Behavioral and Psychiatric Phenotypes in 22q11.2 Deletion
Syndrome
Wendy R. Kates, Ph.D.,
Professor, State University of New York Upstate Medical University, Psychiatry and Behavioral
Sciences, 750 East Adams Street, Syracuse, NY 13210, UNITED STATES, 315-464-3270, FAX:
315-464-3163
Kerri L Tang, MA,
SUNY Upstate Medical University
Kevin M Antshel, Ph.D., and
Syracuse University
Wanda P. Fremont, M.D.
SUNY Upstate Medical University
Wendy R. Kates: katesw@upstate.edu
Abstract
22q11.2DS is a chromosomal microdeletion that affects approximately 40–50 genes, and impacts
various organs and systems throughout the body. Detection is typically achieved by fluorescence
in-situ hybridization following diagnosis of one of the major features of the deletion or via
chromosomal microarray or non-invasive prenatal testing. The physical phenotype can include
congenital heart defects, palatal and pharyngeal anomalies, hypocalcemia/hypoparathyroidism,
skeletal abnormalities, and cranial/brain anomalies, although prevalence rates of all of these
features are variable. Cognitive function is impaired to some degree in most individuals, with
prevalence rates of greater than 90% for motor/speech delays and learning disabilities. Attention,
executive function, working memory, visual spatial abilities, motor skills, and social cognition/
social skills are affected. The deletion is also associated with an increased risk for behavioral
disorders and psychiatric illness. The early onset of psychiatric symptoms common to 22q11.2DS
disrupts the development and quality of life of individuals with the syndrome, and is also a
potential risk factor for later development of a psychotic disorder. This review discusses
prevalence, phenotypic features, and management of psychiatric disorders commonly diagnosed in
children and adolescents with 22q11.2DS, including autism spectrum disorders, attention deficit/
hyperactivity disorder, anxiety disorders, mood disorders, and schizophrenia/psychotic disorders.
Guidelines for the clinical assessment and management of psychiatric disorders in youth with this
syndrome are provided, as are treatment guidelines for the use of psychiatric medications.
Correspondence to: Wendy R. Kates,
katesw@upstate.edu.
Conflicts of Interest
The authors have no conflicts of interest to declare
HHS Public Access
Author manuscript
J Dev Behav Pediatr. Author manuscript; available in PMC 2016 October 01.
Published in final edited form as:
J Dev Behav Pediatr. 2015 October ; 36(8): 639–650. doi:10.1097/DBP.0000000000000210.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Introduction
This review of 22q11.2 deletion syndrome (22q11.2DS) is intended to provide guidance for
treatment and management, with the intended audience of developmental behavioral
pediatricians, child psychiatrists, and possibly geneticists and primary care providers.
22q11.2DS is a relatively common multiple anomaly syndrome caused by a deletion of the
q11.2 band of one copy of chromosome 22, affecting roughly 40–50 genes. 22q11.2DS has
an estimated population prevalence of 1:4000 – 1:6000 live births,
1
although a recent
publication cites a frequency as low as 1/992
2
. Although the phenotype varies considerably,
multiple body systems are often affected and typically include characteristic facial features,
cardiac defects, palatal anomalies, immune deficiency, cognitive impairments, and
psychiatric disorders. Throughout the history of the syndrome, 22q11.2DS has been
identified by several clinical descriptors, including velo-cardio-facial syndrome (VCFS),
conotruncal anomalies face syndrome, and DiGeorge syndrome. However, in 1992, it was
discovered that all of these clinical disorders shared the same genetic microdeletion.
3
Since
then, there has been a general movement toward referring to the syndrome as 22q11.2DS as
it is the most descriptive name.
The phenotype for 22q11.2DS includes physical, metabolic, endocrine, and behavioral
features.
4
Although many body systems can be affected, no one anomaly occurs in 100% of
cases. Bassett, et al.
5
reported prevalence rates for multisystem features present in
22q11.2DS, and those rates are used here. The physical phenotype can include congenital
heart defects (50%–75% prevalence), palatal and pharyngeal anomalies (75% prevalence),
vascular anomalies, facial dysmorphism (prevalence >90%) and hypocalcemia/
hypoparathyroidism (60% prevalence).
Arguably, the most commonly (82–100%) occurring symptoms, are behavioral and
developmental issues.
6
A wide range of general cognitive abilities (mild intellectual
disability to average IQ) has been observed with mean full-scale IQ (FSIQ) scores typically
in the borderline range,
7
with approximately 50% of individuals with scores less than 70,
and performance IQ (PIQ) slightly lower than verbal IQ.
6,8,9
It is important to note,
however, that this IQ pattern is not present across all individuals with 22q11.2DS. In studies
of intellectual functioning throughout development in 22q11.2DS, cognitive abilities were
found to be inversely associated with age, with both VIQ and PIQ scores showing a cross-
sectional decline with age.
10,11
Vorstman, et al.,
12
using a large, pooled cross-sectional
dataset from an international research consortium, reported that individuals with 22q11.2DS
between 8 and 24 years of age showed an average 7-point decline in FSIQ, driven by an
average 9-point decline in VIQ and average 5.1-point decline in PIQ. Attention abilities are
impaired,
9,13
as are deficits in executive function, shifting attention, working memory, and
reactive response inhibition.
14–19
Impairments in visuospatial perception and visuospatial
memory are also common in 22q11.2DS,
6,20–23
and are often thought to be the underlying
reason for mathematical deficits.
24
Relative deficits include spatial working memory
21
and
the endogenous cueing function of visual attention (in younger children)
22
.
Academically, children with 22q11.2DS typically fare better in their early school years and
many do not begin to experience impairments until the later elementary school years (3–4
th
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grade), when the focus begins to shift from concrete to more abstract thinking. Receptive
language is typically stronger in the preschool years, and although general language
problems become apparent in the early school years, reading, spelling, and rote verbal
memory remain in the low- to high-average range, with verbal memory being consistently
stronger than visuo-spatial memory.
25
Reading comprehension abilities also often lag
behind reading decoding and phonological processing abilities,
6,20,26,27
and receptive
language abilities are generally stronger than expressive language abilities, although the
opposite pattern has been observed as well.
28
Written language abilities are often impaired
as well, possibly related in part to graphomotor difficulties and/or expressive language
difficulties.
6,25
Accordingly, although the term of non-verbal learning disability has been
applied at times to children with 22q11.2DS, the language based learning difficulties noted
above render this label somewhat misleading, and often inaccurate.
29
Motor deficits have also been reported in children with 22q11.2DS, including early
hypotonia, coordination/balance deficits, delayed walking
30
and, during adolescence,
problems with motor speed.
6
Although fine motor difficulties are also present, generally
gross motor skills are more markedly impaired.
6
In a study of 56 children (mean age = 9.65
years, SD = 1.93), those with 22q11.2DS performed significantly worse than age- and IQ-
matched controls on tasks of manual dexterity, visual perception, and motor coordination,
suggesting that visual-perceptual and visuo-motor integration skills are specifically
affected.
31
Additionally, axial stability is somewhat impaired in those with 22q11.2DS.
32
Behavioral Challenges
The behavioral phenotype of children with 22q11.2DS has been studied extensively.
Children with 22q11.2DS have been described as overactive, impulsive, emotionally labile,
shy/withdrawn, and/or disinhibited.
6,33,34
Indeed, the temperament of children and
adolescents with 22q11.2DS have also been assessed via parent report. Relative to
unaffected siblings and typical controls, children with 22q11.2DS have a generally more
difficult temperament.
35
Specifically, children with the syndrome were rated as being less
regular in their daily habits (e.g. eating at the same time each day, etc.), more rigid and less
able to respond flexibly to changes in the environment, less able to focus/sustain attention,
less cheerful/pleasant and less likely to stay with an activity for a long time. However, in a
study based on parent and teacher reports, Swillen
36
found that school-aged children with
22q11.2DS generally exhibited the similar behaviors as age-, sex-, and IQ-matched children
with idiopathic developmental delays. The exceptions were that children with 22q11.2DS
demonstrated more social withdrawal, and non-syndromal children with developmental
delays demonstrated more aggressive behaviors. In general, many of the behaviors exhibited
by children with 22q11.2DS (e.g., overactivity, impulsivity, poor organizational skills) are
also common in children with idiopathic developmental delays.
37
Therefore, it is difficult to
differentiate behaviors that are primarily psychiatric conditions stemming from the deletion
from behaviors that are due to other risk factors associated with developmental delays and
cognitive/intellectual deficits.
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Social Cognition/Social Skills
Social functioning in 22q11.2DS appears to be affected as well. Youth with 22q11.2DS tend
to have internalized-type social problems (social withdrawal); however, many also tend to
have problems with attention/concentration, which can lead to disinhibition and
impulsivity.
7
A developmental progression has been documented, moving from more of an
externalizing profile (e.g., impulsive, oppositional) at a younger age, to an internalizing
profile in adolescence (e.g., withdrawn, exhibiting somatic complaints, anxiety,
depression).
6
It has been hypothesized that the social withdrawal that is common in youth
with 22q11.2DS may be partly due to their difficulty communicating with others, to
velophyarngeal dysfunction, or to neuropsychological limitations that can make interaction
with others difficult.
7
It remains unclear whether the social impairments are primary or
secondary symptoms of the deletion.
Impairments in social cognition are generally seen as a central aspect of idiopathic
schizophrenia. As such, Jalbrzikowski
38
investigated social cognitive abilities in 22q11.2DS
as predictors of positive and negative symptoms of psychosis. Youth with 22q11.2DS were
impaired on tasks of Theory of Mind (ToM; the ability to understand what another person is
thinking or feeling) and processing speed. ToM emerged as the best indicator of positive
symptoms of psychosis, and processing speed was the best indicator of negative symptoms
of psychosis. Additionally, a cross-sectional study
39
including classic social-cognitive, false-
belief and mentalizing tasks, and social-perceptual face processing tasks, found that younger
children with 22q11.2DS exhibited social-perceptual deficits, including matching faces on
the basis of identity, emotion, facial speech, and gaze. Performance was positively
associated with age, language abilities, and social competence, and negatively associated
with emotional problems.
39
Moreover, in a study of mental state attributions, Ho, et al.
40
found that individuals with 22q11.2DS (aged 6–25 years) had decreased intentionality and
appropriateness scores for ToM, but not for random scenes. ToM was significantly
correlated with scores on the Social Responsiveness Scale. Finally, the authors of a study
that investigated social skills and associated psychopathology in 22q11.2DS suggested that
treating behavioral/emotional disorders (e.g., ADHD, anxiety, internalizing symptoms) may
help improve social skills, as deficits in social skills were found to be more closely related to
emotional/behavioral issues than delays in neurocognition.
41
Psychiatric Phenotype
The early onset of psychiatric symptoms common to 22q11.2DS disrupts the development
and quality of life of individuals with the syndrome, and is also a potential risk factor for
later development of a psychotic disorder. Accordingly, in the following section, we discuss
the prevalence, phenotypic features and management of common psychiatric disorders in
22q11.2DS. Note that these disorders include many of the behavioral and cognitive
problems described above. Likewise, many comorbidities in 22q11.2DS are similar to those
with idiopathic conditions (e.g., schizophrenia, anxiety). Several years ago, Bassett and
colleagues
5
outlined the multisystem features of 22q11.2DS and recommended general
surveillance and management approaches for all common medical and psychiatric
comorbidities. Developmental pediatricians are particularly likely to provide care for those
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patients with 22q11.2DS that also have psychiatric disorders
42
. Thus, we focus on standard
surveillance and management approaches for 22q11.2DS-affected youth with psychiatric
disorders, and provide guidance for issues that may be somewhat specific to the 22q11.2DS
population. Nonetheless, most of these comorbidities can be managed by non-22q specialists
with consideration for medical (cardiac, endocrine, etc.) conditions that might require lower
dosing or more frequent monitoring. We have organized our review by the typical age of
onset, beginning with conditions that characteristically are diagnosed in childhood. We have
also provided a table that summarizes prevalence rates of each disorder in 22q11.2DS, and
information about assessment and evidence-based treatments (See Table 1).
Although the psychiatric phenotype of 22q11.2DS has been the focus of numerous research
studies in recent years, and despite the identification of many important aspects, there
remained inconsistencies regarding prevalence rates of particular psychiatric disorders. Most
studies have been conducted on relatively small samples, and rarely addressed issues of
comorbidity or sex differences. To address these concerns, The International Consortium on
Brain and Behavior in 22q11.2 Deletion Syndrome gathered research groups from North
America, Europe, Australia, and the Middle East to collaborate and share knowledge and
data. This collaboration has resulted in a comprehensive report of the prevalence of
psychiatric disorders across the lifespan, patterns of comorbidity across diagnostic
categories, and sex distributions of psychiatric disorders in 1,402 individuals with
22q11.2DS.
43
Age categories include children (aged 6–12 years), adolescents (aged 13–17
years), emerging adults (aged 18–25 years), young adults (aged 26–35 years), and mature
adults (aged 36 years and over). Prevalence rates listed below (and detailed in Table 1) are
taken from the Consortium report by Schneider and colleagues.
Autism Spectrum Disorders
The Consortium report found that the prevalence of autism spectrum disorders (ASD;
including autistic disorder, Asperger’s syndrome, and pervasive developmental disorder not
otherwise specified) was lowest among children (12.77%), highest among adolescents
(26.54%), then dropped off again in emerging adulthood (16.11%). Unlike the broader ASD
population, gender differences in ASD prevalence rates in 22q11.2DS have not been
observed.
43
A 2006 study found autism or pervasive developmental disorder not otherwise
specified (PDD-NOS) in 50% of a sample of 60 participants with 22q11.2DS aged 9–18
years.
44
Interestingly, 33.3% of the remainder of the sample scored above cutoff levels on
three domains of autistic symptomatology. Similarly, in a 2007 study of 41 children and
adolescents with 22q11.2DS (aged 6.5 – 15.8 years), Antshel et al.
45
found that 20% of their
sample met strictly defined criteria for autism while over 40% met criteria for an autism
spectrum disorder. When compared to children youth with 22q11.2DS and no ASD
diagnosis, those with both 22q11.2DS and ASD were more likely to have comorbid ADHD
and specific phobias, as well as more symptoms of mania.
45
It has consistently been
reported that idiopathic ASD often co-occurs with other psychiatric disorders.
44,45
Thus,
ASD with and without 22q11.2DS is often accompanied by co-occurring psychiatric
diagnoses. Further investigation is required to determine the extent to which the psychiatric
comorbidity found in 22q11.2DS is affected by the presence of ASD, or vice versa. In
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