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Vol:.(1234567890)
J Autism Dev Disord (2017) 47:3728–3740
DOI 10.1007/s10803-016-3015-y
1 3
S.I. : ANXIETY IN AUTISM SPECTRUM DISORDERS
Diverse Profiles ofAnxiety Related Disorders inFragile X,
Cornelia de Lange andRubinstein–Taybi Syndromes
HayleyCrawford1,2 · JaneWaite2· ChrisOliver2
Published online: 31 January 2017
© The Author(s) 2017. This article is published with open access at Springerlink.com
Introduction
Anxiety is evident more often in individuals with intellec-
tual disability than those of typical development. Preva-
lence rates for an anxiety disorder in children and adoles-
cents with an intellectual disability range from 3 to 21.9%
(Reardon et al. 2015; Royston et al. 2016). These preva-
lence rates are higher than those for the general popula-
tion for which the prevalence rate for typically developing
children and adolescents is 3 to 6.5% (Green etal. 2005;
Polanczyk etal. 2015). DSM-5 lists 12 types of anxiety dis-
order (American Psychiatric Association 2013): separation
anxiety disorder, selective mutism, specific phobia, social
anxiety disorder, panic disorder, panic attack, agoraphobia,
generalized anxiety disorder, substance-induced anxiety
disorder, anxiety disorder due to another medical condition,
other specified anxiety disorder and unspecified anxiety
disorder.
Genetic syndromes can be associated with a height-
ened prevalence of particular characteristics (Dykens etal.
2000); for example, heightened levels of self-injurious
behavior in Lesch–Nyhan syndrome, aggression in Angel-
man syndrome and excessive friendliness in Williams syn-
drome (see Waite et al. 2014 for a review). Furthermore,
research has indicated that some genetic syndromes, such
as Williams syndrome, 22q11.2 deletion, fragile X (FXS)
and Cornelia de Lange syndrome (CdLS), are also at
greater risk of anxiety compared to the general population
(CdLS: Basile etal. 2007; FXS: Cordeiro etal. 2011; Wil-
liams syndrome: Dykens 2003; 22q deletion: Fung et al.
2010). These genetic syndromes are often associated with
specific types of anxiety disorder. For example, anxiety in
people with Williams syndrome is more likely to be gen-
eralized, or related to specific phobias and fears, than to
social situations (Leyfer etal. 2009).
Abstract Anxiety disorders are heightened in specific
genetic syndromes in comparison to intellectual disability
of heterogeneous aetiology. In this study, we described and
contrasted anxiety symptomatology in fragile X (FXS),
Cornelia de Lange (CdLS) and Rubinstein–Taybi syn-
dromes (RTS), and compared the symptomatology to nor-
mative data for typically-developing children and children
diagnosed with an anxiety disorder. Scores did not differ
between children diagnosed with an anxiety disorder and
(a) participants with FXS on social phobia, panic/agora-
phobia, physical injury fears, and obsessive–compulsive
subscales (b) participants with CdLS on separation anxi-
ety, generalized anxiety, panic/agoraphobia, physical injury
fears and obsessive–compulsive subscales, and (c) partici-
pants with RTS on panic/agoraphobia and obsessive–com-
pulsive subscales. The results highlight divergent profiles
of anxiety symptomatology between these groups.
Keywords Anxiety· Genetic syndromes· Fragile X
syndrome· Cornelia de Lange syndrome· Rubinstein–
Taybi syndrome· Intellectual disability
* Hayley Crawford
hayley.crawford@coventry.ac.uk
1 Centre forResearch inPsychology, Behaviour
andAchievement, Coventry University, James Starley
Building (JSG12), Priory Street, CoventryCV15FB, UK
2 Cerebra Centre forNeurodevelopmental Disorders, School
ofPsychology, University ofBirmingham, Edgbaston,
BirminghamB152TT, UK
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3729J Autism Dev Disord (2017) 47:3728–3740
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Anxiety has previously been investigated in FXS, CdLS
and Rubinstein–Taybi syndromes (RTS), which form the
focus of the current study. Although previous research has
suggested a heightened risk of anxiety in these populations,
this research has not explored the symptoms of different
types of anxiety disorder using comparable assessment
instruments. Identifying the symptomatology of differ-
ent types of anxiety disorder most associated with these
genetic syndromes will further understanding of the diffi-
culties experienced by these groups. This will provide valu-
able information to clinicians, aiding them in developing
early intervention strategies and targeted syndrome-sensi-
tive interventions.
The aim of the present study is to delineate the profile
of anxiety symptomatology in individuals with FXS, CdLS
and RTS. To aid interpretation, the symptomatology of
anxiety disorders in these genetic syndromes will be com-
pared to normative data from samples of typically devel-
oping children, and children who have received a clinical
diagnosis of an anxiety disorder.
Fragile X Syndrome
FXS affects approximately 1 in 2500–5000 males and 1 in
4000–6000 females (Coffee etal. 2009; Hirst etal. 1993),
and is caused by abnormalities in the Fragile X Mental
Retardation 1 (FMR1) gene located at Xq27.3, resulting
in excessive cytosine–guanine–guanine (CGG) repeats and
reduced production of the FMRP protein. As an X-linked
disorder, males with the full mutation of FXS are more
severely affected than females, and due to these gender dif-
ferences, males form the focus of this study. A recent meta-
analysis indicated that approximately 30% of males with
FXS are diagnosed with autism spectrum disorder (ASD;
Richards etal. 2015), although a milder profile of autism
characteristics is observed than in those with idiopathic
autism (Moss etal. 2013).
Individuals with FXS are more likely to meet criteria
for an anxiety disorder compared to individuals with Wil-
liams syndrome, heterogeneous intellectual disability, and
to the general population. Cordeiro etal. (2011) reported
that 86.2% of males with FXS met criteria for one anxiety
disorder, and 60.3% met criteria for multiple disorders on
an informant interview based on DSM-IV criteria. Specific
phobia and social phobia were most commonly reported;
64.9 and 60.3% respectively. These phobias occurred more
frequently in those meeting criteria for an ASD, but this
was not statistically significant. An additional diagnosis of
ASD, however, was associated with selective mutism; the
third most commonly reported anxiety disorder in males
with FXS. The overall figures for anxiety reported by Cord-
eiro et al. (2011) are similar to those reported by Bailey
et al. (2008), in which parental reports demonstrated that
70% of males with FXS had received a formal diagnosis of
anxiety or were being treated for anxiety symptoms.
Cordeiro et al. (2011) reported that participants with
FXS demonstrated significantly higher rates of anxiety dis-
order than individuals with idiopathic intellectual disabil-
ity and individuals with Williams syndrome. This literature
highlights the heightened prevalence of anxiety in individu-
als with FXS compared to that of other syndrome groups
and those with idiopathic intellectual disability, suggesting
that anxiety is a core phenotypic feature of FXS. The pre-
sent study aims to contribute to this literature by investigat-
ing anxiety in FXS at a symptom-level.
Cornelia de Lange Syndrome
CdLS affects approximately 1 in 40,000 live births (Beck
1976) and is associated with intellectual disability, as well
as specific physical characteristics including distinctive
facial features and limb abnormalities. CdLS is caused pri-
marily by a deletion in the NIPBL gene located on chromo-
some 5 (Gillis etal. 2004; Krantz etal. 2004; Miyake etal.
2005), with fewer cases being caused by mutations on the
SMC3 gene on chromosome 10 (Deardorff etal. 2007), the
SMC1A gene (Musio etal. 2006), the RAD21 gene (Minor
etal. 2014), and the HDAC8 gene (Deardorff etal. 2012).
Similarly to FXS, CdLS is associated with an increased
risk of ASD with current prevalenceestimates around 43%
(Richards et al. 2015). In addition, and similar to FXS,
individuals show a subtly different profile of autism symp-
tomatology with more impairment in social interaction and
communication than in restricted and repetitive behavior
(Moss etal. 2013).
Anxiety has been reported in between 10 and 64% of
individuals with CdLS (Basile et al. 2007; Berney et al.
1999; Gualtieri 1991; Kline et al. 2007), and existing lit-
erature suggests that this increases with age (Basile etal.
2007; Collis et al. 2006; Liu and Krantz 2009) and IQ
(Basile etal. 2007). Although anxiety has been reported in
CdLS, the symptomatology associated with specific types
of anxiety disorder has not yet been extensively investi-
gated in this population.
Social anxiety has been studied independently of other
types of anxiety disorder in CdLS and evidence suggests
that there may be heightened levels of social anxiety when
individuals are presented with particular social demands,
such as communication (Richards etal. 2009). Collis etal.
(2006) found that behavioral indicators of social anxiety
were reported to occur in 75–100% of individuals. This is
in agreement with observations of behavioral markers of
social anxiety in CdLS, such as being shy and quiet, and
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3730 J Autism Dev Disord (2017) 47:3728–3740
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high levels of selective mutism (Goodban 1993; Kline etal.
2007; Moss etal. 2016).
Rubinstein–Taybi Syndrome
RTS is a multiple congenital anomaly syndrome affecting
approximately one in 100,000–125,000 live births and is
caused by mutations, breakpoints, and microdeletions on
chromosome 16p13.3, or by mutations in the E1A Binding
Protein, P300, or CREB-binding protein (Hennekam 2006;
Lacombe et al. 1992; Petrif et al. 1995; Roelfsema etal.
2005).
Levitas and Reid (1998) reported that 31% of 13 indi-
viduals with RTS were diagnosed with a tic/obsessive
compulsive disorder. In support of this, Stevens et al.
(2011) reported that 31% of individuals with RTS had
received a psychiatric diagnosis, and that most of these
were for obsessive compulsive disorder, anxiety, or depres-
sion. Item-level analysis revealed that 33% of participants
were described as having “unreasonable” fears or anxi-
ety. However, the questionnaire used was not standardised
or validated. Rather, it consisted of ‘yes or no’ answers to
140 questions about behavior, independence, education
and medical problems, limiting the extent to which strong
conclusions can be drawn. When comparing anxiety-like
symptoms in those with RTS to those without, internalizing
behavioral problems including anxiety have been reported
to be comparable to a group matched for developmental
level, age and gender (Galéra etal. 2009).
Scores on a measure of anxiety/depression were found
to be higher in older compared to younger individuals with
RTS (Yagihashi et al. 2012). The scores were still in the
typical range, although they approached borderline clinical
cut-off in the older participants. In contrast, a measure of
internalizing, which includes features of anxiety, remained
constant over the two age groups. Scores on this subscale
were within the borderline clinical cut-off range for older
participants with RTS. Item level analyses revealed that
37.5% of younger participants and 64.5% of older par-
ticipants were reported as ‘too fearful or anxious’. Simi-
larly, 31.3% of the younger participants and 67.7% of the
older participants were reported as ‘nervous, high-strung,
or tense’. These results suggest that although anxiety is
reported in individuals with RTS, it may not be of clinical
significance.
Previous research has explored the prevalence of psychi-
atric disorders in individuals with RTS, which has revealed
mixed results. Although these studies provide useful infor-
mation, the research is limited by small sample sizes and a
lack of a comparison groups. Whilst some of these studies
have highlighted the presence of anxiety in individuals with
RTS, exploration of the symptomatology associated with
sub-types of anxiety in this population is warranted.
Summary andAims
In summary, evidence suggests the presence of anxiety in
individuals with FXS, CdLS and RTS. However, knowl-
edge of the symptoms associated with different types of
anxiety in these groups, which is important for targeted
interventions, is limited. Furthermore, cross syndrome
comparisons of anxiety in these populations have not yet
been conducted. These comparisons have the potential to
delineate the relationship between anxiety symptomatol-
ogy, the presence of a particular genetic syndrome, and
intellectual disability, which are important factors associ-
ated with heightened anxiety. Finally, the phenomenology
of anxiety in comparison to individuals with and with-
out diagnosed anxiety disorders has not been extensively
exploredin these populations.
Measuring anxiety in individuals with an intellec-
tual disability poses a challenge. Tools typically used to
assess anxiety include psychiatric interviews, clinical rat-
ing scales, and self- and parent-report measures (Bern-
stein etal. 1996). These often rely on the individualthat is
experiencing anxiety to self-identify and report symptoms,
which may not be possible for people with limited verbal
abilities. The diagnosis of anxiety disorders is based on the
presence and severity of clusters of symptoms. The present
study aims to enhance understanding of anxiety in indi-
viduals with FXS, CdLS and RTS by investigating anxiety
at this symptom-level. Symptom-based approaches have
important implications for assessment, understanding the
experiences of an individual with anxiety, and effectiveness
of treatments (see Watson 2009 for a review). This is par-
ticularly important given the difficulties in applying some
elements of the diagnostic criteria of anxiety to individuals
with an intellectual disability, and the resultant underdiag-
nosis (see Cooray and Bakala 2005 for a review).
Data are presented on parental reports of anxiety symp-
tomatology using the Spence Child Anxiety Scale-Parent
Version (SCAS-P; Spence 1999), which provides a contin-
uous measure of anxiety symptoms. Due to the heightened
prevalence of ASD, particularly in FXS and CdLS, and the
potential associations between anxiety and ASD, chrono-
logical age and adaptive ability, these associations will be
investigated. The anxiety disorders investigated in the cur-
rent study are not inclusive of every disorder listed in the
DSM-5 but do include separation anxiety, generalized anxi-
ety disorder, panic attack and agoraphobia, physical injury
fears, social phobia and obsessive–compulsive disorder.
The SCAS-P was designed as a parental report measure
to assess anxiety symptomatology in children. Although
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3731J Autism Dev Disord (2017) 47:3728–3740
1 3
the present study investigates symptoms of anxiety in chil-
dren and adults with FXS, CdLS and RTS, a parent-report
measure designed for children was deemed most appropri-
ate due to the severity and range of intellectual disability in
these populations. Self-report data, particularly in combi-
nation with other measures, is a valuable source of infor-
mation. However, due to the reliance on understanding and
labeling emotions for accurate self-report of anxiety, along-
side heightened levels of acquiescence in individuals with
an intellectual disability (Stancliffe 2000), and the severity
of intellectual disability of participants in the current study,
a parental measure was most likely to yield robust data in
this case.
The data obtained from participants with FXS, CdLS
and RTS were compared to normative data from typically
developing participants and normative data from par-
ticipants diagnosed with an anxiety disorder (Nauta etal.
2004). Although it was not possible to match the norma-
tive participant samples to the participants with FXS, CdLS
and RTS due to the rarity of the genetic syndrome groups,
the normative data serve as a benchmark for comparison,
which aids interpretation. As existing literature on anxiety
in these populations is limited, these data provide a strong
starting point for further research questions and studies to
be developed.
In this study, we address three primary research ques-
tions: (1) How do individuals with FXS, CdLS and RTS
differ in their profile of anxiety symptomatology? (2) What
is the relationship between anxiety and chronological age,
and anxiety and ASD? (3) How do individuals with FXS,
CdLS and RTS differ in anxiety symptomatology to typi-
cally developing children and individuals diagnosed with
anxiety?
Method
Participants
Parents of 19 individuals with FXS (0 female,
Mage = 24.19, SD 7.51), 13 individuals with CdLS (7
female, Mage = 18.75, SD 9.75), and 27 individuals with
RTS (17 female, Mage = 23.55, SD 10.74) completed
the measures for this study. Participants with FXS were
recruited through the database held at the Cerebra Cen-
tre for Neurodevelopmental Disorders, University of
Birmingham. Participants with CdLS and RTS were
recruited through the Cornelia de Lange Foundation (UK
and Ireland), and the Rubinstein–Taybi Syndrome UK
Support Group, respectively. All participants had previ-
ously received a diagnosis of FXS, CdLS, or RTS from a
pediatrician or clinical geneticist. Participant characteris-
tics are presented in Table1. Due to documented gender
differences in FXS, all participants with FXS were male.
Therefore, participants are not matched on sex. However,
the three participant groups are comparable for chrono-
logical age, global adaptive behavior, verbal adaptive
behavior, and severity of autism symptomatology.
Normative data on typically developing individuals
with and without a diagnosed anxiety disorder (obtained
from Nauta et al. 2004) are used in the present study.
These normative data are from 261 typical controls
aged 6–18 years (Mage = 11.5, SD 2.0) and 484 children
diagnosed with an anxiety disorder aged 6–17 years
(Mage = 10.4, SD 2.5).
Measures
The following measures were completed by the partici-
pant’s primary caregiver.
Vineland Adaptive Behavior Scale—Second Edition,
Survey Interview Form (VABS; Sparrow etal. 2005)
This semi-structured interview was administered to pri-
mary caregivers of participants with FXS, CdLS and RTS,
in order to assess adaptive behavior in the areas of commu-
nication, daily living skills and socialization. The interview
yields an Adaptive Behavior Composite (ABC) and stand-
ard scores based on a sample of 3000 children.
Table 1 Participant
characteristics and comparison
statistics for participants with
FXS, CdLS and RTS
Fragile X Cornelia de Lange Rubinstein–Taybi p value for
comparison
(n = 19) (n = 13) (n = 27)
Chronological age (SD) 24.19 (7.51) 18.75 (9.75) 23.55 (10.74) 0.247
Gender % male 100.00 46.15 37.04 <0.001
Adaptive behavior compos-
ite standard score mean
(SD)
46.05 (16.67) 50.08 (17.50) 43.59 (16.51) 0.522
Verbal adaptive behavior
standard score mean (SD)
38.47 (19.34) 47.23 (22.02) 42.30 (18.78) 0.470
SCQ total score 17.99 (6.61) 19.60 (6.56) 17.76 (6.06) 0.679
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3732 J Autism Dev Disord (2017) 47:3728–3740
1 3
Social Communication Questionnaire (SCQ; Rutter etal.
2003)
The SCQ is an informant questionnaire designed to assess
behaviors associated with ASD such as repetitive behav-
ior, communication and social interaction. The authors of
the SCQ suggest that a score of 15 or above indicates the
presence of ASD, whereas a score of 22 or above indicates
the presence of autism. Internal consistency and concurrent
validity with the Autism Diagnostic Observation Schedule
(Lord etal. 1999) are good (Howlin and Karpf 2004).
The Spence Child Anxiety Scale—Parent Version (Spence
1999)
The SCAS-P is a 38-item informant questionnaire designed
to assess anxiety symptoms in children. The SCAS-P
assesses symptomatology associated with the following six
domains of anxiety: physical injury fears, obsessive–com-
pulsive disorder, separation anxiety, social phobia, panic/
agoraphobia, and generalized anxiety. Psychometric prop-
erties show the scale to significantly differentiate those
with and without an anxiety disorder (Nauta etal. 2004).
In addition, when used with children and adolescents with
ASD, the SCAS-P demonstrates good to excellent internal
consistency for the total score, acceptable to good internal
consistency at a subscale level, and convergent validity
with the Development Behavior Checklist-Parent Version
total score and anxiety subscale (Einfeld and Tongue 2002;
Zainal et al. 2014). Zainal et al. (2014) suggested that
psychometric properties of the SCAS-P are similar when
the measure is used with children and adolescents with
and without ASD, based on data reported by Nauta et al.
(2004), and that a diagnosis of a neurodevelopmental disor-
der such as ASD does not appear to compromise the valid-
ity of the measure. The measure has also been described as
robust for use in the ASD population (Wigham and McCo-
nachie 2014).
Procedure
The measures in this study were included in a questionnaire
pack given to parents and caregivers of participants taking
part in a larger study on cognitive and social difficulties in
FXS, CdLS and RTS (Crawford et al. 2016). Parents and
carers of participants were given the questionnaire pack
either at a syndrome support group meeting or during a
research visit. The questionnaires were either returned on
the same day or via post following the meeting or visit. The
VABS was either administered during the research visit or
over the phone following the meeting or visit.
Data Analysis
All data were subjected to the Shapiro–Wilk test for nor-
mality. Non-parametric tests were used to confirm results
from parametric tests for data that were not normally dis-
tributed. For consistency, results from parametric tests are
reported where non-parametric tests revealed the same
results. Except where mentioned, the alpha level for signifi-
cance was 0.05.
Results
Figure1 displays the mean scores on each subscale for par-
ticipants with FXS, CdLS and RTS, as well as the mean
scores from normative data on typically developing chil-
dren and children with an anxiety disorder. The total scores
on the SCAS-P were: FXS: Mean = 19.71, SD 16.50;
CdLS: Mean = 27.66, SD 13.08; RTS: Mean = 15.32, SD
11.05. The total scores on the SCAS-P from normative data
are: typically developing children: Mean = 14.2, SD 9.7;
anxiety disorder: Mean = 31.8; SD 14.1 (Nauta etal. 2004).
The percentage of participants scoring outside of the nor-
mal range, as defined by the mean + 1 standard deviation
using the national normal data, is displayed in Table2.
Syndrome Group Comparison
One-way ANOVAs revealed a significant between-groups
difference in the following subscales of the SCAS-P: sepa-
ration anxiety (F (2, 58) = 6.379, p = 0.003), generalized
anxiety (F (2, 58) = 3.667, p = 0.032), and total score (F
(2, 58) = 3.697, p = 0.031). There were no between-groups
differences in the subscales assessing panic attack and ago-
raphobia, physical injury fears, social phobia, and obses-
sive–compulsive disorder (p > 0.05). Bonferroni post-hoc
analyses revealed that differences in the separation anxi-
ety subscale were due to participants with CdLS scoring
higher than participants with FXS (p = 0.038) and RTS
(p = 0.002). Differences in the generalized anxiety subscale
were also due to participants with CdLS scoring higher
than participants with FXS (p = 0.033) and par ticipants
with RTS (p = 0.006). Finally, differences in the total score
were due to participants with CdLS scoring higher than
participants with RTS (p = 0.026).
Relationship Between Anxiety, Chronological Age
andAutism Symptomatology
Spearman’s rho correlational analyses were conducted for
each group to investigate whether there was a relationship
between any subscale on the SCAS-P and chronological
age, global adaptive behavior, verbal adaptive behavior and
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3733J Autism Dev Disord (2017) 47:3728–3740
1 3
autism symptomatology. The alpha level was adjusted to
0.01 to account for multiple correlations. Significant cor-
relations are depicted in Fig.2.
For the FXS group, the analyses revealed a positive
relationship between scores on the obsessive–compulsive
subscale and chronological age (Fig. 2a; rs (17) = 0.643,
p = 0.003), and a negative relationship between scores
on the obsessive–compulsive subscale and global adap-
tive behavior (Fig. 2b; rs (17) = −0.597, p = 0.007). For
the CdLS group, significant positive relationships were
revealed between chronological age and scores on the panic
attack and agoraphobia subscale (Fig. 2c; rs (11) = 0.688,
p = 0.009), and the obsessive–compulsive subscale
(Fig. 2a; rs (11) = 0.785, p = 0.001), and a marginally sig-
nificant positive relationship was revealed between chrono-
logical age and scores on the generalized anxiety disorder
subscale (Fig.2d;rs (11) = 0.680, p = 0.011). There were no
significant correlations between the subscales of the SCAS-
P and participant characteristics for the RTS group.
Comparison toNormative Data
One sample t tests were carried out using the mean and
standard deviation on each subscale of the SCAS-P for
each syndrome group in order to compare their data to nor-
mative data for typically developing individuals with and
without a diagnosed anxiety disorder (obtained from Nauta
etal. 2004). For children with an anxiety disorder, means
and standard deviations on each subscale of the SCAS-P
are also available by the type of anxiety disorder that they
have been diagnosed with (separation anxiety, generalized
anxiety, social phobia, panic/agoraphobia, specific phobia
and OCD). Where possible, for any subscale in which par-
ticipants with FXS, CdLS or RTS scored similarly to the
group of children with an anxiety disorder, further com-
parisons were made to investigate whether scores remained
similar when compared to children diagnosed with the sub-
type of anxiety reflected in the subscale of the SCAS-P. For
example, if participants with FXS did not score differently
-5
-3
-1
1
3
5
7
9
11
13
Mean subscale score
SCAS-P subscale
FXSCdLSRTS TD Anxiety diagnosis
*
*
*
*
*
*
*
**
**
*
*
*
**
*
*
Fig. 1 The mean scores on each subscale of the SCAS-P for each syndrome group and two normative comparison groups. Error bars represent
standard deviation, as standard error data were not available for normative data
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3734 J Autism Dev Disord (2017) 47:3728–3740
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Table 2 Summary of comparisons between syndrome groups and
normative data on subscales of the SCAS-P (< group at the top of
the table scored lower than the group listed in the column, = no dif-
ference between scores, > group at the top of the table scored higher
than the group listed in the column)
Significant associations between subscale scores and participant characteristics (+ positive correlation; − negative correlation), and the percent-
age of participants scoring above the normal range, are also noted. Significant differences are indicated in bold
TD typically developing, AD anxiety diagnosis
a Marginally significant result
Fragile X (FXS) Cornelia de Lange (CdLS) Rubinstein–Taybi (RTS)
Separation anxiety <CdLS >FXS =FXS
=RTS >RTS <CdLS
=TD >TD =TD
<AD =AD <AD
Percentage of participants scoring
above normal range
26.3% 61.5% (50% of males, 71.4% of
females)
14.8% (20% of males, 11.8% of
females)
Social phobia =CdLS =FXS =FXS
=RTS =RTS =CdLS
=TD =TD <TD
=AD <AD <AD
Percentage of participants scoring
above normal range
15.8% 7.7% (16.7% of males, 0% of females) 3.7% (10% of males, 0% of females)
Generalized anxiety <CdLS >FXS =FXS
=RTS >RTS <CdLS
=TD >TD =TD
<AD =AD <AD
Percentage of participants scoring
above normal range
26.3% 61.5% (33.3% of males, 85.7% of
females)
18.5% (30% of males, 11.8% of
females)
Trajectory +Agea
Panic/Agoraphobia =CdLS =FXS =FXS
=RTS =RTS =CdLS
>TDa>TD >TD
=AD =AD =AD
Percentage of participants scoring
above normal range
47.4% 53.8% (50% of males, 57.1% of
females)
37% (50% of males, 29.4% of females)
Trajectory +Age
Physical injury fears =CdLS =FXS =FXS
=RTS =RTS =CdLS
=TD >TD =TD
=AD =AD <AD
Percentage of participants scoring
above normal range
36.8% 46.2% (33.3% of males, 57.1% of
females)
22.2% (40% of males, 11.8% of
females)
Obsessive–compulsive disorder =CdLS =FXS =FXS
=RTS =RTS =CdLS
=TD =TD >TD
=AD =AD =AD
Percentage of participants scoring
above normal range
36.8% 38.5% (33.3% of males, 42.9% of
females)
40.7% (60% of males, 29.4% of
females)
Trajectory +Age
−Adaptive behavior +Age
Total score =CdLS =FXS =FXS
=RTS >RTS <CdLS
=TD >TD =TD
<AD =AD <AD
Percentage of participants scoring
above normal range
36.8% 53.8% (50% of males, 57.1% of
females)
18.5% (30% of males, 11.8% of
females)
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3735J Autism Dev Disord (2017) 47:3728–3740
1 3
to the children with an anxiety disorder on the social pho-
bia subscale of the SCAS-P, their scores were then com-
pared to scores of children diagnosed with social phobia.
As a specific type of anxiety disorder does not represent the
physical injury fears subscale, the above comparisons were
not conducted when there were no differences between
participants with FXS, CdLS or RTS and children with an
anxiety disorder on the physical injury fears subscale. Due
to multiple analyses, the p-value was adjusted to 0.01.
Fragile X Syndrome
In comparison to normative data collected from typically
developing participants, participants with FXS only scored
marginally higher on the panic/agoraphobia subscale (t
(279) = 2.570, p = 0.01). On all other subscales, no signifi-
cant differences were revealed between participants with
FXS and normative data collected from typically develop-
ing participants (all p > 0.01).
Scores did not differ between children diagnosed with
an anxiety disorder and participants with FXS on the social
phobia subscale (t (502) = −2.170, p = 0.03), the panic
attack/agoraphobia subscale (t (502) = 0.019, p = 0.985),
the physical injury fears subscale (t (502) = −0.706,
p = 0.481), and the obsessive–compulsive disorder subscale
(t (502) = −2.033, p = 0.043). For all other subscales and
the total score, participants with FXS scored significantly
lower than the children diagnosed with an anxiety disorder
(all p < 0.01).
Cornelia de Lange Syndrome
Participants with CdLS scored higher than a normative
sample of typically developing children on the separation
anxiety subscale (t (273) = 4.671, p < .001), t he generalized
anxiety subscale (t (273) = 2.940, p = 0.004), the panic/ago-
raphobia subscale (t (273) = 3.284, p = 0.001), the physical
injury fears subscale (t (273) = 3.009, p = 0.003), and on the
total score (t (273) = 3.677, p < 0.001). No differences were
revealed between participants with CdLS and the norma-
tive sample of typically developing children on the social
phobia subscale and the obsessive–compulsive disorder
subscale (all p < 0.01).
No differences were revealed between participants with
CdLS and children diagnosed with an anxiety disorder
on any subscale (all p > 0.01), except on the social pho-
bia subscale, where participants with CdLS scored sig-
nificantly lower than children with an anxiety disorder (t
(495) = −0.704, p < 0.001). No differences were revealed
between participants with CdLS and children diagnosed
with generalized anxiety disorder on the generalized anxi-
ety subscale (t (175) = −1.411, p = 0.160).
0
5
10
15
20
25
30
35
40
45
50
0246810 12
Chronological Age
Obsessive-Compulsive Subscale Score
0
10
20
30
40
50
60
70
80
0246810 12
ABC Score
Obsessive-Compulsive Subscale Score
0
5
10
15
20
25
30
35
40
45
50
0510 15 20
Chronological Age
Panic Aack and Agoraphobia Subscale Score
0
5
10
15
20
25
30
35
40
45
50
02468101214
Chronological Age
Generalized Anxiety Disorder Subscale Score
ab
cd
Fig. 2 The relationship between participant characteristics and the SCAS-P for each syndrome group
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3736 J Autism Dev Disord (2017) 47:3728–3740
1 3
Rubinstein–Taybi Syndrome
Participants with RTS scored significantly lower than the
normative typically developing sample on the social pho-
bia subscale (t (287) = −5.662, p < 0.001), and significantly
higher than typically developing children on both the panic
and agoraphobia subscale (t (287) = 3.163, p = 0.002) and
the OCD subscale (t (287) = 2.633, p = 0.009). Scores
between typically developing participants and participants
with RTS did not differ on the other subscales of separation
anxiety, generalized anxiety, physical injury fears, and the
total score (all p > 0.01).
Participants with RTS did not evidence significantly dif-
ferent scores to children with an anxiety disorder on the
subscales of panic/agoraphobia and obsessive–compulsive
disorder (t (509) = −0.587, p = 0.557), but they did evi-
dence lower scores than children diagnosed with obses-
sive–compulsive disorder (t (43) = −5.337, p < 0.001). For
all other subscales, participants with RTS scored signifi-
cantly lower than the children diagnosed with an anxiety
disorder (all p < 0.01). The results from the comparative
and correlational analyses are presented in Table2.
Discussion
This study conducted subscale level analysis using the
SCAS-P to identify similarities and differences in the pro-
file of anxiety symptomatology in individuals with FXS,
CdLS and RTS. The relationship between anxiety and
participant characteristics was also examined. In addition,
subscale scores on the SCAS-P were compared to norma-
tive data available from typically developing children, chil-
dren diagnosed with an anxiety disorder, and, where pos-
sible, children diagnosed with the specific anxiety disorder
reflected in each subscale of the informant report measure.
To summarise, participants with CdLS scored higher
than participants with FXS and RTS on the separation
anxiety and generalized anxiety subscales of the SCAS-P.
In addition, there were no differences between participants
with FXS and children diagnosed with an anxiety disorder
on the social phobia, panic attack/agoraphobia, obsessive-
compulsive disorder,or the physical injury fears subscales.
There were also no differences between participants with
RTS and children diagnosed with an anxiety disorder
on the panic attack/agoraphobia and obsessive–compul-
sive disorder subscales. Finally, there were no differences
between participants with CdLS and children diagnosed
with an anxiety disorder on the separation anxiety, general-
ized anxiety, panic attack/agoraphobia, physical injury and
obsessive–compulsive disorder subscales, and on the total
score. When compared to children diagnosed with specific
types of anxiety disorder reflected in the subscales of the
SCAS-P, only the scores from participants with CdLS on
the generalized anxiety subscale could not be differentiated
from those diagnosed with generalized anxiety disorder.
It is important to note that the genetic syndrome groups
were not matched to the typically developing children and/
or children diagnosed with an anxiety disorder. Therefore,
these normative data should be viewed as a benchmark
comparison to aid interpretation of the results from the
genetic syndrome groups.
Positive associations were reported between the chron-
ological age of participants with CdLS and their scores
on the generalized anxiety, panic attack/agoraphobia and
obsessive–compulsive disorder subscales, supporting exist-
ing literature indicating that heightened anxiety may coin-
cide with increasing age in this group (Basile etal. 2007;
Collis et al. 2006). The associations between anxiety and
chronological age were not seen in the RTS group and only
emerged in the FXS group on the obsessive–compulsive
disorder subscale. In addition, there was no relationship
between autism symptomatology and anxiety for any par-
ticipant group. This supports previous research indicating
no difference in anxiety symptomatology in participants
with FXS and an additional diagnosis of ASD compared
to those without an additional diagnosis (Cordeiro et al.
2011).
The findings of this study support previous literature
demonstrating elevated levels of social phobia, panic disor-
der with agoraphobia, and obsessive–compulsive disorder
in individuals with FXS compared to a matched compari-
son group (Cordeiro etal. 2011), and extends this by sug-
gesting the severity of symptomatology of these disorders
are similar in FXS to those seen in individuals diagnosed
with an anxiety disorder. In addition, heightened levels of
specific phobia have been reported in FXS (Cordeiro etal.
2011). Whilst the measure utilized in the present study
did not assess specific phobia, it did demonstrate elevated
scores on the ‘physical injury fears’ subscale, which may
be considered a specific phobia. Previous research has also
demonstrated higher rates of generalized anxiety disorder
in FXS (Cordeiro etal. 2011), a finding not replicated in
the present study. A potential reason for these contrasting
findings is the utilization of different methodologies to
study anxiety diagnosis versus anxiety symptomatology.
For example, in the present study, a parent-report measure
was used to delineate the profile and investigate the symp-
tomatology of different subtypes of anxiety, whereas the
study conducted by Cordeiro etal. (2011) investigated the
prevalence rates of individuals with FXS meeting diagnos-
tic criteria for a range of anxiety disorders. It is important
to note that, in the present study, the FXS group did not
score higher on any subscales of the measure used than
the other two genetic syndrome groups matched for adap-
tive behavior and chronological age. Therefore, the higher
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3737J Autism Dev Disord (2017) 47:3728–3740
1 3
levels of social phobia, panic with agoraphobia, physical
injury fears, and obsessive–compulsive disorder may be
related to developmental ability, although the comparison
groups have also been associated with anxiety both in the
present study and in previous literature.
The findings reported here document the severity and
breadth of anxiety symptomatology in individuals with
CdLS. In particular, individuals with CdLS demonstrated
higher levels of generalized anxiety disorder and separation
anxiety than both typically developing children and indi-
viduals with different genetic syndromes associated with
intellectual disability. For these two types of anxiety disor-
der, no differences were revealed between individuals with
CdLS and those diagnosed with an anxiety disorder, high-
lighting the severity of anxiety disorders in this population.
Aside from social phobia, participants with CdLS demon-
strated similar levels of all other types of anxiety disorders
measured here to normative data obtained from individuals
diagnosed with an anxiety disorder, thus highlighting the
broad nature of anxiety disorder in this group. The results
from the present study support previous literature sug-
gesting obsessive–compulsive features in individuals with
CdLS (Kline etal. 2007), and extends this to indicate the
range of additional anxiety disorders present in this group.
In the present study, individuals with RTS did not dem-
onstrate heightened levels of anxiety in comparison to the
other genetic syndrome groups. However, levels of panic
attack/agoraphobia and obsessive–compulsive disorder
were reported to be higher in RTS than typically develop-
ing children, and similar to those diagnosed with an anxi-
ety disorder. This supports previous literature highlight-
ing the presence of obsessive–compulsive features in this
population (Levitas and Reid 1998; Stevens etal. 2011). It
is important to note that repetitive behavior is a well-doc-
umented characteristic of RTS (Waite etal. 2015). There-
fore, the elevated scores on the obsessive–compulsive dis-
order subscale may reflect heightened levels of repetitive
behavior, rather than the full range of symptomatology
associated with obsessive-compulsive disorder.
The results reported here highlight that different types
of anxiety disorder may be problematic for individuals
with different genetic syndromes. However, it is possible
that whilst there may be similarities in the ways in which
these anxiety disorders manifest behaviorally in individu-
als with genetic syndromes and the general population,
differences may exist between these populations in the
mechanisms subserving these behaviors. This notion is
supported by the conceptual differences in anxiety that
have been reported between individuals with and with-
out ASD (Kerns etal. 2014). In particular, it may be the
case that ASD-related impairments, such as adherence
to routine, may contribute to the anxiety in individuals
with ASD that are not consistent with anxiety diagnostic
categories such as intolerance to uncertainty (Rodg-
ers et al. 2016). In the current study, elevated levels of
panic attack and agoraphobia symptomatology in indi-
viduals with FXS may be related to hypersensitivity of
sensory stimuli, a common feature of this genetic syn-
drome (Baranek et al. 2009; Cornish et al. 2008). This
behavioral characteristic may contribute to anxiety in set-
tings where sensory input is heightened, such as crowded
places like shopping centers and busy playgrounds. The
presence of anxiety in crowded places features as an
item of the panic attack and agoraphobia subscale of the
SCAS-P. Further understanding the underlying mecha-
nisms of anxiety disorder in neurodevelopmental disor-
ders is paramount to developing targeted interventions.
The results of the present study should be considered in
light of some limitations. First, whilst the genetic syndrome
groups were statistically comparable on chronological age,
these groups were not matched to the samples from which
normative data were obtained. Therefore, comparisons
between the syndrome groups and normative data groups
should be treated with caution and future research should
conduct comparisons with matched groups. Second, the
SCAS-P was designed to measure anxiety symptomatol-
ogy in young, typically developing children. There is a
lack of suitable measures of anxiety that are designed for
children and adults with an intellectual disability and fur-
ther research is required to develop such measures. Despite
the limitations, this study conducted an initial investiga-
tion into the profile of anxiety disorder and has reported
elevated levels of symptoms associated with different sub-
types of anxiety in individuals with three different genetic
syndromes. This requires further investigation using diag-
nostic parent report measures alongside behavioral obser-
vation and clinical consultation. Extrapolating these pheno-
typic differences is crucial to further understand the nature
and severity of anxiety that people with these genetic syn-
dromes experience.
Acknowledgments The research reported here was supported
by a grant from the Economic and Social Research Council (Grant
Number: ES/I901825/1) awarded to HC and by Cerebra. The authors
would like to thank all participants and their families. The authors are
indebted to the Cornelia de Lange Foundation UK & Ireland and the
Rubinstein–Taybi Syndrome Support Group for their assistance with
recruitment of children and adults with Cornelia de Lange syndrome
and Rubinstein–Taybi syndrome, respectively. The authors are grate-
ful to Robyn Dowlen and Laura Groves for their help with recruitment
and posting questionnaires to participants.
Authors’ Contributions HC conceived of the study, participated
in its design and coordination, performed the statistical analyses, par-
ticipated in the interpretation of the data, and drafted the manuscript.
JW participated in the interpretation of the data and helped to draft
the manuscript. CO conceived of the study, participated in its design
and interpretation of the data, and helped to draft the manuscript. All
authors read and approved the final manuscript.
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3738 J Autism Dev Disord (2017) 47:3728–3740
1 3
Funding This study was funded by a grant from the Economic
and Social Research council (Grant Number: ES/I901825/1) and by
Cerebra.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict
of interest.
Ethical Approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional research committee and with the 1964 Helsinki decla-
ration and its later amendments or comparable ethical standards.
Informed Consent Informed consent was obtained from all indi-
vidual participants included in the study.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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