Articles
Brain morphology in
Klinefelter syndrome
Extra X chromosome and testosterone supplementation
A.J. Patwardhan, MS; S. Eliez, MD; B. Bender, PhD; M.G. Linden, MS; and A.L. Reiss, MD
Article abstract—Objective: This study focuses on variation in brain morphology associated with supernumerary X
chromosome and Klinefelter syndrome (KS). Using an unselected birth cohort of KS subjects and high-resolution MRI, the
authors investigated the neuroanatomic consequences of the 47,XXY karyotype in the presence and absence of exogenous
testosterone supplementation. Methods: Regional brain volumes were measured in 10 subjects with KS and 10 agematched control men. Five of the KS subjects had received testosterone supplementation since puberty (KS⫹T) and five
had not (KS⫺T). Results: KS subjects showed significant ( p ⬍ 0.01) reduction in left temporal lobe gray matter volumes
compared with normal control subjects. Differences in left temporal gray volumes were also significant between the KS⫹T
and KS⫺T groups ( p ⬍ 0.01). Verbal fluency scores were significantly different between the KS⫹T and KS⫺T groups as
well. Conclusion: Supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray
matter, a finding that is consistent with the verbal and language deficits associated with KS. Also, relative preservation of
gray matter in the left temporal region is associated with exposure to exogenous androgen during development. A history
of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients. Key
words: Brain morphology—Klinefelter syndrome—Extra X chromosome—Testosterone supplementation.
NEUROLOGY 2000;54:2218–2223
Cognitive and neurodevelopmental deficits associated with most forms of sex chromosome aneuploidy
are directly or indirectly related to the addition or
absence of X-chromosomal material. Most information on the neuroanatomic effects of sex chromosome
aneuploidy exists for Turner’s syndrome and the
45,X karyotype. Individuals with X monosomy and
Turner’s syndrome have visual-spatial and executive
function abnormalities associated with morphologic
anomalies of the parietal lobe.1-3 The significant
amount of data about X monosomy is in marked
contrast to the lack of information regarding the
neuroanatomic basis of cognitive impairments in
Klinefelter syndrome (KS).
KS is a genetic disorder caused by the addition of
an extra X chromosome in phenotypic men occurring
in an estimated 1:600 live infants. Features of men
with KS include a generally normal appearance,
slower growth rates, taller stature, smaller head cir-
cumferences, increased incidence of gynocomastia,
low basal testosterone levels, small testes, and infertility. Many studies provide evidence that men with
KS perform normally on tests of nonverbal abilities
and general intelligence but are specifically impaired
on measures of language skills. These deficits seem
to be most apparent in areas of verbal fluency and
expression4,5 and are consistent with the high incidence of reading disabilities frequently diagnosed in
47,XXY children.6 Individual expression for the KS
phenotype, however, is variable.
The purpose of this study was to investigate the
neuroanatomic basis of the cognitive phenotype in an
unselected population with KS. The morphologic effects of extra X chromosomal material on the brain
in the presence and absence of exogenous testosterone supplementation also was examined. We postulate that impaired verbal and language abilities in
unselected men with KS may be associated with de-
See also page 2201
From the Stanford Psychiatry Neuroimaging Laboratory, Department of Psychiatry and Behavioral Sciences (A.J. Patwardhan, and Drs. Eliez and Reiss),
Stanford University School of Medicine, CA; and the Department of Pediatrics (Dr. Bender and M.G. Linden), National Jewish Medical and Research Center,
Denver, CO.
Supported by National Institutes of Health grants HD10032-22, MH01142, and HD31715; and the David and Lucile Packard Foundation.
Received September 29, 1999. Accepted in final form January 24, 2000.
Address correspondence and reprint requests to Dr. Allan L. Reiss, Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, 401 Quarry Road, Stanford, CA 94305-5719.
2218
Copyright © 2000 by the American Academy of Neurology
creased cortical gray matter volumes, particularly in
the areas of the temporal lobe and superior temporal
gyrus (STG).
Materials and methods. Patients. Patients in the KS
sample were recruited from an unselected cohort of 40,000
consecutive newborns screened for sex chromosome aneuploidy by X-chromatin examination between 1964 and
1974.7 Of the 68 patients with sex chromosome aneuploidy
followed longitudinally, 13 had the 47,XXY karyotype. Ten
of these nonmosaic patients were involved in our present
study, including five who chose to receive testosterone supplementation (KS⫹T; mean age at supplementation, 17.4
years; SD, 2.70) and five who received no exogenous testosterone (KS⫺T). Cumulatively, the discontinuous intervals
of testosterone supplementation ranged from 2 to 10 years
for each KS⫹T patient.
The 10 propositi recruited by the National Jewish Medical and Research Center underwent research MRI scans
at University Hospital in Denver, CO; they ranged in age
from 24 to 32 years (mean, 27.32; SD, 2.99) at the time of
image acquisition. Ten individually age-matched control
men were recruited and scanned at both University Hospital in Denver (n ⫽ 7) and at the Stanford University
School of Medicine, Stanford, CA (n ⫽ 3). Control subjects
were matched within 2 years of age (mean, 26.81; SD,
3.28). Informed consent was obtained from all patients
prior to scanning and testing.
Neuroimaging. All MR data were acquired using 1.5tesla GE Signa scanners (Milwaukee, WI) located at the
two imaging centers. Coronal three-dimensional volumetric spoiled gradient echo (SPGR) series were acquired with
identical protocols in both centers (repetition time [TR] ⫽
35, echo time [TE] ⫽ 6, flip angle ⫽ 45°; number of excitations ⫽ 1, field of view ⫽ 24, matrix ⫽ 256 ⫻ 192; 124
1.5-mm–thick partitions with 0-mm gap) and were used for
all measurements and analysis. All raw formatted image
data acquired in Colorado were transferred via digital tape
to the Stanford Psychiatry Neuroimaging Laboratory for
morphometric analysis.
The SPGR image data were imported into the program
BrainImage娀 (Reiss, 1999) for semi-automated image processing, analysis, and quantification. Volumetric assessment of segmented image data in BrainImage娀8 requires a
stepwise process of data importation, removal of nonbrain
voxels, correction of image nonuniformity, positional normalization, and fuzzy tissue segmentation. Brain tissue
was isolated9 and subdivided into cerebral lobe, subcortical, cerebellum, and brainstem regions using a modified
Talairach stereotaxic grid.10,11 Segmentation of whole tissue into white, gray, and CSF compartments relies on a
constrained fuzzy algorithm based on voxel intensity and
tissue boundaries.12 Additionally, a single rater manually
circumscribed regions of the STG for the 10 KS patients
and 10 control subjects in coronal images oriented perpendicular to the anterior commissure–posterior commissure
plane according to a protocol previously developed in our
laboratory. The boundaries of the STG were defined by the
cortical surface and medially by a line connecting the deepest extension of the superior temporal sulcus to the furthest extent of the inferior ramus of the sylvian fissure.
Anteriorly, the STG coincided with the half-way point between the head of the putamen and the anterior commis-
sure. The most posterior slice of the STG was the first slice
where the crus of the fornix was clearly distinct from the
pulvinar. Interrater reliability for this procedure was previously established as 0.96 as measured by the intraclass
correlation coefficient.
Neuropsychological testing. The relation between testosterone supplementation and IQ for patients with KS
was also examined to ensure that the five KS⫹T patients
had not been self-selected by receiving testosterone supplementation. Wechsler Intelligence Scale for Children–Revised (WISC-R) scores of performance IQ, verbal IQ, and
full-scale IQ were gathered for all KS patients prior to
initial testosterone treatments (mean age, 8.5 years; SD,
2.38) and at comparative ages in the KS⫺T group (mean,
8.2 years; SD, 1.10).
Verbal abilities of adult KS men were assessed within 3
years of the each patient’s MRI scan. Standard scores from
the Memory for Sentences subtest13 of the WoodcockJohnson Language Battery were recorded to assess deficits
in verbal memory. Verbal fluency total scores were also
gathered from the Controlled Oral Word Association Test
(COWAT).14 All testing was done at the National Jewish
Medical and Research Center in Denver.
Statistics. Total brain volumes were distributed normally among the KS and control groups. Group differences
in regional volumes were assessed with analysis of variance (ANOVA) that took diagnosis as a between-subject
factor. Analysis of covariance (ANCOVA) was also used to
assess subregion comparisons after adjusting for the effects of total (cerebral) or regional (temporal lobe) compartmental volumes. Fisher’s protected least significant
difference (PLSD) test for post hoc comparisons was used
to further investigate multiple comparisons between the
control subjects and the KS⫹T and KS⫺T groups for significantly different regions of interest. A two-sided p-value
of 0.01 was the significance threshold for all analyses.
Unpaired Student’s t-tests were used to compare preadolescent IQ data between the KS⫹T and KS⫺T groups.
Student’s t-test was also used to compare the standard
Memory for Sentences subtest scores and COWAT scores
between the KS⫹T and KS⫺T groups. The association between left temporal gray volumes and COWAT scores of
KS patients was measured using the Spearman rank correlation coefficient (␳).
Results. Control subjects versus KS patients. Wholebrain tissue (gray plus white) volumes were roughly equivalent between the control and KS groups. However,
ANOVA revealed reductions ( p ⱕ 0.01) in total temporal
gray and left temporal gray volumes in KS patients compared with control subjects (differences in right temporal
gray volumes also approached significance). These differences did not persist during ANCOVA after adjusting for
differences in total cerebral gray volumes between the KS
and control groups.
Total STG gray, right STG gray, left STG gray, and
right STG total tissue (gray ⫹ white) volumes were also
reduced in the KS patients compared with control subjects
( p ⱕ 0.01). To assess the influence of the STG on reduced
temporal lobe volumes, ANCOVA was used to analyze total, right, and left STG gray measures using total right or
left temporal lobe gray volumes as covariates. None of
these STG volumes remained significantly reduced in the
June (2 of 2) 2000
NEUROLOGY 54
2219
Table Whole (gray plus white) tissue and gray tissue volumes
Tissue volume
Control subjects, n ⫽ 10
KS total, n ⫽ 10
KS⫹T, n ⫽ 5
KS⫺T, n ⫽ 5
1267.1 (111.33)
1220.5 (128.93)
1214.1 (103.00)
1226.9 (163.37)
636.0 (50.66)
608.3 (63.85)
607.3 (48.31)
609.2 (82.70)
Whole brain tissue (gray plus white)
volume, cm3 (SD)
Whole brain
Right
Left
631.1 (61.14)
612.2 (65.62)
606.8 (55.40)
617.7 (80.89)
212.0 (23.02)
191.8 (22.19)
202.0 (23.57)
181.6 (17.10)
Right
105.6 (12.35)
95.9 (12.06)
100.1 (11.26)
91.8 (12.55)
Left
106.4 (11.46)
95.9 (10.95)
101.9 (12.41)
89.8 (4.90)
Temporal lobe
STG
36.8 (3.74)
32.3 (3.53)
33.8 (4.29)
30.8 (2.03)
Right
19.2 (2.23)
16.3 (1.67)*
17.1 (1.78)
15.5 (1.31)*
Left
17.6 (1.60)
16.0 (2.04)
16.7 (2.65)
15.2 (0.97)
Gray tissue volume, cm3 (SD)
Whole brain
717.2 (69.62)
665.8 (67.62)
682.4 (44.21)
649.1 (87.40)
Right
362.4 (30.71)
333.2 (32.98)
343.0 (19.06)
323.3 (42.90)
Left
354.8 (39.48)
332.6 (35.20)
339.4 (25.69)
325.8 (44.87)
143.2 (14.60)
123.7 (18.73)*
135.6 (11.19)
111.9 (17.71)*
Right
70.1 (7.40)
61.1 (9.66)
66.3 (6.39)
55.9 (10.11)
Left
73.1 (7.55)
62.6 (9.55)*
69.3 (5.05)
56.0 (8.27)*†‡
Temporal lobe
STG
25.3 (2.93)
21.5 (2.41)*
23.1 (1.71)
20.0 (2.11)*
Right
12.6 (1.61)
10.5 (1.38)*
11.3 (0.80)
9.7 (1.42)*
Left
12.7 (1.35)
11.1 (1.28)*
11.8 (1.17)
10.4 (1.03)*
* Analysis of variance (ANOVA) and Fisher’s protected least significant difference (PLSD) show significance compared to controls.
† ANOVA and Fisher’s PLSD show significance compared to KS⫹T group.
‡ Analysis of covariance (ANCOVA) with total brain gray volume as a covariate. Fisher’s PLSD shows significance compared to control
and KS⫹T groups.
KS ⫽ Klinefelter syndrome; KS⫹T ⫽ KS subjects with testosterone supplementation; KS⫺T ⫽ KS subjects without testosterone supplementation; STG ⫽ superior temporal gyrus.
KS group after adjusting for reduced total temporal lobe
volumes (table).
Other tissue compartments of the cerebrum and posterior fossa did not differ between groups. Differences were
absent for ventricular CSF volumes, a region previously
reported to be significantly increased in KS patients when
compared with age-matched control subjects.15
Testosterone effects in KS morphology. Post hoc analyses revealed that total and left temporal gray, total STG
gray, right STG gray, left STG gray, and right STG total
tissue volumes were significantly reduced in the KS⫺T
group compared with the control group. KS⫹T volumes
were not significantly different from control subjects for
any regions of interest. Left temporal gray volume was
significantly reduced in the KS⫺T compared with the
KS⫹T group (figure 1).
In order to investigate whether temporal gray volume
reductions in KS reflects disproportionate regional volume
loss in the brain, total temporal gray and left temporal
gray volumes were further analyzed using ANCOVA with
total cerebral gray volumes as the covariate. Post hoc analysis showed that KS⫺T patients had significantly reduced
left temporal gray volumes when compared with both the
control and KS⫹T groups. However, after covarying, total
temporal gray volumes (right plus left) were no longer
2220 NEUROLOGY 54
June (2 of 2) 2000
significantly reduced in the KS⫺T compared with KS⫹T
patients.
Testosterone effects in KS cognition. IQ scores taken
prior to initial testosterone treatment in KS⫹T patients
and for comparative ages in KS⫺T patients indicated that
the groups had comparable cognitive abilities at the time
when five of the 10 KS patients received testosterone therapy. Unpaired Student’s t-test revealed no significant differences between the KS⫹T and KS⫺T groups for
performance IQ, verbal IQ, and full-scale IQ scores on the
WISC-R.
Verbal abilities in adult KS men were also examined in
areas of verbal memory and verbal fluency (figure 2). The
groups were not significantly different in scores of the
Memory for Sentences subtest for assessing verbal memory. For verbal fluency, however, the unpaired Student’s
t-tests revealed reduced COWAT scores ( p ⱕ 0.01) for
KS⫺T patients compared with KS⫹T adults.
The association between left temporal gray volumes and
COWAT scores was investigated in the KS group (figure 3)
using the Spearman rank correlation coefficient. A ␳ of
0.542 was not significant indicating only a trend for increased COWAT scores to be associated with increased left
temporal gray volumes. However, testosterone’s distinguishing effect on the morphology and verbal abilities of
Figure 1. Left temporal lobe gray volumes (cm3) for control subjects, Klinefelter syndrome (KS) subjects with testosterone supplementation (KS⫹T), and KS subjects
without testosterone supplementation (KS⫺T).
adults with KS is reflected in figure 3, which indicates
both increased left temporal gray volumes and COWAT
scores in KS⫹T patients.
Discussion. Limitations. The results of this
study are tempered by the potential selection bias
that is introduced when only five of the 10 patients
with KS chose to receive testosterone therapy. The
cognitive, environmental (e.g., socioeconomic status),
or physiologic variables occurring in KS may predispose some individuals to seek testosterone supplementation more than others and may contribute to
the segregated KS⫹T versus KS⫺T results presented in this paper. Scores of general intelligence
were not significantly different between KS⫹T and
KS⫺T groups as assessed by the WISC-R administered prior to puberty and testosterone supplementation. It appears, therefore, that general intelligence
was not a predictor for whether a patient received
testosterone treatment or not. As this is an indirect
measure of intergroup compatibility, however, other
unassessed variables may be relevant in selecting for
testosterone-treated KS patients.
All of the KS⫹T patients began supplementation
5 to 10 years prior to the MR scan. However, the
retrospective nature of this study makes it difficult
to precisely document the timing of testosterone usage. Although the effect of testosterone supplementa-
tion is associated with preserved verbal fluency
scores and left temporal lobe volumes, the supplementation was discontinuous and highly variable
among these patients. Of the five KS⫹T patients,
one received testosterone supplementation continuously to date, one received treatment sporadically,
two received treatment continuously except for a single 6 to 12 month interval, and one had had no
supplementation 2 years prior to the MRI. This variability may be a confounding factor in comparing
KS⫹T and KS⫺T patients and may blur the distinction between the two groups.
Although volumetric measurements using the Talairach coordinate system are sensitive to total lobar
differences between groups, they do not reflect differences that may occur in smaller subregions of the
brain. Specific areas of the frontal and parietal lobes
may be anomalous in KS and may correlate to deficits in phonologic processing, verbal fluency, and
reading that occur in men with KS. Our manual
delineation was limited to the STG—a structure
thought to be integral in language processing. Future investigations, however, should explore other
neuroanatomic areas that are of functional interest
in KS but may not be assessed by the Talairach
system.
Implications. Our results show evidence of significant variation in cortical gray volumes in the
temporal lobe of persons with KS, particularly on the
left. For KS, reduced performances on tests of retrieval, reading skill, verbal IQ,16,17 and auditory
short-term memory6,18 stand in contrast to relatively
preserved abilities on tests of visual-spatial and
math skills. It has been proposed that left-hemisphere–associated tasks such as verbal fluency and
auditory short-term memory are diminished in KS
individuals due to a reduction of the normal cerebral
lateralization that occurs in euploidic men.19 In normally developing men these skills are thought to be
strongest in the left hemisphere with lateralized verbal abilities occurring primarily in the temporal lobe.
Our finding of reduced left temporal lobe gray volumes in patients with KS provides a potential structural basis for the observed neuropsychological
deficits. This result remains even after adjusting for
the slight differences in whole brain volumes between KS patients and control subjects.
The high incidence of dyslexia in men with KS
also implicates functional abnormalities in areas of
the brain thought to be essential for reading. Reduced STG gray volumes in both hemispheres of
the brain are consistent with the bilateral reduction
of gray matter within the temporal lobe. However,
ANCOVAs reveal that the STG does not specifically
or principally account for this temporal gray matter
reduction in KS patients, and that there may be
more extensive loss of tissue within the entire lobe.
While the STG is thought to play an essential role in
reading, it is possible that the neuropathology associated with developmental reading disorders is also
June (2 of 2) 2000
NEUROLOGY 54
2221
Figure 2. Verbal abilities in Klinefelter
syndrome (KS). Controlled Oral Word
Association Test (COWAT) total scores
(verbal fluency) and Memory for Sentences Test standard scores (verbal
memory) for KS subjects with testosterone supplementation (KS⫹T) and without testosterone supplementation
(KS⫺T) in adulthood.
distributed to areas of the temporal lobe not assessed
in this study.
Subgroup KS⫹T and KS⫺T comparisons seem to
indicate that androgen supplementation may affect
KS morphology and cognition. Temporal lobe gray
and STG measures for the KS⫹T group were not
significantly reduced compared with control subjects,
indicating a preservation of temporal lobe gray matter bilaterally in this group. Conversely, the untreated KS⫺T group illustrates the morphologic
consequences of KS in the absence of exogenous androgen supplementation particularly in the left temporal lobe (see figure 1).
Left temporal gray matter preservation in KS⫹T
patients may be related to a preservation of cognitive
abilities associated with this area. Memory for Sentences subtest scores revealed no significant differences between KS⫹T and KS⫺T groups, indicating
relatively equivalent abilities in verbal memory.
However, the COWAT scores revealed higher abilities in verbal fluency among the KS⫹T group (see
figure 2) compared with the KS⫺T group. An association between left temporal gray volumes and COWAT scores is difficult to assess with such a small
sample size. However, the relatively segregated distribution between the KS⫹T and KS⫺T groups (see
figure 3) indicates that testosterone supplementation
was a potential influence on both COWAT scores and
left temporal lobe gray volumes. Given the phenotypic variability that normally occurs among individuals with KS, the almost complete nonoverlap
between KS⫹T and KS⫺T groups for left temporal
gray volumes and COWAT scores may reflect a
strong effect of exogenous testosterone.
The cerebral cortex may retain plasticity well into
adulthood, allowing it to be continually modified by
externally supplemented and endogenous hormones.
The ability to reverse right and left patterns of cerebral asymmetry was previously demonstrated in go2222 NEUROLOGY 54
June (2 of 2) 2000
nadectomized male and female adult rats. The
original hemispheric patterns can be restored in
these animals with hormone replacement.20
Human studies suggest a role for endogenous testosterone in determining spatial abilities and functional lateralization in children21 and adults.22
Netley23 showed a strong correlation of verbal IQ
with testosterone levels and early pubertal onset in a
birth cohort of KS patients measured during three
intervals of sexual maturation. Recent evidence also
illustrates the cognitive effects of hormone replace-
Figure 3. Left temporal lobe gray volumes and verbal fluency in Klinefelter syndrome (KS). Controlled Oral Word
Association Test (COWAT) total scores (verbal fluency)
versus left temporal gray volumes in KS subjects with testosterone supplementation (䢇) and without testosterone
supplementation (f).
ment therapy in surgically menopausal and healthy
postmenopausal women.24,25 Verbal memory scores
were shown to be preserved or increased in women
receiving estrogen replacement therapy after abdominal hysterectomy and bilateral salpingo-oophorectomy
when compared with preoperative scores and control
subjects who did not receive supplementation. With
exogenous estrogen administration, Sherwin and Tulandi26 demonstrated a reversal of verbal memory deficits caused by decreased estrogen levels in women
treated with gonadotropin-releasing hormone agonists
for uterine myomas.
Although the language abilities of testosteronetreated KS men have not previously been compared
with those of untreated KS men, other studies demonstrated the increased behavioral benefits after
supplementation, even in adulthood.27,28 The mechanism of testosterone’s effectiveness, however, is not
well established, given the hormonal competition occurring in pituitary-gonadal function in KS. Early
pubertal boys with KS show increased estradiol levels even when serum testosterone levels are relatively normal. These elevated levels persist when
testosterone levels drop off by midpuberty.29 Exogenous testosterone may exert its influence in the
brain through its competition with serum free estrogen and other hormonal factors (follicle stimulating
hormone, luteinizing hormone), or may be mediated
through the aromatization of testosterone into estradiol30 in specific areas of brain.
Men with KS show cognitive deficits prior to puberty, even when basal testosterone levels are comparatively normal.31 The putative role of testosterone
as a primary predictor of cognitive functioning in
men, therefore, is doubtful. However, our investigation of this unselected KS cohort suggests that
testosterone supplementation is associated with preserved left temporal gray tissue volume, even in
postpubertal men with KS. The small sample size
makes it difficult to draw any conclusions about the
structural basis of the cognitive phenotype of KS;
however, our results support the left temporal lobe’s
role in diminished verbal fluency. With a larger sample size and a randomized testosterone treatment
condition, future investigations using functional MRI
should focus on the neurocognitive aspects of KS and
the neurodevelopmental effects of exogenous testosterone supplementation.
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