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Cognitive-behavioral features of children with WolfЦHirschhorn syndrome Preliminary report of 12 cases.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:252– 256 (2008)
A R T I C L E
Cognitive-Behavioral Features of Children With
Wolf–Hirschhorn Syndrome: Preliminary Report of
12 Cases
GENE S. FISCH,* AGATINO BATTAGLIA, BARBARA PARRINI, JANEY YOUNGBLOM, AND
RICHARD SIMENSEN
As a subset of genetic abnormalities, subtelomeric deletions have been found in 7–10% of individuals with
mental retardation (MR). One subtelomeric deletion, Wolf-Hirschhorn syndrome (WHS), causes mild to severe
MR, but the cognitive-behavioral features of individuals with WHS have not been studied systematically. To that
end, we administered a comprehensive cognitive-behavioral battery to 12 children with WHS, ages 4–17 years,
who also had some expressive language. Using the Stanford-Binet (4th Edition), we found cognitive deficits
ranged from mild to severe, with mean IQ ¼ 44.1. Interviewing parents with the Vineland Adaptive Behavior
Scales, we found mean adaptive behavior score (DQ) ¼ 37.3, with females exhibiting slightly higher scores than
males. Cognitive profiles indicated relative strengths in Verbal and Quantitative Reasoning. Adaptive behavior
profiles noted significant relative strengths in the Socialization Domain. These cognitive-behavioral profiles
differed from children with other subtelomeric deletion syndromes, 2q37 or 8p23. Attention deficits and
hyperactivity (ADHD) were observed in 7/12 (58%) of the children we tested. One child attained a score on the
Child Autism Rating Scale (CARS) suggestive of mild autism. We conclude that different genetic disorders, which
cause MR, produce diverse cognitive-behavioral profiles. Consequently, cognitive-behavioral profiles of children
with MR need to be assessed more comprehensively. ß 2008 Wiley-Liss, Inc.
KEY WORDS: genetics; Wolf–Hirschhorn syndrome; subtelomeric deletions; mental retardation; adaptive behavior; ADHD; autism; learning
impairment; cognitive-behavioral profiles
How to cite this article: Fisch GS, Battaglia A, Parrini B, Youngblom J, Simensen R. 2008.
Cognitive-behavioral features of children with Wolf–Hirschhorn syndrome: Preliminary report of
12 cases. Am J Med Genet Part C Semin Med Genet 148C:252–256.
INTRODUCTION
Gene S. Fisch is currently Senior Biostatistician and Research Professor at NYU Colleges of
Dentistry and Nursing, and Adjunct Professor at Yeshiva University. His research interests include
genetic disorders that produce learning impairment and/or autism. He has studied cognitivebehavioral development in children with the fragile X mutation, William–Beurens syndrome, and
Neurofibromatosis Type 1. He is also interested in the epistemology of pervasive developmental
disabilities and autism.
Agatino Battaglia is Contract Professor of Child Neuropsychiatry at the Postgraduate Medical
School, University of Pisa, Italy; and Adjunct Professor of Pediatrics at the University of Utah
Health Sciences Center, Division of Medical Genetics, Department of Pediatrics, Salt Lake City,
UT, USA. He is board certified in Clinical Pediatrics and in Neurology. He is Director of the Clinical
Dysmorphology Unit, Head of the Center for the Study of Congenital Malformation Syndromes,
and Director of Research in Neuropsychiatric Genetics, at the Stella Maris Clinical Research
Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy. He has a
strong research interest in clinical dysmorphology, neuropsychiatric genetics, and clinical
neurophysiology.
Dr. Barbara Parrini is a psychologist working at the Stella MarisClinical Research Institute for
Child and Adolescent Neuropsychiatry. She has strong research interests in the neuropsychological and behavioural profiles of individuals with chromosomal and pervasive
developmental disorders.
Janey Youngblom is Professor of Biology, California State University, Stanislaus. Her interests
include microarray analysis of individuals with deletion 8p23, and the training genetic counselors.
Richard Simensen is a neuropsychologist at the Greenwood Genetics Center, South Carolina.
His research interests include studies of children with the fragile X mutation, William-Beurens
syndrome, and X-linked mental retardation.
*Correspondence to: Gene S. Fisch, Ph.D., Bluestone Clinical Research Center, NYU Colleges
of Dentistry & Nursing, 421 First Ave., 2nd Fl., New York, NY 10010. E-mail: gene.fisch@nyu.edu
DOI 10.1002/ajmg.c.30185
Published online 16 October 2008 in Wiley InterScience (www.interscience.wiley.com)
ß 2008 Wiley-Liss, Inc.
The role genetics has played in causing
cognitive impairment has become better
understood over the last 50 years as
cytogenetic and microarray techniques
have evolved and made possible identification of defects that may be found on
individual chromosomes. At the same
time, molecular genetic techniques are
now able to detect single gene and
contiguous gene genotypes. A decade
ago, Sarimski [1997] reported that
there were about 1,000 genetic causes
of mental retardation (MR), and their
phenotypes were many and varied. It
now appears that genetic abnormalities
that produce MR occur in more than 1%
of the general population [Fisch, 2000].
As a subgroup of genotypes,
subtelomeric deletions have been
detected in 7 – 10% of individuals
with MR [Lam et al., 2006], as well
ARTICLE
as in children diagnosed with autism
[Koolen et al., 2004]. Given their
relatively infrequent occurrence,
studies assessing cognitive ability and
other aspects of behavior in individuals with these abnormalities have
been problematic.
One such subtelomeric deletion that
produces MR is deletion 4p16 [also
known as Wolf–Hirschhorn syndrome
(WHS)]. WHS is associated with a variety
of clinical features: growth retardation,
unusual craniofacial features; seizures,
and developmental delay, among others
[Lurie et al., 1980]. Surprisingly, only
recently has the natural history of WHS
been assessed [Battaglia et al., 1999]. In
addition, there has been only one study of
speech and language in a small group of
children with WHS [Sabbadini et al.,
2002]. Attempts have been made to
identify genotype–phenotype correlations [Zollino et al., 2000], but cognitive-behavioral aspects of individuals
associated with the genotype have not
been studied systematically. This is
Attempts have been made to
identify genotype–phenotype
correlations, but
cognitive-behavioral aspects of
individuals associated with the
genotype have not been studied
systematically.
unfortunate since cognitive-behavioral
profiles and age-related features of cognitive-behavioral deficits may permit
researchers to describe more completely
the natural history of the disorder, and
draw inference about brain development.
Therefore, the purpose of our study
was to determine the cognitive profiles,
adaptive and maladaptive behavior profiles, aspects of temperament and emotional behavior, attentiveness and activity
levels, and to ascertain autism status in
children diagnosed with WHS. The
results we present here are preliminary
findings in our ongoing study of cognitive-behavioral features of children with
subtelomeric deletions.
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
METHODS
Participants
Twelve children with WHS, diagnosed
previously by fluorescent in situ hybridization, ages 4–17 years. Six children
were male, six were female. As expressive speech and language are essential
features of our standard cognitive test,
inclusion criteria for cognitive testing
required that children be able to communicate verbally and have some expressive speech and language. Participants
were recruited from six major sites in
two countries: the USA (N ¼ 10); and
from Pisa, Italy (N ¼ 2). As part of
our ongoing investigation of cognitive
features of subtelomeric deletion syndromes we had previously studied seven
children with 2q37 deletion and seven
with 8p23 deletion.
Materials
Participants with WHS were administered a cognitive-behavioral battery
which consisted of five standardized
valid and reliable instruments to assess
behavior.
Cognitive-Behavioral Measures
Cognitive abilities were obtained using
the Stanford-Binet (4th Edition)
(SBFE). The SBFE contains standard
area scores (SAS) for four major areas of
assessment: verbal reasoning (VR);
abstract/visual reasoning (AVR); quantitative reasoning (QR); and short-term
memory (STM). Adaptive behavior
skills were assessed with the Vineland
adaptive behavior scale (VABS) contains
four domains: communication; daily
living skills (DLS); socialization; and
motor skills for children less than 6-year
of age. The VABS also contains two
scales to assess Maladaptive Behavior.
Attention/Activity
Activity levels and attentiveness were
assessed using the Conners rating scale
(CRS). The CRS examines several
scales associated with behavioral genotypes: oppositional; cognitive problems/
inattention; hyperactivity; anxious/shy;
perfectionism; social problems; and
253
psychosomatic problems. More importantly, DSM-IV symptoms/indices specifically associated with attention deficit
disorder (ADD) and attention deficit/
hyperactivity disorder (ADHD) can be
obtained from the CRS.
Emotionality/Temperament
To evaluate the child’s emotionality and
temperament, parents completed the
child behavior checklist (CBCL). The
CBCL assesses emotional behavior
along two major dimensions: internalizing and externalizing behaviors. Internalizing behaviors contain the following
scales: withdrawn; somatic complaints;
anxious/ depressed; social problems;
thought problems; attention. externalizing behaviors contain two scales:
delinquent; aggressive.
Autism
To ascertain the child’s status with regard
to autism, The child autism rating scale
(CARS) was employed. The CARS
consists of 15 subscales associated with
DSM-IV criteria associated with autistic
behavior. Each item is rated from ‘‘0’’
(behavior typical for a child that age) to
‘‘4’’ (Extremely abnormal behavior for a
child that age). Item scores are summed
and summated scores 30 are considered in the autism range.
Procedure
To obtain measures of their cognitive
abilities, one of us (G.S.F.) administered
the SBFE to all 10 children recruited from
sites in the U.S. Children recruited for
the study in Italy were administered the
Griffiths (N ¼ 1) or the Leiter (N ¼ 1).
IQ scores from the Griffiths and the
Leiter are strongly correlated with the
SBFE. All participants’ parents or caregivers were interviewed using the VABS
and CARS. All parents and caregivers
also completed the CRS and CBCL. All
assessments in the U.S. were scored by
one of us (G.S.F.).
RESULTS
Mean IQ score for our sample of
children with WHS was 44.1 (range:
254
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
33–64). When we compared males
(n ¼ 6) to females (n ¼ 6) we found no
significant differences between the two
groups. Mean IQ score for females was
45 (range: 33–60); for males, mean IQ
was 43 (range: 36–64). Mean IQ scores
for children in the WHS group were
compared to mean IQ scores for children
with two other subtelomeric deletion
syndromes: 2q37 (n ¼ 7) or 8p23
(n ¼ 7). The results are shown in
Figure 1. Mean IQ scores for children
with WHS were lower than those for the
other subtelomeric deletion syndromes,
but the differences were not statistically
significant.
Mean adaptive behavior (DQ) score
for children with WHS was 37.3 (range:
19–63). We also compared DQ scores
for males and females. Results show that
the mean DQ score for females was
41.67 (range19–63) was higher than the
mean DQ for males, 33.0 (range 23–
47), but the difference in the mean DQ
scores was not statistically significant.
Mean DQ scores for children in the
WHS group were compared to mean
DQ scores for children with deletion
2q37 and 8p23. The results are shown
in Figure 2. Mean DQ scores for
children with WHS were lower than
those with other subtelomeric deletions,
but the differences were not statistically
significant.
To examine cognitive profiles in
children with WHS, we analyzed their
SAS scores, after which we compared
mean SAS scores for verbal reasoning,
abstract/visual reasoning, quantitative
reasoning, and short-term memory, to
their respective mean SAS scores for
children with deletion 2q37 and 8p23.
Results are shown in Figures 3a,b. In
Figure 3a, mean VR (49.67) and QR
(49.86) SAS scores were greater than
mean AVR (43.88) and STM (43) SAS
scores, but the differences were not
statistically significant. The three subtelomeric genotypes and Standard
Area were compared statistically using
a mixed effects ANOVA model.
Results (see Table I) show that there
Figure 1. Mean composite IQ scores (SD) for children with subtelomeric
deletions 2q37, 8p23, and 4p16.
Figure 2. Mean composite DQ scores (SD) for children with subtelomeric
deletions 2q37, 8p23, and 4p16.
ARTICLE
are statistically significant differences in
the SAS patterns of subtelomeric deletion genotypes (P < 0.02), but individual SAS areas were not significantly
different statistically across genotypes
(Fig. 4).
Adaptive behavior profiles were
similarly evaluated. We computed mean
Communication, DLS, Socialization
Domain scores for children with WHS,
after which we compared those scores
with mean domain scores for the other
two subtelomeric deletions. Results
show that, among children with WHS,
mean Socialization score (51.75) was
significantly higher than mean Communication score (38.42) or DLS (32.67)
Results show that, among
children with WHS, mean
Socialization score (51.75) was
significantly higher than mean
Communication score.
(w2 ¼ 5.94; P ¼ 0.05). When domain
scores for children with WHS were
compared with the other two subtelomeric deletions, however, no statistically
significant differences were found.
Using the CRS, we calculated the
proportion of children whose activity
levels and lack of attentiveness were
consistent with a diagnosis of ADD or
ADHD. Among children with WHS, 7/
12 (58%) of the children in our sample
met those criteria. Among children with
2q37, 5/7 (72%) met those criteria,
while 4/7 (58%) children with 8p23
met those criteria.
Using the CBCL, we computed the
proportion children with WHS who had
significant emotional problems. We
found that, despite their strong Socialization skills, 5/12 (42%) were recognized with social problems, 4/12 (33%)
attention problems, and 1/12 (8%) was
considered to have thought problems.
Finally, using the CARS, we interviewed parents and examined participants to ascertain the autism status of
children with WHS. We found one child
(8%) whose CARS score 30. This was
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
255
a much lower proportion than that
which was observed in children with
deletion 2q37 (3/7 or 42%) or 8p23 (5/7
or 58%).
Figure 3. a,b: Mean SAS scores from the SBFE for children with subtelomeric
deletions 2q37, 8p23, and 4p16.
TABLE I. Mixed Effects Model to Examine the Effects of Subtelomeric
Genotype and SBFE Standard Area on SAS Scores for Children With 2q37,
8p23, or WHS
Effect
Genotype
Area
Genotype area
Num DF
Den DF
F-value
Pr > F
2
3
6
55
55
55
3.82
0.46
0.17
0.0279
0.7113
0.9847
Figure 4. a,b: Mean domain scores from the VABS for children with subtelomeric
deletions 2q37, 8p23, and 4p16.
Finally, using the CARS, we
interviewed parents and
examined participants to
ascertain the autism status of
children with WHS. We found
one child whose CARS score
30. This was a much lower
proportion than that which was
observed in children with
deletion 2q37 or 8p23.
SUMMARY AND
DISCUSSION
Microdeletions in the 4p16.3 region are
variable in size but may produce similar
clinical features in the phenotype that
characterizes WHS. Zollino et al. [2000]
found that the severity of the WHS
phenotype is related to the deletion size
and region. At this preliminary stage of
our study, however, we are unable to
ascertain a relationship between deletion
size and cognitive-behavioral abilities.
Moreover, by excluding children who
have no expressive speech and language,
we are likely assessing children who are
functioning at the upper end of cognitive
ability for this disorder. Nonetheless, it
will be important to establish a genotype–phenotype relationship in children
with WHS; and, we hope to expand this
aspect of our study.
To elaborate the phenotype more
completely, we examined the cognitive
skills and behavioral repertoire of 12
children, ages 4–17 years, who were
diagnosed with WHS and who have
some speech and expressive language.
We found that their cognitive deficits
ranged from mild to severe MR. In
general, their cognitive abilities were
lower than children with other subtelomeric deletions, 2q37 and 8p23.
256
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Children with WHS exhibited
relative strengths in Verbal and Quantitative Reasoning, and relative weaknesses in Abstract/Visual Reasoning and
Short-term Memory. The pattern of
strengths and weaknesses found in children with WHS differs from those we
observed in children with deletions 2q37
and 8p23 who present relatively flat
Children with WHS exhibited
relative strengths in Verbal
and Quantitative Reasoning,
and relative weaknesses in
Abstract/Visual Reasoning
and Short-term Memory. The
pattern of strengths and
weaknesses found in children
with WHS differs from those
we observed in children with
deletions 2q37 and 8p23
cognitive profiles. The inability to attain
statistical significance between strengths
in verbal and quantitative reasoning on
the one hand, and weaknesses in
abstract/visual reasoning and short-term
memory on the other, is likely due to the
variability in SAS scores relative to the
small sample size.
Previously, we characterized the cognitive-behavioral profiles in children with
other genetic disorders that produce
MR—the fragile X mutation (FRAXA)
and William-Beurens syndrome (WBS)—
and found a similar pattern of strengths and
weaknesses [Fisch et al., 2007] in verbal and
quantitative reasoning. However, verbal
reasoning scores for children with FRAXA
or WBS were significantly higher than
those with WHS (P < 0.03; data not
shown). Children with WHS also scored
lower on quantitative reasoning, abstract/
visual reasoning, and short-term memory,
but these scores were not significantly
lower (data not shown).
Adaptive behavior skills of all children with WHS we assessed were lower
than adequate. However, children with
WHS exhibit a significant relative
strength in Socialization compared to
their communication and daily living
skills. In comparison, children with
deletion 2q37 or 8p23 display a low,
relatively flat profile of adaptive behavior
skills. However, Socialization scores of
children with deletion 2q37 or 8p23
were not significantly different from
those with WHS. When compared to
children we tested previously who were
diagnosed with FRAXA or WBS,
children with WHS had significantly
different pattern of adaptive behavior
domain skills (P < 0.0001; data not
shown) and marginally lower individual
domain skills (P ¼ 0.06; data not
shown).
We also noted hyperactivity levels
and inattentiveness in children with
WHS that are consistent with a diagnosis
of ADD or ADHD. However, ADHD
and ADD are frequently observed comorbid features of individuals with MR.
We also found high rates of ADHD in
subtelomeric deletions 2q37 and 8p23.
Emotional and temperament problems
were found primarily to be associated
with impediments to relating well
socially and difficulty maintaining attention.
Autistic-like behavior plays a less
prominent role in children with WHS
than among other children with subtelomeric deletions. In our study, we
found that children with 2q37 and 8p23
have much higher rates of autism than
children with WHS.
Our study of children with WHS
supports our conviction that different
genetic disorders produce differing cognitive-behavioral profiles; and, that
cognitive-behavioral profiles of children
with genetic disorders that produce
MR or LD need to be explored more
comprehensively.
ACKNOWLEDGMENTS
We thank Wendy Trout, President of
the Wolf-Hirschhorn Parent Support
Group, for inviting families of children
ARTICLE
with WHS to participate in our study;
Faith Callis-Daley, genetics counselor
from Columbus OH, who contacted
families of children with 8p23; and
Marnie Beacham, Salt Lake City, UT,
who contacted families of children with
2q37. We gratefully acknowledge the
support from the Fondation Jérôme
Lejeune, Paris, France, who provided
funding for our project, without which
we could not have performed our
study.
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