Received: 25 February 2020 Revised: 2 May 2020 Accepted: 7 May 2020

DOI: 10.1002/ajmg.c.31801

RESEARCH REVIEW

Specific learning disorders in sex chromosome aneuploidies:

Neural circuits of literacy and mathematics

Iliana I. Karipidis | David S. Hong

Center for Interdisciplinary Brain Sciences

Research, Department of Psychiatry and
Behavioral Sciences, School of Medicine,
Stanford University, Stanford, California
Correspondence
Iliana I. Karipidis, Center for Interdisciplinary
Brain Sciences Research, Department of
Psychiatry and Behavioral Sciences, School of
Medicine, Stanford University, Stanford, CA.
Email: ilianak@stanford.edu
Funding information
U.S. National Institutes of Health
Abstract
Sex chromosome aneuploidies (SCA) are associated with an increased risk for specific
learning disorders (SLD). Individuals with Klinefelter Syndrome (KS) show an increased
incidence of developmental dyslexia and individuals with Turner Syndrome (TS) are
often affected by developmental dyscalculia. Accordingly, KS frequently coincides with
verbal deficits, and TS with visual–spatial impairments. Though neurocognitive profiles
of KS and TS are well‐established, little is known about the neurobiology underling
learning in SCA. This review summarizes current structural and functional magnetic res-
onance imaging (MRI) studies in KS and TS related to literacy and mathematical skills. It
includes studies that focus on correlates between brain anatomy and cognition in SCA
and on functional brain responses during learning‐related tasks and at rest. We highlight
important neural circuits that are related to domain‐specific skills of literacy and mathe-
matics. We discuss how identifying neuroendophenotypes of learning in SCA might
contribute to developing a novel framework for SLD that accounts for potential genetic
effects on learning, and from the X and Y chromosomes specifically. Future research
directions are considered to establish clear brain‐behavior relationships that might ulti-
mately improve the treatment of SLD in SCA across development.

KEYWORDS

brain MRI, Klinefelter syndrome, sex chromosomes, specific learning disorders, Turner
syndrome

1 | I N T RO DU CT I O N
Specific learning disorders (SLD) are commonly part of the
neurocognitive profile in sex chromosome aneuploidies (SCA)—condi-
tions characterized by an abnormal number of X or Y chromosomes.
The prevalence of reading disorders in Klinefelter syndrome (KS;
47XXY) has estimated rates of up to 75% (Geschwind, Boone, Miller,
& Swerdloff, 2000). In contrast, literacy development in Turner
syndrome (TS; 45X) is typically within the normative range with some
evidence even suggesting advantages in language‐specific skills
(Printzlau, Wolstencroft, & Skuse, 2017). Conversely, TS co‐occurs
with mathematical learning disorders in ~50% of all individuals
(Mazzocco & Hanich, 2010), while mathematical deficits are less fre-
quently observed as part of the cognitive profile in KS (Boada, Janusz,
Hutaff‐Lee, & Tartaglia, 2009). This apparent dosage effect relating the
number of sex chromosomes with the prevalence and type of specific
learning disorder, is putatively related to similar dosage‐dependent
patterns of structural and functional brain differences across SCA
(Hong & Reiss, 2014).
More broadly, SLD are neurodevelopmental disorders that lead
to unexpected difficulties in the skills of reading (dyslexia), writing
(dysgraphia), or arithmetic (dyscalculia), despite normal intellectual
abilities and adequate access to schooling. SLD are among the most
frequently diagnosed disorders in childhood and tend to run in fami-
lies (Shalev et al., 2001; Snowling, Gallagher, & Frith, 2003). Yet
the understanding of the genetic factors driving heritability in SLD
remains unclear. In the case of dyslexia, several candidate genes have
been proposed, but these findings are not well replicated and existing

Am J Med Genet. 2020;1–13. wileyonlinelibrary.com/journal/ajmgc © 2020 Wiley Periodicals, Inc. 1

2 KARIPIDIS AND HONG
animal models, mainly based on the neural migration hypothesis which
assumes a defect in neural migration to language‐related brain regions
during early stages of cortical development, have not been reliably
replicated (Guidi et al., 2018). Despite some early evidence for a dys-
lexia susceptibility gene on the X chromosome (DYX9; De Kovel
et al., 2004; Fisher et al., 2002), genome‐wide association studies in
this domain remain scarce, and of the more recent analyses that have
been completed, few have included the X chromosome (Gialluisi
et al., 2019), thereby omitting about 5% of the haploid human genome
(“Accounting for sex in the genome,” 2017). Given the disproportion-
ately high prevalence rates of SLD among individuals with SCA, these
conditions represent important models to provide a critical under-
standing of the genetic basis for learning‐related deficits and associ-
ated neural circuitry.
Here, we summarize current knowledge about cognitive pheno-
types of learning in SCA and review structural and functional magnetic
resonance imaging (MRI) studies in KS and TS that have investigated
the neurobiological mechanisms underlying neurocognition of learn-
ing. We focus on learning in the domains of literacy and mathematics,
given that difficulties in SLD primarily fall within these two domains.
We demonstrate how relating neurocognitive profiles of SCA to
brain function and structure will establish a potential neurobiological
framework parsing the influence of sex‐specific genes on learning.
Importantly, SLD are significant components of the SCA phenotype,
however, they are often underdiagnosed and undertreated, despite
their profound impact on individual outcomes and wellbeing. We dis-
cuss the challenges of existing neuroimaging studies in SCA and
emphasize the pressing need to examine learning and its underlying
neurobiological mechanisms in future research in SCA.
2 | NEUROCOGNITIVE PROFILES
Characteristic neurocognitive profiles have been identified and consis-
tently replicated in SCA (Printzlau et al., 2017). In particular, KS and TS
demonstrate similar cognitive impairments in the domains of executive
functions and social cognition but show distinct and opposing charac-
teristics in language‐related and visuospatial skills (Hong & Reiss, 2014).
The most common neurocognitive profile in KS is characterized by
language‐related deficits (Gravholt et al., 2018), and TS is typically
characterized by weaker nonverbal skills compared with verbal skills
(Mazzocco, 2006). While individuals with KS and TS both achieve full
scale IQ in the normative range, these scores are also generally 5–10
points below their typically developing siblings, likely driven by a sex
chromosome dosage effect affecting subcomponents of full scale
IQ. Specifically, an imbalance between performance IQ and verbal IQ,
generally demonstrates individuals with KS scoring higher in perfor-
mance IQ compared with verbal IQ and individuals with TS showing
the opposite pattern (Hong & Reiss, 2014; Savic, 2012).
The discrepancy between verbal IQ and performance IQ is pre-
sumably a result of language‐related skills and deficits that are already
emerging in SCA during the early stages of development. Five‐year‐
old school starters with TS have been shown to have enhanced
phonological and language skills (Temple & Shephard, 2012), while defi-
cits in lexical skills and syntactic abilities are already present in 18‐
month‐old children with KS (Zampini et al., 2018). The impact of lan-
guage and literacy deficits that are present in preschool children with KS
becomes more pronounced in later stages of development as academic
demands increase (St John et al., 2019). Similarly, visuospatial deficits in
TS emerge early in development, being already evident at the age of 6
years and persisting through adolescence (Baker, Klabunde, Jo, Green, &
Reiss, 2020). This suggests genetic vulnerabilities that influence
neurocognitive profiles of TS and KS to diverge from typical develop-
mental trajectories by early stages of development.
Notably, cognitive profiles of SCA largely overlap with known
neurocognitive characteristics of SLD. While weaker working memory
skills and reduced processing speed are common across all SLD
(Toffalini, Giofrè, & Cornoldi, 2017), dyslexia and dyscalculia also have
distinct and independent cognitive deficits (Landerl, Fussenegger,
Moll, & Willburger, 2009), with most prevailing accounts correlating
dyslexia to phonological deficits (Vellutino, Fletcher, Snowling, &
Scanlon, 2004) and dyscalculia to an impairment in number sense
(Wilson & Dehaene, 2007). In dyslexia, the three cognitive aspects of
phonology that are often affected include phonological awareness,
that is, the ability to recognize and manipulate sublexical elements
such as syllables; phonological working memory, that is, holding
speech‐based information; and lexical access, that is, accessing ortho-
graphic representations such as words (Landerl et al., 2009). Although
phonological deficits characterize dyslexia in many cases, isolated def-
icits in processing speed, naming speed, and language skills or a com-
bination of multiple deficits can also underlie difficulties in reading
(Pennington et al., 2012). In dyscalculia, the deficit in number sense
describes difficulties in the ability to recognize quantities and to
manipulate numerosities, that is, the number of elements in a set
(Landerl et al., 2009).
In relating the broader specific learning disorder literature to SCA,
certain consistent patterns emerge in neurocognitive profiles of dys-
lexia and dyscalculia that are commonly encountered in SCA. While
cognitive phenotypes in dyslexia and dyscalculia demonstrate a
degree of heterogeneity with regard to core deficits not always being
the same across all affected individuals, learning‐related cognitive pro-
files in SCA have been described as more homogenous, suggesting
that specific subtypes of dyslexia and dyscalculia could be more prev-
alent in SCA.
2.1 | Klinefelter syndrome
Language functions in individuals with KS are characterized by diffi-
culties in receptive and expressive language skills (Savic, 2012) which
broadly include phonemic processing, syntactic processing, semantic
memory, verbal fluency, and articulation (Bender, Linden, &
Robinson, 1993; Graham Jr., Bashir, Stark, Silbert, & Walzer, 1988;
Gravholt et al., 2018; Walzer, Bashir, & Silbert, 1990). While these
findings were typically in older cohorts, deficits in these core domains
supporting language development suggest a functional link to speech
KARIPIDIS AND HONG
impairments and dyslexia in earlier development. Similarly, phonemic
language deficits that interfere with processing spoken and written
language could be related to impairments of auditory processing in KS
(Geschwind & Dykens, 2004) that have been suggested to impact suc-
cessful reading, writing, and literacy (Rovet, Netley, Keenan, Bailey, &
Stewart, 1996). From an etiological standpoint, structural language
skills appear to follow a sex chromosome dosage pattern and decrease
with increasing numbers of sex chromosomes (Lee et al., 2012). Inter-
estingly, individuals with KS demonstrate phonological deficits with a
pattern of higher semantic than phonemic fluency skills that are not
present in other SCA, such as XYY, sex chromosome tetrasomies and
pentasomies (Udhnani et al., 2018), suggesting that sex chromosome
number selectively impacts phonological skills, while semantic lan-
guage processing might be related to genetic contributions from the X
and Y chromosomes specifically. Notably, there is significant inter-
individual variation within SCA and many individuals with KS do not
demonstrate language‐specific imbalance in their neurocognitive pro-
file (Boone et al., 2001; Ross et al., 2008), which requires further
understanding. Nevertheless, the consistency of these neurocognitive
findings paired with the high prevalence rates of developmental dys-
lexia relative to the general population, underscore the need for better
identification of individuals with KS who would benefit from earlier
educational support and language treatment. Considering that lan-
guage impairment increases the risk for reading disabilities (Peterson,
Pennington, Shriberg, & Boada, 2009), detecting receptive and expres-
sive language deficits during early speech development may hold par-
ticular promise for remediating impairments in phonological skills and
processing speed that are crucial for basic literacy acquisition.
2.2 | Turner syndrome
In TS, the increased prevalence of dyscalculia and mathematical
difficulties are characterized by deficits in the domains of counting,
calculation, cognitive estimations, and subitizing, that is, the ability
to quickly recognize small numbers of elements without counting
them (Bruandet, Molko, Cohen, & Dehaene, 2004; Murphy &
Mazzocco, 2008; Rovet, 1993). While simple symbolic number
processing is reportedly unaffected in TS, likely due to increased verbal
skills (Temple & Marriott, 1998), basic numerical cognition is impaired
presumably as a result of deficits in spatiotemporal and visuospatial
functions (Simon et al., 2008). It has been proposed that during arith-
metic processing, individuals with TS tend to rely more on verbal skills
than on visuospatial abilities (Rovet, Szekely, & Hockenberry, 1994) as
a compensatory mechanism for characteristic deficits in visuospatial
functions (Pennington, Bender, Puck, Salbenblatt, & Robinson, 1982;
Romans, Stefanatos, Roeltgen, Kushner, & Ross, 1998). A recent study
demonstrated that deficits in visuospatial processing are associated
with math performance in TS (Baker et al., 2020). A meta‐analysis
reported that reduced response time in TS also affects performance in
arithmetic tasks and discussed the possibility that impairments in
higher‐order cognitive processes might lead to deficits in mathematics
(Baker & Reiss, 2016).
3
2.3 | Shared cognitive characteristics across SCA
Impaired numerical magnitude processing in TS is at least partially
explained by underlying deficits in spatial working memory (Brankaer,
Ghesquière, De Wel, Swillen, & De Smedt, 2017) and short‐term
memory skills (Attout, Noel, Nassogne, & Rousselle, 2017). Deficits
in working memory and cognitive flexibility are also present in KS
(Bender et al., 1993; Fales et al., 2003; van Rijn & Swaab, 2015). In
addition, impaired attention and inhibition is common in both TS and
KS, as is the comorbidity with attention deficit hyperactivity disorder
(Green et al., 2015; Kompus et al., 2011; Ross et al., 2008; van Rijn &
Swaab, 2015). Thus, deficits in executive function seem to be charac-
teristic for both SCA and are less likely to be subject to sex chromo-
some dosage. On the other hand, domain‐specific deficits that affect
learning seem to correlate more clearly to sex chromosome number,
with sex chromosome monosomy, as in TS, being associated with defi-
cits in arithmetic and visuospatial cognition, and trisomy, as in KS, co‐
occurring with deficits in verbal skills and literacy. Anatomical and
functional MRI studies could provide insights to neural circuits of
learning in SCA and how they are related to the cognitive phenotypes
described above.
3 | NE U R O A N A T O M Y O F L E A R N I N G
Structural MRI studies comparing individuals with KS to euploid con-
trols have consistently shown decreased gray matter volume in the
temporal gyri, insula, and amygdala, while increased gray matter vol-
ume has been found in sensorimotor cortices, occipital areas, and pari-
etal areas (Bryant et al., 2011; DeLisi et al., 2005; Giedd et al., 2007;
Goddard, van Rijn, Rombouts, & Swaab, 2016; Lentini, Kasahara,
Arver, & Savic, 2013; Shen et al., 2004). On the other hand, comparing
individuals with TS to controls has repeatedly demonstrated gray mat-
ter volume reduction in occipital and parietal regions, and volumetric
increases in the superior temporal cortex (Green et al., 2014; Lepage
et al., 2013; Lepage, Mazaika, Hong, Raman, & Reiss, 2013; Marzelli,
Hoeft, Hong, & Reiss, 2011; Rae et al., 2004; Raznahan et al., 2010;
Xie et al., 2015; Zhao & Gong, 2017). A direct comparison of struc-
tural MRI data in TS and KS has corroborated that these GMV differ-
ences are subject to a sex chromosome gene dosage effect (Hong
et al., 2014).
Abnormalities in gray matter volume have been associated with
developmental delays (Gogtay & Thompson, 2010), which can be
either genetically determined or linked to environmental risk factors
(Beckwith et al., 2020). In neurodevelopmental disorders, the over-
growth of brain volume is not uncommon in early developmental
stages. In many cases, developmental delays are also reflected in later
stages of development, for example, in puberty, with either reduction
of gray matter volume in specific brain regions, or local increases in
gray matter volume that possibly result from protracted pruning and
compensatory brain maturation processes (Karolis et al., 2017). Gen-
erally, developmental deviations in terms of volumetric increases and
decreases observed across SCA are putatively related to the sex
4 KARIPIDIS AND HONG

chromosome dosage effect, though the biological mechanisms under-
lying this dosage‐dependent relationship still need to be investigated.
In addition, genetic factors have been found to be associated not
only with gray matter volume but also with cortical thickness (Winkler
et al., 2010). In this context, a higher count of sex chromosomes has
been shown to be associated with increased cortical thickness in the
prefrontal cortex and decreased cortical thickness in the lateral tem-
poral cortex (Xenophontos et al., 2019). Anatomical brain differences
and neurocognitive skills that follow the same sex chromosome
dosage effect are often assumed to be directly associated with each
other. Thus, aberrant neuroanatomy in SCA is often explained as a
cause of neurocognitive profiles of learning. Although many published
articles have made such assumptions, only a few have conducted ana-
lyses using structural neuroimaging data and learning‐related behav-
ioral data to test the hypothesis of this brain‐behavior relationship.
3.1 | Klinefelter syndrome
and hippocampal volume, and reading scores with hippocampal volume.
Itti et al. (2006) calculated brain‐behavior correlations across both KS
and control participants and found that ventricular volume correlated
negatively with verbal processing speed, verbal executive functions, and
nonverbal processing speed. In right‐handed KS participants and con-
trols, left temporal lobe volume correlated positively with language
scores and verbal processing speed (Figure 1a; Itti et al., 2006). Exclud-
ing left‐handed subjects from this analysis accounted for possible
lateralization effects that might be associated to the increased chance of
left‐handedness in KS (Ross et al., 2008). More recent studies have
failed to find any significant association between gray matter volume
and cognitive measures in both KS and control participants (Bryant
et al., 2011; Skakkebæk et al., 2014) indicating the need for further
studies to confirm structural neuroimaging findings of dyslexia in non‐
SCA populations, including consistently identified cortical volume differ-
ences in left‐hemispheric temporoparietal and inferior frontal regions
which are associated with verbal skills and other cognitive aspects of
literacy.

In KS, only a few structural MRI studies have examined the relationship
between brain structure and neurocognitive measures. Patwardhan,
Eliez, Bender, Linden, and Reiss (2000) studied the relationship between
gray matter volume in the left temporal cortex and verbal fluency
scores, which resulted in a positive trend in correlation. DeLisi
et al. (2005) reported significant brain‐behavior correlations only for
controls, with Stroop performance being correlated with frontal lobe
3.2 | Turner syndrome
In TS, several studies have failed to find a significant relationship
between measures of brain volume and neurocognitive measures,
including Full Scale and Performance IQ (Brown et al., 2002; Fryer,
Kwon, Eliez, & Reiss, 2003; Li et al., 2019) as well as visual–spatial skills

F I G U R E 1 Brain‐cognition correlations: (a) Klinefelter Syndrome (KS): Left temporal lobe volume correlated positively with language skills and
verbal processing speed in right‐handed participants with KS and controls (Itti et al., 2006). (b) Turner Syndrome (TS): Cortical thickness in the
right inferior parietal cortex (red) has been positively associated with performance IQ (PIQ; Lepage, Hong, et al., 2013). Higher full scale IQ (FSIQ)
and verbal IQ (VIQ) have been linked to increased cortical thickness in the right middle temporal gyrus (yellow). Lower FSIQ in TS has been
related to decreased cortical thickness in frontal areas, including the right middle frontal gyrus, the right superior dorsolateral frontal gyrus, and
the left rolandic operculum (blue; Xie et al., 2015).Total tissue volume in the right superior temporal gyrus (green) has been shown to negatively
correlate with VIQ (Kesler et al., 2003)
KARIPIDIS AND HONG
(Reiss, Mazzocco, Greenlaw, Freund, & Ross, 1995). Nevertheless, a
series of MRI studies have described the effects of IQ measures on brain
anatomy in TS (Figure 1b). Kesler et al. (2003) reported that STG total
tissue volumes were negatively correlated with full scale IQ, an effect
that seems to be driven by verbal IQ scores rather than performance
IQ. Negative correlation with Verbal IQ was significantly stronger for TS
than controls (Kesler et al., 2003). Given that STG volume was overall
increased in TS compared with controls (Kesler et al., 2003), the nega-
tive correlations likely reflect that participants with TS who had higher
cognitive abilities had smaller increases of STG volume and thus smaller
volumetric differences to controls. In a study that investigated the effect
of parent‐of origin in X‐chromosome monosomy on cortical thickness,
significant brain‐behavior correlations were only found for TS with an
X‐chromosome of paternal origin (Xp) (Lepage, Hong, et al., 2013). In Xp
TS, cortical thickness in the right inferior parietal cortex correlated posi-
tively with performance IQ, while cortical thickness in the right middle
temporal gyrus correlated positively with both verbal and performance
IQ (Lepage, Hong, et al., 2013). Xie et al. (2015) found significant brain
by group interactions for cortical thickness in frontal areas and scores in
full scale IQ and perceptual reasoning. In TS, higher scores in these cog-
nitive domains were associated with reduced cortical thickness. Addi-
tionally, lower cortical thickness in a wide network of frontal, parietal
and superior temporal regions was found to be related to higher work-
ing memory skills in TS but lower working memory skills in controls (Xie
et al., 2015). Hence, cognitive skills that are decisive for learning have
been shown to have divergent anatomical correlates in TS, mainly in
right‐hemispheric parietal and temporal regions.
3.3 | Neural basis of literacy and mathematics
Neuroimaging studies in the domains of literacy and mathematics
have delineated specialized neural circuits that develop during child-
hood in order to meet the cognitive demands associated with these
highly complex skills and show distinct structural and functional differ-
ences in children with dyslexia and dyscalculia. Core regions of the
neural network of literacy are comprised of: firstly, temporoparietal
areas, including perisylvian brain regions such as the STG, which
are essential for speech perception, secondly, the left ventral
occipitotemporal cortex that enables processing print, and thirdly, left
inferior frontal areas that support higher cognitive demands of liter-
acy, such as sublexical and semantic processing (Vandermosten,
Hoeft, & Norton, 2016). During literacy acquisition and with increas-
ing reading experience, this neural circuitry adapts as a result of devel-
oping higher phonological skills and to enable fast word recognition
based on the retrieval of associated phonological and semantic
content (Jacquemot, Pallier, LeBihan, Dehaene, & Dupoux, 2003;
Schlaggar & McCandliss, 2007). On the other hand, the coarse neural
network responsible for number processing consists of parietal areas
enabling magnitude representation, left perisylvian areas involved in
verbal number representation and ventral visual areas specialized for
visual number representation (Kucian & von Aster, 2015). This neural
circuit including the intraparietal sulcus (IPS) as a key region for
5
numerical processing forms the basis for calculation and arithmetic
skills (Butterworth & Walsh, 2011). This brain network undergoes
important developmental changes during childhood, mainly character-
ized by a gradual anterior to posterior shift from a stronger engage-
ment of frontal areas to a more dominant recruitment of the IPS to
allow for more automated number processing (Kaufmann, Kucian, &
von Aster, 2014).
3.4 | Summary
So far, structural MRI studies in TS and KS have consistently shown
dose‐dependent neuroanatomical phenotypes of SCA, but brain‐
behavior relationships of brain anatomy patterns and neurocognitive
profiles of learning remain less clear. There is a lack of studies that sys-
tematically investigate how brain structure is related to neurocognitive
characteristics of SLD in SCA, such as reduced phonological skills
and deficits in number sense. Early structural MRI studies mainly
included measures of gray matter volume, while more recent publica-
tions also report effects on cortical thickness. While cortical volume
encompasses both cortical thickness and area measures, a separate anal-
ysis can provide higher specificity in describing clinical phenotypes
(Rimol et al., 2012). Given that genetics seem to have distinct effects on
volume‐based and surface‐based structural brain measures (Winkler
et al., 2010), a more comprehensive analysis of structural MRI data may
uncover additional evidence on how SCA modulates specific brain‐
behavior associations.
At the same time, most neuroimaging studies in SCA do not suffi-
ciently account for developmental effects that are particularly crucial
for learning, making it difficult to map neuroimaging findings in SCA
onto the evidence base in SLD where the developmental context
in critical. Indeed, in many cases, participants with a wide age range
are included in study samples, making it difficult to account for effects
of cortical specialization that occur in early stages of learning and con-
trol for overall decreases of cortical volume and thickness that are
expected in the course of development from early childhood to adult-
hood (Tamnes et al., 2017). Nevertheless, a few correlations of
domain‐specific skills with cortical volume and thickness in SCA have
been found in brain regions that are related to cognitive mechanisms
of literacy and mathematics. For example, differences in the percep-
tual reasoning index between TS and controls were reflected in the
cortical thickness of the right middle fontal gyrus that is implicated in
numerical operations (Xie et al., 2015). In addition, the link between
verbal skills and cortical volume of the left temporal lobe in adults
with KS (Itti et al., 2006) is not surprising, given that the cognitive
phenotype of KS is to a large extent characterized by features associ-
ated with dyslexia, such as difficulties in word decoding (Bender
et al., 1993). Unfortunately, it has not been possible to reliably repli-
cate this brain‐behavior correlation (Bryant et al., 2011), at least
across age cohorts. The lack of a robust relationship between brain
structure and cognition calls for more functional studies to investigate
the link between cognitive and neurobiological phenotypes in SCA
(Skakkebæk et al., 2014).
6 KARIPIDIS AND HONG

4 | N E U R O F U N C T I O N A L U N D E RP I N N I N G S lateralization in adults with KS compared to controls (van Rijn

O F L E A RN I N G
Using functional MRI (fMRI), several studies have attempted to measure
brain activation that is related to specific domains of learning in SCA.
Task‐based fMRI studies identify brain circuits that are involved in par-
ticular cognitive processes, which can be systematically manipulated,
while resting‐state fMRI tracks spontaneous brain activation patterns at
rest which provides insight into how different regions of the brain are
networked together. Particularly measures of functional brain connectiv-
ity offer clues about whether neural responses in specific brain regions
are synchronized or not. These functional brain measures can provide
information about neural responses in brain regions of literacy and
mathematics and significantly complement structural MRI findings.
et al., 2008). In an adaptation of the Stroop task involving auditory
and visual processing of words, increased activation was found in the
primary motor cortex of men with KS during motor responses, while
no effects of Stroop adaptation were observed (Table 1; Wallentin
et al., 2016). In addition, when processing words, adults with KS
showed a higher response in auditory cortices than controls and lower
responses in the ventral occipitotemporal cortex, namely in the visual
word form area, a secondary visual region that is specialized in
processing print (Wallentin et al., 2016). This aberrant activation pat-
tern for processing words is in line with what we would expect in dys-
lexia and could reflect the effects of a developmental delay
characterized by reduced fast and automatic word processing in the
ventral occipitotemporal cortex and increased engagement of phono-
logical regions enabling more effortful word processing.

4.1 | Klinefelter syndrome

4.2 | Turner syndrome
Few fMRI studies have been conducted in individuals with KS, particu-
larly in the domains of language processing and executive functions. Studies on arithmetic processing in TS compared with controls have
An fMRI study on language processing showed reduced language shown reduced brain activation in the anterior cingulate cortex (ACC;

TABLE 1 fMRI studies in KS and TS related to literacy and mathematics

Coordinates
Study Task Contrast Region Hemisphere MNI (x, y, z)
Wallentin et al., 2016 Visual stroop condition with motor KS > CTR Primary motor Left −34 −22 62
response cortex
KS < CTR vOT Left −48 −68 −14
Auditory non‐stroop condition KS > CTR STG Right 62–12 −6
MTG Right 56 0–18
Molko et al., 2003 Arithmetic processing TS < CTR ACC/SFG Left −12 40 35
Kesler, Menon, & Reiss, 2006 Arithmetic processing (two‐operand TS > CTR ACC Left −7 −2 48
equations) PreCG Right 43–12 36
STG Left −48 −1 −13
Arithmetic processing (three‐operand TS < CTR SMG Left −45 −41 26
equations) ACC Left −6 38 6
MFG Right 45 34 34
IFG Right 43 9 37
Cuneus Right 6–76 17
Kesler, Sheau, Koovakkattu, & Arithmetic processing (two‐operand Training effect Parietal lobe Right 12–70 62
Reiss, 2011 two‐digit equations) TS post>pre
Kesler et al., 2004 Visuospatial processing (judgment of TS < CTR IPL Right 43–34 28
line task) IPL Right 36–40 34
Visuospatial processing (judgment of TS < CTR SFG Left −25 −4 45
line task—increased difficulty) ACC Right 2 24 40
TS > CTR PCC Right 2–34 30
mPFC 0 60–2
MTG Left −57 −18 −20

Abbreviations: ACC, anterior cingulate cortex; CTR, control group; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; KS, Klinefelter syndrome; MFG, middle
frontal gyrus; mPFC, medial prefrontal cortex; MTG, middle temporal gyrus; MTG, middle temporal gyrus.; PCC, posterior cingulate cortex; PreCG, precentral
gyrus; SFG, superior frontal gyrus; SMG, supramarginal gyrus; STG, superior temporal gyrus; TS, Turner Syndrome; vOT, ventral occipitotemporal cortex.
KARIPIDIS AND HONG
Molko et al., 2003) and increased recruitment of frontal and parietal
regions for easy calculations (Table 1; Kesler et al., 2006). Kesler
et al. (2011) showed that after a computerized intervention program,
which increased basic math skills, children with TS showed stronger
brain activation mainly in the right parietal lobe when solving chal-
lenging mathematical operations. Interestingly, activation in frontal
and parietal regions, including the right IPS, as well as in regions of the
limbic system, superior temporal, and middle temporal gyri decreases
in TS compared with controls as the difficulty of the arithmetic task
increases (Table 1; Kesler et al., 2006; Kesler et al., 2011; Molko
et al., 2003). While these reduced activation patterns may reflect the
lower performance of subjects with TS in difficult tasks, the increased
activation in frontal brain areas found in the control group for difficult
compared with easy operations is possibly associated with increased
cognitive demands (Kesler et al., 2006).
The judgment of line orientation task has been used to investigate
brain function in TS during visuospatial processing. Kesler et al. (2004)
found reduced activation for TS in right motor and sensory cortices,
right cingulate, and right IPL. With increasing task difficulty, TS
showed weaker activation also in frontal and occipital brain areas and
increased engagement of superior and middle temporal gyri, and the
dorsal striatum (Table 1; Kesler et al., 2004). In a more recent study,
these group differences were not replicated, possibly because a more
stringent statistical threshold was applied (Bray, Hoeft, Hong, &
Reiss, 2013). However, this study was able to show increased func-
tional connectivity from the bilateral supramarginal gyrus to lateral
occipitotemporal cortices and lingual gyri. Functional connectivity
from left posterior superior parietal lobule was increased to lingual
gyri, calcarine sulci, and STG in controls, and to middle frontal gyrus,
SMA, paracentral lobule, and right posterior superior parietal gyrus in
TS (Bray et al., 2013).
In addition, studies on working memory have repeatedly shown
that TS is characterized by reduced engagement of a frontoparietal net-
work of regions, including the IPS, (Bray, Dunkin, Hong, & Reiss, 2011;
Haberecht et al., 2001; Hart, Davenport, Hooper, & Belger, 2006) and
reduced functional connectivity from IPS to MFG (Bray et al., 2011).
Resting‐state functional connectivity analysis in TS showed reduced
whole‐brain functional connectivity strength bilaterally in the cuneus,
the IPS, the angular gyrus, and the right cerebellum (Xie et al., 2017).
Interestingly, functional connectivity strength within a frontoparietal
network during rest (incl. IPS, posterior superior/middle frontal gyrus)
was found to be correlated with math ability, highlighting that this func-
tional frontoparietal network might be associated with math‐related
deficits in TS, as is often the case in dyscalculia in non‐SCA populations
(Xie et al., 2017).
4.3 | Summary
Overall, functional brain activation during cognitive tasks reveals aber-
rant activation patterns that seem to be related to cognitive weak-
nesses and strengths in SCA. Participants with TS show differential
brain activation in frontal and parietal regions known to be involved in
7
arithmetic tasks and often implicated in dyscalculia. Evidence from
functional connectivity in TS suggests increased functional connectiv-
ity from the parietal lobe to superior temporal and occipital regions,
and decreased functional connectivity to the MFG. In KS, fMRI data
suggest reduced activation in auditory and visual brain areas, in line
with the prevalent language‐related impairments in dyslexia. How-
ever, fMRI studies including participants with both TS and KS are
needed to study neural brain mechanisms of learning across SCA to
more clearly delineate contributory effects related to sex chromosome
number.
5 | DI SCU SSION
Accumulating evidence from structural and functional brain imaging
studies suggests a brain‐behavior relationship between neuroimaging
measures and cognitive profiles of SCA. However, several effects are
not reliably replicated, and it still remains largely unclear how domain‐
specific learning skills are associated with distinct neuroendophenotypes
of SCA.
5.1 | Brain signatures of learning in SCA
When reviewing the current evidence in KS and TS, it becomes evi-
dent that a subset of phenotypic traits associated with SCA follow a
sex chromosome dosage effect. One of the most consistent findings
is the neuroanatomical differences in the temporal cortex (Hong &
Reiss, 2014) and in particular the reduced cortical volume in the STG
for KS (Bryant et al., 2011; DeLisi et al., 2005) and increased gray mat-
ter volume in TS (Marzelli et al., 2011). It is striking that verbal and
reading skills also follow this sex chromosome dosage effect, with a
high comorbidity of dyslexia in KS and elevated reading and decoding
skills in TS (Temple & Carney, 1996). To better understand the effect
of sex chromosomes on learning, further investigation to establish
clear brain‐behavior links is critically needed, for instance by investi-
gating whether the anatomical differences in the temporal cortex are
associated with the literacy skill variations encountered in SCA.
In addition, gray matter volume in the parietal lobe is higher with
increasing number of sex chromosomes, following a similar pattern to
mathematical skills (Hong & Reiss, 2014). However, neuroimaging stud-
ies so far have not been able to show a robust relationship between
neuroanatomical and cognitive phenotypes in SCA which would con-
firm the hypothesis that these two phenotype features are coupled.
Understanding the neurobiological mechanisms of how the number of
sex chromosomes influence learning skills would help us answer the
question of why SCA show differential vulnerability to SLD. Eventually,
this could enable targeting specific cognitive mechanisms of learning to
develop evidence‐based interventions for learning disorders in SCA.
The current clinical practice guidelines for TS recommend academic
accommodations and applications of empirically supported interven-
tions, using neuroscience research‐supported methods that target key
deficits of dyscalculia, such as numerical magnitude representations
8 KARIPIDIS AND HONG
(Gravholt et al., 2017). Analogous clinical practice guidelines with
evidence‐based recommendations and suggestions are also needed
for KS.
5.2 | Interdependence of neurodevelopment and
learning
Addressing the question of how neuroimaging findings in SCA are
related to their cognitive phenotypes could, therefore, improve the
treatment of SLD. When studying cognitive skills that depend on
development and schooling, an additional question arises whether
certain brain measures are a cause, or rather a consequence of these
skills. To address these questions more studies on early development
and longitudinal studies focusing on developmental trajectories of
brain structure and function in SCA are needed. Some neurobiological
differences that have been found to be dependent on sex chromo-
some dosage in schoolchildren and adults are likely to already be
present in earlier stages of development and therefore precede the
formation of the neurocognitive phenotypes of SCA. For example,
a recent study suggested that decreased gray matter volume in the
parieto‐occipital cortex is already present in 1‐year‐old children
with TS (Davenport et al., 2019). On the other hand, some neurobio-
logical differentiations will emerge in later developmental stages as a
consequence of neurocognitive characteristics and learning experi-
ences. Atypical developmental trajectories of the parietal cortex and
visual–spatial skills in TS (Green et al., 2014) suggest that develop-
mental effects might be able to contribute to the understanding of
neurocognitive profiles in SCA. Developmental trajectories are of par-
ticular interest when developing intervention tools for early child-
hood, given that remediation effects of these interventions have been
shown to be most effective in neurodevelopmental conditions.
Reading and mathematics are relatively new skills in human
evolution that rely on the ability of the human brain to reorganize
and specialize to the cognitive demands of these skills (Dehaene &
Cohen, 2007). Thus, brain‐behavior relationships in this domain are
often bidirectional, making it challenging to establish a simple cause‐
or‐consequence model. In the case of dyslexia, neuroanatomical dif-
ferences in the temporal gyri have been suggested to precede reading
acquisition (Vandermosten et al., 2016), but it has also been demon-
strated that functional differences for processing written language in
the ventral occipitotemporal cortex do not emerge until phonological
associations to written information are learned (Brem et al., 2010;
Pleisch et al., 2019). Studying neuroendophenotypes on learning in
SCA elucidates the impact of genetic variations on brain functioning
preceding formal schooling and on the cortical reorganization pro-
cesses that occur as a result of learning. Distinguishing between these
two effects, could clarify which neurobiological effects are genetically
driven and which are a result of environmental influences. This would
also help to discern risk factors, as well as protective factors that lead
to interindividual variability of cognition within SCA.
The developmental interplay between cognition and brain function
underlines the need for a clear distinction between findings of studies
with adults and with children diagnosed with SCA. For example, verbal
deficits might not be as prominent in adults with KS as they are in chil-
dren, as individuals with KS likely develop compensatory strategies over
the years (Ganou, Grouios, Koidou, & Alevriadou, 2010). Identifying
neurocognitive deficits that are specific to certain developmental stages
is particularly important to develop adaptive support for struggling
learners throughout their lifespan. Learning disorders can have profound
psychosocial consequences that subsequently lead to internalizing and
externalizing symptoms, such as anxiety or depression (Auerbach,
Gross‐Tsur, Manor, & Shalev, 2008; Mugnaini, Lassi, La Malfa, &
Albertini, 2009). Identifying learning difficulties early and treating them
while accounting for developmental factors could thus ameliorate other
symptoms of SCA in the domains of social and emotional development
(Gravholt et al., 2018). At the same time, learning impairments of adults
with SCA are also associated with severe functional impacts and should
therefore not be undervalued and merit further research. Unraveling
how sex chromosome dosage effects impact learning in different devel-
opmental stages will ideally lead to the development of more efficacious
therapeutic interventions.
5.3 | Accounting for comorbidities—Isolating
neuroendophenotypes of learning
SLD not only show alarming comorbidities with depression and anxiety
but sometimes also co‐occur with other neurodevelopmental disorders,
such as ADHD and autism, which are also common in the clinical pheno-
type of SCA. These comorbidities can present a challenge when
studying neurocognitive phenotypes of learning, because one cognitive
domain may be affected by the symptomatology of several disorders.
This is particularly important for SCA, considering that common deficits
across SCA, such as impairments in executive functions, likely influence
the neurocognitive profiles that are characterized by distinct learning‐
related strengths and vulnerabilities. Neuroimaging studies carefully
matching groups of controls and SCA, including TS(X0), KS(XXY), XXX,
XYY, will help disentangle the impact of distinct cognitive characteristics
on brain structure and function and will allow us to infer of how sex
chromosome variations interact with such neuroendophenotypes. In
addition, research in SCA has the potential to uncover shared genetic
heritability across neurodevelopmental disorders, similar to observed
genetic coheritability in psychiatric disorders, particularly in genes that
direct neurodevelopment (Schork et al., 2019).
Many children diagnosed with a specific learning disorder show
isolated deficits in the domains of reading, spelling, or arithmetic.
While combined deficits in reading and spelling are more common, a
combination of deficits in arithmetic and literacy skills has been esti-
mated to range from 20 to 50% (Moll, Kunze, Neuhoff, Bruder, &
Schulte‐Körne, 2014; Willcutt et al., 2019). It has been proposed that
SLD in the domains of arithmetic and literacy are etiologically linked
to unique genetic influences but also have shared underlying genetic
influences that possibly increase the risk for comorbidities (Willcutt
et al., 2019). This shared genetic foundation may be responsible for
the overlap of cognitive endophenotypes of certain subtypes of
KARIPIDIS AND HONG
dyslexia and dyscalculia. For instance, besides deficits in basic number
processing and visuospatial skills, children with dyscalculia often pre-
sent with deficits in phonological processing and working memory,
cognitive aspects that can also be part of the cognitive profile in dys-
lexia (Wilson & Dehaene, 2007). Systematically studying cognitive
profiles in SCA and how they are associated with brain structure and
function, will help elucidate why it is more common to observe com-
orbidities of multiple SLD in some karyotypes than in others. For
example, comorbid dyslexia and dyscalculia can both manifest in the
clinical phenotype of KS but has not been reported in the literature
for TS. Thus, broader evidence across SCA could help discern genetic
influences that make unique contributions to specific domains of
learning, including the associated neural circuits, and genetic influ-
ences with an impact on neurocognitive domains that are fundamen-
tal for both literacy and mathematics.
5.4 | Limitations of current evidence and future
directions
When focusing on genetic variations in SCA and their
neuroendophenotypes, several additional factors need to be consid-
ered. Mosaic variation is common in both TS and KS, and are excluded
in many studies, thus not accounting for all levels of sex chromosome
dosage in SCA. It is essential for future studies to account for mosai-
cism in SCA and also include other sex chromosome variations
that are typically underrepresented in the SCA literature on learning
(e.g., XXX, XYY). In addition, genetic risk factors that are not related to
SCA but based on familial history for learning disorders need to be
considered when studying learning in SCA. For instance, the cognitive
phenotype of KS is influenced by familial risk for SLD (Samango‐
Sprouse et al., 2014). From neuroimaging studies in SLD we know that
a family history of a disorder may also affect brain structure and func-
tion (Vandermosten et al., 2016). However, it remains unknown to
what extent the familial genetic risk described in SLD and genetic vari-
ations in SCA converge in explaining the variability of learning‐related
cognitive phenotypes. Demonstrating such a genetic overlap could
help update current frameworks of genetic mechanisms underlying
SLD, while also delineating distinct environmental factors.
Lastly, effects of hormonal changes on learning during development
also need to be taken into account. It has been argued that decreased
testosterone levels are not associated with cognitive deficits in KS, as
learning profiles are already present before the onset of puberty when
hormonal differences typically emerge (Savic, 2012). However, an MRI
study with a relatively small sample size reported increased verbal flu-
ency scores in men with KS that had received testosterone supplemen-
tation that was also associated with higher gray matter volume in the
left temporal lobe compared to men with KS that had not received tes-
tosterone supplementation (Patwardhan et al., 2000). Similarly, andro-
gen treatment over 4 years in girls with TS resulted in a small decrease
in incidence of dyscalculia (Ross et al., 2009). Interestingly, it has been
suggested that structural neuroimaging measures, such as GMV and dif-
fusion measures, are influenced by levels of gonadal hormones, while
9
measures of functional connectivity are more likely to be directly associ-
ated with genetic differences in SCA (Li et al., 2019), emphasizing the
need for better understanding of the role of sex steroids in learning
neurocircuitry.
Going forward, brain imaging studies will have to carefully match
groups for age, learning‐related skills, genetic and environmental risks,
and include participants with SCA, participants with SLD, participants
at familial risk and typically developing participants to further investi-
gate how cognitive profiles of learning which are subject to sex chro-
mosome dosage effects are related to the neurobiology of SCA. Of
note, studies focusing on the association between brain measures and
neurocognitive scores have mostly computed either total correlations
across groups or within‐group correlations, accounting for the exis-
tence of two or more distinct groups in the data. Future studies
should calculate both within‐group and between‐group correlations,
as reporting only one of these comparisons may miss important
insights (e.g., Simpson's paradox). In addition, longitudinal follow‐ups
of SCA cohorts are needed to provide insights of sex‐chromosome‐
dependent developmental trajectories. Disentangling neural mecha-
nisms that precede those that follow the behavioral difficulties in
learning will contribute to the understanding of SLD in childhood.
6 | CONC LU SIONS
SCA are associated with distinct neurocognitive profiles of learning
that are at least in part, consistent with a sex chromosome dosage
effect. Evidence from MRI studies suggests that certain brain circuits
are comparably influenced by the number of sex chromosomes. Indi-
viduals with KS and TS show aberrant brain anatomy and function in
key regions of literacy and mathematics respectively. However, it
remains to be further investigated whether findings of neuroimaging
studies can serve as neuroendophenotypes of learning. Future studies
focusing on the neurobiology of domain‐specific learning in SCA will
allow development of a brain‐behavior framework of SLD that com-
prehensively accounts for genetic and developmental factors.
CONFLIC T OF INT ER E ST
This research was funded by the U.S. National Institutes of Health.
The authors have no conflict of interest to declare.
OR CID
Iliana I. Karipidis https://orcid.org/0000-0002-4885-0309
David S. Hong https://orcid.org/0000-0001-9515-881X
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