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A review of neurocognitive functioning of children with sex chromosome trisomies (SCT): Identifying targets for early intervention

Authors:

Abstract

Sex chromosome trisomies (SCT) are among the most common chromosomal duplications in humans. Due to recent technological advances in non‐invasive screening, SCT can already be detected during pregnancy. This calls for more knowledge about the development of (young) children with SCT. This review focused on neurocognitive functioning of children with SCT between 0‐18 years, on domains of global intellectual functioning, language, executive functioning, and social cognition, in order to identify targets that could benefit from early treatment. Online databases were used to identify peer‐reviewed scientific articles using specific search terms. In total 18 studies were included. When applicable, effect sizes were calculated to indicate clinical significance. Results of the reviewed studies show that although traditionally, the focus has been on language and IQ in this population, recent studies suggest that executive functioning and social cognition may also be significantly affected already in childhood. These findings suggests we should extend neuropsychological screening of children diagnosed with SCT, to also include executive functioning and social cognition. Knowledge about these neurocognitive risks is important to improve clinical care and help identify targets for early support and intervention programs to accommodate for the needs of individuals with SCT. This article is protected by copyright. All rights reserved.
REVIEW
A review of neurocognitive functioning of children
with sex chromosome trisomies: Identifying targets
for early intervention
Evelien Urbanus
1,2
| Sophie van Rijn
1,2
| Hanna Swaab
1,2
1
Clinical Child and Adolescent Studies, Leiden
University, Leiden, the Netherlands
2
Leiden Institute for Brain and Cognition,
Leiden, the Netherlands
Correspondence
Evelien Urbanus, Wassenaarseweg 52, Room
4B57, 2333 AK, Leiden, the Netherlands
Email: e.l.urbanus@fsw.leidenuniv.nl
Funding information
Nederlandse Organisatie voor
Wetenschappelijk Onderzoek, Grant/Award
Number: 016.165.397
Abstract
Sex chromosome trisomies (SCT) are among the most common chromosomal duplica-
tions in humans. Due to recent technological advances in non-invasive screening, SCT
can already be detected during pregnancy. This calls for more knowledge about the
development of (young) children with SCT. This review focused on neurocognitive
functioning of children with SCT between 0 and 18 years, on domains of global intel-
lectual functioning, language, executive functioning, and social cognition, in order to
identify targets that could benefit from early treatment.
Online databases were used to identify peer-reviewed scientific articles using specific
search terms. In total 18 studies were included. When applicable, effect sizes were
calculated to indicate clinical significance.
Results of the reviewed studies show that although traditionally, the focus has been on
language and intelligence (IQ) in this population, recent studies suggest that executive
functioning and social cognition may also be significantly affected already in childhood.
These findings suggest that neuropsychological screening of children diagnosed with
SCT should be extended, to also include executive functioning and social cognition.
Knowledge about these neurocognitive risks is important to improve clinical care and
help identify targets for early support and intervention programs to accommodate
for the needs of individuals with SCT.
KEYWORDS
neurocognitive functioning, sex chromosome trisomies, XXX, XXY, XYY
1|INTRODUCTION
Chromosome trisomies are genetic variations caused by a spontane-
ous error during early cell division.
1
Sex chromosome trisomies
(SCT), trisomies involving the X or Y chromosomes, are among the
most common chromosomal duplications in humans,
2
with an esti-
mated prevalence ranging from 1-650 to 1-1000 live births.
3-5
SCT
can lead to a 47,XXY (Klinefelter syndrome) or 47,XYY (XYY
syndrome) karyotype in males, and a 47,XXX (Trisomy X syndrome)
karyotype in females.
Although SCT are relatively common genetic variations, they are
also one of the most frequently underdiagnosed chromosomal condi-
tions; up to 75% of individuals with SCT are never diagnosed.
6
This high
percentage may be explained by several factors. First, physical charac-
teristics are relatively subtle.
7,8
Secondly, individuals may be treated for
symptoms without knowledge of the underlying genetic condition.
Received: 29 March 2019 Revised: 22 May 2019 Accepted: 4 June 2019
DOI: 10.1111/cge.13586
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2019 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
156 Clinical Genetics. 2020;97:156167.wileyonlinelibrary.com/journal/cge
Finally, cognitive as well as behavioral symptoms are variable,
9,10
rang-
ing from severe impairments in some individuals, with other individuals
functioning on an average or above average level. The subtle physical
characteristics, and the variability of symptoms often does not prompt
to genetic testing. There are certain moments in life when the develop-
ing brain is especially sensitive to environmental influences regarding
the development of specific neurocognitive functions.
11
It is possible
that when the genetic diagnosis is not made or delayed, the so called
window of opportunityto explicitly support specific developmental
stages passes, which could result in more severe cognitive and/or
behavioral difficulties.
12
Focusing on the neurocognitive underpinnings of behavior rather
than behavioral symptoms itself is important as behavioral problems
may arise as a consequence of different information processing defi-
cits. Also, cognitive deficits may serve as early predictors of behavioral
problems in later life, and may function as markers for children at risk
for neurodevelopmental problems.
Over the last decade, the technology to detect genetic variations
in unborn children has advanced significantly; one advantage being
that they can be non-invasive, for example by screening maternal
blood. These advanced technological developments and the increased
possibility to detect SCT during the pregnancy could lead to more
individuals being diagnosed on the genetic, instead of the behavioral
level.
13
This calls for more knowledge about the development of
(young) children with SCT, so children can get the appropriate support
as early as possible when needed. The identification of a profile of
neurocognitive risks, and knowledge about the mechanisms underly-
ing these risks, could help improve early screening for neurobehavioral
problems in young children with SCT and help identify targets for
early, tailored support and intervention programs, which in turn could
hopefully optimize outcomes in later life. Although some of these
neurocognitive mechanisms are still under constructionin early
childhood, and for that reason are more apparent in late childhood or
adolescence, precursors of some of these mechanisms can already be
measured in early childhood.
Through a narrative review of the literature we evaluated evi-
dence for cognitive impairments on the domains of global intellec-
tual functioning (GIF), language development, executive functioning,
and social cognition in children with SCT. Earlier reviews have
focusedonthedevelopmentofindividuals with SCT over the life-
span, primarily during adolescence and adulthood. In contrast, in
this review, neurocognitive functioning of children with SCT was
reviewed, with a focus on early development. As the domains of
GIF, language development, social cognition, and executive func-
tioning (EF) are vulnerable domains based on studies in adolescents
and adults, and may be key factors that could drive the emotional
and behavioral problems that can be found in individuals with
SCT,
14
it is important to monitor possible developmental risk in
these domains already early in life. For that reason our first aim was
to review to what degree impairments in areas of GIF, language
development, social cognition, and EF have been studied in children
with SCT, and identify possible gaps in research that future research
should focus on. Secondly, in addition to identifying the type of
impairments, we also aimed to determine the degree of impairment,
to establish clinical significance and identify risk-factors that should
be closely monitored from early development onwards or that
should be included in standard clinical neuropsychological screening
to identify potential targets for support and intervention. Knowl-
edge about the functioning of children with SCT in these domains is
important to be able to identify children who are at risk for lowered
adaptive functioning, academic challenges, and psychopathology,
and whom thus may be in need of close monitoring and early
support or intervention.
2|METHOD
2.1 |Search strategy
A structured approach was used to identify and review articles. The
online database Web of Knowledge was used to identify eligible peer-
reviewed scientific articles that were published before July 1, 2018.
An overview of the used search terms can be found in Figure 1. The
Web of Knowledge categories filter was used to include publications
in the following categories: Behavior sciences, education, genetics
heredity, language and linguistics, neurosciences, pediatrics, psychia-
try, and psychology (clinical, developmental, and multidisciplinary).
Using the same search strategy, the online database PubMed was
consulted, but no additional relevant articles were identified. Finally,
reference lists from identified papers were consulted to trace addi-
tional papers.
2.2 |Study selection
After removing duplicates using the EndNote automatic duplicate
removal function, the retrieved articles were scanned for relevance by
author 1. Titles and abstracts were assessed by authors 1 and 2 before
assessing full texts of studies and discrepancies were resolved via
consensus. The inclusion criteria specified that to be eligible for the
review (a) Participants in the studies were aged between 0 and
18 years, or when the study included a broader age range, the effect
of age was assessed, (b) Studies were published in international peer-
reviewed journals and available as a full-text article written in English,
(c) Studies included 15 participants, (d) The main focus of the study
was on global intellectual functioning, language development, social
cognition, or executive functioning. In addition, studies were included
regardless of recruitment strategy, including newborn screening stud-
ies, as well as studies that included prenatally diagnosed participants,
and postnatal follow-up studies. Ascertainment bias plays a role in
much of the literature on SCT. By including studies regardless of
recruitment strategy (and thus clinical ascertainment) we aimed to
describe as much of the variability on the reviewed domains, even
though these outcomes may not be fully representative for the entire
SCT population. This means that clinical ascertainment is also part of
this review. Table 1 gives an overview of the sample ascertainment of
the included studies. Also, studies were included when children with
SCT were compared to a (matched)-control group, or when validated
URBANUS ET AL.157
instruments were used to compare children with SCT with a normed
reference group, an overview of study design of the included studies
can be found in Table 1. Finally, studies were included regardless of
used instrument type, including both parent report and performance-
based tests.
In total, 18 publications met our criteria. For each publication, par-
ticipant characteristics, study design, and results were summarized in a
spreadsheet, which were the basis for the tables in this manuscript. As
this is a narrative review, a formal meta-analysis or methodological
appraisal was not conducted. However, to indicate the clinical
Full-text articles excluded
(n = 18)
-N=8 Age (range)
-N=3 case studies or small
sample sizes
-N=6 focus on behavioral
outcomes
-N=1 focus on brain
imaging
Box A: In Title
XXX OR XXY OR XYY OR SCT OR
SCA OR (”Trisomy X”) OR
“Klinefelter” OR (”Triple X”) OR KS
OR (”sex
chromosome trisom*”) OR (”sex
chromosome aneuploid*”) OR “sex
chromosome abnormality”) OR (”X
aneuploidy”) OR (”sex chromosome
aberration”)
Box B: In Topic
Language OR expressive OR receptive OR
communication OR speech OR IQ OR Intelligence OR
cognition OR cognit* OR (global intellectual
function*”) OR inhibition OR (”mental exibility”) OR
(”sustained attention”) OR (”executive functioning”) OR
(”working memory”) OR (”social cognition”) OR (”social
communication”) OR (”theory of mind”) OR (ToM) OR
(”affect recognition”) OR (”emotion
recognition”) OR development
Records Identied through
database search box A + box B
(n = 293)
Additional records identied
through other sources
(n = 6)
Records after duplicates removed
(n= 289)
Records screened
(n=289)
Full-text articles assessed
for eligibility
(n=33)
Records excluded
(n=256)
Studies included
(n=18)
Search termsIdenticationScreeningEligibilityIncluded
FIGURE 1 PRISMA flow chart of search strategy and included studies
158 URBANUS ET AL.
significance of the outcomes reported in the included studies, effect
sizes were calculated when applicable.
3|RESULTS
3.1 |Global intellectual functioning
Eight studies met our inclusion criteria regarding GIF. Main findings of
the included studies, in addition to used instruments and studied
populations can be found in Table 2.
Ross et al
15
studied 47 boys with XXY aged 4-18 years and com-
pared scores to a normed reference group. The 4-to-9-year olds
showed relative strengths on the non-verbal reasoning subtests (ie,
matrices, sequential and quantitative reasoning) and on the spatial
subtests (ie, recall of design, pattern constructions), in contrast to sub-
tests on the verbal cluster (ie, word definitions, similarities). The
10-18-year olds showed low average scores on the verbal and non-
verbal reasoning subtests, whereas they had average scores on the
spatial cluster subtests. When comparing the younger and older sub-
groups, it appeared that the older children performed worse on the
matrices subtest, and had slightly lower general conceptual ability
than the younger boys.
A second study by Ross et al
16
included 93 boys with XXY,
21 boys with XYY, and 36 matched control boys, aged 4-18 years.
General conceptual ability was lower in the XXY and XYY groups,
compared to controls. Overall, performance was similar in XXY and
XYY boys, with the exception of nonverbal spatial cognitive abili-
ties, which were better (ie, not different from controls) in boys
with XYY.
A cohort of boys aged 4-18 years was included in the study of
Cordeiro et al.
17
Results of GIF were obtained for 95 boys with XXY
and 29 boys with XYY. Results showed a wide range of intellectual
TABLE 1 Ascertainment and study design of included studies
Authors Included karyotypes Prenatal diagnosed (%) Study design
Ross et al, 2008 XXY 60 Cross-sectional, comparison with normed reference group
Ross et al, 2009 XXY 55 Cross-sectional, comparison with age-matched controls
XYY 29
Cordeiro et al, 2012 XXY 56 Cross-sectional, comparison with normed reference group
XYY 33
Bruining et al, 2009 XXY 51 Cross-sectional, comparison with normed reference group
Ratcliffe, 2009 XXY 100 Cross-sectional, comparison with controls and siblings
XYY 95 Cross-sectional, comparison with social class matched controls
XXX 100 Cross-sectional, comparison with female controls and siblings
Rovet et al, 1995; 1996 XXY 100 Cytogenetic survey followed by longitudinal follow-up
comparison with sibling controls
Netley, 1986 XXY N/A
a
Summary of several cytogenetic surveys with longitudinal
follow-up, comparison group differed between groups,
including family member, unrelated controls, or a normed
reference group
XXX
XYY
Zampini et al, 2018 XXX/XXY 100 Cross-sectional, comparison with controls
Haka-Ikse et al, 1978 XXY 100 Cytogenetic survey followed by longitudinal follow-up
comparison with normed reference group
Bishop et al, 2011 XXX 51 Cross-sectional, comparison with sibling controls
XXY 100
XYY 36
Lee et al, 2015 XXY/XXX 100 Cross-sectional, comparison with controls matched on
chronological age and maternal education level
Van Rijn & Swaab, 2015 XXX/XXY 53 Cross-sectional, comparison with controls
Samango-Sprouse et al, 2018 XXY (NL) 55 Cross-sectional, comparison with normed reference group
XXY (United States) 91
Ross et al, 2015 XYY 35 Cross-sectional, comparison with controls matched on
chronological age
Van Rijn et al, 2014a XXX/XXY 53 Cross-sectional, comparison with controls
Van Rijn et al, 2018 XXY 24 Cross-sectional, comparison with normed reference group
Van Rijn et al, 2014b XXX/XXY 49 Cross-sectional, comparison with controls
a
Percentage prenatal diagnosed is not explicitly stated in this summary overview.
URBANUS ET AL.159
abilities, with a total intelligence (IQ) ranging from extremely/very
low to very superior/high. There were no significant differences
between the XXY and XYY groups; in both groups, verbal intelli-
gence quotient (VIQ) was significantly lower than performance intel-
ligence quotient (PIQ).
The wide variability of intellectual abilities was also found in a
study by Bruining et al.
18
Forty-seven boys with XXY aged between
6 and 19 years participated. Total IQ and PIQ scores ranged from
extremely low to superior, whereas VIQ scores ranged from extremely
low to high average.
In the Edinburgh cohort, 19 boys with XXY, 19 boys with XYY,
and 16 girls with XXX were followed from birth until the ages of 16 to
27. Intelligence was tested between the ages of 6 and 8 years. The
XYY boys scored slightly, but significantly, lower than controls mat-
ched on social class and sibling controls, especially in the verbal
domains. The XXY boys, as well as the XXX girls, scored significantly
lower than controls and siblings in both the verbal and the perfor-
mance domains, and showed a wide variability in scores.
19
In the Toronto cohort, boys with XXY were followed from birth
until the age of 20 years. Intelligence was measured over time at sev-
eral age intervals, with the sample size ranging from 21 to 29 partici-
pants. Results showed that scores on the performance domain were
only lower in boys with XXY when compared to controls at the youn-
gest age interval (ie, 6-8 years), whereas scores on the verbal domain
were lower in boys with XXY at all ages, except when they were
15-17 years. Boys with XXY had poorer verbal scores compared to
performance scores at all ages.
20,21
Netley
22
summarized results of several longitudinal studies,
including data from the Boston, Denver, Edinburgh, Japan, Toronto,
and Winnipeg cohorts. In total 73 boys with XXY, 32 girls with XXX,
and 28 boys with XYY participated and were compared to normed
scores. Results showed that boys with XXY scored lower on the ver-
bal, but not performance domains, whereas girls with XXX scored
lower on both the verbal and performance domain, with better perfor-
mance than verbal scores. Finally, no significant differences in GIF
were found in boys with XYY.
TABLE 2 Included studies global intellectual functioning
Authors N Age Comparison Subdomain(s) Instrument(s) Results
Ross et al, 2008 47 XXY 4-9;11 years
10-17;8 years
Normed
scores
GCA DAS Older boys < younger
boys
Ross et al, 2009 93 XXY
21 XYY
4-18 years Control
group
GCA DAS XXY = XYY < controls
VP XXY = XYY < controls
NVP XXY = XYY < controls
Spatial cluster XXY < XYY = controls
Cordeiro et al, 2012 95 XXY
29 XYY
4-18 years Normed
scores
VIQ-PIQ Gap DAS, WASI or WISC XXY VIQ < PIQ
XYY VIQ < PIQ
Bruining et al, 2009 47 XXY 6-19 years Normed
scores
FSIQ WISC or WASI XXY < controls
PIQ XXY < controls
VIQ XXY < controls
Ratcliffe, 1999 19 XXY
19 XYY
16 XXX
6-8 years Control
group
PIQ WISC XXY < controls
XYY < controls
XXX < controls
VIQ XXY < controls
XYY < controls
XXX < controls
Rovet et al, 1995;
1996
21-29
XXY
6-18 years Control
group
PIQ WISC or WASI XXY < controls
VIQ XXY < controls
VIQ-PIQ Gap XXY VIQ < PIQ
Netley, 1986 73 XXY
32 XXX
28 XYY
Mxxy = 10.3 years
Mxxx = 10.5 years
Mxyy = 9.5 years
Normed
scores
FSIQ WISC or WASI XXY < controls
XXX < controls
XYY n.s.
PIQ XXY n.s.
XYY n.s.
XXX < controls
VIQ XXY < controls
XXX < controls
XYY n.s.
VIQ-PIQ Gap XXX VIQ < PIQ
Abbreviations: DAS, Differential Ability Scales; FSIQ, full scale intelligence quotient; GCA, General Conceptual Ability; n.s., no significant differences; IQ,
intelligence; NVP, Nonverbal Performance; PIQ, performance intelligence quotient; WASI, Wechsler Abbreviated Scale of Intelligence; VIQ, verbal
intelligence quotient; VP, Verbal Performance; WISC, Wechsler Intelligence Scale for Children.
160 URBANUS ET AL.
3.2 |Language development
Five studies met our inclusion criteria regarding language develop-
ment in children with SCT. Main findings of the included studies, in
addition to used instruments and studied populations can be found in
Table 3. When applicable, effect sizes were calculated to indicate the
clinical significance.
Zampini et al,
23
studied 15 boys and girls with an extra X chromo-
some at the age of 24 months. Parents from children with an extra X
reported that their child produced significantly less words than par-
ents of control children. In addition, 60% of the children with an extra
X were at risk for language impairments. In a semi-structured play
session between children and their parent, spontaneous utterances,
verbal productions, and gestures of the child were coded and classi-
fied. During this play session, children with an extra X showed less
verbal utterances, and more simple vocal productions. In addition
possibly to compensatethe extra X group showed more pointing
gestures. When comparing the boys and girls in the extra X group, no
significant differences were found, indicating that, although less pro-
nounced in girls, the language difficulties could be similar in XXX
and XXY.
This early risk for language problems was also found in a study by
Haka-Ikse et al,
24
who studied 25 boys with XXY between the ages of
3 and 6 years, and used the revised Yale Developmental Schedules to
TABLE 3 Included studies language domain and calculated effect sizes
Authors N Age Comparison Subdomain(s)
Instrument(s)
+ Type(s) Results Effect sizes
Zampini
et al,
2018
15 XXX
/XXY
24 months Control
group
Vocabulary size CDI (P) XXX/XXY < controls d= 2.18***
Verbal productions Structured-play
session (O)
XXX/XXY < controls d
range
= .99-1.44***
Number of
Utterances
XXX/XXY < controls d
range
= 1.76-2.08***
Pointing gestures XXX/XXY > controls d= 1.03***
Haka-Ikse
et al,
1978
25 XXY 36-72 months Normed
scores
Language
difficulties
YDS (P) >50% N/A
Ross et al,
2008
47 XXY 4-9; 11 years
10-17;
8 years
Normed
scores
Complex levels of
language
processing
TLC-E (C) XXY < controls;
Older boys < younger
boys
d= 1.45***
Expressive
vocabulary
EOWPVT (C) n.s.
Receptive
vocabulary
ROWPVT (C) n.s.
Semantic fluency DKEFs (C) n.s.
Phonetic fluency n.s.
Phonological
processing
CTOPP (C) n.s.
Ross et al,
2009
93 XXY
21 XYY
4-18 years Control
group
Receptive
vocabulary
ROWPVT (C) XYY < XXY < controls d
xxy
= 1.15***
d
xyy
= 1.85***
Complex levels of
language
processing
TLC-E (C) XXY = XYY < controls d
xxy
= 1.63***
d
xyy
= 1.33***
Expressive
vocabulary
EOWPVT (C) XXY = XYY < controls d
xxy
= .96***
d
xyy
= 1.17***
Phonetic fluency DKEFs (C) XXY = XYY < controls d
xxy
= .97***
d
xyy
= 1.08***
Phonological
processing
CTOPP (C) Inconclusive results
Semantic fluency DKEFs (C) n.s.
Bishop
et al,
2011
58 XXX
19 XXY
58 XYY
4-17 years Control
group
Structural and
pragmatic
difficulties
CCC (P) XXX 44%-68%
XXY 50%
XYY 38%-85%
N/A
Note:*** High clinical significance; ** Moderate clinical significance; *Low clinical significance; N/A, not applicable; n.s., no significant differences.
Abbreviations: C, Performance Task Child; CCC, Children's Communication Checklist; CDI, MacArthur Communicative Development Inventories; CTOPP,
Comprehensive Test of Phonological Processing; DKEFs, Delis-Kaplin Executive Function system; EOWPVT, Expressive One-Word Picture Vocabulary
Test; O, Observation; P, Parent Report; ROWPVT, Receptive One Word Picture Vocabulary Test; TLC-EL, Test of Language CompetenceExpanded
Edition; YDS, Yale Developmental Schedules.
URBANUS ET AL.161
assess performance on several domains including language. This study
showed that already at preschool age, boys with XXY show a mild
developmental delay in language development; with more than half of
the children experiencing problems with language.
Two studies used more extensive language assessments and
included measures for expressive language, receptive language, pho-
nological processing, phonemic fluency, semantic fluency, and com-
plex levels of language processing (ie, semantics, syntax, and
pragmatics). The first study found age-appropriate development of
expressive and receptive vocabulary, as well as normal verbal fluency
development in 47 boys with XXY aged 4-18 years.
15
More complex
levels of language processing, however, were impaired. When com-
paring 4-to-9-year olds with 10-to-18-year olds, it appeared that the
older group had significantly more difficulties with these complex
levels of language processing. The second study compared boys
between the ages of 4-18 years with XXY (N = 93), XYY (N = 21), and
controls matched on age.
16
Results showed that both boys with XXY
and XYY perform significantly worse than controls on measures of
expressive and receptive language, with the XYY boys performing
worse than the XXY boys. In addition, phonetic fluency was lower in
XXY and XYY boys compared to controls, whereas semantic fluency
and phonological processing were unimpaired. Finally, complex levels
of language processing were impaired in both boys with XXY and
XYY. The authors conclude that although boys with XXY and XYY
both experience language difficulties, these difficulties appear to be
more severe in boys with XYY.
Bishop et al
25
relied solely on parent reports. This study included
children between the ages of 4 and 16 years, and compared children
who were diagnosed prenatally vs children who were diagnosed post-
natally. More than half of the children with SCT received language
therapy, compared to 10% of the sibling controls. Rates of language
therapy were significantly higher among children who were diagnosed
postnatally (68%) than children diagnosed prenatally (44%); and more
common in boys with XYY (88%) than boys with XXY (47%) or girls
with XXX (41%). Parents reported a similar profile of impairments
across the SCT groups; however impairments appeared to be greater
in boys than in girls, and in children with a postnatal diagnosis com-
pared to children with a prenatal diagnosis.
3.3 |Executive functioning
Five studies met our inclusion criteria regarding EF in children with
SCT. Main findings of the included studies, in addition to used instru-
ments and studied populations can be found in Table 4. When appli-
cable, effect sizes were calculated to indicate the clinical significance.
One study used parent report to assess difficulties with EF and
showed that parents with children aged 5-18 years with an extra X
chromosome (N = 30) reported more difficulties than parents with typi-
cally developing children on all domains (ie, inhibition, ability to shift
behavior, emotional control, working memory, planning/organizing, initi-
ating behavior, and organization of materials). In addition, a cross-
sectional study with the same group of participants showed age-effects
in the extra X group; although there appeared to be developmental
stability (ie, difficulties did not differ across the age-groups) on most
domains, difficulties on initiating and planning/organizing domains,
became more pronounced with increased age.
26
Four studies used performance-based tasks to examine processing
speed, sustained attention, response inhibition, and inhibitory control.
In the first study age-appropriate performance on cognitive inhibition
tasks was found in 47 boys with XXY.
15
When comparing 4-to-9-year
olds with 10-to-18-year olds, it appeared that younger, but not older
boys had difficulties with sustained attention. The second study com-
pared boys with XXY (N = 93) or XYY (N = 21) with age-matched con-
trols between the ages of 4 and 18 years.
16
Results showed
significantly more difficulties with sustained attention in the XXY
group, but not the XYY group. However, both the XXY and the XYY
group had increased reaction times, and showed more variability dur-
ing the sustained attention task. On inhibition tasks, the XYY, but not
the XXY group displayed significantly more difficulties in both
inhibiting a cognitive response, and switching between rules within
the task, indicating more problems with mental flexibility in boys with
XYY. The third study used both computerized performance-based
tasks as well as parent reports to assess EF in 23 boys with XXY and
17 girls with XXX all aged between 9 and 18 years.
27
This study found
no significant differences between the extra X groups and a group of
controls on information processing speed, focused attention, or verbal
working memory. However, significant group differences were found
on measures of sustained attentional control, inhibition, mental flexi-
bility, visual working memory, and daily life EF (as reported by par-
ents). The results for XXY boys and XXX girls were not significantly
different, although processing speed was lower in girls with XXX.
Finally, differences between children who were diagnosed prenatally
vs children with a postnatal diagnosis were not found. The fourth
study used the same computerized tasks as the previous study to
measure sustained attentional control, inhibition, and mental flexibility
in two groups of boys with XXY from the Netherlands (N = 44) and
from the United States (N = 54).
28
Developmental risk was calculated
as a percentage of children that scored in the significantly impaired
range (ie, Z> 2.0). Results showed that 19%-23% experienced signifi-
cant and clinically relevant difficulties with sustained attention. How-
ever difficulties with attention regulation (ie, stability of reaction
times) occurred in 22% of the US boys, and 57% of the Dutch boys.
The authors note that time of diagnosis was a significant predictor for
attention regulation, and that 46% of the Dutch boys received a pre-
natal diagnosis, compared to 91% of the US boys. On the inhibition
task, 26%-28% of the children experienced significant and clinically
relevant difficulties, and on the mental flexibility task 35%-36% expe-
rienced significant and clinically relevant difficulties, showing a devel-
opmental risk for several EF.
3.4 |Social cognition
Six studies met our inclusion criteria regarding social cognition in chil-
dren with SCT. Main findings of the included studies, in addition to
used instruments and studied populations can be found in Table 5.
162 URBANUS ET AL.
When applicable, effect sizes were calculated to indicate the clinical
significance.
Three studies used parent reports to assess social cognition in
children with SCT. The first study included 18 boys with XYY between
the ages of 4 and 14 years.
29
The XYY boys had higher scores than
controls, indicating more difficulties with social cognition. A second
study included children and adolescents with XXY (N = 102) and XYY
(N = 40) aged 4-to-18 years.
17
Parents of boys with XXY and XYY
reported more impairments with social cognition, than parents in the
normative sample. Parents of XYY boys also reported more impair-
ments than parents of XXY boys. In addition, parents of the XXY and
XYY groups both reported more variability in scores compared to the
normative sample, indicating a wide range of social cognitive abilities
in boys with SCT. The third study included 60 boys and girls with an
extra X chromosome, between the ages of 9 and 18 years.
30
Parents
of children with an extra X chromosome reported more difficulties in
TABLE 4 Included studies executive functioning domain and calculated effect sizes
Authors N Age Comparison Subdomain(s)
Instrument(s)
+ Type(s) Results Effect sizes
Lee et al, 2015 15 XXY
15 XXX
5-18 years Control
group
Daily life executive
functioning
BRIEF (P) XXX/XXY > controlsN/A
Ross et al, 2008 47 XXY 4-18 years Normed
scores
Sustained attention
omissions
C(K)CPT (C) XXY > controlsN/A
Sustained attention
variability
XXY > controlsN/A
Sustained attention
reaction time
XXY > controlsN/A
Inhibition DKEFS-
CWIT (C)
n.s.
Mental flexibility n.s.
Ross et al, 2009 93 XXY
21 XYY
4-18 years Control
group
Sustained attention
omissions
C(K)CPT (C) XXY > XYY = controlsd
xxy
= .83***
Sustained attention
variability
XXY = XYY > controls
d
xxy
= .80***
d
xyy
= .86***
Sustained attention
reaction time
XXY = XYY > controlsd
xxy
= 1.02***
d
xyy
= 1.04***
Sustained attention
commissions
n.s.
Inhibition DKEFS-CWIT
(C)
XYY < XXY < controls d
xyy
= 1.09***
Mental flexibility XYY < XXY < controls d
xyy
= 1.71***
Van Rijn & Swaab,
2015
40 XXX/XXY 9-18 years Control
group
Sustained attentional
control
ANT (C) XXX/XXY < controls d= .33*
Inhibition XXX/XXY < controls d= .38*
Mental flexibility XXX/XXY < controls d= .45*
Visual working
memory
XXX/XXY < controls d= .68**
Focused attention n.s.
Verbal working
memory
n.s.
Daily life executive
functioning
DEX (P) XXX/XXY < controls d= 1.37***
Samango-Sprouse
et al, 2018
44 XXY (NL)
54 XXY
(United
States)
8-18 years Normed
scores
Sustained attention; %
significant impaired
ANT (C) 19%-57% N/A
Inhibition; %
significant impaired
26%-28% N/A
Mental flexibility; %
significant impaired
35%-36% N/A
Note:*** High clinical significance; ** Moderate clinical significance; *Low clinical significance; N/A, not applicable; n.s., not significant; higher scores
denote more problems.
Abbreviations: ANT, Amsterdam Neuropsychological Tasks; BRIEF, Behavior Rating Inventory of Executive Function; C, Performance Task Child; C(K)CPT,
Conners' (Kiddie) Continuous Performance Test; DEX, Dysexecutive Questionnaire; DKEFS-CWIT; Delis-Kaplin Executive Functioning Color-Word
Interference Test; P, Parent Report.
URBANUS ET AL.163
social cognition compared to parents of typically developing children.
No significant differences were found in the reported difficulties
between boys and girls with an extra X chromosome, indicating similar
impairments in social cognition.
Three studies were identified that used child-assessments to mea-
sure social cognition skills, such as theory of mind (ToM) and (facial)
emotion recognition. The first study involved 70 boys and men with
XXY, and although age ranged from 8 to 60 years, the effect of age
was assessed.
31
Social cognition was assessed using computerized
tasks of pattern identification, face recognition, and facial emotion
recognition. Accuracy in performance in the XXY group differed from
the control group specifically when stimuli were of a more social
nature (ie, during facial emotion recognition). The XXY group on aver-
age needed more time to identify facial expressions, although perfor-
mance accuracy did not increase with more time. The results were
independent of age, suggesting that the difficulties with emotion rec-
ognition are already apparent during childhood. The second study
used the same computerized tasks to study face processing and
TABLE 5 Included studies social cognition domain and calculated effect sizes
Authors N Age Comparison Subdomain(s)
Instrument
(s) + Type(s) Results Effect sizes
Ross et al, 2015 18 XYY 4-14 years Control
group
Social cognition SRS (P) XYY > controlsd= .68**
Cordeiro et al,
2012
102 XXY
40 XYY
4-18 years Normed
scores
Social cognition SRS (P) XYY > XXY > controlsd
xxy
= .93***
d
xyy
= 1.80***
Van Rijn et al,
2014a
60 XXX/XXY 9-18 years Control
group
Social cognition SRS (P) XXX/XXY > controlsd= 1.61***
Van Rijn et al,
2018
70 XXY 8-60 years Normed
scores
Pattern recognition
reaction time %
impaired
ANT (C) 17% N/A
Pattern recognition
accuracy % impaired
9% N/A
Face processing
reaction time %
impaired
26% N/A
Face processing
accuracy % impaired
13% N/A
Facial emotion
recognitionreaction
time % impaired
33% η
2
= .40***
Facial emotion
recognition
accuracy % impaired
13% η
2
= .16**
Samango-
Sprouse
et al, 2018
44 XXY (NL)
54 XXY
(United
States)
8-18 years Normed
scores
Face processing%
impaired
ANT (C) 23%-25% N/A
Facial emotion
recognition%
impaired
16%-44% N/A
Van Rijn et al,
2014b
46 XXX/XXY 9-18 years Control
group
Theory of Mind
egocentric role
taking
SCST (C) XXX/XXY < controls d= .85***
Theory of Mind
subjective role taking
XXX/XXY < controls d= 1.03***
Theory of Mindself-
reflective role taking
XXX/XXY < controls d= .69**
Theory of Mind
mutual role taking
XXX/XXY < controls d= .83***
Facial affect
identificationangry
faces
KDEF (P) XXX/XXY < controls d= 3.30***
Note:*** High clinical significance; ** Moderate clinical significance; *Low clinical significance; N/A, not applicable; n.s., not significant; higher scores
denote more problems.
Abbreviations: ANT, Amsterdam Neuropsychological Tests; C, Performance Task Child; KDEF, Karolinska Directed Emotional Faces; P, Parent Report;
SCST, Social Cognitive Skills Tests; SRS, Social Responsiveness Scale.
164 URBANUS ET AL.
emotion recognition skills in in two groups of boys with XXY from the
Netherlands (N = 44) and from the United States (N = 54).
28
Develop-
mental risk was calculated as a percentage of children that scored in
the significantly impaired range (ie, Z> 2.0). Results showed that 23%-
25% of the children experienced significant and clinically relevant diffi-
culties with face processing. In addition, 16%-44% of the children expe-
rienced significant and clinically relevant difficulties with emotion
recognition (ie, identifying sad, happy, or angry emotions) The third
study tested a group of 46 boys and girls with an extra X chromosome,
between the ages of 9 and 18 years.
32
Measures included assessments
of ToM and emotion recognition. Children with an extra X chromosome
performed more poorly on the ToM task than the control group. In
addition, on average children with an extra X chromosome showed dif-
ficulties in the ability to identify emotional faces which was expressed
in the reduced accuracy, rather than reaction times, and most promi-
nent for angry faces. No differences were found in the performance of
the XXX vs the XXY group, nor in the performance of children in the
prenatal follow-up vs the referred group.
4|DISCUSSION
The aim of this review was two-fold. The first aim was to review to
what degree impairments in areas of global intellectual functioning,
language development, social cognition, and EF have been studied in
children with SCT, and identify possible gaps in research that future
research should focus on. The second aim, was to establish clinical sig-
nificance of these impairments and identify risk-factors that should be
closely monitored from early development onwards or that should be
included in standard clinical neuropsychological screening to identify
potential targets for support and intervention.
With regard to the first aim, the reviewed studies collectively gave
the following results. On the domain of GIF, seven studies report out-
comes in children between the ages of 4 and 18 years, with three
studies focusing on children from the age of 4 years, and four studies
studying school-aged children. To our knowledge, there were no stud-
ies that examined GIF in children with SCT before the age of 4 years.
On the domain of language development, five studies reported out-
comes in children between the ages of 2 and 18 years. To our knowl-
edge, there were no studies that examined language development in
children with SCT before the age of 2 years. Of the seven studies,
two studies used only parent reports, the other three studies used
either a performance task or a combination of parent report and per-
formance tasks. On the domain of executive functioning, five studies
reported outcomes in children between the ages of 4 and 18 years.
To our knowledge, there are no studies to date that assess (precursors
of) EF in children with SCT before the age of 4 years. In addition, all
studies included children with XXY; two studies also included girls
with XXX, and one study also included boys with XYY. Finally, one
study used parent report, with the other four studies using
performance-based tasks or a combination of both. On the domain of
social cognition, six studies reported outcomes in children between
the ages of 4 and 18 years. To our knowledge, there are no studies to
date that assess (precursors of) social cognition in children with SCT
before the age of 4 years. In addition, until the age of 8 years, and in
XXX and XXY groups only, social cognition has not been tested with
performance-based measures, but has solely been assessed with par-
ent reports. To this date, no studies have reported child-data on social
cognition in boys with XYY. Taken together, although GIF and lan-
guage have received relatively much attention, there is a great need
for more studies in areas of EF and social cognition in children with
SCT. Also, research should rely more on performance-based measures
in addition to parent report. Finally, we stress the importance of fol-
lowing children over time. Longitudinal studies are needed to keep an
eye on the developmental trajectory, and could help determine which
difficulties in early life are predictive of outcomes in later life.
With regard to the second aim, the researched studies collectively
gave the following result. On the domain of global intellectual func-
tioning, from the age of 4 years there appears to be a general finding
that the GIF of children with SCT is variable, and ranges from impaired
to above average with mean GIF in the average to low-average range.
There might be to be some differences between the three karyotypes,
with XXX girls showing reductions in both VIQ and PIQ, XXY boys
showing reduced VIQ compared to PIQ, and XYY boys functioning
variably. On the domain of language development, it appears that lan-
guage difficulties can already be detected during the toddler-age, and
can be persistent throughout adolescence. Difficulties with language
development have not only been reported by parents, but have also
been observed during language assessments. All calculated effect
sizes indicated high clinical significance; stressing the need for early
detection and support programs on the domain of language. Especially
complex levels of language, such as semantics, syntax, and pragmatics
seem to be impaired. In addition, one study reported that older chil-
dren appear to experience more difficulties than younger children. It
is possible that children experience more (severe) difficulties, or that
problems become more apparent during a certain age because of dif-
ferent task demands. A possible explanation for this is the phenome-
non of growing into deficit; which occurs when age increases, while
the expected rate of progress stays behind, resulting in a growing def-
icit (as compared with typically developing peers), and a growing
impact on daily life.
33
The reported language difficulties appear to be
somewhat similar in girls with XXX and boys with XXY. Only one
study compared boys with XXY and XYY, with XYY boys experiencing
more difficulties in receptive vocabulary, but performing similarly with
XXY boys on other areas of language development. On the domain of
executive functioning, two studies indicated that parents of children
with SCT report more difficulties with executive functioning. For one
of these studies, we were able to calculate an effect size, which indi-
cated high clinical significance. The studies that used performance-
based tasks report somewhat variable outcomes, partially depending
on the included participant groups. All five studies included boys with
XXY and have reported poorer performance and/or more difficulties
when compared to controls, effect sizes were calculated for two of
these studies, with one study indicating high clinical significance on
the subdomain of sustained attention, inhibition, and mental flexibility,
whereas the other study, which included slightly older children, indi-
cated low to moderate clinical significance on these domains. Two
URBANUS ET AL.165
studies included girls with XXX (in combination with boys with XXY)
and reported poorer performance and/or more difficulties when com-
pared to controls on the subdomains of sustained attentional control,
inhibition, mental flexibility, and visual working memory, effect sizes
indicated low to moderate clinical significance. One study included
boys with XYY and reported more variability and longer reaction times
on tasks that measure sustained attention. Effect sizes indicated high
clinical significance. On the domain of social cognition, three studies
indicated that parents of children with SCT report more difficulties
with social cognition. Calculated effect sizes for all three studies indi-
cated high clinical significance. One study that used a performance-
based task reported difficulties in boys with XXY on the subdomain of
Theory of Mind; with effect size indicating high clinical significance.
Three of the studies that included boys with XXY reported difficulties
with facial emotion recognition, with effect sizes indicating high clini-
cal significance. One study included girls with XXX (in combination
with boys with XXY) and reported poorer performance on facial effect
identification, in particular when identifying angry faces. Calculated
effect sized indicates very high clinical significance.
In conclusion, from a developmental perspective it is important to
monitor neuropsychological functioning of children with SCT at the
start, or even before, the sensitive developmental period when these
skills typically develop, and identify precursors and early markers of
developmental risk. Considering the increased prevalence of (charac-
teristics of) behavioral and neurodevelopmental disorders, such as
ADHD, autism spectrum disorders, anxiety, and depression in the SCT
population,
14,34,35
more knowledge of developmental neurocognitive
risk markers could lead to more timely, preventive support, hopefully
reducing the risk for these behavioral and neurodevelopmental disor-
ders in the future. In addition, the results of this review call for more
studies on early neurocognitive vulnerabilities, which are expected
based on the impact of the extra chromosome on the development of
the brain.
36
It is important to learn more about the involvement of
genes on the sex chromosomes in order to identify how expression of
these genes can lead to the behavioral phenotype of individuals with
SCT and how different genes on different sex chromosomes can lead
to the similarities and differences in the behavioral profile of children
with XXX, XXY, and XYY. There is a specific need for more knowledge
in areas in EF and social cognition, not only because more extensive
research has shown these domains appear to be affected in
adulthood,
14
but also because these cognitive domains are crucial for
behavioral and socio-emotional development, adaptive functioning,
and quality of life. Also, the results of this review illustrate that more
attention should be given to timely screening for cognitive vulnerabil-
ities, that these should be monitored during relevant developmental
stages, and that interventions should be tailored to these risk profiles.
Finally, it is also important to gain more insight in the karyotype-
specific profiles of neurocognitive functioning, as the presence of an
extra X or Y may have similar ánd different effects on development of
brain areas involved in social cognition and language, and therefore
could have effect on neurocognitive development. This may help in
understanding expected neurodevelopmental profiles and related, tai-
lored, intervention options.
Recruitment strategy will always lead to variance in the SCT phe-
notype with overestimation of some difficulties (eg, because these dif-
ficulties led to genetic screening in postnatally diagnosed individuals),
whereas other difficulties may be underestimated (eg, because prena-
tally diagnosed individuals may have benefited from early preventive
support, such as speech therapy). For that reason, it is difficult to
assess the full spectrum of strengths and weaknesses in individuals
with SCT when using only one strategy. By including all studies
regardless of the used recruitment strategy, we have attempted to
balance bias, even though the described outcomes may not be fully
representative for the total population children with SCT.
To conclude, this review of studies shows that the presence of an
extra sex chromosome, may have impact on neurocognitive functioning
of children with SCT, and identified that domains of language develop-
ment, executive functioning, and social cognition should be closely
monitored in these children. In addition, it is important to gain more
insight in the early development of children with SCT population, espe-
cially before the age of 4 years on the domains of social cognition and
executive functioning. Finally, it is important that social cognition and
EF will be included in the standard screening and assessment methods,
as this review showed that social cognition and EF in addition to lan-
guage development, are domains that require close monitoring, and are
targets for early support and intervention programs. With more knowl-
edge about the development of young children with SCT, existing
evidence-based (preventive) intervention programs can be tailored to
the SCT profile in hopes of reducing these difficulties, and by reducing
these neurocognitive underpinnings of behavior, could possibly prevent
neurobehavioral problems in later life.
ACKNOWLEDGEMENTS
This work was supported by a personal grant (to SvR, grant number
016.165.397) from the Netherlands Organization for Scientific Research
(NWO).
CONFLICT OF INTEREST
None.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
ORCID
Evelien Urbanus https://orcid.org/0000-0002-4706-9086
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How to cite this article: Urbanus E, van Rijn S, Swaab H. A
review of neurocognitive functioning of children with sex
chromosome trisomies: Identifying targets for early
intervention. Clin Genet. 2020;97:156167. https://doi.org/
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URBANUS ET AL.167
... SCT is characterized by a mild physical phenotype shared across SCT variants, with minimal atypical facial characteristics, tall stature, and low muscle tone [3]. On social behavioral level, SCT is associated with increased risk for challenges in social adaptive functioning, including shyness, social immaturity, difficulties in forming interpersonal relationships, increased levels of social anxiety, social impulsivity, and impairments in underlying social-cognitive mechanisms (see for reviews: [4][5][6][7]). ...
... Even when the most conservative prevalence rate is considered and acknowledging some level of ascertainment bias in previous studies, there is consistent evidence that SCT is associated with a significantly elevated risk for ASD relative to population estimates. However, information on early developmental pathways in young children with SCT before the age of 6 years precursing these social impairments later in life is extremely limited, as shown by a review [7]. This is unfortunate, as early childhood is a period in which brain networks that biologically underpin social (cognitive) development rapidly mature and specialize [12]. ...
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The objective of the present study is to investigate the impact of Sex Chromosome Trisomy (SCT; XXX, XXY, XYY) on the early appearance of Autism Spectrum Disorder (ASD) symptoms, and the predictive value of Joint Attention for symptoms of ASD. SCTs are specific genetic conditions that may serve as naturalistic ‘at risk’ models of neurodevelopment, as they are associated with increased risk for neurobehavioral vulnerabilities. A group of 82 children with SCT (aged 1–8 years) was included at baseline of this longitudinal study. Joint Attention was measured at baseline with structured behavior observations according to the Early Social Communication Scales. ASD symptoms were assessed with the Modified Checklist for Autism in Toddlers questionnaire and Autism Diagnostic Interview-Revised in a 1-year follow-up. Recruitment and assessment took place in the Netherlands and in the United States. The results demonstrate that ASD symptoms were substantially higher in children with SCT compared to the general population, with 22% of our cohort at clinical risk for ASD, especially in the domain of social interaction and communication. Second, a predictive value of Joint Attention was found for ASD symptoms at 1-year follow-up. In this cohort, no differences were found between karyotype-subtypes. In conclusion, from a very early age, SCT can be associated with an increased risk for vulnerabilities in adaptive social functioning. These findings show a neurodevelopmental impact of the extra X or Y chromosome on social adaptive development associated with risk for ASD already from early childhood onward. These findings advocate for close monitoring and early (preventive) support, aimed to optimize social development of young children with SCT.
... Previous studies in children [6,7] showed that compared to controls, girls with TXS have significantly lower Full-Scale IQ (FSIQ), VIQ (verbal IQ), and PIQ (performance IQ) scores, measured using the Wechsler Intelligence Scale for Children -Revised (WISC-R) [8]. Among a group of adolescents and young adults with TXS (aged [11][12][13][14][15][16][17][18][19][20][21][22][23][24], FSIQ ranged from 53-112 and IQ scores were clustered in the 85-90 range, significantly lower than in siblings [9]. The range is similar to the range in the general population, but the TXS group is skewed to the left in comparison with the control group [1,9]. ...
... For example, maturation of the brain and brain plasticity may underlie the development of cognitive functioning during adulthood [18], and this development may be sex-specific [19]. In addition, maturation of the brain -and subsequent cognitive development -may also depend on extrinsic factors such as early intervention involving training of social functioning and/or additional support provided at school [20]. In TXS, cognitive functioning may be affected throughout the individual's lifespan, similar to findings in individuals with trisomy 21 [21]. ...
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Background: Triple X syndrome (TXS, also known as trisomy X or 47,XXX) has been associated with impaired overall neurocognitive functioning in children and relatively young adults. However, neurocognitive functioning in adults with TXS is poorly understood. The aim of this study was, therefore, to examine cognitive functioning in adults with TXS. Methods: In this cross-sectional study, data were collected from 34 adult women with TXS (mean age = 32.9; SD = 13.1) and 31 controls (mean age = 34.9; SD = 13.7). General intellectual functioning, semantic/verbal memory, visual/episodic memory, psychomotor speed, and attention and executive functioning were then compared between these two groups. Results: We found that general intellectual functioning was significantly lower in the TXS group compared to the control group. In addition, women with TXS had more attention problems and lower psychomotor speed, particularly motor processing speed. When the analyses were adjusted for IQ, the strength of these associations decreased. The women in the TXS group also scored significantly lower at free recall in the verbal memory test, but not in immediate or delayed recognition. Finally, visual/episodic memory and executive functioning did not differ significantly between groups. Conclusions: Our analysis revealed that women with TXS score lower in general intellectual functioning and have impairments in motor processing speed and attention compared to controls, but do not differ with respect to executive functioning. These results offer new insights for improving the support of adults with TXS both at school and in the workplace.
... These social processing skills are largely independent of other cognitive abilities, such as language, intelligence, and attention [29]. A recent review of the scarce literature on social cognitive abilities in children with SCT [39] suggests that (although these abilities are not yet fully matured) the development of social cognition, assessed by parent-report and performance-based tests, is already found to be affected from age 8 years and older. However, social cognitive functioning was not studied in younger age groups. ...
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Background About 1:650–1000 children are born with an extra X or Y chromosome (47,XXX; 47,XXY; 47,XYY), which results in a sex chromosome trisomy (SCT). This international cross-sectional study was designed to investigate gaze towards faces and affect recognition during early life of children with SCT, with the aim to find indicators for support and treatment. Methods A group of 101 children with SCT (aged 1–7 years old; Mage= 3.7 years) was included in this study, as well as a population-based sample of 98 children without SCT (Mage= 3.7). Eye gaze patterns to faces were measured using an eye tracking method that quantifies first fixations and fixation durations on eyes of static faces and fixation durations on eyes and faces in a dynamic paradigm (with two conditions: single face and multiple faces). Affect recognition was measured using the subtest Affect Recognition of the NEPSY-II neuropsychological test battery. Recruitment and assessment took place in the Netherlands and the USA. Results Eye tracking results reveal that children with SCT show lower proportion fixation duration on faces already from the age of 3 years, compared to children without SCT. Also, impairments in the clinical range for affect recognition were found (32.2% of the SCT group scored in the well below average range). Conclusions These results highlight the importance to further explore the development of social cognitive skills of children with SCT in a longitudinal design, the monitoring of affect recognition skills, and the implementation of (preventive) interventions aiming to support the development of attention to social important information and affect recognition.
Article
When it comes to neurodevelopmental differences, a genetic test result can provide compelling answers. However, it is not always clear what the relevant question is. If we want to understand the impact of a genetic diagnosis such as NGLY1 deficiency or the fragile X, trisomy X, or 22q11.2 deletion syndromes on people with neurodevelopmental differences, we must be mindful about what exactly a genetic test is supposed to tell us, where and for whom it matters, and which avenues for action it opens or forecloses. These are all moving targets. Specifically, I discuss the shifting ways a genetic test result can answer the following questions. What is this person's diagnosis? What symptoms and developmental differences are they likely to experience? What is the best way to approach their development, treatment, and care? Will they have a life worth living? When you unpack the sociological nuances of each question, the history behind them, and the uneven ways they are asked, the meanings of the answers change quite radically. I discuss the implications for social inequalities and urge experts and stakeholders to exercise agency when they interpret a genetic diagnosis.
Article
Children with sex chromosome aneuploidies (SCAs) are at an increased risk for neurocognitive and behavioral disorders that may interfere with academic success, including early developmental delays, learning disabilities, executive function problems, and social communication deficits. The present national survey aimed to update and extend our understanding of school supports and educational outcomes for students with these increasingly common genetic diagnoses. Parents of children with a diagnosed SCA, birth to 21 years, living in the United States (N = 248), responded to an electronic survey with questions focused on school support plans, academic accommodations, educational therapies, school completion, and perceptions of educator awareness of SCAs. Results revealed high rates of delayed kindergarten, grade retention in primary years, and educational support plans (IEPs = 71%; Section 504 Plans = 26%). A majority (73%) of respondents with children over age 18 years (N = 41) reported their children successfully completed high school, and nearly half (46%) pursued post-secondary education opportunities. Many parents reported their children's educators had little to no knowledge of SCA conditions, justifying a need to train teachers and policy makers in the unique educational needs of children and adolescents with SCAs. School psychologists should be aware of the frequent need for accommodations and individualized support plans in this population so they can support children and families by advocating for early and comprehensive evaluations and intervention plans.
Article
Sex chromosomal trisomies (SCT) are associated with impairments in executive functions in school-aged children, adolescents, and adults. However, knowledge on preschool development of executive functions is limited but greatly needed to guide early intervention. The current study examined emerging executive functions in young children with SCT. Participants were 72 SCT children and 70 population-based controls, aged 3-7 years, who completed a neurocognitive assessment of both global executive function (MEFS) and verbal executive function skills (NEPSY Word Generation). Caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF) questionnaire to capture real-world behavioral manifestations of impairments in executive functions. Results showed that impairments were significantly more prevalent in SCT than in controls and already present from 3 years, specifically verbal executive functions and working memory. Broader more pronounced impairments were found in older children with SCT. Age was significantly related to executive functions, but specific domains showed different relations with age. For example, deficits in planning and organizing remained evident with older age in SCT whereas it declined with age in controls. Impairments in executive functions were present across different levels of intelligence. Already at an early age, impairments across executive functions should be considered part of the neurodevelopmental profile of SCT, which appear more prominent at later age. Future studies should investigate developmental pathways of executive functions in SCT, given its relevance in cognitive, social, and emotional development. Executive functions should be screened and monitored in children with SCT and could be an important target of preventive intervention.
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Individuals with Sex Chromosome Trisomies (SCT; XXX, XXY, XYY) have an increased vulnerability for developing challenges in social adaptive functioning. The present study investigates social interaction behavior in the context of varying social load, and Autism Spectrum Disorder (ASD) symptomatology in young children aged 1–7.5 years old, with SCT (N = 105) and control children (N = 101). Children with SCT show less interaction behaviors and more social withdrawal, as compared to their control peers, which were most evident in the high social load condition. Second, social impairments related to ASD are more prevalent, as compared to controls (27.1% at clinical level). These findings stress the importance of early monitoring and (preventive) support of early social development in young children with SCT.
Article
Objective: To investigate pragmatic language abilities in young children with an increased risk for adverse neurobehavioral and neurocognitive outcomes due to an extra X or Y chromosome (sex chromosome trisomy; SCT) and to investigate to what degree early structural and pragmatic language abilities are predictive of neurobehavioral problems one year later. Method: In total, 72 children with SCT and 71 controls aged 3-7 years were included. Language assessments included parent-reported pragmatic language skills and direct assessment of structural language abilities. Parent-reported behavioral outcomes were measured one year after the initial language assessment. Results: Children with SCT demonstrated weaker pragmatic language skills compared to controls. These differences were not driven by karyotype, time of diagnosis, or ascertainment bias and irrespective of the presence of structural language impairment. Odds of having pragmatic difficulties was 23 times higher in the SCT group, with 25% of the children not meeting age-expectations. In addition, language, in particular pragmatic language, was an important predictor for later affective, oppositional defiant, pervasive developmental, attention deficit, and social-emotional problems in young children with SCT. Conclusions: This study is one of the first studies that directly illustrates the relationship between language and behavioral outcomes in children with SCT. Our results stress the importance to closely monitor pragmatic language in addition to structural language in clinical care of children with SCT, as pragmatic language abilities could serve as an early marker for children at risk for developing behavioral problems.
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Sex chromosome trisomies (SCTs) are characterized by an extra X‐ or Y‐chromosome (XXX, XXY, XYY). The present study aims to investigate early signs of social communication and social emotional development in very young children with SCT. Thirty‐four children with SCT (aged 12–24 months) were included in this study, as well as 31 age‐matched controls. Social communication was measured with structured behavior observations according to the Early Social Communication Scales, and social emotional developmental level with the Bayley Social Emotional parental questionnaire. Recruitment and assessment took place in the Netherlands and in the United States. On average, 12–24‐month old children with SCT showed difficulties with early social communication, more so in responding to others as compared to initiating social communications. During social interactions, children with SCT made less frequent eye contact, compared to controls. Also, difficulties in acquiring social emotional milestones were found in 1‐year old children with SCT, with 44% of the children having social emotional vulnerabilities in the borderline or extremely low range, compared to typically developing children. In this cohort, no significant predictive effects of karyotype‐subtype (XXX, XXY, XYY) were found. Already from a very early age, SCT can be associated with increased risk for vulnerabilities in adaptive social functioning. These findings suggest that SCT impact the maturation of the social brain already from an early age, and stress the importance of early monitoring and (preventive) support early social development in young children with SCT.
Article
Students with sex chromosome aneuploidies (SCAs) are at increased risk for learning disabilities and often require individualized supports in the school setting. Parents of students with rare disorders such as SCAs possess a unique understanding of their child’s educational experiences and play a crucial role in the development of successful school support plans. This international survey study aimed to inductively capture parent perspectives on educational needs and supports for students with SCAs. Parents of youth with SCAs ages 5‐21 years (n = 305) provided free‐text responses to open‐ended questions about their child’s education. Qualitative content analysis using a bioecological systems framework resulted in three overarching themes. Overall, parents identified multiple factors related to the SCA diagnosis that act as barriers to learning, a strong need for school‐based social and emotional supports, and elusive or incomplete educational support plans. Based on these findings, we recommend developing robust family‐school partnerships, increased collaboration between the school and the child’s medical team, and acknowledgement of the significant role the genetic condition plays in the educational experiences of students with SCAs. Specific suggestions for school support plans for students with SCAs are explored, such as providing school‐based behavioral health supports and explicit teaching of executive function strategies.
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Executive functions (EF) are thought to be impaired in Down syndrome (DS) and sex chromosome trisomy (Klinefelter and Trisomy X syndromes; +1X). However, the syndromic specificity and developmental trajectories associated with EF difficulties in these groups are poorly understood. The current investigation (a) compared everyday EF difficulties in youth with DS, +1X, and typical development (TD); and (b) examined relations between age and EF difficulties in these two groups and a TD control group cross-sectionally. Study 1 investigated the syndromic specificity of EF profiles on the Behavior Rating Inventory of Executive Function (BRIEF) in DS (n = 30), +1X (n = 30), and a TD group (n = 30), ages 5-18 years. Study 2 examined age effects on EF in the same cross-sectional sample of participants included in Study 1. Study 3 sought to replicate Study 2's findings for DS by examining age-EF relations in a large independent sample of youth with DS (n = 85) and TD (n = 43), ages 4-24 years. Study 1 found evidence for both unique and shared EF impairments for the DS and +1X groups. Most notably, youth with +1X had relatively uniform EF impairments on the BRIEF scales, while the DS group showed an uneven BRIEF profile with relative strengths and weaknesses. Studies 2 and 3 provided support for fairly similar age-EF relations in the DS and TD groups. In contrast, for the +1X group, findings were mixed; 6 BRIEF scales showed similar age-EF relations to the TD group and 2 showed greater EF difficulties at older ages for +1X. These findings will be discussed within the context of efforts to identify syndrome specific cognitive-behavioral profiles for youth with different genetic syndromes in order to inform basic science investigations into the etiology of EF difficulties in these groups and to develop treatment approaches that are tailored to the needs of these groups.
Article
Purpose of review: About one in 650-1000 children is born with an extra X or Y chromosome, referred to as sex chromosome trisomies (SCTs). Studying SCTs may uncover unique insights in neurodevelopmental pathways underlying the risk for neurobehavioral problems and psychopathology. There is also a clinical need for more knowledge about the phenotype of SCT with the recent introduction of noninvasive prenatal screening. Recent findings: The reviewed studies illustrate an increased vulnerability for psychopathology such as (symptoms of) autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, depression and, to a lesser degree, psychotic disorders. Although traditionally the primary focus has been on language and learning problems, recent research suggests that impairments in executive functioning, social cognition and emotion regulation may also be key factors underlying the risk for neurobehavioral problems. Summary: The research field of SCT is in need of a more longitudinal perspective to identify early markers of 'at risk' development, and to assess the effectiveness of early interventions. Neurocognitive markers that signal compromised neurodevelopment may prove to be helpful in this. Variability in the SCT phenotype provides a unique opportunity to identify not only genetic but also environmental factors that shape neurodevelopmental outcome, calling for studies focused on understanding individual differences.
Article
XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty-four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures.
Article
About 1 in 650 boys are born with an extra X chromosome (47,XXY or Klinefelter Syndrome). 47,XXY is associated with vulnerabilities in socio-emotional development. This study was designed to assess types of cognitive deficits in individuals with 47,XXY that may contribute to social-emotional dysfunction, and to evaluate the nature of such deficits at various levels: ranging from basic visuo-spatial processing deficits, impairments in face recognition, to emotion expression impairments. A total of 70 boys and men with 47,XXY, aged 8 to 60 years old, participated in the study. The subtests Feature Identification (FI), Face Recognition (FR) and Identification of Facial Emotions (IFE) of the Amsterdam Neuropsychological Tasks were used. Level of intellectual functioning was assessed with the WISC or WAIS. Reaction time data showed that in the 47,XXY group, 17 % had difficulties in visuo-spatial processing (no social load), 26 % had difficulties with face recognition (medium social load) and an even higher number of 33 % had difficulties with facial expressions of emotions (high social load). Information processing impairments increased as a function of 'social load' of the stimuli, independent of intellectual functioning. Taken together, our data suggest that on average individuals with XXY may have more difficulties in information processing when 'social load' increases, suggesting a specific difficulty in the higher-order labeling and interpretation of social cues, which cannot be explained by more basic visuo-spatial perceptual skills. Considering the increased risk for social cognitive impairments, routine assessment of social cognitive functioning as part of neuropsychological screening is warranted.
Article
Background: Children with sex chromosome trisomies [SCT] frequently show problems in language development. However, a clear description of the communicative patterns of these children is still lacking. Aims: The present study aimed to describe the first stages of language development in children with SCT in comparison with those in typically developing [TD] children. The purpose was to verify the existence of possible differences in communicative skills (in both vocal and gestural modality) and identify the presence of possible early predictors (i.e., low vocabulary size and low gesture production) of later language impairment in children with SCT. Methods & Procedures: Fifteen 24-month-old children with SCT (8 males with Klinefelter syndrome [KS] and 7 females with triple X syndrome [TX]) and 15 24-month-old TD children (8 males and 7 females) participated in the study. Their spontaneous communicative productions were assessed during a semi-structured play session in interaction with a parent. In addition, their vocabulary size was assessed using a parental report (the Italian version of the MacArthur Communicative Development Inventories). Outcomes & Results: With regards to their vocabulary size, 60% of children with SCT (75% of children with KS and 43% of children with TX) were at risk for language impairments (i.e., they had a vocabulary size lower than 50 words). In addition, TD children showed better lexical and syntactic skills than children with SCT in their spontaneous communicative productions. However, the production of communicative gestures was higher in children with SCT than in TD children. Boys with KS appeared to differ from TD males in more aspects of communication than girls with TX differed from TD females. Conclusions & Implications: The study showed the importance of early detection of language risk factors in children with SCT, while also considering the use of compensatory strategies (e.g., the use of communicative gestures).
Article
Objective: The purpose of this paper is to provide an overview of the 47, XXY syndrome, which is the most commonly occurring X and Y chromosomal variation. This paper seeks to review what is currently known of noninvasive prenatal testing (NIPT) and 47, XXY, and investigate potential risks and benefits of prenatal identification. Method: A literature review of NIPT and 47, XXY was performed to identify limitations of current NIPT techniques. Results: As NIPT becomes an increasingly more routine procedure, prenatal findings of 47, XXY may increase. Awareness of this disorder and appropriate genetic counseling is necessary. Conclusion: X and Y chromosomal variations will be identified through this screening, and the benefits and limitations to this finding need to be thoughtfully considered.
Article
The X chromosome has played a critical role in the development of sexually selected characteristics for over 300 million years, and during that time it has accumulated a disproportionate number of genes concerned with mental functions. There are relatively specific effects of X-linked genes on social cognition, language, emotional regulation, visuospatial, and numerical skills. Many human X-linked genes outside the X–Y pairing pseudoautosomal regions escape X-inactivation. Dosage differences in the expression of such genes (which constitute at least 15% of the total) are likely to play an important role in male–female neural differentiation, and in cognitive deficits and behavioral characteristics, particularly in the realm of social communication, that are associated with sex chromosome aneuploidies.
Article
Triple X syndrome (47, XXX) occurs in approximately 1:1,000 female births and has a variable phenotype of physical and psychological features. Prenatal diagnosis rates of 47, XXX are increasing due to non-invasive prenatal genetic testing. Previous studies suggest that prenatal diagnosed females have better neurodevelopmental outcomes. This cross-sectional study describes diagnosis, physical features, medical problems, and neurodevelopmental features in a large cohort of females with 47, XXX. Evaluation included review of medical and developmental history, physical exam, cognitive, and adaptive testing. Medical and developmental features were compared between the prenatal and postnatal diagnosis groups using rate calculations and Fisher's exact test. Cognitive and adaptive tests scores were compared using t-tests. Seventy-four females age 6 months–24 years (mean 8.3 years) participated. Forty-four (59.5%) females were in the prenatal diagnosis group. Mean age of postnatal diagnosis was 5.9 years; developmental delay was the most common indication for postnatal genetic testing. Common physical features included hypertelorism, epicanthal folds, clinodactyly, and hypotonia. Medical problems included dental disorders (44.4%), seizure disorders (16.2%), genitourinary malformations (12.2%). The prenatal diagnosis group had higher verbal (P < 0.001), general ability index (P = 0.004), and adaptive functioning scores (P < 0.001). Rates of ADHD (52.2% vs. 45.5%, P = 0.77) and learning disabilities (39.1% vs. 36.3%, P = 1.00) were similar between the two groups. These findings expand on the phenotypic features in females with Triple X syndrome and support that prenatally ascertained females have better cognitive and functional outcomes. However, prenatally diagnosed females are still at risk for neurodevelopmental disorders. Genetic counseling and treatment recommendations are summarized.
Article
Neuroimaging studies have shown that having an extra X chromosome is associated with abnormal structure and function of brain areas in the frontal lobe, which is crucially involved in executive functioning. However, there is little of knowledge of the type and severity of executive dysfunction, and the impact on emotional and behavioral problems. The present study aims to provide in this. In total, 40 children (23 boys with 47,XXY and 17 girls with 47,XXX) with an extra X chromosome and 100 non-clinical controls (47 boys and 53 girls) participated in the study. The participants were 9 to 18 years old. Processing speed and executive functioning were assessed using the Amsterdam Neuropsychological Testbattery (ANT) and the Dysexecutive Questionnaire (DEX). Problems in emotional and behavioral functioning were assessed with the Childhood Behavior Checklist (CBCL). Children with an extra X chromosome showed deficits in inhibition, mental flexibility, sustained attention and visual working memory. Parental report showed high levels of everyday manifestations of executive dysfunction. More severe inhibition difficulties were associated with higher levels of thought problems, aggression, and rule breaking behavior. Boys and girls with an extra X chromosome could not be differentiated based on severity of executive dysfunction, however girls had lower information processing speed than boys. These findings suggest that executive dysfunction may be part of the phenotype of children with an extra X chromosome, impacting the ability to function adequately in everyday life. Furthermore, children with impairments in inhibition may have more problems in regulating their thinking, emotions and behavior. This article is protected by copyright. All rights reserved.
Article
IntroductionThe male sex chromosome disorder 47,XYY syndrome (XYY) is associated with increased risk for social-emotional difficulties, attention deficit (ADHD), and autism spectrum disorders (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes.Methods We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression, and autistic behaviors (from questionnaires) in boys with XYY.ResultsThe XYY cohort had increased risk of ASD behaviors on the Social Responsiveness Scale (SRS) and increased attention deficits on the Conners’ DSM-IV Inattention and Hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY versus TD controls was increased two-fold in the XYY group. Results from the SRS Total and Autistic Mannerisms scales but not the attention, anxiety or depression measures correlated with peripheral expression of NLGN4Y in boys with XYY.Conclusions Males with XYY have social phenotypes that include increased risk for autism related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted.