Content uploaded by Joanne F Rovet
Author content
All content in this area was uploaded by Joanne F Rovet on Dec 10, 2014
Content may be subject to copyright.
Child Neuropsychology
2004, Vol. 10, No. 4, pp. 262–279
Turner Syndrome: A Review of Genetic and Hormonal
Influences on Neuropsychological Functioning
Joanne Rovet
Department of Pediatrics and Psychology, University of Toronto, Toronto, Ont., Canada
ABSTRACT
Turner syndrome (TS) is a gene tic disorder affecting mainly females that arises from a loss of X
chromosome material, most usually one of the two X chromosomes. TS is associated with a number of
characteristic physical features such as short stature and absent ovaries as well as a set of common
neuropsychological deficits and social and behavioral features. This paper will serve to review the cognitive,
social, and psychoeducational abilities of individuals with TS as well as neuroimaging findings. Several
putative genetic mechanisms contributing to their particular neurocognitive deficits will also be described
including candidate genes. In addition, the available evidence on how hormones affect specific abilities in TS
will be reviewed. It will be concluded that the TS neurobehavioral profile arises from an atypical cerebral
organization caused by the complex interplay of insufficient expression of certain (unknown) genes on the X
chromosome and by abnormal hormonal levels; however, it is still not clear exactly how the specific genes
affect broader cognitive abilities. Future research needs to identify the elemental processes that are disturbed
in TS and map these both to events in early brain development and subsequent brain function and to specific
gene and hormonal contributions.
Turner syndrome (TS) is a genetic disorder that
affects approximately 1/2500 females due to the
loss of some X chromosome material, most often
one of the two X chromosomes. TS is associated
with a number of characteristic physical features,
as well as a common set of neurocognitive
deficits, which include weak visuospatial skills
and poor math ability. Individuals with TS also
often display atypical social and behavioral
characteristics. Because both the genetic mech-
anisms contributing to their particular physical
and psychological features and the neuroana-
tomic manifestations of their neurocognitive
deficits can now be identified, this condition
offers a unique model for understanding complex
issues in brain development. Also, because sex
steroid hormone production is abnormal in TS,
this condition serves as a model to study the
impact of hormonal deviations on selective as-
pects of neurobehavioral functioning. The pres-
ent review will emphasize some of the factors
that influence variability in the TS population
and the different genetic and hormonal mecha-
nisms that contribute to their particular profile of
deficits. Examined will be their neuropsy-
chological characteristics in several of the major
functional domains, neuroanatomic findings, and
recent attempts at identifying the specific ge-
netic mechanisms influencing outcome in this
population.
Address correspondence to: Joanne Rovet, Ph.D., Brain and Behaviour Program, The Hospital for Sick Children,
555 University Avenue, Toronto, Ont., Canada M5G1X8. Tel.: þ1-416-813-8283. Fax: þ1-416-813-8839. E-mail:
joanne.rovet@sickkids.ca
Accepted for publication: July 11, 2003.
0929-7049/04/1004-262$16.00 # Taylor & Francis Ltd.
DOI: 10.1080/09297040490909297
BACKGROUND AND ETIOLOGY
The first TS report dates back to 1805, when
Dr. Charles Pears of England described a 29-
year-old female patient with short stature, ab-
sent secondary sexual characteristics and unusual
behavioral characteristics and he queried if these
were in any way linked (Pears, 1805). In 1930,
Ullrich from Germany described a group of
female patients who had a cluster of physical
abnormalities that included short stature, lack of
ovaries, and infantilism (Ullrich, 1930). Then in
1938, Dr. Henry Turner from Oklahoma, whose
name became eponymous with the syndrome,
reported on five women who presented with
sexual infantilism, short stature, an abnormality
of elbow formation, and webbing of the neck
(Turner, 1938). Later, Polani, Lessoff, and Bishop
(1956) suggested that TS might be caused by a
single X-chromosome complement since affect-
ed individuals showed an increased incidence of
color blindness and shortly thereafter, Ford,
Jones, and Polani (1959) proved this was the case.
As shown in Table 1, approximately 50% of
individuals with TS are missing an entire X
chromosome and among these individuals, 2/3
have a maternal X chromosome (designated as
X
m
) while the remaining 1/3 has only a paternal X
chromosome or X
p
(Jacobs et al., 1997). The
monosomy-X etiology occurs during the stage
of meiosis when the duplicate DNA strands divide
and separate providing each ovum or sperm with a
single set of chromosomal strands. TS arises when
one strand from an X chromosome becomes lost
such that on fertilization, the resulting embryo has
the normal complement of 22 autosome pairs, but
only one X chromosome. This chromosome can
come from either the mother or father depending
on whose gonad contained the normal egg or
sperm. Recently, reasons as to why the paternal
sex chromosome is twice as likely to become
lost (e.g., alcoholism) have been investigated
(Kagan-Krieger, Selby, Vohra, & Koren, 2002).
Although the 45,X condition is mainly seen in
females, there are very rare instances of males
with this karyotype. These individuals have lost
all of the paternal Y except for the small testis-
determining region of the Y chromosome contain-
ing the SRY gene (Lahn & Page, 1999), which was
translocated to an autosome (e.g., Da
´
valos et al.,
2002) and so was sufficient for male differentia-
tion during embryogenesis. Like females, these
boys are infertile and have a similar set of physical
features as that seen in females with TS.
Among the remaining 50% of individuals with
TS, most (30% of the TS population) present with
a mosaic karyotype, the most common of which
contains both a normal 46,XX and an abnormal
45,X cell line. Mosaicism occurs after fertiliza-
tion has taken place, typically during an early
stage of mitotic cell division. At this time, the
dividing cell loses an X chromosome and passes
on this single X complement to all future cells in
the same cell line. Other mosaic combinations
include combinations of three cell lines (one
normal and two abnormal) as well as cell
lines involving a 47,XXX karyotype (Ferna
´
ndez,
Me
´
ndez, & Pa
´
saro, 1996). In a small proportion of
Table 1. Characterization of Turner Syndrome Etiologies.
Karyotype Frequency (%) Description
Monosomy X 45,X 45–50 2/3 maternally derived; occurs during
meiosis
Mosaicism 45,X/46,XX or
45,X/46,XY
30 Occurs early in mitotic cell division;
almost all are female
Isochromosome 46,isoX
m
or 46,isoX
p
10 Occurs during anaphase when
chromosome strand divides in
transverse direction, not axially
Deletions, rearrangements,
and translocations
10 Abnormality during meiotic division
Ring X 2–5 Loss of centromere causing
ring to form
TURNER SYNDROME 263
cases, mosaicism can also involve a normal male
chromosome complement (XY) and a missing X,
referred to as 45,X/46,XY, and it is seen mostly in
females. In these females, the 45,X cell line was
probably expressed during the stage of sexual
differentiation, whereas in males with this karyo-
type, it was the 46,XY cell line that was expressed
during sexual differentiation.
The remaining 20% of individuals with TS
include those with an ‘‘isochromosome’’, a ring
chromosome, or a deleted, rearranged, or translo-
cated region of one of the two X chromosomes.
An isochromosome, which contains two long or
two short arms (as opposed to one long and one
short arm), occurs during the anaphase lag stage
of meiosis and results when instead of a chromo-
some dividing in a transverse direction, it divides
axially so as to contribute two short arms or two
long arms. A ring-X chromosome occurs when
the centromere region of the X is missing result-
ing in a ring formation (Abd et al., 1997; Migeon
et al., 2000). Deletions, rearrangements, and
translocations represent abnormalities of meiotic
division.
PHYSICAL PHENOTYPE
The TS physical phenotype is characterized by
abnormalities in three basic systems: the skeletal,
the lymphatic, and the reproductive systems.
Skeletal defects include short stature, cubitus
valgus or an unusual carrying angle of the elbows
and arms (see Fig. 1), as well as a short 4th-digit
Fig. 1. Cases with Turner syndrome. Variation in presentation. Photographs provided by courtesy of Judy Ross.
Permission granted for all cases.
264 JOANNE ROVET
metacarpal, micrognathia, and a high arched
palate. Until recently, females with TS were
typically more than 2 standard deviations below
peers in height and would achieve a final height of
about 4
0
–7
00
. However, since the advent of growth
hormone therapy, as well as other hormones to
augment growth, they now achieve heights within
the bottom end of the normal range. The high
arched palate, can give rise to initial feeding
difficulties and later articulation problems. Be-
cause their facial abnormalities can cause an
abnormal orientation of the ear canal, children
with TS are at high risk of ear infections
(Stenberg, Nyle
´
n, Windh, & Hultcrantz, 1998).
The lymphatic system defect occurs from
abnormal lymphatic clearance and this can give
rise to a brain hygroma in utero. While permanent
neck webbing can result after the hygroma
recedes, in many cases the hygroma is so severe
as to cause fetal demise. Many neonates present
with severe edema, which is often the reason for
the diagnosis of TS.
Regarding reproductive-system defects, most
females with TS have ovarian dysgenesis due to
streak ovaries containing no ova. As a result, they
lack endogenous estrogen and have reduced
androgen production (Gravholt, Svenstrup,
Bennett, & Christiansen, 1999). Unless they
receive hormonal replacement therapy during
adolescence, they remain sexually infantile
throughout life. Although the majority of females
with TS are infertile, a few individuals do spon-
taneously produce estrogen and undergo nor-
mal pubertal development (Pasquino, Passeri,
Pucarelli, Segni, & Municchi, 1997). There are
also a handful of women with karyotypes other
than 45,X who have successfully reproduced. In
addition, individuals with TS are at risk for
cardiac abnormalities due to coarctation of the
aorta and renal abnormalities from horseshoe
kidneys. Most have multiple pigmented nevi and
nail dysplasia.
Despite the consistency of these physical fea-
tures, there is wide variability among affected
individuals and few if any have every abnormal-
ity. Generally, a more severe presentation is
associated with a complete loss of a single X
chromosome or the ring X condition while the
least severe presentation is associated with a
mosaic karyotype involving a normal 46XX cell
line. Deletions, rearrangements, or translocations
of the X chromosome represent intermediary
conditions. The treatment of TS entails biosyn-
thetic recombinant human growth hormone to
increase height, estrogen to initiate puberty and
maintain normal female functioning, and andro-
gens to advance linear bone growth.
THE TS PSYCHOLOGICAL PHENOTYPE
Intelligence and Cognitive Functioning
An intellectual deficit in TS was first reported
more than 50 years ago (Haddad & Wilkins,
1959) while subsequently it was acknowledged
that their lower IQs reflected a significant
reduction in Performance IQ, whereas Verbal IQ
was normally distributed (Garron, 1977; Money
& Alexander, 1966; Schaffer, 1962). Accordingly,
Money coined the term ‘‘space-form blindness’’
to describe their particular pattern of difficulty
and to this day, their visuospatial problems re-
present their cardinal cognitive deficit (Money,
1963). However, selective deficits in attention,
memory, and executive processing are also seen.
Although their verbal abilities are for the most
part spared, individuals with TS may show re-
duced fluency, poor articulation, and difficulty
processing syntactic structures (Inozemtseva,
Mtute, Zarabozo, & Ramirez-Duenas, 2002;
Temple, 2002). A large number of individuals
with TS demonstrate excellent musical aptitude.
On testing with the Wechsler scales, individ-
uals with TS display subnormal Full Scale IQs
with Performance IQs 12–15 points below Verbal
IQ (Rovet, 1990). They typically score below
population norms on Arithmetic, Digit Span,
Picture Completion, Coding, and Object Assem-
bly subtests (McGlone, 1985; Ross, Roeltgen, &
Cutler, 1995; Silbert, Wolff, & Lilienthal, 1977).
There are inconsistencies in the literature as to
Block Design (Lahood & Bacon, 1985; Waber,
1979) with most researchers claiming perfor-
mance on this task to be weak (e.g., Rovet, 1990).
Results from visuospatial processing testing
(see Table 2) reveal the TS group attains signifi-
cantly lower scores than controls on measures of
visual construction (Murphy et al., 1994), design
TURNER SYNDROME 265
copying (Waber, 1979), directional sense
(Alexander, Walker, & Money, 1964), extraperso-
nal space perception (Alexander & Money, 1966),
mazes (Nielsen, Nyborg, & Dahl, 1977), mental
rotation (Berch & Kirkendall, 1986; Rovet &
Netley, 1982), part-whole perception (Silbert
et al., 1977), rod and frame (Nyborg, 1990),
spatial and visual reasoning (Money &
Alexander, 1966; Murphy et al., 1994), visual
discrimination (Silbert et al., 1977), visual imag-
ery (Downey et al., 1991), visual memory
(Murphy et al., 1994; Ross et al., 1995), visual
sequencing (Robinson et al., 1986) and visual-
motor integration (Lewandowski, Costenbader, &
Richman, 1985). Ross (1996) reported they had
greater difficulty in determining how things went
together and with spatial location and orientation
than with identifying objects.
In addition to visuospatial problems, girls with
TS also exhibit motor clumsiness and problems
with selective aspects of attention, executive
function, and memory deficits (Cornoldi,
Marconi, & Vecchi, 2001; Romans, Roeltgen,
Kushner, & Ross, 1997; Ross et al., 1995;
Temple, Carney, & Mullarkey, 1996; Williams,
Richman, & Yarbrough, 1991). Attention test
findings reveal difficulties with inhibitory control
but not sustaining or focusing attention (Romans
et al., 1997; Ross, Zinn, & McCauley, 2000) while
executive function testing indicates difficulties
with distraction, planning, and fluent production
but not set shifting (Romans et al., 1997; Temple
et al., 1996). Regarding memory, problems
include difficulties with short-term recall as well
as poor visual working memory (Buchanan,
Pavlovic, & Rovet, 1998). In a study attempting
to identify the most strongly affected of the
neuropsychological abilities, Ross, Kushner, and
Zinn (1997) used discriminant function analysis
(DFA) and showed that weaknesses in auditory
attention, visual discrimination and perception,
abstract figure drawing, and word reading most
strongly differentiated individuals with TS from
controls.
Hepworth and Rovet (2001) reported that the
defect underlying poor visuospatial processing in
TS seemed to be more general than previously
thought. The findings from a single child showed
a primary deficit in ‘‘global’’ or configural pro-
cessing but intact ‘‘local’’ or featural processing
ability. For example, while the child could copy
the Rey figure (albeit poorly), she lost the figure’s
configuration totally in both the immediate and
the delayed recall conditions. Even more striking
was the observation that her global deficit
extended to other aspects of cognitive function-
ing, including her language, which was primarily
feature-based and lacked any gestalt or integrative
quality. For example, when shown a playground
scene, she described all of the individual items in
the picture but could not relay what the picture
was about.
Recent studies of women with Turner syn-
drome have also focused on their face processing
Table 2. Neurocognitive Deficits in Turner Syndrome.
Domain Affected areas Not affected areas
Spatial ability Block construction, puzzle assembly,
mazes, directional sense, mental rotation
Visualization Part-whole perception, rod and frame, visual
discrimination, visual imagery
Visuomotor Design copying, visual sequencing, visuomotor
integration
Memory Visual memory, short-term recall, working
memory
Verbal memory, rote memory
Attention Inhibitory control, auditory attention Sustained attention, focusing
Executive function Planning, fluent production Shifting set
Language Verbal fluency, articulation, complex syntactic
knowledge
Word knowledge, expressive
abilities, pragmatics, receptive
abilities
266 JOANNE ROVET
capabilities. Elgar and colleagues, for example,
reported that persons with TS performed more
poorly than controls on tasks of face recognition,
emotion processing, and familiar face recognition
(Elgar, Campbell, & Skuse, 2002; Elgar, Kuntsi,
Coleman, Campbell, & Skuse, 2003). Unlike non-
TS females, who typically find it harder to recog-
nize inverted than upright faces, women with TS
found both formats equally difficult. This finding
suggests they may have been processing the
individual facial features, not the configurations.
Furthermore, these women also exhibited greater
than normal difficulty processing anger and fear
as well as understanding the gaze of others,
especially ascribing social intention to gaze
(Elgar et al., 2002).
Most of the observations seen in children with
TS have been found to persist into adulthood
(Downey et al., 1991; Ross et al., 2002), par-
ticularly their visuospatial and visual memory
deficits. However, some abilities do show im-
provements with age (Romans, Stefanatos,
Roeltgen, Kushner, & Ross, 1998). For example,
weaknesses in perceptual judgment seem to catch
up in late adolescence, signifying a developmen-
tal lag in this ability. Motor planning skills also
appear to improve from childhood in adults with
TS (Romans et al., 1998).
Psychoeducational Abilities
and Vocational Status
On tests of academic achievement, individuals
with TS demonstrate considerable difficulty with
arithmetic (Schaffer, 1962) but perform at par for
age in terms of their reading and spelling and they
are often described as avid readers. They typically
score several grades below current grade level
in arithmetic and show difficulty in most aspects
of arithmetic processing. Analyses of their math
errors suggested problems in fact learning as well
as selective operational/procedural difficulties
(Rovet, Szekely, & Hockenberry, 1994; Temple
& Marriott, 1998). They also made more align-
ment errors than controls (Mazzocco, 1998).
At school, many ‘‘individuals with TS’’ are
identified as having a non-verbal learning dis-
ability (Rovet, 1995) and have increased need
for special education (Rovet, 1993). A substantial
proportion also experiences grade retention. The
majority of individuals with TS hold clerical or
semi-professional positions (i.e., teaching, nur-
sing, early childhood education) and they tend
to be over-represented in child-care positions.
Fewer than 5% achieve higher professions,
although a few individuals with TS hold graduate
degrees and have become physicians or lawyers.
There is a high incidence of dependence with
many living at home with parents as adults (Ross,
Zinn, & McCauley, 2000) while issues with au-
tonomy are also reported (Kagan-Krieger, 1998).
Psychosocial and Behavioral
Characteristics
Psychosocially, females with TS show a definite
female gender identity, assume a typical female
gender role (Pavlidis, McCauley, & Sybert, 1993),
and reportedly display exaggerated female play
behavior. The one boy with TS I have seen has a
definite male gender identity and is typically
boyish in his behavior (Rovet, unpublished data).
Social immaturity is often described in individ-
uals with TS and their social relations are often
difficult, particularly during adolescence when
they are maturationally ‘‘out of synch’’ with their
peers (McCauley, Feuillan, Kushner, & Ross,
2001; McCauley, Kay, Ito, & Treder, 1987).
The majority have few friends (McCauley et al.,
1987) and they often experience significant
teasing and sometimes bullying. As adults,
difficulties with relationships and coping with
TS are commonly reported (Kagan-Krieger,
1998). Due to their particular set of physical
stigmata, they generally have a poor body image
and low self esteem (McCauley, Sybert, &
Ehrhardt, 1986).
In childhood, a significant proportion tends to
be hyperactive (Mazzocco, Baumgardner, Freund,
& Reiss, 1998; McCauley, Ito, & Kay, 1986;
Rovet & Ireland, 1994) while up to 10% have
ADHD at adolescence (McCauley et al., 2001).
However, many others are extremely inhibited
and shy, especially in adolescence, which is a
particularly unhappy time for teenagers with TS
(Mambelli, Perulli, Casella, et al., 1995). Although
anxiety is commonly described, a recent study of
girls and adolescents with TS failed to show
differences from controls on standardized ques-
tionnaires or observed hand and face movements
TURNER SYNDROME 267
other than fewer facial movements (Lesniak-
Karpiak, Mazzocco, & Ross, 2003). Difficulties
with social cognition are frequently seen, partic-
ularly as they often fail to respect interpersonal
boundaries and property, intrude on the physical
space of others, and have difficulty with face
processing (Elgar et al., 2002; McCauley et al.,
1987).
NEUROANATOMIC
AND NEUROIMAGING FINDINGS
In early studies, EEG abnormalities were fre-
quently reported although there was no consistency
as to wave-form abnormality, severity, locus, or
extent of localization (Palm, Pfeiffer, Ammermann,
& Schulte, 1973; Poenaru, Stanesco, Poenaru, &
Stoian, 1970; Tsuboi & Nielsen, 1976). Palm et al.
(1973) reported an over-representation of low
amplitude and a diffuse beta and alpha–beta
mixture while Tsuboi and Nielsen (1976) found
EEG abnormalities in 60% of cases reflecting
increased beta waves, diffuse abnormalities, or
frontal dominant abnormalities. Epilepsy is rarely
seen rare this population.
Autopsy studies revealed different develop-
mental abnormalities ranging from a migration
defect to localized changes in the posterior right
hemisphere, to the absence of abnormality (Brun
& Skold, 1968; Reske-Nielsen, Christensen, &
Nielsen, 1982). Early studies using lateralization
techniques showed that TS individuals had atypi-
cal hemispheric specialization. For example,
Netley and Rovet (1982) reported the TS group
was less likely than controls to process verbal
information in the left hemisphere and more
likely to engage their left hemispheres in the
processing of music and visual information than
controls.
Studies using event-related potentials have
found that females with TS show functional
differences in brain organization. For example,
Schucard, Schucard, Clopper, and Schachter
(1992) reported a deficit in the ability to use
right hemisphere resources for non-verbal skills.
Johnson (1995) similarly found significantly
delayed event-related potential latencies during
visuospatial processing tasks suggesting that
females with TS may be using different strategies
and neural resources to process this kind of
information.
A recent MRI report of a woman with a 45,X/
47,XXX karyotype who had seizures and mental
retardation indicated bilateral brain dysgenesis
including an asymmetric irregularity in the gyral
pattern with uneven thickness of the cortex and
absence of gyri in the left frontal lobe (Tereo,
Hashimoto, Nukina, Mannen, & Shinohara, 1996).
Table 3 summarizes the findings from three
volumetric MRI studies and from two PET studies
on adults (Murphy et al., 1993) and children with
TS (Brown et al., 2002; Reiss, Eliez, Schmitt,
Patwardhan, & Haberecht, 2000; Reiss et al.,
1993). In comparison to age-matched female con-
trols, patients with TS show smaller sized poster-
ior cortical structures (occipital or parietal) as
well as reduced caudate, thalamic, and hippocam-
pal volumes (Murphy et al., 1993). Larger vol-
umes were seen in the medial temporal lobes
(Reiss, Mazzocco, Greenlaw, Freund, & Ross,
1995) as well as cerebellar gray matter (Brown
et al., 2002) and amygdala (not shown in Table 3,
reported in Elgar et al., 2003). The study by Reiss
et al. (1993), which compared brain volumes in a
set of 10-year-old twins discordant for TS,
showed the child with TS had smaller occipital,
parietal, and frontal volumes as well as increased
sulcal widths and increased CSF volumes com-
pared to her unaffected co-twin. The two PET
studies on women with TS reported reduced
posterior activation during rest (Clarke, Klonoff,
& Hayden, 1990) as well as decreased activation
in the insula, superior temporal cortex, left infe-
rior frontal lobe (Murphy et al., 1997).
Two studies have used fMRI to understand the
neural correlates of information processing in in-
dividuals with TS. In the first, Haber Echt et al.
(2001) compared 12 children with Turner syn-
drome to normal controls on a spatial ‘‘n-back’’
task in which they had to determine whether the
position of an object on the screen matched that of
the one immediately preceding it (the 1-back
condition) or two back from it with one stimulus
intervening (the 2-back condition). Compared to
controls, the group with TS showed increased
activation in bilateral parietal regions (suggesting
more effort) in the 1-back condition while in the
268 JOANNE ROVET
Table 3. Neuroimaging Findings in TS.
Study N Age Occ Pariet Temp Front Caud Lent Insula Thal Put Amygd Hipp Cereb
Volumetric MRI
Murphy et al. (1993) 18 30 TS < CTS¼ CTS¼ CTS¼ CTS< CTS< CTS< CTS¼ CTS< CTSC
Reiss et al. (1993) 2
(twins)
10.9 TS < CTS< CTS< CTS¼ CTS¼ C
Reiss et al. (1995) 30 6–17 TS < CTS> CTS¼ C
Brown et al. (2002)
a
26 13.2 TS < C
b
TS < CTS¼ CTS¼ CTS C
TS CTS¼ CTS¼ CTS¼ CTS¼ C
PET studies
Clarke et al. (1990) 5 27.8 TS < CTS< C
Murphy et al. (1997) 10 28 TS < CTS< CTS< CTS< CTS< C
Note.
a
Upper line for gray matter; lower for white matter.
b
Trend only.
TURNER SYNDROME 269
2-back condition, they were less likely to engage
the frontal lobes, premotor cortex, and caudate.
The authors interpreted these findings to mean the
TS group exhibited greater effort than controls in
the 1-back condition and less engagement (lead-
ing to poorer performance) in the 2-back. More
recently, Tamm, Menon, and Reiss (2003) gave 11
adolescents with TS monosomy age-matched
controls a ‘‘go-no-go’’ paradigm in the scanner.
Results indicated the TS group activated a more
extensive functional network, which was thought
to signify the TS group was compensating for
their executive dysfunction by recruiting addi-
tional prefrontal cortical regions.
GENETIC-NEUROBEHAVIORAL
CORRELATIONS
The Role of Karyotype
As described previously, TS can be caused by
various abnormalities of X chromosome comple-
ment including a missing entire X chromosome, a
ring X chromosome, a deletion or rearrangement
of the X chromosome, an isochromosome or
various forms of mosaicism. Generally, the ring
X karyotype is associated with the most severe
deficits, mental retardation, absence of the corpus
callosum, and extremely large ventricles (Abd,
Turk, & Hill, 1995; Kuntsi, Skuse, Elgan, Morris,
& Turner, 2000).
Studies comparing individuals with TS by
karyotype have found much lower WISC Perfor-
mance IQs in the 45,X group than groups with
other karyotypes. For example, Temple and
Carney (1995) in comparing children with (i) a
pure 45,X chromosome condition, (ii) an isochro-
mosome, and (iii) a mixed condition involving a
deletion or rearrangement reported the 45,X group
had significantly lower Performance IQs than the
other groups but there were no differences in
Verbal IQ. Ross, Kusher, and Zinn (1997) com-
pared the discriminant function analysis (DFA)
scores (see above) of adults with TS by karyotype
and found lower scores in the 45,X, ring X, and
isochromosome karyotype groups than the mosaic
group, who scored comparably to controls.
O’Neill, Ghelani, Rovet, and Chitayat (2000)
studied the neuropsychological abilities of pre-
school children identified on amniocentesis with
45,X/46,XX. As shown in Figure 2, these children
scored above the mean of test norms on most
indices except NEPSY Narrative Memory and
they were significantly higher than the norms on
Memory for Faces. Several of these children were
also quite tall and few showed any of the char-
acteristic physical features of TS.
Rovet and Ireland (1994) compared the socio-
behavioral features of children with TS participat-
ing in a national clinical trial of growth hormone
by karyotype. Results from the Child Behavior
Checklist completed by parents at the trial’s base-
line session revealed the children with rearrange-
ments and isochromosomes had the poorest social
skills followed by those with a 45,X karyotype
while those with mosaic conditions, deletions,
and the presence of a Y chromosome showed
normal social skills. In contrast, children with
rearrangements or deletions were more likely to
exhibit significant behavior problems than the
others, while those with (a) a Y chromosome
were moderately affected, (b) 45,X or isochromo-
some karyotype were minimally affected, and
(c) mosaicism scored above normal. These find-
ings suggest that children with rearranged X
chromosomes are at the greatest risk for both
social and behavior problems while children
with isochromosomes are at risk for social prob-
lems and those with deletions for behavior prob-
lems. Children with mosaicism are the least
affected.
Imprinting Effects
One genetic mechanism that has received con-
siderable attention recently is the phenomenon
known as genomic-imprinting (Hall, 1997) or the
parent from whom the child originally received
her X chromosome (Barlow, 1995). It appears that
there is differential expression of certain genes
depending on the parent of origin as seen for
example in Prader-Willi and Angelman syn-
dromes. These are two very different disorders
that emanate from the same gene defect on chro-
mosome 15 but Prader-Willi is paternal in ori-
gin while Angelman’s is maternal in origin. The
mechanism in genomic-imprinting is thought to
reflect different methylation from the two par-
ents with one (usually the mother) preferentially
270 JOANNE ROVET
silencing a particular gene. This means that if a
gene on the maternal chromosome is inactivated,
then females with TS who inherit their single X
chromosome from the father will still be able to
express the gene, whereas those who inherit it
from the mother will be deficient in that gene
(Brown et al., 2002).
In a study comparing 55 females with mater-
nally derived X-monosomy and 25 with paternally
derived X-monosomy to chromosomally normal
males and females in terms of outcome and
selective abilities, Skuse et al. (1997) showed
the maternally derived monosomy X group was
more likely than the paternally derived group to
need special education, have low IQs and social
difficulties, and be disinhibited on cognitive tasks.
In contrast, the paternally derived group had scores
that were almost identical to chromosomally nor-
mal subjects. Bishop et al. similarly studying X-
imprinting effects on memory performance,
showed material specific differences (Bishop
et al., 2000). As seen in Figure 3, the paternally
derived X chromosome (X
p
) group did poorly on
tests of verbal retention but were similar to con-
trols on tests of visual retention. In contrast, those
with a maternally derived X chromosome (X
m
)
showed deficits on tests of visual retention but
performed comparably to controls on verbal
Fig. 2. Neuropsychological test results of children with Turner syndrome diagnosed with a 45,X/45,XX karyotype
prenatally. Results are presented as difference scores from test norms expressed in standard deviation (z-score)
units. Striped bars represent NEPSY subtest scores, stipled bars represent the Wide Range Assessment of
Visuomotor Abilities results, and the horizontal striped bar represents the Beery Test of Visuomotor
Integration.
Fig. 3. Effect of imprinting on memory test performance
for visual and verbal information. Turner syn-
drome groups are shown with solid lines and
filled symbols. The maternally derived X group
is represented by circles, paternally derived X
group by squares. Normal controls are shown
with broken lines and unfilled circles (females)
or squares (males). This work is adapted from
Bishop et al. (2000). Reprinted with permission
from Pergamon press.
TURNER SYNDROME 271
memory tests. In other words, having only a
paternally derived X chromosome impairs verbal
memory performance but spares visual memory,
whereas having only a maternally derived X
chromosome impairs visual but not verbal mem-
ory. It is interesting to note that the X
m
group
showed a similar, albeit lower, profile as normal
boys, who also only get their X chromosome from
their mother.
Neuroimaging findings also reveal that the
X
m
group is more aberrant bilaterally than the
X
p
group and also has a larger than normal
right superior temporal gyrus (Elgar, Lawrence,
Kuntsi, Coleman, Campbell, & Skuse, in
press).
Haploinsufficiency Effects
It has been posited that one of the two X
chromosomes in females is normally inactivated
and gene expression is randomly maternal or
paternal in origin, a theory known as the Lyon
Hypothesis (1962). However, because this theory
cannot account for the situation in the Turner
syndrome monosomy group (who should be just
like normal males who also have a single X
chromosome), it was proposed that some genes
within specific regions of the X chromosome
behave like autosomes (pseudoautosomes), such
that one needs both copies of these genes to
express a trait properly. These genes have
homologous regions on the X and Y chromo-
somes. In females with TS who have only one
gene copy, there will be a reduced gene dosage or
a haploinsufficiency leading to reduced produc-
tion of certain critical proteins, namely those
required for growth or certain aspects of brain
development (Zinn & Ross, 1998).
To identify these ‘‘pseudoautosomal’’ regions,
researchers have studied the rare cases with par-
tial X deletions or rearrangements. In one such
study, Zinn et al. (1998) found evidence of pseu-
doautosomes in several loci on the short arm of
the X chromosome (designated as Xp in contrast
to the long arm designated as Xq) in the region
from Xp11.2 to Xp22.1. Patients missing this
region had high arched palates and ovarian dys-
genesis, whereas those who had this region but
were missing another did not show these char-
acteristics. For example, Zinn’s study contained
two mother–daughter pairs (or triplets meaning a
mother and her two daughters) all of whom were
missing a region quite high up on the X chromo-
some but had an intact region from p11.2 to p22.1.
Since these mothers were obviously fertile,
whereas individuals missing the region below
this had ovarian dysgenesis, it was posited that
genes involved in ovarian production must be
located within the former region. Short stature
was localized to a much smaller region midway
within that general area.
Are genes in this region also responsible for
the cognitive phenotype in TS? Ross, Roeltgen,
Kushner, Wei, and Zinn (2000) compared visuo-
spatial abilities in 34 children and adults with
partial Xp (i.e., short arm) monosomy. Cases
were stratified according to whether their dis-
criminant function analysis (DFA) scores were
negative (meaning poor visuospatial ability) or
positive (meaning adequate visuospatial ability).
Since all individuals with negative DFA scores
were missing the part of the X chromosome
within pseudoautosomal region (Xp22.3) known
to escape X inactivation, this signifies that both
copies of genes in this region must be present to
express this trait properly. The task now is to
identify which of the seven known genes in this
region cause the spatial deficit and how exactly
this occurs.
Candidate Genes
The earliest gene to be identified in TS was the
SHOX or short homeobox gene (Rao et al.,
1997). This gene, which is located at Xp22 or
Yp11.3, is important for growth and if missing or
abnormal, causes growth failure and idiopathic
short stature. SHOX was first discovered in the
condition Le
´
ri-Weill dyschondrosteosis (LWD),
which is a dysplastic condition involving short
stature, short arms and legs, and the ‘‘Madeline
deformity’’ or an unusual carrying angle of the
elbows and a short fourth metacarpal (Ross
et al., 2001) much like that seen in TS. SHOX
mutations or deletions are also seen in about 5%
of children with idiopathic short stature (Binder,
Schwarze, & Ranke, 2000). Within the TS
population, SHOX deletions are found to be
associated with skeletal abnormalities (Clement-
Jones et al., 2000; Kosho et al., 1999) while TS
cases with rearrangements involving three SHOX
copies (e.g., due to a short arm isochromosome)
272 JOANNE ROVET
had tall stature (Binder, Eggermann, Enders,
Ranke, & Dufke, 2001). Although no studies
have as yet linked SHOX to the neurocognitive
deficits in TS, Ross et al. (2000) showed that
individuals the lowest DFA scores (a marker of
visuospatial abilities, see above) were missing a
region 15–30 kilobases from the centromere
(which contains SHOX).
A different region of the X chromosome may
be responsible for some of the social adjustment
difficulties in TS. Skuse, Good, Elgar, Thomas,
and Morris (2001) similarly examined partial-X
monosomies and found a region at Xp11.3 (which
is closer to the centromere than SHOX) was
associated with these types of difficulties. Individ-
uals who lacked this region of the X chromo-
some had difficulties processing fear emotions in
faces, poor social adjustment, and limbic system
abnormalities in their neuroimaging scans (Elgar
et al., 2003).
THE ROLE OF HORMONES
ON OUTCOME
Individuals with TS lack endogenous estrogen
production and also have reduced androgen pro-
duction. Thus, they are exposed to insufficient
levels of both hormones until replacement therapy
is provided. While estrogen therapy is commonly
given in adolescence to bring on puberty and
sustain normal menstrual functioning, androgen
therapy is given only to augment growth. In
addition, most children are now treated with
biosynthetic growth hormone to increase final
height. The findings from a number of studies to
determine how variations in their hormone levels
affect cognitive and behavioral functioning are
summarized in Table 4.
Estrogen Effects
Although the majority of females with TS lack
normal estrogen production, there are exceptional
cases with estrogen production. These individuals
are diagnosed with TS because of the other phy-
sical features.
One of the first studies to link estrogen levels
to specific aspects of cognitive processing exam-
ined event-related potentials (ERPs) in response
to different kinds of information (Johnson,
Rohrbaugh, & Ross, 1993). Prior to puberty,
there were few differences between the children
with TS and normal controls in ERP parameters,
whereas by late adolescence, controls showed
the developmental phenomenon known as the
O-wave, which appears in the frontal region but
adolescents with TS did not, unless they were
receiving estrogen therapy or had endogenous
estrogen production. Recent studies of women
with TS taking estrogen exogenously showed no
effects of estrogen on visuospatial task perfor-
mance, regardless of whether they were taking
estrogen or not (Ross et al., 2002). By contrast,
visual perceptual and motor planning skills seem
Table 4. Effect of Hormones on Selective Neurobehavioral Functions.
Hormone Positive effects Lack of effect
Estrogen ERP O-wave Spatial abilities
Perceptual abilities
Motor Planning skills
Motor speed
Memory
Androgen Verbal working memory Verbal abilities
Spatial abilities
Executive function
Growth hormone Psychological functioning Cognitive abilities
Internalizing behaviors
Arithmetic
TURNER SYNDROME 273
to be improved with exogenous estrogen therapy
(Roman et al., 1998; Ross et al., 2000).
In a randomized controlled study of estrogen
treatment, Ross, Roeltgen, Feuillan, Kushner, and
Cutler (1998) found the estrogen-treated group had
superior speeded motor performance and faster
cognitive processing speeds than the non-treated
groups. However, groups did not differ in their
visuospatial abilities. Similarly studies with chil-
dren show those receiving low dose estrogen repla-
cement therapy had bettermemory functioning than
those not receiving estrogen (Ross et al., 2000).
Androgen Effects
In contrast to estrogen, androgens used to facilitate
growth may positively affect selective aspects of
memory functioning in TS, particularly skills im-
plicating the hippocampus (Murphy et al., 1994). In
a recent treatment study involving oxandrolone,
Ross and colleagues reported a positive effect of
oxandrolone on verbal working memory but not on
verbal abilities, spatial cognition, and executive
function (Ross et al., 2003).
Growth Hormone Effects
Young girls with TS are not truly growth-hormone
deficient, although abnormalities are seen after
age 9 (Ross, Long, Loriaux, & Cutler, 1985).
Regardless, studies providing growth hormone
replacement therapy to children and adolescents
with TS show improved height on average with
little effect on cognitive abilities (Ross, Feuillan,
Kushner, Roeltgen, & Cutler, 1997). In contrast,
growth hormone therapy is associated with
improved psychological well-being, fewer inter-
nalizing emotional problems, and slightly better
arithmetic abilities than seen in individuals not
receiving this therapy (Siegel, Clopper, & Stabler,
1998). Although Stabler (1995) reported a very
modest (non-significant) gain in IQ after 2 years
of growth hormone therapy, the effects of growth
hormone on overall neuropsychological function-
ing have not been adequately studied.
SUMMARY AND CONCLUSIONS
To summarize, TS represents a genetic disorder
that affects females primarily although very rare
cases of males with TS have been described. TS is
associated with a characteristic set of physical
stigmata and psychological features. In particular,
individuals with TS show a specific cognitive
deficit affecting primarily their visuospatial
abilities while dysfunction in attention, executive
function, memory areas and math processing
areas are also frequently seen. Deficits in social
cognition and difficulty with selective aspects of
face processing have additionally been reported.
Many children with TS also exhibit a non-verbal
learning disability and need special education at
school.
Neuroimaging studies reveal abnormalities in
structural brain development reflecting reduced
volumes in posterior cortical and subcortical
structures as well as increased size of the medial
temporal lobe, cerebellum, and amygdala. Neu-
ropsychological studies point to abnormal hemi-
spheric lateralization suggesting a unique cerebral
architecture. Recent functional neuroimaging stu-
dies support this view showing that different brain
substrates are recruited during different informa-
tion processing tasks thereby suggesting atypical
cerebral networks. Certain fundamental processes
such as integrating information into meaningful
units or configurations may be particularly dis-
turbed in TS as has been shown in other disorders.
These elemental problems may be contributing to
both the cognitive and psychoeducational profiles
seen in TS.
There is marked variability in presentation of
the individual features among individuals with TS
and these variations reflect both genetic and
hormonal factors. Genetic factors include the
child’s particular karyotype and genomic-imprint-
ing and gene dosage effects. Regarding hormones,
TS is associated with a hormonal imbalance in
estrogen, androgen, and growth hormone supplies
and these different hormonal abnormalities may
also contribute to different aspects of cognitive
dysfunction. Studies of hormonal therapies have
shown that treatment with estrogen improves
attention and executive function skills and with
androgens (to enhance growth), verbal working
memory. While growth hormone therapy has little
effect on cognitive skills per se, it is associated
with improved behavior and arithmetic. These
findings have implications for treating patients
274 JOANNE ROVET
with TS and for the choices in selecting particular
hormone replacement therapies. In addition, these
findings are important for furthering our general
knowledge regarding the role of hormones in
brain development and later brain functioning
since TS offers a unique experiment of nature to
study these effects.
While the particular findings on TS have
implications for designing remedial strategies
for them, further work is clearly needed to under-
stand for example why their math deficits are so
prominent when they first appear and how they
may be initially rectified. It is important to deter-
mine what their basic visual defect is and how and
why this impacts on visual special functioning as
well as math concepts. Clearly more studies of
young children with TS are needed to answer
these questions.
Regarding the genetic studies, recent research
is making headway as to candidate genes and
underlying genetic mechanisms contributing to
the particular profile in TS. However, further
studies in this area are definitely warranted. The
recent genetic studies identifying restricted chro-
mosomal regions contributing to different pheno-
typic characteristics promises to be fruitful in
discovering the particular genes that contribute
to specific cognitive functions. Furthermore, this
approach may also advance our knowledge of sex
differences in behavior. As more rare cases with
deletions become identified, it is important to
examine their particular abilities and neuroima-
ging status. However, because these cases are so
rare, large-scale international studies are recom-
mended. Future research also needs to identify the
elemental processes that are particularly disturbed
in TS and link these to specific alterations in brain
formation. One area of research on TS that has
been particularly limited is the study of their
development longitudinally and in particular
examining how different genetic and hormonal
mechanisms impact on these children at different
stages of development. Only once the research on
this disorder is conducted at this elemental level
and over time will the identification of what the
genes on the X chromosome do be possible, as in
conditions such as Williams syndrome (Donnai &
Karmiloff-Smith, 2000; Paul, Stiles, Passarotti,
Bavar, & Bellugi, 2002) and fragile X syndrome
(Loesch, Huggins, Bui, Taylor, & Hagerman,
2003).
REFERENCES
Abd, S.E., Turk, J., & Hill, P. (1995). Psychological
characteristics of Turner syndrome. Journal of Child
Psychology and Psychiatry, 36, 1109–1125.
Abd, S.E., Wilson, L., Howlin, P., Patton, M.A.,
Wintgens, A.M., & Wilson, R. (1997). Agenesis of
the corpus callosum in Turner syndrome with ring
X. Developmental Medicine and Child Neurology,
39, 119–124.
Alexander, D., & Money, J. (1966). Turner’s syndrome
and Gernstmann’s syndrome: Neuropsychologic
comparisons. Neuropsychologia, 4, 265–273.
Alexander, D., Walker, H., & Money, J. (1964). Studies
in direction sense. Archives of General Psychiatry,
10, 337–339.
Barlow, D.P. (1995). Gametic imprinting in mammals.
Science, 270, 1610–1613.
Berch, D.B., & Kirkendall, K.L. (1986). Spatial
information processing in 45,X children. Presented
at the American Association for the Advancement
of Science meeting, Philadelphia, PA.
Binder, G., Eggermann, T., Enders, H., Ranke, M.B., &
Dufke, A. (2001). Tall stature, gonadal dysgenesis,
and stigmata of Turner’s syndrome caused by a
structurally altered X chromosome. Journal of
Pediatrics, 138, 285–287.
Binder, G., Schwarze, C.P., & Ranke, M.B. (2000).
Identification of short stature caused by SHOX
defects and therapeutic effect of recombinant
human growth hormone. Journal of Clinical Endo-
crinology and Metabolism, 85, 245–249.
Bishop, D.V., Canning, E., Elgar, K., Morris, E., Jacobs,
P.A., & Skuse, D.H. (2000). Distinctive patterns of
memory function in subgroups of females with
Turner syndrome: Evidence for imprinted loci on
the X-chromosome affecting neurodevelopment.
Neuropsychologia, 38, 712–721.
Brown, W.E., Kesler, S.R., Eliez, S., Warofsky, I.S.,
Haberecht, M., Patwardhan, A., Ross, J.L., Neely,
E.K., Zeng, S.M., Yankowitz, J., & Reiss, A.L.
(2002). Brain development in Turner syndrome: A
magnetic resonance imaging study. Psychiatric
Research, 116, 187–196.
Brun, A., & Skold, G. (1968). CNS malformations in
Turner’s syndrome: An integral part of the syn-
drome? Acta Neuropathologica, 10, 159–161.
Buchanan, L., Pavlovic, J., & Rovet, J.F. (1998). A
reexamination of visuospatial deficit in Turner
Syndrome: Contributions of working memory.
Developmental Neuropsychology, 14, 341–367.
TURNER SYNDROME 275
Clark, C., Klonoff, H., & Hayden, M. (1990). Regional
cerebral glucose metabolism in Turner syndrome.
Canadian Journal of Neurological Science, 17,
140–144.
Clement-Jones, M., Schiller, S., Rao, E., Blaschke, R.J.,
Zuniga, A., Zeller, R., Robson, S.C., Binder, G.,
Glass, I., Strachan, T., Lindsay, S., & Rappold,
G.A. (2000). The short stature homeobox gene
SHOX is involved in skeletal abnormalities in Turner
syndrome. Human Molecular Genetics, 9,695–702.
Cornoldi, C., Marconi, F., & Vecchi, T. (2001).
Visuospatial working memory in Turner’s syn-
drome. Brain and Cognition, 4,90–94.
Da
´
valos, I.P., Rivera, H., Vasquez, A.I., Gutierrez-
Angulo, M., Hernandez-Vazquez, M.C., Cortina-
Luna, F.A., Wong-Ley, L.E., & Dominguez-Quezada,
M.G. (2002). A 45,X sterile male with Yp disguised
as 21p. American Journal of Medical Genetics, 111,
202–204.
Donnai, D., & Karmiloff-Smith, A. (2000). William
Syndrome: From genotype through to the cognitive
phenotype. American Journal of Medical Genetics,
97, 164–171.
Downey, J., Elkin, E.J., Ehrhardt, A.A., Meyer-
Bahlburg, H.F.L., Bell, J.J., & Morishima, A.
(1991). Cognitive ability and everyday functioning
in women with Turner syndrome. Journal of
Learning Disabilities, 24,32–39.
Elgar, K., Campbell, R., & Skuse, D. (2002). Are you
looking at me? Accuracy in processing line-of-sight
in Turner syndrome. Proceedings Royal Society of
London, Basic Biological Science, 269, 2415–2422.
Ferna
´
ndez, R., Me
´
ndez, J., & Pa
´
saro, E. (1996). Turner
syndrome: A study of chromosomal mosaicism.
Human Genetics, 98,29–35.
Ford, C.E., Jones, K.W., & Polani, P.E. (1959). A sex
chromosome anomaly in a case of gonadal dysgen-
esis (Turner’s syndrome). Lancet (i), 711–713.
Garron, D.C. (1977). Intelligence among persons with
Turner’s syndrome. Behavior Genetics, 7, 147–152.
Good, C.D., Lawrence, K., Thomas, N.S., Price, C.J.,
Ashburner, J., Friston, K.J., Frackowiak, R.S.J.,
Oreland, L., & Skuse, D.H., Dosage-sensitive
X-linked locus influences the development of
amygdala and orbitalfrontal cortex, and fear recog-
nition in humans. Brain, 126, 2431–2446.
Gravholt, C.H., Svenstrup, B., Bennett, P., &
Christiansen, J.S. (1999). Reduced androgen levels
in adult Turner syndrome: Influence of female sex
steroids and growth hormone status. Clinical
Endocrinology, 50, 791–800.
Haberecht, M.F., Menon, V., Warsofsky, I.S., White,
C.D., Dyer-Friedman, J., Glover, G.H., Neely, E.K.,
& Reiss, A.L. (2001). Functional neuroanatomy of
visuo-spatial working memory in Turner syndrome.
Human Brain Mapping, 14,96–107.
Haddad, H., & Willkins, L. (1959). Congenital abnor-
malities associated with gonadal aplasia: Review of
55 cases. Pediatrics, 23, 885–902.
Hall, J.G. (1997). Genomic imprinting: Nature and
clinical relevance. Annual Review of Medicine, 48,
35–44.
Hepworth, S., & Rovet, J. (2001). Visuospatial
integration difficulties in a female with Turner
Syndrome. Impact on Verbal abilities. Child Neu-
ropsychology, 6, 262–273.
Inozemstseva, O., Matute, E., Zarabozo, D., &
Ramirez-Duenas, L. (2002). Syntactic processing
in Turner’s syndrome. Journal of Child Neurology,
17, 668–672.
Jacobs, P., Dalton, P., James, R., Mosse, K., Power, M.,
Robinson, D., & Skuse, D. (1997). Turner syn-
drome: A cytogenetic and molecular study. Annals
of Human Genetics, 61, 471–483.
Johnson, R.R. (1995). Event-related potential indica-
tions of altered brain development in Turner
syndrome. In J. Rovet (Ed.), Turner syndrome
across the lifespan (pp. 97–101). Markham, Ont.,
Canada: Klein Graphics.
Johnson, R.R., Rohrbaugh, J.W., & Ross, J.L. (1993).
Altered brain development in Turner’s syndrome.
Neurology, 43, 801–808.
Kagan-Krieger, A. (1998). Women with Turner syn-
drome: A maturational and developmental perspec-
tive. Journal of Adult Development, 5, 125–135.
Kagan-Krieger, S., Selby, P., Vohra, S., & Koren, G.
(2002). Paternal alcohol exposure and Turner
syndrome. Alcohol and Alcoholism, 37, 613–617.
Kosho, T., Muroya, K., Nagai, T., Fujimoto, M.,
Yokoya, S., Sakamoto, H., Hirano, T., Teresaki,
H., Ohashi, H., Nishimura, G., Sato, S., Matsuo, N.,
& Ogata, T. (1999). Skeletal features and growth
patterns in 14 patients with haploinsufficiency of
SHOX: Implications for the development of Turner
syndrome. Journal of Clinical Endocrinology
Metabolism, 84, 4613–4621.
Kuntsi, J., Skuse, D., Elgar, K., Morris, E., & Turner, C.
(2000). Ring-X chromosomes: Their cognitive and
behavioural phenotype. Annals of Human Genetics,
64, 295–305.
Lahn, B.T., & Page, D.C. (1999). Retroposition of
autosomal mRNA yielded testis-specific gene
family on human Y chromosome. Nature Genetics,
21, 429–433.
Lahood, B.J., & Bacon, G.E. (1985). Cognitive abilities
of adolescent Turner’s syndrome patients. Journal
of Adolescent Health Care, 6, 358–364.
Lawrence, K., Kuntsi, J., Coleman, M., Campbell, R.,
& Skuse, D. (2003). Face and emotion recognition
deficits in Turner syndrome: A possible role for
X-linked genes in amygdala development. Neuro-
psychology, 17,39–49.
276 JOANNE ROVET
Lesniak-Karpiak, K., Mazzocco, M.M.M., & Ross, J.L.
(2003). Behavioral assessment of social anxiety in
females with Turner or Fragile X syndrome. Journal
of Autism and Developmental Disorders, 33,55–67.
Lewandownski, L., Costenbader, V., & Richman, R.
(1985). Neuropsychological aspects of Turner
syndrome. International Journal of Neuropsychol-
ogy, 1, 144–147.
Loesch, D.Z., Huggins, R.M., Bui, Q.M., Taylor, A.K.,
& Hagerman, R.S. (2003). Relationship of deficits
of FRM1 gene specific protein with physical
phenotype of fraxX males and females in pedigrees.
A new picture. American Journal of Medical
Genetics, 118, 127–134.
Lyon, M.F. (1962). Sex chromatin and gene action in
the mammalian X-chromosome. American Journal
of Human Genetics, 14, 135–148.
Mambelli, M.C., Perulli, L., Casella, S., Leventaki, R.,
Perini, C., Gozzi, G., Panizzolo, C., Rigon, F., &
Condini, A. (1995). Difficulties and experiences in
dealing with the needs of patients with Turner
syndrome and their families: The usefulness of
a multidisciplinary approach. In J. Rovet (Ed.),
Turner syndrome: Across the lifespan (pp. 108–
112). Markham, Ont.: Klein Graphics.
Mazzocco, M.M.M. (1998). A process approach to
describing mathematics difficulties in girls with
Turner syndrome. Pediatrics, 102, 492–496.
Mazzocco, M.M.M., Baumgardner, T., Freund, L.S., &
Reiss, A.L. (1998). Social functioning among girls
with fragile X or Turner syndrome and their sisters.
Journal of Autism and Developmental Disorders,
28, 509–517.
McCauley, E., Feuillan, P., Kushner, H., & Ross, J.L.
(2001). Psychosocial development in adolescents
with Turner syndrome. Journal of Developmental
Behavioral Pediatrics, 22, 360–365.
McCauley, E., Ito, J., & Kay, T. (1986). Psychosocial
functioning in girls with Turner’s syndrome and
short stature: Social skills, behavior problems, and
self concept. Journal of American Academy of Child
Psychiatry, 25, 105–112.
McCauley, E., Kay, T., Ito, J., & Treder, R. (1987). The
Turner’s syndrome: Cognitive deficits, affective
discrimination and behavior problems. Child
Development, 58, 4644–4673.
McCauley, E., Sybert, V., & Ehrhardt, A. (1986).
Psychosocial adjustment of adult women with
Turnery syndrome. Clinical Genetics, 29, 284–290.
McGlone, J. (1985). Can spatial deficits in Turner’s
syndrome be explained by focal CNS dysfunction or
atypical speech lateralization? Journal of Clinical
and Experimental Neuropsychology, 7, 375–394.
Migeon, B.R., Ausems, M., Giltay, J., Hasley-Royster,
C., Kazi, E., Lydon, T.J., Engelen, J.J., & Raymond,
G.V. (2000). Severe phenotypes associated with
inactive ring X chromosomes. American Journal of
Medical Genetics, 93,52–57.
Money, J. (1963). Cyntogenetic and psychosexual
incongruities with a note on space-form blindness.
American Journal of Psychiatry, 119, 820–827.
Money, J., & Alexander, D. (1966). Turner’s syndrome:
Further demonstration of the presence of specific
cognitional deficiencies. Journal of Medical Genet-
ics, 3,47–48.
Murphy, D., Allen, G., Haxby, J., Largay, K.A., Daly,
E., White, B.J., Powell, C.M., & Schapiro, M.B.
(1994). The effects of sex steroids, and the X
chromosome, on female brain function: A study of
the neuropsychology of adult Turner syndrome.
Neuropsychologia, 32, 1309–1323.
Murphy, D., DeCarli, C., Daly, E., Haxby, J.V., Allen,
G., White, B.J., McIntosh, A.R., Powell, C.M.,
Horwitz, B., Rapoport, S.I., & Schapiro, M.B.
(1993). X-chromosome effects on female brain: A
magnetic resonance imaging study of Turner’s
syndrome. The Lancet, 342, 1197–2000.
Murphy, D., Mentis, M.J., Pietrini, P., Grady, C., Daly,
E., Haxby, J.V., De La Granja, M., Allen, G.,
Largay, K., White, B.J., Powell, C.M., Horwitz, B.,
Rapaport, S.I., & Schapiro, M.B. (1997). A PET
study of Turner’s syndrome: Effects of sex steroids
and the X chromosome on the brain. Biological
Psychiatry, 41, 285–298.
Netley, C., & Rovet, J. (1982). Atypical hemispheric
lateralization in Turner syndrome subjects. Cortex,
18, 377–384.
Nielsen, J., Nyborg, H., & Dahl, G. (1977). Turner’s
syndrome: A psychiatric-psychological study of 45
women with Turner’s syndrome, compared with
their sisters and women with normal karyotypes,
growth retardations, and primary amenorrhea. Acta
Jutlandica, 45, 190.
Nyborg, H. (1990). Sex hormones, brain development,
and spatio-perceptual strategies in Turner syndrome.
In D. Berch & B. Bender (Eds.), Sex chromosome
abnormalities and human behavior: Psychological
studies (pp. 100–129). Boulder, CO: Westview
Press.
O’Neill, S., Ghelani, K., Rovet, J., & Chitayat, D.
(2000). Physical and psychological development of
individuals prenatally diagnosed with 45,X/46,XX.
American Society of Human Genetics Meeting,
Philadelphia, 2000.
Palm, D., Pfeiffer, R.A., Ammermann, M., & Schulte,
H. (1973). EEG-Befunde bei Turner-Syndrome.
Mschr. Kinderheilk, 121, 289–292.
Pasquino, A.M., Passeri, F., Pucarelli, I., Segni, M.,
& Municchi, G. (1997). Spontaneous pubertal
development in Turner’s syndrome. Journal of
Clinical Endocrinology and Metabolism, 82,
1810–1813.
TURNER SYNDROME 277
Paul, B.M., Stiles, J., Passarotti, A., Bavar, N., &
Bellugi, U. (2002). Face and place processing in
William Syndrome. Evidence for a dorsal-ventral
dissociation. Neuroreport, 13, 1115–1119.
Pavlidis, K., McCauley, E., & Sybert, V. (1993).
Psychosocial and sexual functioning in women with
Turner syndrome. Clinical Genet, 47,85–89.
Pears, C. (1805). The case of a full grown woman in
whom the ovaria are deficient. Philosophical
Transactions Royal Society of London, 95, 225–227.
Poenaru, S., Stanesco, V., Poenaru, L., & Stoian, D.
(1970). EEG dans le syndrome de Turner. Acta
Neurologica Belgica, 70, 509–522.
Polani, P.E., Lessof, M.H., & Bishop, P.M.F. (1956).
Colour-blindness in ‘‘ovarian agenesis’’ (gonadal
dysplasia). Lancet, 2, 118–119.
Rao, E., Weiss, B., Fukami, M., Rump, A., Niesler, B.,
Mertz, A., Muroya, K., Binder, G., Kirsch, S.,
Winkelmann, M., Nordsiek, G., Heinrich, U.,
Breuning, M.H., Ranke, M.B., Rosenthal, A., Ogata,
T., & Rappold, G.A. (1997). Pseudoautosomal
deletions encompassing a novel homeobox gene
cause growth failure in idiopathic short stature and
Turner syndrome. Nature Genetics, 16,54–63.
Reiss, A.L., Eliez, S., Schmitt, J.E., Patwardhan, A., &
Haberecht, M. (2000). Brain imaging in neurogen-
etic conditions: Realizing the potential of behav-
ioral neurogenetics research. Mental Retardation
and Developmental Disabilities Research Review, 6,
186–197.
Reiss, A.L., Freund, L., Plotnick, L., Baumgardner, T.,
Green, K., Sozer, A.C., Reader, M., Boehm, C., &
Denckla, M.B. (1993). The effects of X monosomy
on brain development: Monozygotic twins discor-
dant for Turner’s syndrome. Annals of Neurology,
34,95–107.
Reiss, A.L., Mazzocco, M.M., Greenlaw, R., Freund,
L.S., & Ross, J.L. (1995). Neurodevelopmental
effects of X monosomy: A volumetric imaging
study. Annals of Neurology, 38, 731–738.
Reske-Nielsen, E., Christensen, A.L., & Nielsen, J.
(1982). A neuropathological and neuropsychological
study of Turner’s syndrome. Cortex, 18, 181–190.
Robinson, A., Bender, B., Borelli, J., Puck, M.,
Salbenblatt, J., & Winter, J. (1986). Sex chromoso-
mal aneuploidy: Prospective and longitudinal stu-
dies. In S. Ratcliffe & N. Paul (Eds.), Prospective
studies on children with sex chromosome aneuploidy
(pp. 23–73). New York: Liss.
Romans, S.M., Roeltgen, D., Kushner, H., & Ross, J.L.
(1997). Executive function in girls with Turner’s
Syndrome. Developmental Neuropsychology, 13,
23–40.
Romans, S.M., Stefanatos, G., Roeltgen, D.P., Kushner,
H., & Ross, J.L. (1998). Transition to young
adulthood in Ullrich–Turner syndrome: Neurodevel-
opmental changes. American Journal of Medical
Genetics, 79,140–147.
Ross, J.L. (1996). Estrogen therapy in the treatment of
Turner syndrome. In J. Rovet (Ed.). Turner
syndrome across the lifespan (pp. 93–96).
Markham, Ont.: Klein Graphics.
Ross, J.L., Feuillan, P., Kushner, H., Roeltgen, D., &
Cutler, G.B. (1997). Absence of growth hormone
effects on cognitive function in girls with Turner
syndrome. Journal of Clinical Endocrinology and
Metabolism, 82, 1814–1817.
Ross, J.L., Kushner, H., & Zinn, A.R. (1997).
Discriminant analysis of the Ullrich–Turner syn-
drome neurocognitive profile. American Journal of
Medical Genetics, 72, 275–280.
Ross, J.L., Long, L.M., Loriaux, D.L., & Cutler, G.B.
Jr. (1985). Growth hormone secretory dynamics
in Turner syndrome. Journal of Pediatrics, 106,
202–206.
Ross, J.L., Roeltgen, D., & Cutler, G.B. (1995). The
neurodevelopmental transition between childhood
and adolescence in girls with Turner syndrome. In
K.A. Albertsson-Wikland & M.B. Ranke (Eds.),
Turner syndrome in a life span perspective:
Research and clinical aspects (pp. 296–308).
Amsterdam: Elsevier.
Ross, J.L., Roeltgen, D., Feuillan, P., Kushner, H., &
Cutler, G.B. (1998). Estrogen effects on nonverbal
processing speed and motor function in girls with
Turner syndrome. Journal of Clinical Endocrinol-
ogy and Metabolism, 83, 3198–3204.
Ross, J.L., Roeltgen, D., Feuillan, P., Kushner, H., &
Cutler, G.B. (2000). Use of estrogen in young girls
with Turner syndrome: Effects on memory. Neurol-
ogy, 54, 164–170.
Ross, J.L., Roeltgen, D., Kushner, H., Wei, F., & Zinn,
A.R. (2000). The Turner syndrome-associated
neurocognitive phenotype maps to distal Xp.
American Journal of Human Genetics, 67, 672–681.
Ross, J.L., Roeltgen, D., Stefanatos, G.A., Feuillan, P.,
Kushner, H., Bondy, C., & Cutler, G.B. (2003).
Angrogen-responsive aspects of cognition in girls
with Turner syndrome. Journal of Clinical Endo-
crinology and Metabolism, 88, 292–296.
Ross, J.L., Scott, C., Marttila, P., Kowal, K., Nass, A.,
Papenhausen, P., Abboudi, J., Osterman, L., Kushner,
H., Carter, P., Ezaki, M., Elder, F., Wei, F., Chen, H.,
& Zinn, A.R. (2001). Phenotypes associated with
SHOX deficiency. Journal of Clinical Endocrinology
and Metabolism, 86, 5674–5680.
Ross, J.L., Stefanatos, G.A., Kushner, H., Zinn, A.,
Bondy, C., & Roeltgen, D. (2002). Persistent
cognitive deficits in adult women with Turner
syndrome. Neurology, 58, 218–225.
Ross, J., Zinn, A., & McCauley, E. (2000). Neurode-
velopmental and psychosocial aspects of Turner
278 JOANNE ROVET
syndrome. Mental Retardation and Developmental
Disabilities Research Review, 6, 135–141.
Rovet, J. (1990). The cognitive and neuropsychological
characteristics of females with Turner syndrome. In
D.B. Berch & B.G. Bender (Eds.), Sex chromosome
abnormalities and human behavior (pp. 38–77).
Boulder, CO: Westview Press.
Rovet, J.F. (1993). The psychoeducational character-
istics of children with Turner syndrome. Journal of
Learning Disabilities, 26, 333–341.
Rovet, J.F. (1995). Turner syndrome. In B.P. Rourke
(Ed.), Syndrome of nonverbal learning disabilities:
Neurodevelopmental manifestations (Chapter 13,
pp. 351–371). New York: Guilford Publications.
Rovet, J., & Ireland, L. (1994). Behavioral phenotype in
children with Turner syndrome. Journal of Pediatric
Psychology, 19, 779–790.
Rovet, J., & Netley, C. (1982). Processing deficits in
turner’s syndrome. Developmental Psychology, 18,
77–94.
Rovet, J., Szekely, C., & Hockenberry, M.N.
(1994). Specific arithmetic calculation deficits
in children with Turner syndrome. Journal of
Clinical and Experimental Neuropsychology, 16,
820–839.
Schaffer, J.W. (1962). A specific cognitive deficit
observed in gonadal aplasia (Turner syndrome).
Journal of Clinical Psychology, 18,15–36.
Schucard, D.W., Shucard, J.L., Clopper, R.R., &
Schachter, M. (1992). Electrophysiological and
neuropsychological indices of cognitive processing
deficits in Turner syndrome. Developmental Neu-
ropsychology, 8, 299–323.
Siegel, P.T., Clopper, R., & Stabler, B. (1998). The
psychological consequences of Turner syndrome
and review of the National Cooperative Growth
Study psychological substudy. Pediatrics, 1998,
102, 488–491.
Silbert, A., Wolff, P.H., & Lilienthal, J. (1977). Spatial
and temporal processing in patients with Turner’s
syndrome. Behavior Genetics, 7,11–21.
Skuse, D.H., Good, C.D., Elgar, K., Thomas, N.S., &
Morris, J.S. (2001). Gene–brain mechanisms in
Turner syndrome. Paper presented at the Genesis
conference.
Skuse, D.H., James, R.S., Bishop, D.V., Coppin, B.,
Dalton, P., Aamodt-Leeper, G., Bacarese-Hamilton,
M., Creswell, C., McGurk, R., & Jacobs, P.A.
(1997). Evidence from Turner’s syndrome of an
imprinted X-linked locus affecting cognitive func-
tion. Nature, 387, 705–708.
Stabler, B. (1995). Behavior change in patients with
Turner syndrome undergoing growth hormone
therapy. In J. Rovet (Ed.), Turner syndrome across
the lifespan (pp. 81–90). Markham, Ont., Canada:
Klein Graphics.
Stenberg, A.E., Nyle
´
n, O., Windh, M., & Hultcrantz, M.
(1998). Otological problems in children with
Turner’s syndrome. Hearing Research, 124,85–90.
Tamm, L., Menon, V., & Reiss, A.L. (2003). Abnormal
prefrontal cortex function during response inhibi-
tion in Turner syndrome: Functional magnetic
resonance imaging evidence. Biological Psychiatry,
53, 107–111.
Temple, C.M. (2002). Oral fluency and narrative
production in children with Turner’s syndrome.
Neuropsychologia, 40, 1419–1427.
Temple, C.M., & Carney, R.A. (1995). Patterns of
spatial functioning in Turner’s syndrome. Cortex,
31, 109–118.
Temple, C.M., Carney, R.A., & Mullarkey, S. (1996).
Frontal lobe function and executive skills in
children with Turner’s Syndrome. Developmental
Neuropsychology, 12, 343–363.
Temple, C.M., & Marriott, A.J. (1998). Arithmetical
ability and disability in Turner’s syndrome: A
cognitive neuropsychological analysis. Develop-
mental Neuropsychology, 14,47–67.
Tereo, Y., Hashimoto, K., Nukina, N., Mannen, T., &
Shinohara, T. (1996). Cortical dysgenesis in a
patient with Turner mosaicism. Developmental
Medicine and Child Neurology, 38, 455–466.
Tsuboi, R., & Nielsen, J. (1976). Electroencephalo-
graphic examination of 50 women with Turner’s
syndrome. Acta Neurologica Scandinavica, 54,
359–365.
Turner, H. (1938). A syndrome of infantilism, con-
genital webbed neck, and cubitus valgus. Endo-
crinology, 23, 566.
Ullrich, O. (1930). Ber typische komginationshbilder
multipler Abartung. Zeitschfrift fu
¨
r Kinderheilk-
unde, 49, 271–276.
Waber, D.P. (1979). Neuropsychological aspects of
Turner’s syndrome. Developmental Medicine and
Child Neurology, 21,58–70.
Williams, J., Richman, L., & Yarbrough, D. (1991). A
comparison of memory and attention in Turner
syndrome and learning disability. Journal of Pedia-
tric Psychology, 16, 585–593.
Zinn, A.R., & Ross, J.L. (1998). Turner syndrome and
haploinsufficiency. Current Opinion in Genetics
Development, 8, 322–327.
Zinn, A.R., Tonk, V.S., Chen, Z., Flejter, W.L., Gardner,
H.A., Guerra, R., Kushner, H., Schwartz, S., Sybert,
V.P., Van Dyke, D.L., & Ross, J.L. (1998). Evidence
for a Turner syndrome locus or loci at Xp11.2–
p22.1. American Journal of Human Genetics, 63,
1757–1766.
TURNER SYNDROME 279
