offer the chance to examine a claim
made by Rourke w38x that it is disturbances in white
matter connectivity that are at the root of NVLD, the
very pattern of cognitive deficit which seems to best
characterize children with VCFS.
5. Psychiatric concerns
A wide range of behavioral and psychiatric concerns
has been reported in children with the 22q microdeletion.
These include concerns related to hyperactivity and
inattention, and anxieties and social withdrawal w4,6x.
Studies utilizing parent report data (i.e. Child Behavior
Checklist) indicate significantly elevated rates of attention and internalizing problems in children with VCFS
w4,51,52x. It is not clear whether the attentional concerns
are specific to the syndrome or whether they simply
reflect the commonly observed traits of children with
developmental disabilities, but the social skills deficits
and anxieties may relate to the NVLD profile w1,2x.
Autism also has been reported in a small number of
children with the microdeletion w39x, but this again may
be related to the mental retardation that is found in some
subjects, rather than to the direct effects of the
microdeletion.
More severe psychiatric disorders have been reported
in older adolescents and adults with VCFS. The first
indication of these came from Shprintzen et al. w40x,
who reported that a large percentage developed psychotic disorders. This finding was confirmed in subsequent reports, all of which noted an elevated incidence
of schizophrenia and schizoaffective disorders among
adults with this genetic condition w41x. Furthermore, at
least four studies have demonstrated an overrepresentation of the 22q11.2 deletion in samples of persons with
a diagnosis of schizophrenia; 2–6% of persons with
schizophrenia in these samples had the 22q11.2 deletion
w42,43x. Moreover, recent reports by Nicolson et al. w44x
indicate that 3 of 47 children with child-onset schizophrenia were discovered to have a 22q deletion upon
T.J. Simon et al. / Progress in Pediatric Cardiology 15 (2002) 109–117
115
FISH testing. Publications that address the association
between VCFS and schizophrenia generally concur that
25–30% of children with the syndrome will eventually
develop schizophrenia or psychosis w45x, making VCFS
the highest known risk factor identified to date for
development of this psychiatric disorder. However, the
exact nature of the psychiatric manifestations of the
disorder remains unclear: Papolos et al. w46x have
reported an unusually high prevalence (64%) of bipolar
spectrum disorders in VCFS patients, and some studies
have linked bipolar disorder to this region of chromosome 22 w47,48x.
While fewer studies have employed structured diagnostic interviews in younger children with VCFS, colleagues at CHOP found psychotic disorders were present
in 3y31 cases (9%), which is over 50-fold the base rate
of these disorders in children w49x. Rates of ADHD,
ODD and anxiety disorders were also elevated, although
at only two to three times their base rates. Furthermore,
sub-syndromal symptoms of attention and mood disturbance were endorsed in almost all cases (88%). Similarly, a recent study by Arnold et al. w50x found
psychiatric disorders to be present in 12y20 adolescent
VCFS patients (60%), as compared to 3y11 (27%) of
their unaffected siblings. Mood disorder was the most
frequent diagnosis. Notably, three patients diagnosed
with depressive disorder also had prominent schizotypal
traits, and two of these three later developed schizophrenia. These findings indicate that the psychiatric
disorders observed in adult patients are present, at least
to some degree, in early childhood, and highlight the
importance of investigating the developmental trajectory
of VCFS.
deletions. This could be partly explained by the lower
educational status of the affected parent providing a less
enriched environment within which to learn. With a
growing number of children with VCFS approaching
adulthood, and the fact that 50% of children they
produce are also likely to have the deletion, this should
be an area of real concern. Finally, it is clear that the
development of psychiatric disorders, schizophrenia in
particular, can have an independent, negative effect on
cognitive outcome.
6. Summary
Acknowledgments
Clearly, most children with VCFS have some serious
cognitive deficits that have negative implications for
outcomes. Little or no formal investigation appears to
have taken place concerning what might be called
‘situational’ implications of the syndrome for cognitive
development. However, children with VCFS face a range
of medical challenges and procedures early in life, and
the effect of these on opportunities for early learning
and the implications for brain development will be
important to understand. Once these children proceed
from preschool to regular classes, they will have adjustment problems. The social withdrawal often described
may be as much due to situational factors, including
their relatively small stature, unclear speech and lack of
academic or sporting prowess. This has the potential to
engender a negative attitude towards school, and thus
have a deleterious effect on outcome in the educational
domain. In addition, Swillen et al. w4x reported that
patients with a deletion inherited from one parent had
lower mean FSIQ scores than those with de novo
We thank the children, adults and families who have
participated in our studies of VCFS. Dr Michael F.
Woodin, Mr David O. Aleman and others have greatly
contributed to these studies. Much of the research
described and the writing of this manuscript were
supported in part by grants from the National Institutes
of Health, DC 02027 and HD 01174.
7. Future approaches
Clearly the time and conditions are now right for
extensive studies of brain and cognitive implications of
VCFS. Links to specific cognitive processes underlying
a range of deficits in VCFS are now being made. In
addition, new neuroimaging techniques allow researchers to examine how and why differences in brain
structure and function may alter the way these processes
work in individuals with VCFS. Many questions remain
about the precise role of cardiac defects in those neurocognitive processes, and there is a clear need for
controlled, prospective brain and cognition studies
involving children with and without the 22q11.2 deletion
who have undergone the same cardiac repairs early in
life, as well as deleted patients who do not have a
cardiac defect. Finally, findings in all of these areas will
hopefully contribute to the design and implementation
of cognitive and other kinds of interventions that can
exploit early brain plasticity to change the trajectory of
cognitive development in VCFS, and hopefully contribute to more positive outcomes.
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