Introduction

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by a sporadic microdeletion of 26–28 genes on chromosome 7q11.23 (Hillier et al. 2003) and is associated with characteristic physical, cognitive and behavioral abnormalities, including a “hypersociable” personality and mild to moderate intellectual disability with an uneven cognitive profile (Searcy et al. 2004; Mervis and Klein-Tasman 2000). Despite the initial portrayals of WS as the “opposite” of Autism Spectrum Disorder (ASD) in terms of socio-emotional profiles, the considerable overlap with the autism spectrum in terms of both core ASD features, such as impairments in social reciprocity, and common co-morbid problems including anxiety, in addition to pronounced hetereogenity observed in both ASD and WS, suggest that a more nuanced approach to similiarities and disimilarites of these two disorders is warranted.

The most common co-morbid feature in the WS socio-emotional profile relates to anxieties and abnormal fears that affects between 40 and 50% of individuals with WS, irrespective of age, with specific phobias, and generalized anxiety disorder being the most prevalent anxiety subtypes (Dykens 2003; Cherniske et al. 2004; Hocking 2017; Kirk et al. 2013; Klein-Tasman and Mervis 2003; Leyfer et al. 2006, 2009; Riby et al. 2014; Rodgers et al. 2012; Woodruff-Borden et al. 2010; Kennedy et al. 2006; Ng et al. 2014). Yet, the close similarities to some of the socio-communicative features on the autism spectrum (Klein-Tasman et al. 2007; Lincoln et al. 2007), alongside high levels of anxiety in WS, highlight the critical need to examine the extent to which these risk factors interact with each other.

However, unlike in ASD, where significant inroads into understanding the development, maintenance and exacerbation of anxiety have been made (Davis et al. 2014), factors underlying the high prevalence of anxiety in WS are largely unknown. Similar to ASD, individuals with WS exhibit social and communication impairments such as for example atypical social attention and communication (Isaac and Lincoln 2011; Klein-Tasman et al. 2011; Kirk et al. 2013; Porter et al. 2010; Riby and Hancock 2009). Furthermore, atypical patterns of brain activity during socio-emotional tasks have been found, for example hypoactivation of the amygdala in response to emotional faces (Haas et al. 2009; Meyer-Lindenberg et al. 2005). As such, it is perhaps not surprising that despite an overtly outgoing and gregarious personality, at least 70% of individuals with WS report a lack of meaningful friendships and social isolation (Davies et al. 1998; Udwin et al. 1987).

Apparent overlap between ASD and WS with regards to deficits in reciprocal social interaction and communication can offer some insights into the mechanisms underlying anxiety in WS. It has been theorized that social dysfunction contributes to the development of anxiety in ASD (Wing 1992; Bellini 2004, 2006; Attwood 1998; Tantam 2000). According to this view, early deficits in social functioning may limit the individual’s opportunity to interact with and learn from others in an optimal way. This in turn may lead to increased isolation as a result of repeated social failures, which eventually contribute to the emergence of anxiety (Wing 1992). Consistent with this account, previous studies have shown associations between the severity of social and communication deficits and anxiety in ASD (Bellini 2006; Sukhodolsky et al. 2008), and elevated ASD traits have been found among children diagnosed with anxiety disorders (van Steensel et al. 2013). Importantly, there is evidence of a link between atypical social functioning and anxiety in WS, where those who experience a greater degree of anxiety also show more severe social dysfunction (Riby et al. 2014), and atypical attention to emotional faces (Kirk et al. 2013).

Furthermore, atypical sensory processing features are prevalent across neurodevelopmental disorders, including both ASD (Uljarević et al. 2017) and WS (Janes et al. 2014; John and Mervis 2010; Riby et al. 2013). It has been suggested that sensory features, in particular sensory hyper-sensitivity (i.e. overresponsiveness to sensory stimulation) are important factors in the development and maintenance of anxiety in ASD (Green and Ben-Sasson 2010; Green et al. 2012; Lidstone et al. 2014; Wigham et al. 2015). However, there have been no studies that have addressed the interplay between heightened responses to sensory input, social dysfunction and anxiety in individuals with WS.

Intolerance of uncertainty (IU), characterized by the belief that uncertainty is negative and leads to increased perceived ambiguity across contexts, has also been considered as a major risk factor for the development and maintenance of anxiety in the general population (Aron et al. 2012; Carleton et al. 2016; McEvoy and Mahoney 2011), and more recently in ASD. Indeed, intolerance of uncertainty has been consistently shown to be associated with elevated levels of anxiety in both children and adults with ASD (Boulter et al. 2014; Hodgson et al. 2016; Neil et al. 2016; Wigham et al. 2015; Maisel et al. 2016) and their parents (Uljarević et al. 2016a). The IU construct bears some similarities to the nature of generalized anxiety disorder in WS in which their fears mainly refer to anticipation about (either positive or negative) future events (Green et al. 2012; Leyfer et al. 2006). Thus, a possible mechanism for development of anxiety in WS may relate to a tendency to perceive novel or unpredictable situations as threatening and therefore react negatively to them. This, coupled with unusually heightened responses to sensory stimuli in WS may increase the likelihood to perceive their environment as threatening and unpredictable, which in turn leads to increased levels of anxiety. However, this model has not yet been formally tested in WS.

The main aim of this study was to explore the interrelationships between IU, sensory hyper-sensitivity and anxiety in WS, and to establish whether these relationships bear some resemblance to the factors underlying anxiety in ASD. It was expected that more severe socio-communciative difficulties, sensory hyper-sensitivity, and higher levels of intolerance of uncertainty would be associated with more severe anxiety in WS.

Method

Participants and Procedures

Thirty-two parents or guardians of individuals with Williams syndrome (children: 13 males, 19 females; Mage = 24.76 years, SD = 7.55; range 14.55–43.16 years) took part in this study. Ethics approval for the study was obtained as part of a larger study from the La Trobe University’s Human Research Ethics Committee (Ref: S16–75) and the Australian Catholic University’s Human Research Ethics Committee (Ref: 2015–104H). Participants were recruited from a range of different sources including the Williams Syndrome Family Support Group (Victoria), Williams Syndrome Associations of Western Australia, Williams Syndrome Association of South Australia, Williams Syndrome Association of Australia, Williams Syndrome Global Support Facebook group, and other parent support groups.

Measures

Dimensional Anxiety Scale (DAS; Möller et al. 2014) total score was used. DAS is a parent report questionnaire consisting of 70 items. Each item is rated on a five point likert scale ranging from 0 to 4 (“never” to “always”) with higher scores reflecting greater degree of anxiety. The DAS has been shown to have high internal consistency (α = .88 for mother and .90 for father report), moderate to high correlations with the Screen for Child Anxiety Related Disorders (SCARED) and good sensitivity (Möller et al. 2014).

Intolerance of Uncertainty Scale: Parent Version (IUS-P;Carleton et al. 2007) is a 12-item parent report questionnaire adapted from the longer 27-item IUS (Freeston et al. 1994). Parents are asked to respond to each statement as to whether it is like their child on a scale ranging from 1 (“not at all like them”) to 5 (“entirely like them”). The parent version has been found to have excellent psychometric properties in individuals with ASD and typically developing children (internal consistency α = .90) (Boulter et al. 2014).

Adult/Adolescent Sensory Profile (AASP; Brown and Dunn 2002) contains 60 items divided into six sensory processing modalities: taste/smell, movement, vision, touch, activity level, and auditory processing. Each item is rated on a five-point scale ranging from 1 ‘almost never’ to 5 ‘almost always’. Although the AASP has been commonly used as a self-report measure, the instrument was modified to use as a parent-report measure by rewording the items from the first to the third person perspective. The AASP is based on Dunn’s Model of sensory processing and defines the principles of neurological thresholds and behavioral responses which form four quadrants: low registration, sensation seeking, sensory sensitivity and sensation avoiding. Internal consistency for the four quadrants range from 0.63 to 0.78 (Brown and Dunn 2002). The sensory sensitivity scale was used for this study.

Social Responsiveness Scale-2 Parent-report (SRS-2; Constantino et al. 2003) is a 65-item parent report designed to assess social reciprocity abilities/impairments that is characteristic of ASD. The measure provides an overall score for social functioning, and is divided into five subscales including social awareness, social cognition, social communication, motor mannerisms and routines (Ingersoll et al. 2011). Internal consistency has been found to be excellent (> .85) (Constantino et al. 2003).

Results

Internal consistency analysis (Cronbach α) was excellent for DAS (.98) and IUS-P (.94), good for AASP (.82) and the SRS-2 Communication (.89) and Cognition (.81), but unacceptable for SRS-2 Awareness (.46). All of the analyses were conducted using bootstrapping with 1000 resamples in order to generate more reliable, robust statistics. Full descriptives are shown in Table 1.

Table 1 Means, standard deviations, assessment of normality
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Pearson correlations between IUS-P, AASP, SRS-2 and DAS are shown in Table 2. These analyses showed that anxiety was significantly associated with IUS-P, sensory hyper-sensitivity and SRS-2 communication subscale. None of the variables of interest were associated with chronological age. Linear regression analysis was conducted to explore the relative contribution of associated variables in predicting levels of anxiety. Only variables significantly associated with DAS total score were entered in the model. The overall model was significant F = 17.16, p < .001, accounting for 63.4% of the total variance. IUS-P (β = .38, t = 2.50, p = .018, BCa 95% CI [.42; 3.07]) and sensory hyper-sensitivity (β = .65, t = 3.82, p = .001, BCa 95% CI [1.87; 4.67]) were unique independent predictors, while SRS-2 communication score was not (β = − .14, t = − .79, p = .37, BCa 95% CI [− 1.98; .89]).

Table 2 Correlations among variables of interest
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Additional mediation analyses were performed to further examine the interrelationships between anxiety, IUS-P and sensory hyper-sensitivity. Serial mediation models using PROCESS tool with bootstrapping with 5000 resamples were run to explore whether the relationship between sensory hyper-sensitivity and anxiety was mediated by IU-12 (Model 1), or whether the relationship between IU-12 and anxiety was mediated by sensory hyper-sensitivity (Model 2). These analyses showed that Model 1 was not supported: IUS-P did not significantly predict DAS Total score after controlling for sensory hyper-sensitivity, t = .057; BCa 95% CI [91–.04; 2.] (Fig. 1).

Fig. 1
figure 1

Mediation model 1

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In the next mediation analysis, Model 2 was supported. These analyses showed that the relationship between IUS-P and anxiety was mediated by sensory hyper-sensitivity total effect b = 2.87, p = .001; indirect effect b = 1.44, BCa 95% CI [.63, 2.59], with the mediator accounting for 50.06% of the total effect (Fig. 2).

Fig. 2
figure 2

Mediation model 2

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Discussion

The current study investigated the effects of intolerance of uncertainty (IU), sensory hyper-sensitivity and social communication difficulties on levels of anxiety in individuals with WS. It was found that both communication impairments and sensory hyper-sensitivity were associated with more severe anxiety symptoms in individuals with WS as assessed by parent/guardian report. In addition, IU and sensory hyper-sensitivity were unique predictors of severity of anxiety, and sensory hyper-sensitivity was part of a significant mediating relationship. Overall, this pattern of interrelationships bears strong resemblance to the pattern seen in ASD (Bellini 2006; Green et al. 2012; Lidstone et al. 2014; Neil et al. 2016; Rodgers et al. 2012; Sukhodolsky et al. 2008).

Our findings are consistent with previous studies showing elevated rates of social and communication deficits (Klein-Tasman et al. 2011; Lincoln et al. 2007), and links between these deficits and higher levels of anxiety in WS (Riby et al. 2014). This suggests that there is more overlap between WS and ASD in terms of anxiety correlates than previously thought. Further evidence to support this interpretation comes from our novel finding that sensory hyper-sensitivity was also associated with increased levels of anxiety in WS. Although previous studies have found that sensory hyper-sensitivities were associated with problem behaviours and adaptive functioning in children with WS (John and Mervis 2010), the current findings show for the first time that sensory hyper-sensitivity is a strong predictor of anxiety in individuals with WS.

On the basis that IU is a well-established risk factor for the development of anxiety in ASD (Boulter et al. 2014; Wigham et al. 2015; Maisel et al. 2016), we tested two mediation models. Our analysis provided support for the second model where the relation between IU and anxiety was mediated by sensory hyper-sensitivity. Notably, the first model where sensory hypersensitivity and anxiety were related through IU, was not supported. These findings are not consistent with previous studies in children and adolescents with ASD (Wigham et al. 2015; Neil et al. 2016; Boulter et al. 2014) and their parents (Bellini 2006). Rather, our findings supported the second model in that sensory hyper-sensivity mediated the relationship between IU and anxiety. Thus, it is conceivable that IU plays a more dominant role than sensory hyper-sensivity in adults with WS, since elevated IU may enhance the perception of novel sensory stimuli as threatening, and thereby increase levels of anxiety. One possible explanation for opposing directionality effects in regards to IU and sensory hypersensitivity in WS and ASD might be due to the divergent anxiety profiles across these neurodevelopmental disorders. We speculate that increased generalized anxiety and obsessive compulsive symptoms in WS (Hocking 2017) might be more tightly linked to IU consistent with typically developing child and adult populations (e.g. Carleton et al. 2012; Lee et al. 2010), whereas the higher levels of specific phobias in ASD might be driven primarily by sensory processing abnormalities. Although our findings suggest a crucial role of IU in the manifestation of anxiety in WS, it is not possible to determine the causal directionality of the effect and it is possible for sensory hyper-sensitivity to play key role early in development but that the IU component may become more dominant over time; however, a longitudinal design would be needed to test any causal directionality effects in WS.

This study has a number of limitations. First, this study was limited by a small sample size which was unavoidable due to the relatively low prevalence of WS. Second, the use of only parent-report questionnaires is another limitation, however there is evidence of a strong positive relationship between parental and self-reports of anxiety in adults with WS (Stinton et al. 2012). Third, we did not employ a direct measure of cognitive ability and mental age in WS, however it should be acknowledged that previous studies have found no association between IQ and anxiety levels in WS (Leyfer et al. 2006; Riby et al. 2013; Woodruff-Borden et al. 2010). Fourth, it should be acknowledged that the DAS measure of anxiety has not yet been validated in a population with intellectual disability, however this measure has a number of advantages due to its dimensional nature that overcomes ceiling or floor effects common in this population. Currently there is a lack of anxiety measures specifically designed for individuals with neurodevelopmental disorders and future studies are needed to address this issue (Uljarević et al. 2016b; but see Kerns et al. 2017 and; Rodgers et al. 2016). Finally, as already noted, the cross-sectional design of the study is a limitation, and future studies employing longitudinal designs to determine causal directional effects of IU and sensory hypersensitivity on anxiety would be of great benefit.

The current study is the first to explore the interrelationships between IU, sensory hyper-sensitivity, and anxiety in WS. These findings have potential clinical applications, and emphasize the need for development of anxiety interventions that attempt to reduce negative beliefs about unpredictable situations in WS. Further investigation into shared risk factors for development of anxiety in WS and ASD will be critical for development of targeted interventions for reducing distress for individuals with WS.