Based on our study of children ages 7-14 years with 22q11.2DS, anxiety symptoms are quite common and negatively related to adaptive functioning. This has serious clinical implications because, from our sample, anxiety appears to be underidentified by health care professionals despite known elevated risk in this population [4
]. Only 19% of our participants had been given a prior diagnosis of an anxiety disorder, yet 58% of them demonstrated elevated BASC-2 or SCAS scores representing significant anxiety symptoms. Certain subtypes of anxiety were more frequent than others, with fear-based symptoms (i.e. separation anxiety and fear of physical injury) present in approximately 60% of children, compared to a 20% rate of obsessive compulsive or panic-agoraphobia symptoms. This discrepancy may provide insight for future study of the physiological mechanisms involved in these types of anxiety, along with targeted interventions.
Our initial study protocol addressed a global measure of anxiety from the BASC-2, with approximately 38% of children with 22q11.2DS scoring in the elevated range. While this was consistent with the prevalence of anxiety disorders reported in the literature for this population [4
], this also seemed to underestimate the actual rate given our clinical impression of frequent anxiety symptoms causing significant impairment and was our motivation for our secondary analysis using the SCAS. The mean BASC-2 anxiety score in the 22q11.2DS group was in the average range, although it was significantly higher than the mean BASC-2 anxiety score in the typical group by 7 points. This may be related to the heavy loading of questions in the BASC-2 relating to generalized anxiety (mostly worries), which on the SCAS was present on only around 40% of children, and the inability of some children with 22q11.2DS to explicitly express or communicate anxiety symptoms due to verbal and intellectual impairments. Inadequate treatment of identified mental health conditions in children with 22q11.2DS has also been reported [22
], and together with our findings that anxiety symptoms are common and often unidentified, there is a demonstrated need to address this pervasive problem that is a prime target for intervention.
We started collecting more detailed information on DSM-IV related anxiety subtypes using the SCAS to evaluate our hypothesis that the general nature of the BASC-2 was underestimating the prevalence of anxiety in children with 22q11.2DS. While mean scores on the different anxiety measures were mostly in the average range, there was a wide spread of scores, with at least 18% of the children with 22q11.2DS having elevated t-scores on any anxiety subscale and up to 60% with elevations for certain anxiety subtypes such as separation anxiety. Importantly, it was these children that had the greatest difficulty with everyday living skills, which highlights the need to treat anxiety in this population. The same pattern held also for the general measures from the BASC-2.
Specific subtypes of anxiety may predict lower adaptive functioning, including panic-agoraphobia, physical injury, and obsessive compulsive disorder. Separation anxiety, social phobia, and generalized anxiety disorder, while present in greater than 40% of our sample, do not seem to affect adaptive functioning and further study of what types of anxiety symptoms influence this outcome should be pursued.
Anxiety symptoms are common in other neurogenetic disorders, such as Down syndrome [23
], fragile X syndrome [24
], and the sex chromosome aneupoidies such as XXY [25
] and Trisomy X [26
]. Few studies have looked at the relationship between anxiety and adaptive function, with high anxiety related to lower IQ in typical populations [27
], but this is not the case in some developmental disorders such as autism, where higher anxiety is found in those with high IQ [28
]. Our findings indicate that in 22q11.2DS, anxiety may affect individuals across all levels of cognition, thereby suggesting other modulatory factors such as environmental demands. This may have broader applicability to other neurodevelopmental disorders and there is a need for further study of the relationship between anxiety and IQ across disorders.
Our findings highlight the importance of identifying and treating anxiety symptoms in children with 22q11.2DS. While intellectual potential is certainly an important outcome measure, there are other factors that influence long-term function. Anxiety interferes with the deployment of one’s cognitive potential to attain maximal adaptive functional skills, as evidenced by the lack of relationship between IQ and adaptive functioning in our 22q111.2DS sample. In our control group of typically developing children who had a low prevalence of anxiety, higher IQ scores were related to better adaptive functioning, consistent with what is reported in the literature for typical and many developmentally delayed populations. We postulate that this lack of correlation between IQ and adaptive functioning is related to anxiety, as anxiety may potentially alter one’s interaction with the environment through modulation of attention and fear conditioning [29
] so that anxious children miss out on learning opportunities because relatively benign situations are perceived as threatening. Another possibility is that anxious children are less aware or engaged during routine learning environments because there is competition for their attentional resources that are instead focused on perceived threat. Interventions, both behavioral and pharmacologic, to reduce anxiety are available and may improve adaptive functioning and quality of life in the immediate future. Further, evidenced-based interventions targeting anxiety are more readily available than interventions geared towards improving cognition. Behavioral techniques that teach useful coping skills and encourage positive environmental interactions allow one to better perform to the maximum of his/her cognitive potential in order to encourage independent functioning and improve relationships.
It is also possible that early anxiety reduction and the attainment of coping skills could protect against the development of serious psychopathology later in life, which is particularly relevant to the 22q11.2DS population given these individuals’ elevated risk for schizophrenia. In our analysis, the obsessive compulsive and panic-agoraphobia subscales of the SCAS were more strongly related to adaptive function. In the general population, there is an increased risk of schizophrenia in individuals previously diagnosed with an anxiety disorder [32
] and anxiety disorders and schizophrenia are often comorbid [33
]. In schizophrenia, anxiety affects quality of life and may mediate social and functional impairment [33
]. The only longitudinal study of which we are aware that examined this relationship in children with 22q11.2DS indicated that those with any anxiety, but particularly OCD, appeared be at higher risk for schizophrenia at follow-up 5 years later [6
]. Mental health screening is particularly important in order to identify difficulties early and provide treatment.
In the context of early negative life events, ongoing cognitive and socioemotional challenges and a genetic diathesis, the contribution of stress from poor coping skills and high levels of anxiety may account for some of the elevated risk of schizophrenia in adolescents and young adults with 22q11.2DS [9
]. Chronic anxiety and panic symptoms may contribute to poor developmental outcomes through prolonged activation of the physiological stress response, including chronically elevated glucocorticoid and catecholamine activation. Chronic glucocorticoid activation has been shown to have deleterious effects on a number of brain regions (including the prefrontal cortex and limbic regions) that could contribute to and also exacerbate emotional dysregulation in a reciprocal and iterative fashion [34
As a result of these findings, we have begun to refer to children with high anxiety and low adaptive functioning scores as “strugglers” and those with the opposite pattern as “copers”. Since, in our sample, coper/struggler status is unrelated to intellectual functioning levels and may modulate risk or resilience with respect to psychiatric illness [9
], we are starting to investigate the factors that contribute to being a “coper” or a “struggler” and how to intervene to convert the latter into the former with evidenced based therapies such as Cognitive Behavioral Therapies and/or SSRI medication and with newer emerging research based strategies [35
Limitations of our study include a smaller sample size (n=34) with more specific measures of anxiety from the SCAS, although our sample size of 78 for general measures is greater than most of the studies on anxiety in 22q11.2DS in the literature, with subject numbers mostly in the 20’s [7
]. Based on our power analysis calculations, our study may have been slightly underpowered to detect smaller differences in anxiety scores between groups, which would tend to underestimate our findings. However, given our significant results, our findings seem quite robust. Given the low rate of general anxiety on the BASC-2, we did not collect more detailed anxiety measures for the TD group, which is another limitation. While we employed the use of standardized behavioral measures such as the BASC-2, SCAS, and ABAS-II, these tools rely on parental report and may not truly represent the child’s internalizing symptoms. Child self-report scales are available, although we chose the parental scales due to the younger age of our population complicated by developmental/intellectual delay, which limits the validity of self-report because of conceptual, linguistic, and social limitations [38
]. In addition, there may be selection bias of families with children experiencing behavioral problems or academic difficulties being more likely to participate in our study because they are seeking help for these conditions, although it is surprising that very few had sought out care through their own medical or mental health care system. However, Young et al. [22
] also note that children in their sample with 22q11.2DS and psychopathology were not receiving needed mental health services and our finding of the dissociation between FSIQ and adaptive function highlight the importance of intervention. One last limitation is the subjective nature of anxiety symptoms, and we did not collect physiological measures of arousal.
Strengths of our study include the inclusion of a typically developing control group and relatively large sample size. Data on adaptive function and anxiety were collected from children participating in a larger study of neurocognition in 22q11.2DS and participants were not recruited from a psychiatry clinic or study specifically focused on anxiety or behavior problems, which decreases ascertainment bias. We add to the literature by relating anxiety symptoms to adaptive functioning, which may be a more pragmatic outcome measure than IQ alone. Our findings suggest that treatment of anxiety symptoms may influence adaptive function and support independent life skills. This is important considering that interventions to decrease anxiety are more readily available than treatments focused on improving IQ.
In summary, anxiety symptoms are prevalent in children with 22q11.2DS and interfere with adaptive functioning. The often-observed relationship between IQ and adaptive functioning is not observed in children with 22q11.2DS, perhaps because of their significant anxiety symptoms. Validation of our findings that panic-agoraphobia and obsessive compulsive disorder more significantly impact daily functioning will be useful for future studies to help identify prognostic factors and implement targeted therapies.