Received: 2 May 2018 Revised: 10 December 2018 Accepted: 14 December 2018

DOI: 10.1002/ajmg.a.61038

RESEARCH ARTICLE

The incidence of anxiety symptoms in boys with 47,XXY

(Klinefelter syndrome) and the possible impact of timing of
diagnosis and hormonal replacement therapy
Carole Samango-Sprouse1,2,3,4 | Patricia Lasutschinkow4 | Sherida Powell1 |
Teresa Sadeghin4 | Andrea Gropman1,2

1
George Washington University, Department
of Pediatrics, Washington, DC 47,XXY (Klinefelter syndrome) is the most common X and Y chromosomal variation (1:660
2
Children's National Health System, males). The incidence of anxiety disorders and the impact of hormonal replacement therapy
Neurodevelopmental Pediatrics and (HRT) is not well understood. Child Behavior Checklist and Screen for Childhood Anxiety
Neurogenetics, Washington, DC
Related Emotional Disorders were completed by parents of 80 boys with 47,XXY. Forty
3
Florida International University, Department
received HRT prior to 10 years of age while 40 did not. HRT (22.5%) received early hormonal
of Human and Molecular Genetics, Miami,
Florida treatment prior to 18 months. About 32.5% received hormone booster treatment between
4
The Focus Foundation, Davidsonville, 5 and 10 years. The remaining 42.5% received both. There were fewer reported social
Maryland (p = .015), thought (p = .012), and affective problems (p = .048) in treated boys when compared
Correspondence to untreated. Boys with both treatments demonstrated fewer symptoms on anxious/depressed
Carole Samango-Sprouse, 820 W. Central Ave. scale (p = .001) compared to those with early treatment only. Within the treated group, prena-
#190, Davidsonville, MD 21035.
tally diagnosed showed fewer indications of anxiety problems (p = .02) than their postnatal
Email: cssprouse@email.gwu.edu
counterparts. This comparative, cross-sectional study expands previous findings on the possible
Funding information
The Focus Foundation positive effect of HRT in boys with 47,XXY. Anxiety disorders appear to be a penetrant aspect
of the 47,XXY phenotype. Further investigation is warranted to explore the relationship
between biological treatment and individual responses to HRT to develop more personalized
and precise medicine.

KEYWORDS

anxiety disorders, hormonal replacement therapy, Klinefelter syndrome, sex chromosome

abnormalities and aneuploidies, X and Y chromosomal variations, 47,XXY

1 | I N T RO D UC T I O N
47,XXY (Klinefelter syndrome) is the most common sex chromosome
aneuploidy, occurring in 1 in 660 males (Nielsen & Wohlert, 1991;
Perwein, 1984; Savic, 2012). It is a multifaceted disorder that includes
increased height velocity, androgen deficiency as well as neurodevelop-
mental dysfunction (Lahlou, Fennoy, Carel, & Roger, 2004; Wosnitzer &
Paduch, 2013). The central nervous system deficits are evident in neuro-
motor skills, motor planning, language-based learning disorders, and
executive dysfunction (Ross et al., 2008; Samango-Sprouse & Rogel,
2002; Zahn-Waxler, Shirtcliff, & Marceau, 2008).
Behaviorally, some boys with 47,XXY may have deficits in inhibi-
tion, thought problems, and rule-breaking behavior (Van Rijn & Swaab,
2015). Most boys with 47,XXY have been characterized as shy, timid,
and withdrawn, particularly in social situations (Robinson, Bender,
Linden, & Salbenblatt, 1991; Tennes, Puck, Orfanakis, & Robinson,
1977). They have scored higher than their typically developing peers in
social anxiety and related symptoms, including difficulty in being asser-
tive and taking social responsibilities (Samango-Sprouse, Stapleton,
Sadeghin, & Gropman, 2013; van Rijn et al., 2014; Van Rijn, Swaab,
Aleman, & Kahn, 2008). Children with 47,XXY with positive family his-
tories of language-based learning disabilities and/or dyslexia exhibit
more severe neurodevelopmental deficits across speech, neuromotor,
and behavior (Bender, Linden, & Robinson, 1991; Samango-Sprouse,
Stapleton, et al., 2013). Additionally, Ross et al. found that children
who were diagnosed prenatally reported having fewer behavioral

Am J Med Genet. 2019;1–6. wileyonlinelibrary.com/journal/ajmga © 2019 Wiley Periodicals, Inc. 1

2 SAMANGO-SPROUSE ET AL.

problems, including less instances of externalizing behaviors, which TABLE 2 Demographics in treated and untreated groups
supports past findings that the timing of diagnosis is highly influential Untreated Treated
on neurodevelopmental outcome (Girardin et al., 2009; Ross et al., (n = 40) (n = 40)

2012; Simpson et al., 2003). CBCL chronological 127.4 117.5

age (months)
In the last 15 years, hormone replacement therapy (HRT) has
SCARED chronological 126 120.7
been studied as a possible treatment for the phenotypic features of age (months)
the neurodevelopmental disturbances of 47,XXY boys (Lanfranco, Birth weight (kg) 3.237 3.236
Kamischke, Zitzmann, & Nieschlag, 2004; Samango-Sprouse, Sadehin, Gravida 1.9 2.16
et al., 2013; Samango-Sprouse et al., 2015). In a recent study in 2017, Maternal age (years) 37.67 36.42
Ross et al. found that, at baseline, boys with 47,XXY were in the clini- Paternal age (years) 38.9 38.14
cal range in behavioral problems (33%), social problems (29%), atten- Maternal educationa 5.07 5.3
tion problems (35%), and withdrawn (35%) on the child behavior Paternal educationa 5.12 5.52
checklist (CBCL; Ross et al., 2017). The treatment group received a Family history 20% have history 17.5% have
of anxiety related a history of
low dosage of oxandrolone for 24 months and showed a significant disorders anxiety-related
improvement in anxiety/depression (p = .03) and social problems disorders
(p = .01) on the CBCL. a
Average parental education level among the untreated and treated
Our study investigates the impact of HRT at various ages on the cohorts, as characterized by Hollingshead criteria.
behavioral phenotype in 47,XXY for the first time. This is a compara-
tive cross-sectional analysis using a historical approach exploring the testosterone enanthate prior to 5 years of age. Fourteen males (35%)

incidence of anxiety and anxiety-related behaviors in males at 10 years received HBT between 5 and 10 years of age prescribed by the physi-

of age with 47,XXY and the influence of HRT during infancy (early
hormonal treatment, EHT) and between 5 and 10 years of age (hor-
monal booster treatment, HBT) on these behaviors. This analysis is
part of a longitudinal, natural history study of X and Y chromosomal
variations spanning 18 years.
cians caring for the child. The remaining 17 boys (42.5%) received
both EHT and HBT prior to their evaluation. The determination of
HRT was based on physical examination, phallus size, and clinical judg-
ment of the patient's pediatric endocrinologist. The blood work was
inconsistently completed by the medical provider, therefore, it could
not be utilized in this study's analysis.

2 | METHODS 2.1 | Assessment

The child behavior checklist (CBCL) for children between 6 and
In this study, 80 boys with 47,XXY were referred by their physicians,
18 years was completed by the parents of all participants. The ques-
parents, and ancillary health care providers throughout the country
tionnaire contains items covering behavioral issues present in the past
for a comprehensive neurodevelopmental assessment. The majority of
6 months using a 3-point scale of “not true,” “somewhat or sometimes
the boys with 47,XXY were diagnosed prenatally and those diagnosed
true,” “very true or often true.” Scores in the borderline and clinical
postnatally were identified prior to 2 years of age (Table 1). Of those
ranges of the CBCL reflect behaviors that are moderately to very devi-
studied, 40 males with 47,XXY received HRT prior to 10 years of age
ant in comparison to the scores from a normative peer sample
and 40 children did not receive HRT (Table 2). Nine of the 40 (22.5%)
(Achenbach & Ruffle, 2000). On the CBCL, a score that falls below the
in the HRT group received EHT; three injections of 25 mg
93rd percentile is considered normal, scores between the 93 and 97th
TABLE 1 Demographics in prenatally and postnatal diagnosed group percentile are borderline clinical, and any score above the 97th per-
centile are in the clinical range. The protocol manager who scored the
Prenally Postnatally
diagnosed diagnosed CBCL was blinded to the hormonal status of all participants.
(n = 60) (n = 20) The screen for childhood anxiety related emotional disorders
CBCL chronological age 124.2 115.8 (SCARED) was also completed for children between 8 and 11 years
SCARED chronological age 124.3 121 by both the children themselves and a parent. The questionnaire has
Birth weight (kg) 3.180 3.370 41 items that are rated on a 3-point scale of “not true or hardly ever
Gravida 2.17 1.64
true,” “somewhat true or sometimes true,” and “very true or often
Maternal age 37.78 33.67
true”. The SCARED measures anxiety through four domains: panic/so-
Paternal age 39.32 35.55
matic, separation anxiety, school avoidance, and generalized anxiety
Maternal educationa 5.31 4.7
over the last 3 months (Birmaher et al., 1999).
Paternal educationa 5.24 5.67
Family history 20% have 17.5% have a
history of history of 2.2 | Parental education
anxiety-related anxiety-related
disorders disorders Parental education was evaluated according to the criteria of Hollings-
a head Four Factor Index of Social Status utilizing a scale from 0 (no formal
Average parental education level among the prenatal and postnatal
cohorts, as characterized by Hollingshead criteria. education) to 7 (graduate/professional training; Hollingshead, 1975).
SAMANGO-SPROUSE ET AL. 3

Other scores include: 1 (less than seventh grade), 2 (junior high school),
3 (partial high school), 4 (high school graduate), 5 (partial college or spe-
cialized training), and 6 (standard college/university graduation; Hollings-
head, 1975). Level of education was averaged for maternal and paternal
to determine if there were significant differences between the treated
and untreated groups, as well as between the different treatment times.

2.3 | Statistical analyses

Group comparisons of CBCL scores were analyzed using nonparamet-
ric (Mann–Whitney) tests, because these variables were not normally
distributed. The Kruskal–Wallis test was used to compare three or
more groups while not assuming normally distributed variables. A FIGURE 1 CBCL results in treated versus untreated groups.
regression approach was utilized to test for a significant association *Statistically different higher scores indicate more complications
[Color figure can be viewed at wileyonlinelibrary.com]
between the treatment groups and timing of diagnosis. Results were
considered significant if the p-value was below .05.
were in the elevated range (above the 93rd percentile) in social prob-
lems, thought problems, internalizing problems, total problems, affec-
2.4 | Editorial policies and ethical considerations tive problems, and anxiety problems. The majority of treated boys had

The IRB was approved for this study protocol (#20081226) and less reported behavioral problems on the CBCL, however 22.5% of

informed consent was completed on each study participant.
3 | RESULTS
As this is a comparative cross-sectional portion of a longitudinal, natu-
ral history on boys with 47,XXY, the patients have been assessed on a
yearly basis for neurodevelopmental assessments which include neu-
rocognitive and behavioral evaluations. No significant differences in
maternal (p = .17) or paternal (p = .18) education or maternal (p = .41)
and paternal (p = .22) age were seen between the untreated and trea-
ted groups. There were no significant differences between the
untreated and treated groups in birth weight (p = .3) or neonatal com-
plications. Parents were contacted typically within 1–2 months of the
completion of treatment to discuss their experience, concerns, and
observations. No physical complications, illnesses, or abnormal physi-
cal changes were reported during or after treatment by parents to
their physicians or to us.
Within the untreated group, over one-fourth were in the clinical
range (above the 97th percentile) in internalizing problems, total prob-
lems, and anxiety problems (Table 3). Additionally, one-third of them
the treated boys were in the clinical range in internalizing problems
and less than one-third in the elevated range in internalizing problems,
total problems, anxiety problems, and anxious/depressed.
There was a significant difference between the HRT group and
the non-HRT group in multiple domains on the CBCL, including fewer
reported social problems (p = .015), thought problems (p = .012), and
affective problems (p = .048) in the treated group as compared to the
untreated group (Figure 1). The untreated group also had a signifi-
cantly higher incidence of symptoms in total problems (p = .040),
ADHD problems (p = .035), and OCD problems (p = .02) compared to
the HRT group. The boys who received both EHT and HBT demon-
strated significantly fewer symptoms on the anxious/depressed scale
(p = .001) as compared to those who had only received EHT. On the
SCARED self-report, a significant difference between children who
received only HBT and those who had both EHT and HBT was
observed. Boys receiving both treatments had fewer reports of symp-
toms in their total risk for any anxiety disorder (p = .03).
There was a significant difference between prenatally and postna-
tally diagnosed children within the treated group with prenatally diag-
nosed children showing fewer indications of anxiety problems
(p = .02). Results on the SCARED also had less reported symptoms in

TABLE 3 CBCL results in the treated and untreated groups

Untreated Treated (HRT)

Variables Normala (%) Borderlineb (%) Clinicalc (%) Normala (%) Borderlineb (%) Clinicalc (%)
Internalizing problems 47.5 12.5 40 65 12.5 22.5
Total problems 52.5 5 42.5 72.5 10 17.5
Anxiety problems 60 12.5 27.5 72.5 15 12.5
Anxious/depressed 67.5 10 22.5 72.5 17.5 10
Social problems 57.5 20 22.5 87.5 7.5 5
Thought problems 65 15 20 92.5 0 7.5
Affective problems 65 10 25 75 12.5 12.5
Externalizing problems 67.5 7.5 25 82.5 7.5 10
a
<93rd percentile.
b
93rd–97th percentile.
c
>97th percentile.
4 SAMANGO-SPROUSE ET AL.
TABLE 4 Anthropometric measurements in the untreated and treated groupsa
Untreated (n = 12) All treated (n = 19)
Chronological age 119.8 126.5
Head circumference (cm) 53.5 54.5
Height (cm) 142.24 147.57
Weight (kg) 36.38 36.92
a
No significant differences were noted between any of the samples. The sample size of HBT was too small to accurately test for significance.
the prenatally diagnosed group in both the child self-report and parent
report when compared to treated and postnatally diagnosed. Fewer
symptoms for generalized anxiety (p = .03), social anxiety (p = .004),
and total score (p = .004) were reported in the prenatal diagnosed and
treated. Postnatally diagnosed children had more reported symptoms
of generalized anxiety (p = .04), separation anxiety (p = .008), social
anxiety (p = .01), and total score (p = .02) by parental report but not
self-report by the child.
The timing of diagnosis revealed significant differences between
the treated and untreated groups. In the untreated group, prenatally
diagnosed children and parents reported fewer symptoms in social
anxiety as compared to postnatally diagnosed children and their par-
ents (p = .03 and p = .02, respectively). Of those in the treated group,
prenatally diagnosed boys and their parents both reported less symp-
toms in generalized anxiety (p = .04 and p = .01, respectively) and
total score (p = .008 and p = .02, respectively) compared to the post-
natal group. In contrast to those prenatally diagnosed, boys with
47,XXY who were treated and postnatally diagnosed reported more
symptoms of social anxiety (p = .04) and significant school avoidance
(p = .03) while their parents reported significantly more symptoms of
separation anxiety (p = .03).
Head circumference, height, and weight were collected whenever
possible on the patients. Analysis from 12 untreated boys and 19 trea-
ted boys found no significant differences between the two groups in
head circumference (p = .22), height (p = .13), and weight (p = .45;
Table 4). In the untreated group, average head circumference was
53.5 cm, height was 142.24 cm, and weight was 36.39 kg. In the trea-
ted group, average head circumference was 54.5 cm, height was
147.57 cm, and weight was 36.92 kg. Due to the small sample size of
HBT samples alone with growth data (n = 4), comparisons between
HBT and untreated were unable to be completed. However, compari-
sons between EHT versus untreated in head circumference (p = .46),
height (p = .19), and weight (p = .44) and EHT and HBT versus
untreated showed no significant differences in head circumference
(p = .42), height (p = .15), or weight (p = .46).
4 | DISCUSSION
For almost 20 years, the possible impact of hormones, and specifically
testosterone, on mood, lability, energy, and executive function on
individuals with 47,XXY has been reported (Mandoki & Sumner, 1991;
Mehta & Paduch, 2012; Patwardhan, Eliez, Bender, Linden, & Reiss,
2000; Ross et al., 2005, 2017; Samango-Sprouse et al., 2015, 2018).
Although this interaction is not yet well understood, previous papers
have described an improvement in the behavioral domains in
EHT only (n = 8) HBT only (n = 4) EHT and HBT (n = 7)
128.6 125.3 124.8
53.5 59.1 53.4
148.34 146.30 147.32
35.52 41.23 36.06
association with the administration of testosterone in individuals with
47,XXY.
Anxiety disorders are currently diagnosed in less than 3% of a
population of typically developing children between the ages of 3 and
17 years based on current statistics from the CDC (2013). To our
knowledge, this is the first study to describe the possible positive
impact of testosterone treatment on multiple symptoms of anxiety in
boys with 47,XXY. This study provides additional support to the com-
plex and possibly synergistic relationship between testosterone treat-
ment and behavioral manifestations in males with the additive
X chromosome (Samango-Sprouse et al., 2015). Our study supports
the findings of the randomized clinical trial study by Ross et al. that
social problems and anxiety problems are elevated in more than 30%
of the untreated population (Ross et al., 2017). Additionally, our study
also revealed novel elevated scores in anxious/depressed (32.5%),
thought problems (35%), and internalizing problems (52.5%). Our find-
ings and several studies support that anxiety is an integral part of the
phenotypic presentation of 47,XXY and may be impactful on behav-
ioral manifestations and dysfunction (Miers, Ziermans, & van Rijn,
2017; Ross et al., 2017; Samango-Sprouse et al., 2015).
These results further indicate that testosterone may be possibly
affecting behavioral outcome in boys with 47,XXY early in life and not
only in adolescence (Ross et al., 2012; Samango-Sprouse et al., 2015;
Samango-Sprouse, Sadehin, et al., 2013). Our study results suggest
that anxiety may be amenable to hormonal treatment early in life in
the majority of boys with 47,XXY. Additionally, this study provides
further credence to a “window of opportunity” for reducing character-
istic features of 47,XXY with the two possible factors of prenatal diag-
nosis and testosterone treatment.
There were fewer reported symptoms in the treated group
related to affective disorders, specifically thought problems, total
problems, and affective problems. Interestingly, a selective subset of
treated boys with 47,XXY remained impacted by anxiety problems
(27.5%), internalizing problems (35%), and affective problems (25%).
This possible lack of responsiveness to the hormonal treatment raises
several queries: could this be related to testosterone resistance
observed in older individuals with 47,XXY; is the parental origin of the
additive X influential in response to treatment; and, finally, is family
history of affective disorders related to treatment responsiveness?
These hypotheses warrant further investigation to develop the opti-
mal and personalized treatment for a child with 47,XXY and his family.
This study does have some limitations in that these findings are
not the result of a randomized clinical trial but rather a comparative
cross-sectional investigation of a very large cohort of boys with
47,XXY within a longitudinal, natural history study. Although we can-
not determine causality, we have demonstrated that the group
SAMANGO-SPROUSE ET AL.
differences are not due to the participants' demographic history.
There were no significant differences between the HRT and non-HRT
groups in maternal and paternal age and education, race, birthweight,
and gravida. By eliminating these as confounding factors, we must
consider that the differences between the two groups are related to
the effects of HRT on symptoms of anxiety in boys with 47,XXY. In
addition, our findings support the previous clinical trial on the inci-
dence of anxiety in the untreated group and further expand the find-
ings of the treated group in the clinical trial by Ross et al. (2017).
Although anthropomorphic measurements in the HBT group were
limited, growth parameters were previously examined in the boys with
EHT and untreated group at 36 and 108 months and there were
no significant differences in height (Sprouse, Stapleton, Sdeghin,
Gropman, & Samango-Sprouse, 2013). In that study, the treated boys
weighed more than those in the untreated group. Although body mass
composition was not completed, the findings were similar to Change
et al. (2015) with treated individuals weighing more but having no dif-
ference in height. Change et al. (2015) described higher lean body
mass and lower total fat mass and body fat percentage (Change et al.,
2015), suggesting a positive impact from HRT.
Boys with 47,XXY in the group who received EHT and HBT had
significantly fewer reported behavioral problems than boys with only
EHT on the SCARED and the CBCL. This is the first study to describe
a possible positive effect of multiple testosterone treatments on
behavioral manifestations. Although our findings are similar to the
results of the clinical trial findings of Ross et al. (2017), the timing and
the duration of treatment are quite different. The similarities of the
results lend further support to the possibility that there is a relation-
ship between androgen deficiency and behavioral manifestation. Fur-
ther investigation is necessary to explore the relationship between
the timing and frequency of biological treatment and individual
responses to HRT to develop effective and individualized treatments
for boys with 47,XXY.
ACKNOWLEDGMNTS
We would like to express our deep gratitude to all our participants
and their families and The Focus Foundation for their continued fund-
ing of our investigative studies.
ORCID
Carole Samango-Sprouse https://orcid.org/0000-0001-9941-0568
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How to cite this article: Samango-Sprouse C,
Lasutschinkow P, Powell S, Sadeghin T, Gropman A. The inci-
dence of anxiety symptoms in boys with 47,XXY (Klinefelter
syndrome) and the possible impact of timing of diagnosis and
hormonal replacement therapy. Am J Med Genet Part A. 2019;
1–6. https://doi.org/10.1002/ajmg.a.61038