Clinical Anatomy 29:606619 (2016)

REVIEW

Anatomical and Clinical Aspects

of Klinefelters Syndrome
REBECCA J. BIRD AND BRADLEY J. HURREN*
Department of Anatomy, University of Otago, Dunedin, 9016, New Zealand

Klinefelters syndrome, the most common sex disorder associated with chro-
mosomal aberrations, is characterized by a plethora of clinical features. Param-
eters for diagnosis of the syndrome are constantly expanding as new
anatomical and hormonal abnormalities are noted, yet Klinefelters remains
underdiagnosed and underreported. This review outlines the key anatomical
characteristics associated with the syndrome, which are currently used for clin-
ical diagnosis, or may provide means for improving diagnosis in the future.
Clin. Anat. 29:606619, 2016. VC 2016 Wiley Periodicals, Inc.

Key words: Klinefelters syndrome; anatomy; sex chromosome disorders; poly-

ploidy; gonads; sex characteristics

INTRODUCTION through amniocentesis screening (Abramsky and

Klinefelters syndrome (KS) was rst described in
nine adult males presenting with small testes, azoo-
spermia (absence of viable, motile sperm in semen)
and gynecomastia (increase in breast tissue size in
males) (Klinefelter et al., 1942). In its initial descrip-
tion, KS was classied largely as an endocrine disor-
der, based on the clinical features of reduced
testicular volume and increased levels of urinary fol-
licle stimulating hormone (FSH) but with normal or
slightly reduced Leydig cell function, indicative of
hypergonadotropic hypogonadism (Klinefelter et al.
1942). Almost two decades later, following identica-
tion of extra sex chromatin bodies in buccal mucosa
(Bradbury et al, 1956; Plunkett and Barr, 1956), cyto-
genetic testing revealed the presence of an extra X
chromosome in males diagnosed with KS (Jacobs and
Strong, 1959), and KS gained recognition as a chro-
mosomal disorder. The majority of KS males have a
47XXY genotype, with increased supernumeracy of
the X chromosome and some mosaicisms, wherein
different genotypes are present in two or more cell
lines in one person, also classied under the syn-
drome (Lanfranco et al. 2004; Bojesen and Gravholt,
2007).
The incidence of KS is believed to be approximately
1 in 600 births (Bojesen et al., 2003), making it the
most common sex disorder and most common genetic
cause of hypogonadism in males (Lanfranco et al.
2004). True prevalence may be higher as only 10% of
KS males are estimated to be identied prenatally
Chapple, 1997), often inadvertently because of the
increasing number of foetal screenings with increasing
maternal age (Bojesen et al., 2003). An additional
26% are identied in childhood, adolescence, or adult-
hood (Abramsky and Chapple, 1997), leaving almost
two thirds of KS males likely to remain undiagnosed.
Identication during childhood, estimated at <10% of
expected numbers (Bojesen et al., 2003), appears
largely as a result of exploring underlying causes of
learning and behavioral disabilities and language
delays (Zeger et al., 2008; Messina et al., 2012), as
few physical phenotypes classically associated with KS
develop prior to puberty, or may be close enough
to normal that clinical features are overlooked
(Aksglaede et al., 2008). For those diagnosed during
adolescence or adulthood, presentation with the
Abbreviations: ADHD, attention deficit hyperactivity disorder;
BMD, bone mineral density; FSH, follicle stimulating hor-
mone; hCG, human choronic gonadotropin; KS, Klinefelters
syndrome; LH, luteinising hormone; TBV, total brain volume
*Correspondence to: Dr. Bradley Hurren, Department of Anat-
omy, University of Otago, PO Box 913, Dunedin, 9054, New
Zealand. E-mail: bradley.hurren@otago.ac.nz
Both authors contributed equally to this work.
Received 21 December 2015; Revised 7 January 2016;
Accepted 15 January 2016
Published online 21 February 2016 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/ca.22695

C
V 2016 Wiley Periodicals, Inc.

classic symptoms of gynecomastia and hypogonadism
tend to be the key identifying factors (Bojesen and
Gravholt, 2007), as well as 1520% of KS males
being identied as a result of investigations into
underlying causes of infertility (Abramsky and Chap-
ple, 1997). That >60% of males with KS are thought
to go undetected may be due to a lack of pronounced
features, as the genotype does not necessarily imply
presence of any of the classic phenotypic features. It
has also been suggested that social stigma surround-
ing the syndrome may reduce self-reporting, as early
studies on KS often focused on small numbers of indi-
viduals in prisons and psychiatric wards (Stochholm
et al., 2012). This resulted in tenuous links between
KS and criminality, violent behavior, and psychosis,
which more recent studies have largely dismissed
(Visootsak and Graham, 2006). A lack of awareness
of the syndrome among clinicians, despite its preva-
lence, may also be a cause of delays in diagnosis
(Lanfranco et al. 2004).
ETIOLOGY
As previously noted, KS is characterized by at least
one additional X chromosome. Between 80% and
90% of KS males are 47XXY, while the remaining
10%20% display increased supernumeracy of sex
chromosomes, such as 48XXYY, 48XXXY and
49XXXXY, various mosaicisms, particularly 46XY/
47XXY, or X chromosomes that are structurally abnor-
mal (Linden et al., 1995; Foresta et al., 1998;
Kamischke et al., 2003; Lanfranco et al., 2004). KS
males with variants resulting from increased aneu-
ploidy are likely to have more severe clinical features
(Ferguson-Smith, 1965; Ferguson-Smith, 1966; Lin-
den et al., 1995; Tartaglia et al., 2011) and may be
diagnosed earlier in life and more frequently because
of the increased incidence of dysmorphic body and
facial features as well as an increased likelihood of
cognitive and behavioral disorders (Tartaglia et al.,
2011). Conversely, many individuals with mosaicism
may present few or none of the classic clinical fea-
tures (Ferguson-Smith, 1966). This, along with the
variation in phenotypes amongst all known KS males
provides a strong argument for a role of increased
gene dosages, skewed inactivation of the X chromo-
some, parental imprinting or CAG repeat polymor-
phism, resulting in less active androgen receptors all
inuencing prevalence and severity of phenotypic fea-
tures (Iitsuka et al., 2001; Zitzmann et al., 2004;
Stemkens et al., 2006). We have observed that some
reports in the literature prefer to reserve the KS des-
ignation for diagnosed adults being treated for clinical
features of the disorder, and refer to fetal and child-
hood KS individuals by their genotype only. For sim-
plicity and to take into account the wealth of
information spanning seven decades which includes
reports published prior to the availability of chromo-
somal diagnosis, all individuals who may be classied
as having KS either through karyotype screening or
clinical presentation are referred to as KS males within
this review. Any variations of clinical features related
Klinefelters Syndrome 607
to varying genotypes is specically noted where
relevant.
Analysis using X-linked markers allows identica-
tion of parental origin of the additional X chromo-
some(s) indicative of KS (Iitsuka et al., 2001).
Maternal origin occurs in 50%60% of cases, with
40%50% of additional chromosomes originating
paternally (Jacobs et al., 1988; Lorda-Sanchez et al.,
1992; Iitsuka et al., 2001; Thomas and Hassold,
2003). When of paternal origin, nondisjunction result-
ing in the extra chromosome occurs only during meio-
sis I (Thomas and Hassold, 2003), while
nondisjunction of a maternally originating aneuploidy
occurs during meiosis I in around 48% of cases, 29%
during meiosis II, and the remaining occurrences
either during mitotic divisions of the zygote or of
unidentiable origin (Thomas and Hassold, 2003).
Little conclusive evidence exists to link parental
age or origin with the presentation or severity of all
known clinical features (Jacobs et al., 1988; Lorda-
Sanchez et al., 1992). Increased risk of nondisjunction
of older gametes may suggest a link to the age of the
parents, and several studies have shown that older
males have a higher rate of aneuploidy in spermato-
zoa (Lowe, et al., 2001; Lanfranco et al. 2004). How-
ever, Carothers and Filippi (1988) described the age
of the father as having no effect on prevalence or
severity of clinical features of KS, but found a link
between maternal age and KS incidence, supporting
earlier ndings (Hook et al., 1983,; Ferguson-Smith
and Yates, 1984). Additionally, one study has shown a
link between paternal origin, motor and speech
impairment, and body size (Stemkens et al., 2006).
OVERVIEW OF GENERAL FEATURES
The varied clinical features of KS, of which there
are no clear denitions, may also account for much of
the underdiagnosis, particularly in prepubescent
males, as several features show variation based on
age and genotype, as well as other inuencing factors.
Attempts have been made to present a conclusive
phenotype for KS (Simpson et al., 2003; Bojesen and
Gravholt 2007; Aksglaede et al., 2011; Pacenza et al.,
2012; Ranganath and Rajangam, 2012), yet it is clear
from these studies that few KS males will present with
a complete array of the known clinical features simul-
taneously (Radicioni et al., 2010). Klinefelter et al
(1942) described KS males as tall, broad at the hip
and narrow at the shoulder, with absent or sparse
body hair, gynecomastia, azoospermia, small testes,
and elevated FSH. Many of these external features are
exemplied in Figure 1 below (Paduch et al., 2009),
which shows the variation in genitalia and body com-
position between a KS and non-KS male.
A growing body of research has broadened these
parameters to include behavioral (Tartaglia et al.,
2010) and learning difculties (Rovet et al., 1996),
unfavorable body composition (Aksglaede et al.,
2008), and decreased bone mineral density (Bojesen
et al., 2011) amongst others. It is also important to
note that some KS males present with no severe clini-
cal features, and lead normal lives, while others
608 Bird and Hurren
exhibit developmental, physical, behavioral, and
learning disabilities and disorders. Whether identied
clinical features of KS are because of hormonal imbal-
ances or the additional X chromosome(s) present in
the genotype is largely unknown, and for many fea-
tures a combination of both inuences seems likely.
Much of the data on clinical features and disease
states associated with KS are based on individual case
studies. While large cohort epidemiological studies
(Price et al., 1985; Hasle et al., 1995; Swerdlow
et al., 2001; Swerdlow et al., 2005; Bojesen et al.,
2006a) have begun to emerge, there is still much
unknown about the long-term effects of KS, although
this disorder does appear to span multiple body sys-
tems (Bojesen and Gravholt, 2007). Epidemiological
data from Bojesen et al. (2004) and Swerdlow et al.
(2005) indicate an increased mortality rate, on aver-
age 40% higher than non-KS males, with a median
survival reduction of 2.1 years. An earlier study sug-
gested that this decrease in life span may be up to as
much as 5 years when compared to non-KS males
(Price et al., 1985). Disease states contributing to this
increased risk range from cancers and autoimmune
diseases to nervous system dysfunction and visceral
complications (Swerdlow et al., 2001; Bojesen et al.,
2004; Swerdlow et al., 2005; Bojesen and Gravholt,
2011). In a study spanning 44 years, an increased
prevalence of breast cancer, lung cancers, and non-
Hodgkins lymphoma was noted, while a decreased
risk of prostate cancer was also observed, possibly
because of the androgen deciency characteristic of
KS (Swerdlow et al., 2005). An increased incidence of
rare mediastinal germ cell tumors has also been noted
in KS males (Nichols et al., 1987, Hasle et al., 1995),
including in prepubertal males experiencing preco-
cious puberty (Vo lkl et al. 2005). Disease states asso-
ciated with KS extend beyond cancers. Autoimmune
disorders have been noted in some KS males, such as
systemic lupus erythematosus (Stern et al., 1977),
rheumatoid arthritis (Kobayashi et al., 1994), and pro-
gressive systemic sclerosis (Kobayashi et al., 1991).
The risk of systemic lupus erythrematosus is 14 times
greater than for non-KS males, a similar risk to that of
women, possibly because of gene dosing from the
additional X chromosome (Sawalha et al., 2009).
Deep vein thrombosis, hypostatic ulceration, and pul-
monary embolism also occur more frequently than in
non-KS males (Campbell and Price, 1981). Other vis-
ceral diseases and complications are outlined later in
this review.
These increased risks for mortality and morbidity
highlight the need for improved and early diagnosis of
KS. Strong arguments persist in the literature that
early treatment with testosterone therapy may
improve secondary sexual development and body
morphology, and mitigate the long-term effects of
hypogonadism based on studies carried out on KS
males (Mhyre et al., 1970; Nielsen et al., 1988) or
from speculation following positive results on non-KS
males with similar clinical features (Behre et al.,
1997; Wang et al., 2004). Lanfranco et al. (2004)
suggest that a likely cause of the underdiagnosis of
KS is a lack of understanding about the clinical fea-
tures of the syndrome.
DIAGNOSIS AND SCREENING
Diagnosis of KS generally occurs at three key peri-
ods: prenatally, during childhood, or following adoles-
cence (Aksglaede and Juul, 2013). Identication via
karyotyping is generally required for a comprehensive
diagnosis of KS at all ages; however, chromosomal
analysis is rarely performed without clinical examina-
tion indicating a need for genetic investigations. Some
ethical concerns have been raised regarding prenatal
screening as termination rates of >70% following pre-
natal diagnosis of KS have been reported in Canada
(Christian et al., 2000), Israel (Sagi et al., 2001),
Denmark (Bojesen et al., 2003), Switzerland (Ham-
amy and Dahoun, 2004) and the USA (Shaffer et al.,
2006). Regardless, strong arguments have been
made regarding the need for both improved rates of
diagnosis, along with early identication of the syn-
drome, to allow time for genetic counselling (Linden
et al., 2002) and early intervention, whether in the
form of hormonal treatment (Simpson et al., 2003) or
therapies to reduce learning and behavioral issues.
Adding to this are studies which suggest that pre-
natally screened KS males exhibit better development
and fewer learning and behavioral disorders than
those diagnosed later in life (Linden et al., 2002; Gir-
ardin et al. 2009). Time and cost are also key consid-
erations for screening and advances are being made
for early detection mechanisms that are inexpensive,
quick and effective for screening of aneuploidies in
large populations. Examples include using multiple
ligation-dependent probe amplication (Yan et al.,
2011), or methylation specic qPCR (Mehta et al.,
2014) to identify chromosomal aneuploidy, or through
identifying increased copy number of the androgen
receptor gene via qPCR (Ottensen et al., 2007).
Despite this, presentation with one or more pheno-
typic features associated with KS is more likely to ini-
tiate investigations leading toward diagnosis during
childhood or adulthood, and as such it is important
that prevalence and variations in anatomical and
physiological features are understood. Variations
related to genotype or age are also important to note
as physical appearance of prepubertal KS males is
often normal or mild enough to be easily disregarded
(Aksglaede et al., 2008; Zeger et al., 2008) and the
classic reproductive and endocrine features that
dene the syndrome are often only apparent from late
stages of puberty.
METHODS OF PRENATAL SCREENING
Karyotyping is currently the most common means
of prenatal identication (Bojesen et al., 2003) since
the majority of KS foetuses do not present with an
abnormal ultrasound scan result. However, as with
several other chromosomal disorders such as triso-
mies 12, 18 and 21, and in 47XXX and 47XYY (Chi-
tayat et al., 2011), an increased nuchal translucency
caused by uid accumulation in the posterior neck
region has been observed in some instances between
the 11th and 14th week of gestation (Spencer et al.,
2000; Zoppi et al., 2002). Other rst trimester

prenatal indicators of chromosomal abnormalities,
such as increased maternal free-beta human choronic
gonadotropin (hCG) and pregnancy-associated plasma
protein A, levels have also been noted in some instan-
ces of KS (Spencer et al., 2000). In the second trimes-
ter, elevated alpha-fetoprotein, hCG, and unconjugated
estriol may also indicate chromosomal aneuploidies
(Heyl et al., 1990; Barnes-Kedar et al., 1993). As these
indicators are not specic for KS, karyotyping therefore
provides a more accurate prenatal diagnosis, although
presence of X chromosome aneuploidy is not indicative
to the range of severity of any clinical features later in
life, as evidenced by the broad spectrum of prevalence
and severity of features in KS males possessing the
same genotype (Radicioni et al., 2010)
ANATOMICAL AND CLINICAL
PRESENTATIONS
Presentation with atypical anatomy and clinical fea-
tures is a key identier for diagnosis in all KS males.
As previously noted, there is considerable variation in
prevalence of these features inuenced by age (Boje-
sen and Gravholt, 2007; Zeger et al., 2008), genotype
(Lanfranco et al. 2004), and socioeconomic factors
(Bojesen et al., 2011). Additionally, while there is a
wealth of data available on KS, relatively few popula-
tion or longitudinal studies exist, and many reports
include small cohorts. Indeed, for many of the
recently identied phenotypes and morbidities associ-
ated with this syndrome, case studies dominate the
literature. Many studies acknowledge such limitations,
but ascertainment bias because of the underreporting
of the syndrome, small cohorts and other limitations
should be considered and caution taken when relating
such reports to the overall population of KS males.
Considering the variation of the phenotype (Simpson
et al., 2003), and the range of factors inuencing
reported morbidities and causes of mortality associ-
ated with the syndrome (Bojesen and Gravholt,
2011), it is difcult to provide a denitive explanation
for the clinical features presented. As is often the cir-
cumstance with genetic disorders, it is difcult to
prove an association between pathology of one sys-
tem as the cause of death, and if it is indeed attribut-
able to the genetic dysfunction itself. This in turn
makes it difcult to assume that the dysfunction may
be a consistent nding or manifestation of the disor-
der in the entire KS population. Because hypogonad-
ism itself can have widespread effects due to
endocrinological imbalances and systemic metabolic
syndromes, the growth and maintenance of many tis-
sues in the body are potentially affected (Bojesen
et al., 2006; Andersen et al., 2008). Below we have
outlined the frequently noted anatomical characteris-
tics of KS, across all affected body systems.
REPRODUCTIVE AND ENDOCRINE
ABNORMALITIES
The effect of KS on the reproductive and endocrine
systems dominates the literature, and for good cause.
Klinefelters Syndrome 609
Not only do the majority of the classical features of
KS fall within these boundaries, as expanded on
below, but additionally many of the other noted fea-
tures such as body composition (Bojesen et al.,
2006a) and neural development (Skakkebk et al.,
2014) may be inuenced by the hormonal imbalances
characteristic of the syndrome.
Common characteristics of the syndrome are
abnormal genitalia and gonads, with a progressive
degeneration of testicular structure and function from
childhood into adulthood. Although some infants may
present with hypospadias (malformation of urethral
opening, on underside of penis) (Cauldwell and Smith,
1972; Hodhod et al., 2015) or cryptorchidism (unde-
scended testes) (Schwartz and Root, 1991), the
gonads and genitalia of KS infants generally fall within
normal expectations (Ratcliffe, 1982). Prepubertal KS
males may have a penis that is normal (Salbenblatt
et al., 1985) or reduced (Cauldwell and Smith 1972;
Ross et al., 2005; Zeger et al., 2008) in size. In adults
although true microphallus is rare, around a quarter of
diagnosed KS males exhibit impaired penile develop-
ment (Paulsen et al., 1968; Ranganath and Rajangam,
2012). Some KS males may experience low libido
(Paduch et al., 2008), and sexual dysfunction is com-
mon (Corona et al., 2010).
Testicular volume may be normal or signicantly
reduced (Ross et al., 2005; Zeger et al., 2008) com-
pared with non-KS males of similar age prior to and at
the start of puberty, with inhibition of normal growth
from midpuberty onwards (Topper et al., 1982). This
results in postpubertal small testes under 2.5 cm in
length and with a volume of 45 ml, below the norm of
10 ml (Wikstro m et al., 2004; Aksglaede et al., 2008).
Small testes are observed in 95% (Wikstro m and Dun-
kel, 2011) to 100% (Smyth and Bremner, 1998; Pace-
nza et al., 2012) of the post-adolescent KS males.
The reduction in testicular size noted in some studies
prior to puberty suggests an early reduction of seminifer-
ous tubule structure and fertility (Ross et al., 2005;
Zeger et al., 2008). Slow degeneration of testicular
structure during childhood, which increases during
puberty to result in widespread hyalinization and brosis
of the seminiferous tubules, is well recognized as charac-
teristic of KS (Aksglaede and Juul, 2013). Wikstro m
et al. (2004) noted that only 50% of peripubertal KS
males had germ cells present in their testes, supporting
the evidence that degeneration of fertility occurs early.
Germ cells are arrested at spermatogonia and early
spermatocyte stages, resulting in cells undergoing apo-
ptosis rather than meiosis at the commencement of
puberty (Wikstro m et al., 2006a). As a result, ejaculate
contains sperm in <10% of KS adults (Lanfranco et al.
2004). Despite impairment of Leydig cells occurring
from late puberty (Topper et al.,1982) illustrated by the
androgen deciency common to the syndrome (Aks-
glaede 2007), normal morphology of these cells is
observed in 80% of cases (Regadera et al., 1991).
HORMONAL ASPECTS
Since its initial description, high levels of FSH and
luteinising hormone (LH), paired with normal or
610 Bird and Hurren
subnormal levels of testosterone have been a key fea-
ture of KS males, and these abnormal serum concen-
trations are seen in the majority of diagnosed adults
(Wang et al., 1975; Aksglaede et al., 2011; Pacenza
et al., 2012), potentially accounting for some of the
clinical features associated with KS. An understanding
of the relative levels of these, and other hormones
prior to and during puberty may shed more light on
factors inuencing development of these clinical fea-
tures, although some disagreement exists in current
reports regarding temporal variations to hormonal
levels.
There is much discussion in the literature as to the
role of minipuberty in KS infants and later develop-
ment. Occurring at approximately three months of
age, minipuberty has been suggested as a key period
of inuence for development and fertility in KS males
(Hadziselimovic et al., 2005) as genital and gonadal
development is inuenced by this early activation of
the hypothalamic-pituitary-gonadal axis (Kuiri-
Ha nninen et al., 2014). There is a lack of agreement
in the literature regarding androgen deciencies in
infancy of KS males. Lahlou et al. (2004) and Ross
et al. (2005) reported low testosterone levels during
minipuberty, while Cabrol et al. (2011) and Aksglaede
et al. (2007) noted observations of low-normal and
high-normal levels respectively. General agreement
exists, however, that childhood levels of teststerone,
LH and FSH (Salbenblatt et al., 1985), prostate-
specic antigen (Kamischke et al., 2003; Wikstro m Dunkel, 2011; Pacenza et al., 2012). Indeed, KS is a
et al., 2006a), anti-Mu llerian hormone (Aksglade
et al., 2011), inhibin B (Christiansen et al., 2003), and
insulin like factor 3 (INSL3) (Wikstro m et al., 2006) all
fall within normal ranges prior to puberty.
Onset of puberty in KS occurs at a similar age to
non-KS males (Topper et al., 1982; Christiansen
et al., 2003), supporting evidence that testosterone
levels are sufciently normal to initiate both puberty
and initial development of secondary sex characteris-
tics (Salbenblatt et al., 1985; Wikstro m et al., 2006b).
Onset of puberty is accompanied by expected
increases in testosterone, inhibin B, and INSL3
(Wikstro m and Dunkel, 2011). By midpuberty, testos-
terone and INSL3 levels drop toward the lower end of
normal range (Salbenblatt et al., 1985; Wikstro m cessful births reported soon after (Palermo et al.,
et al., 2004) indicating abnormal Leydig cell function,
while a sharp decrease in inhibin B to undetectable
levels is typical by the end of puberty and throughout
adulthood (Christiansen et al., 2003; Wikstro m et al.,
2004). Together, these atypical hormonal concentra-
tions partially explain the lack of spermatogenesis
occurring in most KS males at this time (Aksglaede
et al., 2008). Gonadotropins increase from midpub-
erty (Topper et al., 1982) with an earlier and greater
increase of FSH than LH occurring (Wikstro m et al.,
2006a; Aksglaede et al., 2011). These high concentra-
tions of gonadotropins are consistent with the hyper-
gonadotropic hypogonadism characteristic of KS
adults. FSH levels at a greater concentration than LH
are commonly exhibited in most KS adults (Smyth
and Bremner, 1998; LanFranco et al., 2004).
As with other features of KS, there is variance of
reported testosterone levels in adults from subnormal
to normal in range (Paulsen et al., 1968; Lanfranco
et al., 2004; Bojesen et al., 2006a; Aksglaede et al.,
2011). An increased estradiol/testosterone ratio has
been noted in KS males (Hsueh et al., 1978), with
estradiol levels observed to be normal (Bojesen et al.,
2006; Ferlin et al., 2011) or elevated (Lanfranco et al.
2004). Reduction in estradiol via aromatase inhibitors
was described in one study as increasing testosterone
suggesting a possible role in improving sperm produc-
tion in some KS males (Raman and Schlegel, 2002).
As with other endocrine disorders, hormonal treat-
ment has been postulated to be benecial in mitigat-
ing some of the adverse effects. In particular,
testosterone therapies in small cohort, nonrandomized
studies, such as the one by Nielsen et al. (1988) have
shown positive effects in 75% of patients, such as
improved strength and endurance, improved mood
and concentration, and a decrease in fatigue. How-
ever, a lack of large-scale studies prevents any clear
conclusions into the benets of such therapy for all KS
males.
FERTILITY
The degeneration of the seminiferous tubules and
general androgen deciencies make it unsurprising
that azoospermia and infertility are common charac-
teristics of KS, with infertility noted in almost all KS
adults (Smyth and Bremner, 1998; Wikstro m and
common genetic cause of infertility, with 3% of infer-
tile men and 11% of azoospermic males being diag-
nosed with the syndrome (van Assche et al., 1996,
Foresta et al., 1999). Although the majority of non-
mosaic KS males present with azoospermia, it is
worth noting that not all KS males are completely
infertile. Some motile sperm have been identied in
the seminal uid of subjects (Aksglaede et al., 2009)
and some successful spontaneous paternity has been
reported (Laron and Topper, 1982; Terzoli et al.,
1992). Recent advances in assisted fertility have also
allowed KS males to become biological fathers, with
the rst successful testicular sperm extraction occur-
ring in the mid-1990s (Tournaye et al., 1996) and suc-
1998). In their review on KS, Wikstro m and Dunkel,
(2011) noted that than 100 healthy births following
assisted fertility have been reported. In these, and in
rare cases of spontaneous natural paternity, only one
case of chromosomal aneuploidy has been reported
(Ron-El et al., 2000), indicating that KS is unlikely to
be hereditary.
ATYPICAL SECONDARY SEX
CHARACTERISTICS
The abnormalities in hormonal ranges, particularly
that of testosterone during and after puberty are,
likely causes of effected development of secondary
male characteristics. A reduction in hair growth is
common (Ratcliffe, 1982), with 6080% of KS males
exhibiting sparse or absent facial hair, and 30%60%
with sparse or absent pubic hair (Smyth and Bremner,

Fig. 1. The classic descriptions of men with KS are
based on the most severe cases of phenotypic abnormal-
ities. Most teenagers and young adults seen have typical
body proportions, arm span, and penile length as those of
their peers. The only obvious difference that is seen in all
men with KS is clearly visible difference in testicular size
1998). Development of gynecomastia in particular has
been a longstanding characteristic of KS, as noted in
all early descriptions of the syndrome (Klinefelter
et al., 1942), and is likely because of the increased
estradiol/testosterone ratio observed in many cases
(Hsueh et al., 1978). Gynecomastia may affect 30%
(Pacenza et al., 2012) to 88% (Ratcliffe, 1999) of KS
adults, although suggestions have been made that
reported incidences may not accurately reect true
prevalence because of underreporting and poor evalu-
ation of this feature (Visootsak et al., 2001). In one
study, 44% of prepubertal KS males presented with
gynecomastia, although it was noted that this is com-
mon during male puberty and perhaps not indicative
of the KS phenotype at this age (Zeger et al., 2008).
Of the KS boys under age 10 studied by Ratcliffe
(1999), some instances of the observed gynecomastia
were found to be transient. Breast cancer is common
in KS males, and gynecomastia may be considered a
premalignant state due to the imbalance of the estra-
diol/testosterone ratio. Klinefelter (1986) himself rec-
ommended surgical removal of tissue as a precaution.
The incidence of breast cancer in KS males may be as
high as 2030 times more than non-KS males (Brin-
ton, 2011).
BODY COMPOSITION
In many cases, abnormal morphology may provide
initial clues leading to later diagnosis of KS. Infants
Klinefelters Syndrome 611
between men with KS (very small testes) and men with
46,XY karyotype (normal size). Reprinted with permission
from Paduch et al., Semin Reprod Med, 2009, 27, 137
148, VC Thieme Medical Publishers. (http://thieme-con-
nect.com/products/ejournals/journal/10.1055/s-00000072)
with KS commonly present as normal with no or few
distinct clinical features (Lahlou et al., 2011), with
<3% of diagnoses occurring during infancy (Klecz-
kowska et al., 1988). Fifth nger clinodactylyl (curva-
ture of nger toward 4th nger) and other mild
congenital malformations have been noted in 26% of
KS infants (Robinson et al., 1979). Mild hypoplasia of
the midfacial region may be present at birth (Simpson
et al., 2003) although obvious facial dysmorphia is not
common in KS (Visootsak et al., 2001). KS neonates
are within the normal range for mean weight and
length (Visootsak et al., 2001), but with a head
appearing smaller in comparison to the size of the
body (Visootsak et al., 2001; Simpson et al., 2003).
Despite hypotonia noted in some cases (Ross et al.,
2005), gross and ne motor development prior to
nine months of age has been observed to be normal
(Tennes et al., 1977), with a mean age of ambulation
of 18 months (Lahlou et al., 2011).
In childhood, KS males may appear normal on ini-
tial examination; however clinodactylyl has been
reported in 74% of prepubertal KS males and hyper-
telorism (increased distance between the orbits) in
69% (Zeger et al., 2008). Mild elbow dysplasia and an
abnormally high arched palate have also been noted,
providing potential clues to clinicians to aid early diag-
nosis (Zeger et al., 2008). In the same study, 73% of
subjects had an increased height for their age (Zeger
et al., 2008), and a pronounced difference was noted
as early as age two (Zeger et al., 2008). As with
adults, the increase in height has been attributed to
612 Bird and Hurren
longer than normal lower limbs (Tanner et al., 1959;
Cauldwell and Smith, 1972).
On average, adult KS males are 2.5 cm taller than
non-KS males (Stemkens et al., 2006), as well as
having longer arms and legs (Tanner et al., 1959;
Cauldwell and Smith 1972), narrower shoulders and
broad hips (Klinefelter et al., 1942). Height in particu-
lar may be inuenced by an extra copy of the stature
related SHOX gene present on the additional X chro-
mosome rather than as a result of hypogonadism
(Tu ttelmann and Gromoll, 2010).
KS males also frequently present with an unfavora-
ble body composition with decreased muscle mass
and increased body fat (Aksglaede et al., 2008) partic-
ularly of the abdomen (Becker et al., 1966; Bojesen
et al., 2006a), and a BMI of >25 is common (Pacenza
et al., 2012). Hypogonadism and testosterone de-
ciency are recognized predictors of abdominal obesity
(Tsai et al., 2000; van den Bergh et al., 2001) and of
metabolic syndrome (Laaksonen et al., 2003).
Increased incidence of metabolic syndrome has been
observed in KS (Bojesen et al., 2006a) suggesting a
likely effect of the characteristic hypogonadism on
both body composition and increased risk of metabolic
syndrome (Ishikawa et al., 2008). However, KS males
may present with increased body fat mass prior to
puberty (Aksglaede et al., 2008), suggesting that
genotype, as well as testosterone deciencies, may
have a role in this characteristic. This is supported by
a report of testosterone treatment only partially
improving body composition in KS males, although it
is unclear whether adequate levels of testosterone
were administered in this study (Aksglaede et al.,
2008). The unfavorable fat-muscle body ratio is not
limited to post-pubertal KS males. In 75% of KS
males under 6 years of age, a tendency toward
abdominal adiposity has been observed (Ratcliffe
et al. 1999), and 7% of prepubertal males meet the
criteria for metabolic syndrome (Bardsley et al.,
2011). A quarter of KS children also exhibit insulin
resistance (Bardsley et al., 2011), with a signicant
increase in prevalence of diabetes in adult KS males
when compared to non-KS hypogonadic males noted
(Jiang-Feng et al., 2012). An increased risk of death
from diabetes has been observed in at least two epi-
demiological studies (Swerdlow et al. 2005; Bojesen
et al., 2006a).
MUSCULOSKELETAL MORPHOLOGY
Reduced strength of the quadriceps and biceps has
been observed in KS males (Bojesen et al., 2010),
along with a decreased aerobic capacity (Bojesen
et al., 2006b). Decreased muscle mass and strength
is also not limited to adults, with hypotonia being
noted in infants (Ross et al., 2005) as well as in pre-
pubertal KS males (Salbenblatt et al., 1985), with
Zeger et al. (2008) reporting 76% of KS boys pre-
senting with varying degrees of poor muscle tone.
Motor decits in KS males of this age are not uncom-
mon (Linden et al., 2002) and may be linked to this
observed decrease in muscle tone. As with other clini-
cal features, hypotonia of the trunk, limbs and face is
more pronounced in KS males with increased X chro-
mosome supernumeracy (Sprouse et al., 2013).
Reduced bone mineral density (BMD) is a
frequently-noted characteristic of KS (Horowitz et al.,
1992; Bojesen et al., 2011; Ferlin et al., 2011), which
is unsurprising given that general testicular degenera-
tion leading to hypogonadism is a risk factor for
reduced BMD and osteoporosis (Horowitz et al.,
1992). Although normal bone density of the lumbar
region prior to puberty has been observed (Aksglaede
et al., 2008), a decrease in BMD of the spine, hip, and
forearm in KS adults has been observed (Bojesen
et al., 2010; Ferlin et al., 2011), with between 25%
(Horowitz et al., 1992; Aksglaede et al., 2007) to
>40% (Ferlin et al., 2001; van den Bergh et al.,
2001) of KS males presenting with osteopenia or
osteoporosis. Furthermore, epidemiological studies
have shown an increased risk of mortality resulting
from fracture in KS adults (Bojesen et al., 2004). As
with many of the clinical features of KS, treatment
with testosterone may mitigate some of the effects,
particularly given that Seo et al. (2006) noted that
androgen deciency in KS males resulted in inad-
equate bone development and subsequent low bone
mineral density. In contrast, van den Bergh et al.
(2001) showed no effect of testosterone treatment on
BMD but other studies have shown improvement in
KS males with osteoporosis if treatment begins prior
to age 20 (Kubler et al., 1992), adding additional
weight to the need for early diagnosis.
Early studies focused on craniofacial features of KS
adults, describing a prominent facial prole particu-
larly noticeable in the mandible (Brown et al., 1993)
and noting a decreased anterior and posterior facial
height (Babic et al., 1991), a smaller calvarium, and
larger gonial angle (Ingerslev and Krieborg, 1978). An
increase in mandibular and maxillary prognathism
(protrusion of the jaw) has also been observed, which
the authors attributed to a smaller cranial base angle
(Ingerslev and Krieborg 1978). Brown et al. (1993)
hypothesized that KS may inuence the endochondral
growth of the cranial base, additionally affecting jaw
growth. Although no large-scale studies have focused
on facial morphology, rare oral abnormalities have
been noted in some KS males, such as cleft lip and
palate (Leon et al., 1959), and shallow palate (Gorlin
et al., 1965), with increased X chromosome supernu-
meracy believed to increase the frequency of cleft lip
and palate (Fraser et al., 1961; Scherz and Roeckel,
1963).
Abnormalities to the shape and size of tooth crowns
have been observed with up to 30% of KS males
found to have mild hypotaurodontism (enlargement of
pulp chamber and body of molars) of the second or
third molars compared with a prevalence of 2.5% in
the general population (Varrela and Alvesalo, 1988),
likely because of the inuence of extra X chromo-
somes on enamel thickness (Townsend and Alvesalo,
1985). In this regard, genotype, rather than hormonal
inuence appears to be a factor, with Keeler (1973)
hypothesizing that the genetic inuence of KS on inci-
sor development begins as early as three months
before birth, while the effect on the rst permanent
molars spans from the second trimester of gestation

to 9 or 10 years. There is a lack of data on craniofacial
features prior to puberty, although Zeger et al. (2008)
reported a slight increase in mean head circumference
in KS males aged 214 years. The absence of recent
investigations into craniofacial morphology associated
with KS may be because of (i) the subtleties of differ-
ences compared with non-KS males making these fac-
tors poor identiers of the syndrome, and (ii) the
relative lack of long-term negative effects as a result
of these differences compared with more severe fea-
tures associated with other clinical features of KS.
MUSCULOSKELETAL DISORDERS
A variety of musculoskeletal disorders have been
described in case studies, although few epidemiologi-
cal studies have been performed to understand links
between the syndrome and these disorders. Common
disorders noted include 5th nger clinocactylyl, pes
planus, asymmetrical hip rotation, radio ulnar synos-
tosis, scoliosis and kyphosis, as well as both pectus
carinatum and pectus excavatum (bowing outward
and inward of the sternum, respectively) (Simpson
et al., 2003), all of which have been observed in KS
males at various ages and at a range of severities,
with increased aneuplodies more likely to present with
these disorders (Tartaglia et al., 2011; Sprouse et al.,
2013). Muscular dystrophy has been observed in one
KS patient (Zeitoun et al., 1997), and bilateral aplasia
of the mandibular ramus and condyle in another
(Fryns et al., 1996). Rare Perthes disease has been
noted in one instance in a KS male (Hall et al., 1979),
while a rare multiple pterygium syndrome, character-
ized by webbing of the neck, elbows and knees and
small stature, was noted in an 11-year-old KS male
(Nur et al., 2013). Currently no data exist to provide
denitive incidences amongst the KS population of
these abnormalities. In general, it appears that skele-
tal abnormalities increase in severity with increasing
chromosomal supernumeracy (Linden et al., 1995).
NEUROANATOMICAL AND
NEUROBEHAVIORAL ASPECTS
Whilst KS has profound phenotypic traits, predomi-
nantly in the reproductive system and in terms of
physical appearance, reports in the literature on the
physical manifestation of the disorder in the nervous
system are inconsistent and often conicting (Skakke-
bk et al., 2014). However, there are correlations
between behavioral patterns and KS, which indicates
possible dysfunction or decit in normal neuroanat-
omy and neurocircuitry. It is important to note that
there are lines of evidence to suggest that gonadal
sex steroids have pre- and post-natal effects on brain
development and the overall structural organization of
the central nervous system (Geschwind and Gala-
burda, 1985; Witelsen, 1989; Berenbaum and Beltz,
2011; Lombardo et al., 2012). However, reports pub-
lished by groups directly examining the inuence of
sex steroids and brain structure often conict. This is
evident in the studies by Patwardhan et al (2000) and
Klinefelters Syndrome 613
Itti et al (2006), with the former reporting that KS
patients that did not receive testosterone treatment
had smaller temporal volumes than patients that did,
and the latter describing no changes in brain volume
upon testosterone administration. There is evidence
to suggest that sex steroid levels during development
can inuence cognitive skills and behavior, with gen-
der specic differences in task performances that may
be because of differences in gonadal steroid levels
during different developmental periods (Geschwind
and Galabruda, 1985; Collaer and Hines, 1995;
Geschwind et al., 2000). What will follow is a dissemi-
nation of some of the key existing literature on the
neuroanatomy of KS itself, and some of the manifes-
tations it can have in terms of behavior and neurologi-
cal function.
Longitudinal studies have established that one of
the major behavioral identiers of KS is learning dif-
culties during early childhood (Rovet et al., 1996).
This usually manifests as a language-based learning
disability, both in articulating speech and compre-
hending verbal language, as well as understanding
written language (Mandoki et al., 1991; Rovet et al.,
1996; Boada et al., 2009). Throughout childhood and
into adolescence and adulthood, learning difculties
are apparent and are exacerbated over time
compared with age-matched non-KS individuals
(Geschwind et al., 2000). These differences in aca-
demic ability include, but are not limited to, reading,
arithmetic, problem solving, language comprehension,
speech, and spelling (Leonard et al., 1982; Stewart
et al., 1982; Bender et al., 1983, 1991, 1993; Nielsen
and Sorenson, 1984; Graham et al., 1988; Rovet
et al., 1996; Geschwind et al., 2000). Interestingly, all
of these functions that show decit in KS are attrib-
uted to parts of the brain associated with complex
tasks such as language and problem solving, usually
processed in the frontal and pre-frontal areas of the
cortex, which are regions associated with executive
function (Geschwind et al., 2000; Alvarez and Emory,
2006). Furthermore, behavioral disorders such as
attention decit hyperactivity disorder (ADHD), classi-
cally associated with dysfunction of the prefrontal
cortex (Cortese et al. 2012), have been shown to
have a higher prevalence in KS individuals compared
to age matched controls (Bruining et al., 2009). A
recent functional MRI study provided clear evidence
for a decit in processing abilities in language centres
and other cognitive areas of the brain between KS
patients and controls (Steinman et al., 2009). In this
study, a verb generation task was used whilst activity
levels in the prefrontal cortex, Brocas area, hippo-
campus and other language association areas were
measured. During the task, these language associa-
tion and planning areas had markedly reduced activity
levels in KS patients compared with controls (Fig. 2
below, reproduced with permission from the original
manuscript), indicating an impaired ability to process
and carry out the language-related task (Steinman
et al., 2009).
When assessing the neuroanatomical phenotype of
KS, it is of particular note that the total brain volume
(TBV) of KS individuals is consistently reported to be
smaller than non-KS individuals, with reductions in
614 Bird and Hurren
Fig. 2. A: Control subjects exhibited regions of BOLD
activity during the verb generation task involving left
brain regions associated with language recall, processing
and generation. B: KS subjects exhibited a small region
BOLD activity during the verb generation task in the cor-
responding left brain regions associated with language
recall, processing and generation. Reprinted with permis-
sion from Steinman et al., Dev Disabil Res Rev, 2009, 15,
295308 V C John Wiley and Sons. (http://onlinelibrary.
wiley.com/journal/10.1002/(ISSN)1940-5529). [Color
gure can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
volume being attributed to both lowered total gray and
white matter volumes (Warwick et al., 1999; Warwick
et al., 2003; Shen et al., 2004; DeLisi et al., 2005;
Giedd et al., 2007; Bryant et al., 2011; Skakkebk
et al., 2014). Furthermore, this decrease in gray and
white matter is consistent across both hemispheres
(Rezaie et al., 2009; Skakkebk et al., 2014).
Despite consistent volume reductions between
whole hemispheres, specic brain regions associated
with more cognitive-like roles appear to be differen-
tially affected by KS, which may explain some of the
learning difculties seen in many individuals with the
disorder (Skakkebk et al., 2014). Several studies
have shown a reduced gray matter volume in the cau-
date nucleus, an area characteristically associated
with motor functions, but also involved in the circuitry
of memory, learning and executive function
(Alexander et al., 1986; Poldrack et al., 2001; Skak-
kebk et al., 2014). Consistent changes in the vol-
ume of the frontal and temporal lobes, areas that are
associated with behaviors such as socialization and
learning, have also been demonstrated in individuals
with KS (Patwardthan et al., 2000; Kringelbach and
Rolls, 2004; Shen et al., 2004; DeLisi et al., 2005;
Giedd et al., 2007; Skakkebk et al., 2014). Further-
more, decreases in the volume of hippocampal and
parahippocampal gyri have been observed, regions
that are involved in processing of memory and solidi-
fying learned behaviors (Bryant et al., 2011; Skakke-
bk et al., 2014).
Behavioral decits are evident in KS, and these
traits may link to changes in some of the aforemen-
tioned areas (frontal and pre-frontal areas) as well as
components of the limbic system, which is associated
with social responses and emotional processing (Wal-
lentin et al., 2011). Of these limbic areas, alterations
to the morphology of the amygdala have been shown
(Patwardhan et al., 2002; van Rijn et al., 2008; Skak-
kebk et al., 2014), as well as irregularities of the
insula cortex of KS patients (van Rijn et al., 2008;
Skakkebk et al., 2014).
CARDIOVASCULAR
In the case of cardiovascular abnormalities, it
appears that dysfunction of a myriad of components of
the cardiovascular system can contribute to the
decreased life expectancy of individuals with KS (Fricke
et al., 1981, 1984; Bojesen, et al., 2003, 2004, 2006;
Swerdlow et al., 2005; Andersen et al., 2008; Bojesen
and Gravholt, 2011). In particular, mitral valve pro-
lapse is frequent, with one study showing (through
echocardiography) that 55% of assessed KS patients
exhibited mitral valve dysfunction (Fricke et al., 1984).
Andersen and colleagues demonstrated that left ven-
tricular dysfunction, assessed by Doppler cardiogra-
phy, was evident in KS patients and attributed this
nding predominantly to the metabolic effects of
obesity-related inuences and the hypogandotrophic
effects of the disorder (Andersen et al., 2008). One
recent cohort study found several consistent anoma-
lies, including ventricular dysfunction, signicantly
impaired pulmonary function, increased vessel wall
thickness and a profound increase in the incidence of
chronotopic incompetence (55% compared to healthy
age-matched controls), a state where heart rate does
not increase appropriately with increasing levels of
physical exertion (Pasquali et al., 2013). In relation to
the latter nding, this is of particular importance, as
chronotopic incompetence is a key indicator of cardio-
vascular disease, and has been correlated to increased
morbidity (Lauer, 2009; Brubaker and Kitzman, 2011;
Esposito et al., 2012; Pasquali et al., 2013). Vessel wall
thickness, shown to increase in KS, arises from an
increase in thickness of the intima and media layers
compared with controls (Pasquali et al., 2013). Another
large-scale cohort study has suggested an increased
incidence of other vascular complications alongside
KS, such as deep vein thrombosis and pulmonary
embolism (Campbell and Price, 1981).
RESPIRATORY
There are few recent studies that have been pub-
lished assessing in detail the anatomy of the

respiratory tract in KS patients in terms of general pul-
monary capabilities and changes in pulmonary disease
prevalence. One of the rst papers to assess pulmo-
nary function in KS investigated a cohort of 30
patients, which included ve that were admitted to
hospital with respiratory dysfunction such as asthma
(Daly et al., 1968). When analyzed through patient his-
tory, the 30 patients reported profound rates of pulmo-
nary illness and disease: including a history of chronic
bronchitis (57%); at least one episode of pneumonia
(20%); asthma and chronic bronchitis (13%) and 47%
were shown to have obstructive airway disease upon
clinical testing (Daly et al., 1968). Overall, Daly and
colleagues (1968) reported that 60% of KS patients
were symptomatic for bronchitis, asthma, pulmonary
cysts or bronchiecstasis (abnormal widening of the air-
ways), or a combination of these.
These ndings correlate to an earlier report that
compared KS patients to controls, where 10 of 29 KS
patients had chronic pulmonary disease, whereas con-
trol subjects were asymptomatic (Rohde, 1964).
Interestingly, the cohort study by Daly et al. (1968)
also documented that 17% of KS patients had thoracic
deformities including pectus excavatum and kypho-
scoliosis. However, decits in pulmonary function are
usually associated with ventilation problems such as
lowered tidal volumes, yet thoracic deformity did not
cause respiratory dysfunction compared to controls in
some KS patients (two out of ve patients - Daly
et al., 1968). Further cohort studies have provided
evidence that pulmonary function is affected in KS,
including one such study that assessed patient history
and pulmonary function in 24 KS patients (Huseby
and Petersen, 1981). In this cohort report, 8% of
patients exhibited an obstructive disorder; 35% had
restrictive disorders and 46% had decreased func-
tional residual capacitiesalthough it is important to
note that many of the participants were smokers and,
in some instances, heavy smokers (Huseby and
Petersen, 1981).
Recent studies have also corroborated evidence of
pulmonary dysfunction in KS patients, with one report
of 13 patients showing that ve had lung volumes simi-
lar to controls, whereas eight reported restrictive
defects (Morales et al., 1992). However, this study is
problematic, because 11 of the 13 recruited patients
reported that they were smokers or had a history of
smoking (Morales et al., 1992). Furthermore, with the
known increase in mortality alongside the presentation
of KS, respiratory dysfunction (including pneumonia
and chronic obstructive airway disease) has been shown
to be a signicant contributing factor, with 19 KS
patients dying from respiratory-related disorders, com-
pared to 31 control subjects (Bojesen et al., 2004).
GASTROINTESTINAL AND RENAL
Of all the visceral defects described in relation to
KS, gastrointestinal and renal are the least commonly
reported or studied, and are usually presented as inci-
dental ndings within cohorts being assessed on a
broader scale, or via post-mortem analysis. Of partic-
ular note however are the large cohort studies carried
Klinefelters Syndrome 615
out by Swerdlow et al (2001), which was subse-
quently reported alongside data collated by Bojesen
et al (2004). These two studies linked an increased
incidence of mortality in KS to disease of the gastroin-
testinal and urinary tracts, as well as the other vis-
ceral systems. Specically, gastrointestinal disease
primarily contributed to death in seven KS cases com-
pared to 18 controls; whereas urogenital disease con-
tributed to death in six KS patients compared to ve
controls, indicating an increased relative mortality risk
in KS patients from dysfunction of the gastrointestinal
and genitourinary systems (Bojesen et al., 2004).
CONCLUSION
Despite being a prevalent chromosomal disorder,
there is still much unknown about KS, and few large
phenotypic or epidemiological studies exist. This is
likely due to the difculties in diagnosis, which are
largely inuenced by varying clinical features due to
genotype and also age. Considering the high morbid-
ity and mortality rates, identifying more KS males
early in development is crucial in both mitigating neg-
ative features for improved quality of life, and improv-
ing understanding of the syndrome. With this
knowledge in hand, KS individuals themselves, along-
side their families and clinicians, can manage and plan
for many potential outcomes arising from a disorder
that can have far-reaching effects on not only physical
but also mental health.
REFERENCES
Abramsky L, Chapple J. 1997. 47,XXY (Klinefelter syndrome) and
47,XYY: Estimated rates of and indication for postnatal diagnosis
with implications for prenatal counselling. Prenat Diagn 17:363
368.
Aksglaede L, Jrgensen N, Skakkebaek NE, Juul A. 2009. Low semen
volume in 47 adolescents and adults with 47,XXY Klinefelter or
46,XX male syndrome. Int J Androl 32:376384.
Aksglaede L, Juul A. 2013. Testicular function and fertility in men
with Klinefelter syndrome: A review. Eur J Endocrinol 168:R67
R76.
Aksglaede L, Molgaard C, Skakkebaek NE, Juul A. 2008. Normal
bone mineral content but unfavourable muscle/fat ratio in Kline-
felter syndrome. Arch Dis Child 93:3034.
Aksglaede L, Petersen JH, Main KM, Skakkebaek NE, Juul A. 2007.
High normal testosterone levels in infants with non-mosaic Kline-
felters syndrome. Eur J Endocrinol 157:345350.
Aksglaede L, Skakkebaek NE, Almstrup K, Juul A. 2011. Clinical and
biological parameters in 166 boys, adolescents and adults with
nonmosaic Klinefelter syndrome: A Copenhagen experience.
Acta Paediatr 100:793806.
Alexander GE, DeLong MR, Strick PL. 1986. Parallel organization of
functionally segregated circuits linking basal ganglia and cortex.
Annu Rev Neurosci 9:357381.
Alvarez JA, Emory E. 2006. Executive function and the frontal lobes:
A meta-analytic review. Neuropsych Rev 16:1742.
Andersen NH, Bojesen A, Kristensen K, Birkebaek NH, Fedder J,
Bennett P, Chistiansen JS, Gravholt CH. 2008. Left ventricular
dysfunction in Klinefelter syndrome is associated to insulin
resistance, abdominal adiposity and hypogonadism. Clin Endocri-
nol 69:785791.
616 Bird and Hurren
Babic M, Micic M, Jaksic N, Micic S. 1991. An extra X chromosome
effect on craniofacial morphogenesis in men. Eur J Orthodont 13:
329332.
Bardsley MZ, Falkner B, Kowal K, Ross JL. 2011. Insulin resistance
and metabolic syndrome in prepubertal boys with Klinefelter syn-
drome. Acta Paediatr 100:866870.
Barnes-Kedar I, Amiel A, Maor O, Fejgin M. 1993. Elevated human
chorionic gonadotropin levels in pregnancies with sex chromo-
some abnormalities. Am J Med Genet 45:356357.
Becker KL, Hoffman DL, Underdahl LO, Mason HL. 1966. Klinefelters
syndrome. Clinical and laboratory ndings in 50 patients. Arch
Intern Med 118:314321.
Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. 1997. Long-
term effect of testosterone therapy on bone mineral density in
hypogonadal men. J Clin Endocrinol Metab 82:23862390.
Bender BG, Linden M, Robinson A. 1991. Cognitive and academic
skills in children with sex chromosome abnormalities. Reading
Writing 3:315327.
Bender BG, Linden M, Robinson A. 1993. Neuropsychological impair-
ment in 42 adolescents with sex chromosome abnormalities. Am
J Med Genet 48:169173.
Bender BG, Puck MH, Salbenblatt JA, Robinson A. 1983. Hemispheric
organisation in 47,XXY boys [letter]. Lancet 1:132
Berenbaum SA, Beltz AM. 2011. Sexual differentiation of human
behaviour: Effects of prenatal and pubertal organizational hor-
mones. Front Neuroendocrinol 32:183200.
Boada R, Janusz J, Hutaff-Lee C, Tartaglia N. 2009. The cognitive phe-
notype in Klinefelter syndrome: A review of the literature including
genetic and hormonal factors. Dev Dis Res Rev 15:284294.
Bojesen A, Gravholt CH. 2007. Klinefelter syndrome in clinical prac-
tice. Nat Clin Pract Urol 4:192204.
Bojesen A, Gravholt CH. 2011. Morbidity and mortality in Klinefelter
syndrome (47, XXY). Acta Paediatr 100:807813.
Bojesen A, Hst C, Gravholt CH. 2010. Klinefelters syndrome, type
2 diabetes and the metabolic syndrome: The impact of body
composition. Mol Hum Reprod 16:396401.
Bojesen A, Juul S, Birkebaek N, Gravholt CH. 2004. Increased mor-
tality in klinefelter syndrome. J Clin Endocrinol Metab 89:3830
3834.
Bojesen A, Juul S, Birkebaek NH, Gravholt CH. 2006. Morbidity in
Klinefelter syndrome: A Danish register study based on hospital
discharge diagnoses. J Clin Endocrinol Metab 91:12541260.
Bojesen A, Juul S, Gravholt CH. 2003. Prenatal and postnatal preva-
lence of Klinefelter syndrome: A national registry study. J Clin
Endocrinol Metab 88:622626.
Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L,
Bennett P, Laurberg P, Frystyk J, Flyvbjerg A, Christiansen JS,
Gravholt CH. 2006. The metabolic syndrome is frequent in Kline-
felters syndrome and is associated with abdominal obesity and
hypogonadism. Diabetes Care 29:15911598.
Bojesen A, Stochholm K, Juul S, Gravholt CH. 2011. Socioeconomic
trajectories affect mortality in Klinefelter syndrome. J Clin Endo-
crinol Metab 96:20982104.
Bradbury JT, Bunge RG, Boccabella RA. 1956. Chromatin test in Kli-
nefelters syndrome. J Clin Endocrinol Metab 16:689
Brinton LA. 2011. Breast cancer risk among patients with Klinefelter
syndrome. Acta Paediatr 100:814818.
Brown T, Alvesalo L, Townsend GC. 1993. Craniofacial patterning in
Klinefelter (47 XXY) adults. Eur J Orthod 15:185194.
Brubaker PH, Kitzman DW. 2011. Chronotropic incompetence:
Causes, consequences, and management. Circulation 123:1010
1020.
Bruining H, Swaab H, Kas M, van Engeland H. 2009. Psychiatric
characteristics in a self-selected sample of boys with Klinefelter
syndrome. Pediatrics 123:e865e870.
Bryant DM, Hoeft F, Lai S, Lackey J, Roeltgen D, Ross J, Reiss AL.
2011. Neuroanatomical phenotype of Klinefelter syndrome in
childhood: a voxel-based morphometry study. J Neurosci 31:
66546660.
Cabrol S, Ross JL, Fennoy I, Bouvattier C, Roger M, Lahou N. 2011.
Assessment of Leydig and Sertoli cell functions in infants with
nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are
normal and positively correlated with LH levels. J Clin Endocrinol
Metab 96:E746E753.
Caldwell PD, Smith DW. 1972. The XXY (Klinefelters) syndrome in
childhood: Detection and treatment. J Pediatr 80:250258.
Campbell WA, Price WH. 1981. Venous thromboembolic disease in
Klinefelters syndrome. Clin Genet 19:275280.
Carothers AD, Filippi G. 1988. Klinefelters syndrome in Sardinia and
Scotland. Comparative studies of parental age and other aetio-
logical factors in 47,XXY. Hum Genet 81:7175.
Chitayat D, Langlois S, Wilson RD. 2011. Prenatal screening for fetal
aneuploidy in singleton pregnancies. J Obstet Gynaecol Can 33:
736750.
Christian SM, Koehn D, Pillay R, MacDougall A, Wilson RD. 2000. Paren-
tal decisions following prenatal diagnosis of sex chromosome
aneuploidy: A trend over time. Prenat Diagn 20:3740.
Christiansen P, Andersson AM, Skakkebaek NE. 2003. Longitudinal
studies of inhibin B levels in boys and young adults with Klinefel-
ter syndrome. J Clin Endocrinol Metab 88:888891.
Collaer ML, Hines M. 1995. Human behavioural sex differences: A
role for gonadal hormones during early development? Psychol
Bull 118:55107.
Corona G, Petrone L, Paggi F, Lotti F, Boddi V, Fisher A, Vignozzi L,
Balercia G, Sforza A, Forti G, Mannucci E, Maggi M. 2010. Sexual
dysfunction in subjects with Klinefelters syndrome. Int J Androl
33:574580.
Cortese S. 2012. The neurobiology and genetics of attention-decit/
hyperactivity disorder (ADHD): What every clinician should
know. Eur J Paediatr Neurol 16:422433.
Daly JJ, Hunter H, Rickards DF. 1968. Klinefelters syndrome and
pulmonary disease. Am Rev Resp Dis 98:717719.
DeLisi LE, Maurizio AM, Svetina C, Ardekani B, Szulc K, Nierenberg
J, Leonard J, Harvey PD. 2005. Klinefelters syndrome (XXY) as a
genetic model for psychotic disorders. Am J Med Genet B Neuro-
psychiatr Genet 135:1523.
Esposito D, Renzullo A, Accardo G, Barbato f, Salzano A, Cittadini A,
Pasquali D. 2012. Klinefelters syndrome and cardiovascular dis-
ease. Curr Trends Endocrinol 6:9197.
Ferguson-Smith MA, Yates JRW. 1984. Maternal age specic rates
for chromosome aberrations and factors inuencing them:
Report of a collaborative European study on 52 965 amniocente-
ses. Prenat Diagn 4:544.
Ferguson-Smith MA. 1965. Karyotypephenotype correlations in
gonadal dysgenesis and their bearing on the pathogenesis of
malformations. J Med Genet 2:142155.
Ferguson-Smith MA. 1966. Sex chromatin, Klinefelters syndrome
and mental deciency. In: Moore KL, editor. The Sex Chromatin.
Philadelphia: W. B. Saunders Company. p 277-315.
Ferlin A, Schipilliti M, Vinanzi C, Garolla A, Di Mambro A, Selice R,
Lenzi A, Foresta C. 2011. Bone mass in subjects with
Klinefelter syndrome: role of testosterone levels and androgen
receptor gene CAG polymorphism. J Clin Endocrinol Metab 96:
739745.
Foresta C, Galeazzi C, Bettella A, Marin P, Rossato M, Garolla A,
Ferlin A. 1999. Analysis of meiosis in intratesticular germ cells
from subjects affected by classic Klinefelters syndrome. J Clin
Endocrinol Metab 84:38073810.
Foresta C, Galeazzi C, Bettella A, Stella M, Scandellari C. 1998. High
incidence of sperm sex chromosomes aneuploidies in two
patients with Klinefelters syndrome. J Clin Endocrinol Metab 83:
203205.
Fraser JH, Boyd E, Lennox B, Dennison WM. 1961. A case of XXXXY
Klinefelters syndrome. Lancet 11:10641067.
Fricke GR, Mattern HJ, Schweikert HU, Schwanitz G. 1984. Klinefel-
ters syndrome and mitral valve prolapse. An echocardiographic
study in twenty-two patients. Biomed Pharmacother 38:8897.
Fricke GR, Mattern HJ, Schweikert HU. 1981. Mitral valve prolapse in
Klinefelter syndrome. Lancet 26:1414
Fryns JP, Carels C, Schoenaers JH. 1996. Bilateral aplasia of the
mandibular ramus and condyle in Klinefelter syndrome. Genet
Couns 7:74

Geschwind DH, Boone KB, Miller BL, Swerdloff RS. 2000. Neurobe-
havioral phenotype of Klinefelters syndrome. Ment Retard Dev
Disabil Res Rev 6:107116.
Geschwind N, Galaburda A. 1985. Cerebral lateralization: Biological
mechanisms, associations and pathology. Arch Neurol 42:428458.
Giedd JN, Clasen LS, Wallace GL, Lenroot RK, Lerch JP, Wells EM,
Samango-Sprouse C. 2007. XXY (Klinefelter syndrome): A pedi-
atric quantitative brain magnetic resonance imaging case-control
study. Pediatrics 119:e232e240.
Girardin CM, Lemyre E, Alos N, Deal C, Huot C, Van Vliet G. 2009.
Comparison of adolescents with Klinefelter syndrome according
to the circumstances of diagnosis: amniocentesis versus clinical
signs. Horm Res 72:98105.
Gorlin RJ, Redman RS, Shapiro BL. 1965. Effect of X-chromosome
aneuploidy on jaw growth. J Dent Res 44:269282.
Graham J, Bashir A, Stark R, Silbert A, Walzer S. 1988. Oral and
written language abilities of XXY boys: Implications for anticipa-
tory guidance. Pediatrics 81:795806.
Hadziselimovic F, Zivkovic D, Bica DT, Emmons LR. 2005. The impor-
tance of mini-puberty for fertility in cryptorchidism. J Urol 174:
15361539.
Hall DJ, Harrison MH, Burwell RG. 1979. Congenital abnormalities
and Perthes disease. Clinical evidence that children with Perthes
disease may have a major congenital defect. J Bone Joint Surg
Br 61:1825.
Hamamy HA, Dahoun S. 2004. Parental decisions folliwng the prena-
tal diagnosis of sex chromosome abnormalities. Eur J Obstet
Gynecol Reprod Biol 116:5862.
Hasle H, Mellemgaard A, Nielsen J, Hansen J. 1995. Cancer incidence
in men with Klinefelter syndrome. Br J Cancer 71:416420.
Heyl PS, Miller W, Canick JA. 1990. Maternal serum screening for
aneuploidy pregnancy by alpha-fetoprotein, hCG and unconju-
gated estriol. Obstet Gynecol 76:10251031.
Hodhod A, Umurangwa F, El-Sherbiny M. 2015. Prepubertal diagnosis
of Klinefelter syndrome due to penoscrotal malformations: Case
report and review of literature. Can Urol Assoc J 9:333336.
Hook EB, Cross PK, Schreinemachers DM. 1983. Chromosomal
abnormality rates at amniocentesis and in live-born infants.
Jama 249:20342038.
Horowitz M, Wishart JM, OLoughlin PD, Morris HA, Need AG, Nordin
BE. 1992. Osteoporosis and Klinefelters syndrome. Clin Endocri-
nol (Oxf) 36:113118.
Hsueh WA, Hsu TH, Federman DD. 1978. Endocrine features of Kli-
nefelters syndrome. Medicine (Baltimore) 57:447461.
Huseby JS, Petersen D. 1981. Pulmonary function in Klinefelters
syndrome. Chest 80:3133.
Iitsuka Y, Bock A, Nguyen DD, Samango-Sprouse CA, Simpson JL,
Bischoff FZ. 2001. Evidence of skewed X-chromosome inactiva-
tion in 47,XXY and 48,XXYY Klinefelter patients. Am J Med Genet
98:2531.
Ingerslev CH, Kreiborg S. 1978. Craniofacial morphology in Klinefel-
ter syndrome: A roentgencephalometric investigation. Cleft Pal-
ate J 15:100108.
Ishikawa T, Yamaguchi K, Kondo Y, Takenaka A, Fujisawa M. 2008.
Metabolic syndrome in men with Klinefelters syndrome. Urology
71:11091113.
Itti E, Gaw Gonzalo IT, Pawlikowska-Haddal A, Boone KB, Mlikotic A,
Itti L, Mishkin FS, Swerdloff RS. 2006. The structural brain corre-
lates of cognitive defects in adults with Klinefelters syndrome.
J Clin Endocrinol Metab 91:14231427.
Jacobs PA, Hassold TJ, Whittington E, Butler G, Collyer S, Keston M,
Lee M. 1988. Klinefelters syndrome: An analysis of the origin of
the additional sex chromosome using molecular probes. Ann
Hum Genet 52:93109.
Jacobs PA, Strong JA. 1959. A case of human intersexuality having a
possible XXY sex-determining mechanism. Nature 183:302303.
Jiang-Feng M, Hong-Li X, Xue-Yan W, Min N, Shuang-Yu L, Hong-
Ding X, Liang-Ming L. 2012. Prevalence and risk factors of diabe-
tes in patients with Klinefelter syndrome: A longitudinal observa-
tional study. Fertil Steril 98:13311335.
Klinefelters Syndrome 617
Kamischke A, Baumgardt A, Horst J, Nieschlag E. 2003. Clinical and
diagnostic features of patients with suspected Klinefelter syn-
drome. J Androl 24:4148.
Keeler C. 1973. Taurodont molars and shovel incisors in Klinefelters
syndrome. J Hered 64:234236.
Kleczkowska A, Fryns JP, Van den Berghe H. 1988. X -chromosome
polysomy in the male. The Leuven experience 1966-1987. Hum
Genet 80:1622.
Klinefelter HF, Reifenstein EC, Albright F. 1942. Syndrome character-
ized by gynecomastia, aspermatogenesis without a-Leydigism
and increased secretion of follicle-stimulating hormone. J Clin
Endocrinol Metab 26:1522.
Klinefelter HF. 1986. Klinefelters syndrome: Historical background
and development. South Med J 79:10891093.
Kobayashi S, Shimamoto T, Taniguchi O, Hashimoto H, Hirose S.
1991. Klinefelters syndrome associated with progressive sys-
temic sclerosis: Report of a case and review of the literature.
Clin Rheumatol 10:8486.
Kobayashi S, Yamamoto S, Tanaka M, Hashimoto H, Hirose S. 1994.
Klinefelters syndrome and rheumatoid arthritis. Report of a case
and review of the literature. Clin Rheumatol 13:500503.
Kringelbach ML, Rolls ET. 2004. The functional neuroanatomy of the
human orbitofrontal cortex: Evidence from neuroimaging and
neuropsychology. Prog Neurobiol 72:341372.
Kubler A, Schulz G, Cordes U, Beyer J, Krause U. 1992. The inuence
of testosterone substitution on bone mineral density in patients
with Klinefelters syndrome. Exp Clin Endocrinol 100:129132.
Kuiri-Ha nninen TA, Sankilampi UA, Dunkel LB. 2014. Activation of
the hypothalamic-pituitary-gonadal axis in infancy: Minipuberty.
Horm Res Paediatr 82:7380.
Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen
TP, Salonen R, Rauramaa R, Salonen JT. 2003. Sex hormones,
inammation and the metabolic syndrome: A population-based
study. Eur J Endocrinol 149:601608.
Lahlou N, Fennoy I, Carel JC, Roger M. 2004. Inhibin B and anti-
Mullerian hormone, but not testosterone levels, are normal in
infants with nonmosaic Klinefelter syndrome. J Clin Endocrinol
Metab 89:18641868.
Lahlou N, Fennoy I, Ross JL, Bouvattier C, Roger M. 2011. Clinical
and hormonal status of infants with nonmosaic XXY karyotype.
Acta Paediatr 100:824829.
Lanfranco F, Kamischke A, Zitzmann M Nieschlag E., 2004 Klinefel-
ters syndrome. Lancet 364:273283.
Laron Z, Topper E. 1982. Klinefelters syndrome in adolescence.
Arch Dis Child 57:887888.
Lauer MS. 2009. Autonomic function and prognosis. Cleve Clin J Med
76:S18S22.
Leon N, Wajchenberg BL, Montenegro MR, Cintra AB. 1959. The
effects of chorionic gonadotropin in Klinefelters syndrome. J Clin
Endocrinol Metab 19:16671679.
Leonard MF, Sparrow S, Schowalter JE. 1982. A prospective study of
development of children with sex chromosome anomalies: New
Haven Study III: The middle years. Birth Defects Orig Art Ser
18:193218.
Linden MG, Bender BG, Robinson A. 1995. Sex chromosome tetras-
omy and pentasomy. Pediatrics 96:672682.
Linden MG, Bender BG, Robinson A. 2002. Genetic counseling for
sex chromosome abnormalities. Am J Med Genet 110:310.
Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor K,
Hackett G, Bullmore ET, Baron-Cohen S. 2012. Fetal testosterone
inuences sexually dimorphic gray matter in the human brain.
J Neurosci 32:674680.
Lorda-Sanchez I, Binkert F, Maechler M, Robinson WP, Schinzel AA.
1992. Reduced recombination and paternal age effect in Klinefel-
ter syndrome. Hum Genet 89:524530.
Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A, Wyrobek AJ. 2001.
Frequency of XY sperm increases with age in fathers of boys with
Klinefelter syndrome. Am J Hum Genet 69:10461054.
Mandoki M, Sumner G, Hoffman R, Riconda D. 1991. A review of Kli-
nefelters syndrome in children and adolescents. J Am Acad Child
Adolesc Psych 30:167172.
618 Bird and Hurren
Mehta A, Mielnik A, Schlegel PN, Paduch DA. 2014. Novel methyla-
tion specic real-time PCR test for the diagnosis of Klinefelter
syndrome. Asian J Androl 16:684688.
Messina MF, Sgro  DL, Aversa T, Pecoraro M, Valenzise M, De Luca F.
2012. A characteristic cognitive and behavioral pattern as a clue
to suspect Klinefelter syndrome in prepubertal age. J Am Board
Fam Med 25:745749.
Mhyre S, Ruvalcaba RH, Johnson HR, Thuline HC, Kelly VC. 1970.
The effectos of testosterone treatment in Klinefelters syndrome.
J Paediatr 76:267276.
Morales P, Furest I, Marco V, Macian V, Moreno B, Jimenez-Cruz JF.
1992. Pathogenesis of the lung in restrictive defects of Klinefel-
ters syndrome. Chest 102:15501552.
Nichols CR, Heerema NA, Palmer C, Loehrer PJ, Sr, Williams SD,
Einhorn LH. 1987. Klinefelters syndrome associated with media-
stinal germ cell neoplasms. J Clin Oncol 5:12901294.
Nielsen J, Pelsen B, Sorensen K. 1988. Follow-up of 30 Klinefelter
males treated with testosterone. Clin Genet 33:262269.
Nielsen J, Sorensen K. 1984. The importance of early diagnosis of
Klinefelters syndrome. In Bandman H-J, Breit R, editors. Kline-
felters Syndrome. Berlin: Springer-Verlag. p. 170187.
Nur BG, Altok-Clark O, Toylu A, Lu leci G, Mhc E. 2013. The associa-
tion of Klinefelter syndrome and multiple pterygium syndrome:
an unusual presentation. Turk J Pediatr 55:559563.
Ottesen AM, Garn ID, Aksglaede L, Juul A, Rajpert-De Meyts E.
2007. A simple screening method for detection of Klinefelter syn-
drome and other X-chromosome aneuploidies based on copy
number of the androgen receptor gene. Mol Hum Reprod 13:
745750.
Pacenza N, Pasqualini T, Gottlieb S, Knoblovits P, Costanzo PR,
Stewart Usher J, Rey RA, Martnez MP, Aszpis S. 2012. Clinical
presentation of Klinefelters syndrome: Differences according to
age. Int J Endocrinol 2012:324835.
Paduch DA, Bolyakov A, Cohen P, Travis A. 2009. Reproduction in
men with Klinefelter syndrome: The past, the present, and the
future. Semin Reprod Med 27:137148.
Paduch DA, Fine RG, Bolyakov A, Kiper J. 2008. New concepts in Kli-
nefelter syndrome. Curr Opin Urol 18:621627.
Palermo GD, Schlegel PN, Sills ES, Veeck LL, Zaninovic N, Menendez
S, Rosenwaks Z. 1998. Births after intracytoplasmic injection of
sperm obtained by testicular extraction from men with nonmo-
saic Klinefelters syndrome. N Engl J Med 338:588550.
Pasquali D, Arcopinto M, Renzullo A, Rotondi M, Accardo G, Salzano
A, Esposito D, Saldamarco L, Isidori AM, Marra AM, Ruvulo A,
Napoli R, Bossone E, Lenzi A, Baliga RR, Sacca L, Cittadini A.
2013. Cardiovascular abnormalities in Klinefelter Syndrome. Int J
Cardiol 168:754759.
Patwardhan A, Brown W, Bender B, Linden M, Eliez S, Reiss A. 2002.
Reduced size of the amygdala in individuals with 47,XXY and
47,XXX karyotypes. Am J Med Genet 114:9398.
Patwardhan AJ, Eliez S, Bender B, Linden MG, Reiss AL. 2000. Brain
morphology in Klinefelter syndrome: Extra X chromosome and
testosterone supplementation. Neurology 54:22182223.
Paulsen CA, Gordon DL, Carpenter RW, Gandy HM, Drucker WD.
1968. Klinefelters syndrome and its variants: A hormonal and
chromosomal study. Recent Prog Horm Res 24:321363.
Plunkett ER, Barr ML. 1956. Testicular dysgenesis affecting the sem-
iniferous tubules principally, with chromatin-positive nuclei. Lan-
cet 28:5354.
Poldrack RA, Clark J, Pare-Blagoev EJ, Shohamy D, Creso MJ, Myers
C, Gluck MA. 2001. Interactive memory systems in the human
brain. Nature 414:546550.
Price WH, Clayton JF, Wilson J, Collyer S, De Mey R. 1985. Causes of
death in X chromatin positive males (Klinefelters syndrome).
J Epidemiol Community Health 39:330336.
Radicioni AF, De Marco E, Gianfrilli D, Granato S, Gandini L, Isidori
AM, Lenzi A. 2010. Strategies and advantages of early diagnosis
in Klinefelters syndrome. Mol Hum Reprod 16:434440.
Raman JD, Schlegel PN. 2002. Aromatase inhibitors for male infertil-
ity. J Urol 167:624629.
Ranganath V, Rajangam S. 2012. A data prole of phenotypic fea-
tures in 72 Klinefelter syndrome (KFS) males. Int J Hum Genet
12:139143.
Ratcliffe S. 1999. Long-term outcome in children of sex chromo-
some abnormalities. Arch Dis Child 80:192195.
Ratcliffe SG. 1982. The sexual development of boys with the chro-
mosome constitution 47,XXY (Klinefelters syndrome). Clin Endo-
crinol Metab 11:703716.
Regadera J, Codesal J, Paniagua R, Gonzalez-Peramato P, Nistal M.
1991. Immunohistochemical and quantitative study of interstitial
and intratubular Leydig cells in normal men, cryptorchidism, and
Klinefelters syndrome. J Pathol 164:299306.
Rezaie R, Daly EM, Cutter WJ, Murphy DG, Robertson DM, DeLisi LE,
Mackay CE, Barrick TR, Crow TJ, Roberts N. 2009. The inuence
of sex chromosome aneuploidy on brain asymmetry. Am J Med
Genet B Neuropsychiatr Genet 150:7485.
Robinson A, Lubs HA, Nielsen J, Srensen K. 1979. Summary of clin-
ical ndings: proles of children with 47,XXY, 47,XXX and 47,XYY
karyotypes. Birth Defects Orig Artic Ser 15:261266.
Rohde RA. 1964. Klinefelters syndrome with pulmonary disease and
other disorders. Lancet 2:149150.
Ron-El R, Strassburger D, Gelman-Kohan S, Friedler S, Raziel A,
Appelman Z. 2000. A 47, XXY fetus conceived after ICSI of sper-
matozoa from a patient with non-mosaic Klinefelters syndrome:
Case report. Hum Reprod 15:18041806.
Ross JL, Samango-Sprouse C, Lahlou N, Kowal K, Elder FF, Zinn A.
2005. Early androgen deciency in infants and young boys with
47,XXY Klinefelter syndrome. Horm Res 64:3945.
Rovet J, Netley C, Keenan M, Bailey J, Stewart D. 1996. The psycho-
educational prole of boys with Klinefelter syndrome. J Learn
Disabil 29:180196.
Sagi M, Meiner V, Reshef N, Dagan J, Zlotogora J. 2001. Prenatal
diagnosis of sex chromosome aneuploidy: Possible reasons for
high rates of pregnancy termination. Prenat Diagn 21:461465.
Salbenblatt JA, Bender BG, Puck MH, Robinson A, Faiman C, Winter
JS. 1985. Pituitary-gonadal function in Klinefelter syndrome
before and during puberty. Pediatr Res 19:8286.
Sawalha AH, Harley JB, Scoeld RH. 2009. Autoimmunity and Kline-
felters syndrome: When men have two X chromosomes.
J Autoimmun 33:3134.
Scherz RG, Roeckel IE. 1963. The XXXXY syndrome: A report of a
case and review of the literature. J Pediatr 63:10931098.
Schwartz ID, Root AW. 1991. The Klinefelter syndrome of testicular
dysgenesis. Endocrinol Metab Clin North Am 20:153163.
Seo JT, Lee JS, Oh TH, Joo KJ. 2007. The clinical signicance of bone
mineral density and testosterone levels in Korean men with non-
mosaic Klinefelters syndrome. BJU Int 99:141146.
Shaffer BL, Caughey AB, Norton ME. 2006. Variation in the decision
to terminate pregnancy in the setting of fetal aneuploidy. Prenat
Diagn 26:667671.
Shen D, Liu D, Liu H, Clasen L, Giedd J, Davatzikos C. 2004. Auto-
mated morphometric study of brain variation in XXY males. Neu-
roimage 23:648653.
Simpson JL, de la Cruz F, Swerdloff RS, Samango-Sprouse C,
Skakkebaek NE, Graham JM Jr, Hassold T, Aylstock M, Meyer-
Bahlburg HFL, Willard HF, Hall JG, Salameh W, Boone K, Staessen
C, Geschwind D, Giedd J, Dobs AS, Rogol A, Brinton B, Paulsen
CA. 2003. Klinefelter syndrome: expanding the phenotype and
identifying new research directions. Nat Genet Med 5:460468.
Skakkebk A, Gravholt CH, Rasmussen PM, Bojesen A, Jensen JS,
Fedder J, Laurberg P, Hertz JM, Ostergaard JR, Pedersen AD,
Wallentin M. 2014. Neuroanatomical correlates of Klinefelter
syndrome studied in relation to the neuropsychological prole.
NeuroImage Clin 4:19.
Smyth CM, Bremner WJ. 1998. Klinefelter syndrome. Arch Intern
Med 158:13091314.
Spencer K, Tul N, Nicolaides KH. 2000. Maternal serum free beta-
hCG and PAPP-A in fetal sex chromosome defects in the rst tri-
mester. Prenat Diagn 10:390394.
Sprouse C, Tosi L, Stapleton E, Gropman AL, Mitchell FL, Peret R,
Sadeghin T, Haskell K, Samango-Sprouse CA. 2013.

Musculoskeletal anomalies in a large cohort of boys with 49,
XXXXY. Am J Med Genet C Semin Med Genet 163:4449.
Steinman K, Ross J, Lai S, Reiss A, Hoeft F. 2009. Structural and
functional neuroimaging in Klinefelter (47,XXY) syndrome: a
review of the literature and preliminary results from a functional
magnetic resonance imaging study of language. Dev Disabil Res
Rev 15:295308.
Stemkens D, Roza T, Verrij L, Swaab H, van Werkhoven MK,
Alizadeh BZ, Sinke RJ, Giltay JC. 2006. Is there an inuence of
X-chromosomal imprinting on the phenotype in Klinefelter syn-
drome? A clinical and molecular genetic study of 61 cases. Clin
Genet 70:4348.
Stern R, Fishman J, Brusman H, Kunkel HG. 1977. Systemic lupus
erythematosus associated with klinefelters syndrome. Arthritis
Rheum 20:1822.
Stewart DA, Bailey JD, Netley CT, Rovet J, Park E, Cripps M, Curtis
JA. 1982. Growth and development of children with X and Y chro-
mosome aneuploidy from infancy to pubertal age: The Toronto
Study. Birth Defects Orig Art Ser 18:99154.
Stochholm K, Bojesen A, Jensen AS, Juul S, Gravholt CH. 2012.
Criminality in men with Klinefelters syndrome and XYY syn-
drome: A cohort study. BMJ Open 2:e000650
Swerdlow AJ, Hermon C, Jacobs PA, Alberman E, Beral V, Daker M,
Fordyce A, Youings S. 2001. Mortality and cancer incidence in
persons with numerical sex chromosome abnormalities: A cohort
study. Ann Hum Genet 65:177188.
Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA.
Mortality in patients with Klinefelter syndrome in Britain: A
cohort study. J Clin Endocrinol Metab 90:65166522.
Tanner JM, Prader A, Habich H, Ferguson-Smith MA. 1959. Genes on
the Y chromosome inuencing rate of maturation in man: skele-
tal age studies in children with Klinefelters (XXY) and Turners
(XO) syndromes. Lancet 2:141144.
Tartaglia N, Ayari N, Howell S, DEpagnier C, Zeitler P. 2011.
48,XXYY, 48,XXXY and 49,XXXXY syndromes: Not just variants of
Klinefelter syndrome. Acta Paediatrica 100:851860.
Tartaglia N, Cordeiro L, Howell S, Wilson R, Janusz J. 2010. The
spectrum of the behavioral phenotype in boys and adolescents
47,XXY (Klinefelter syndrome). Pediatr Endocrinol 8:151159.
Tennes K, Puck M, Orfanakis D, Robinson A. 1977. The early child-
hood development of 17 boys with sex chromosome anomalies:
A prospective study. Pediatrics 59:574583.
Terzoli G, Lalatta F, Lobbiani A, Simoni G, Colucci G. 1992. Fertility
in a 47,XXY patient: Assessment of biological paternity by deoxy-
ribonucleic acid ngerprinting. Fertil Steril 58:821822.
Thomas NS, Hassold TJ. 2003. Aberrant recombination and the ori-
gin of Klinefelter syndrome. Hum Reprod Update 9:309317.
Topper E, Dickerman Z, Prager-Lewin R, Kaufman H, Maimon Z,
Laron Z. 1982. Puberty in 24 patients with Klinefelter syndrome.
Eur J Pediatr 139:812.
Tournaye H, Liu J, Nagy PZ, Camus M, Goossens A, Silber S, Van
Steirteghem AC, Devroey P. 1996. Correlation between testicular
histology and outcome after intracytoplasmic sperm injection
using testicular spermatozoa. Hum Reprod 11:127132.
Townsend GC, Alvesalo L. 1985. The size of permanent teeth in Kli-
nefelter (47,XXY) syndrome in man. Arch Oral Biol 30:8384.
Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY. 2000. Low serum testos-
terone level as a predictor of increased visceral fat in Japanese-
American men. Int J Obesity Relat Metab Disord 24:485491.
ttelmann F, Gromoll J. 2010. Novel genetic aspects of Klinefelters
Tu
syndrome. Mol Human Reprod 16:386395.
van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G,
Devroey P, Van Steirteghem A, Liebaers I. 1996. Cytogenetics of
infertile men. Human Reprod 11:124.
van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH,
Smals AG. 2001. Bone mineral density and quantitative ultra-
sound parameters in patients with Klinefelters syndrome after
long-term testosterone substitution. Osteoporos Int 12:5562.
Klinefelters Syndrome 619
van Rijn S, Swaab H, Aleman A, Kahn RS. 2008. Social behavior and
autism traits in a sex chromosomal disorder: Klinefelter (47XXY)
syndrome. J Autism Dev Disord 38:16341641.
Varrela J, Alvesalo L. 1988. Taurodontism in 47,XXY males: an effect
of the extra X chromosome on root development. J Dent Res 67:
501522.
Visootsak J, Aylstock M, Graham JM. Jr. 2001. Klinefelter syndrome
and its variants: An update and review for the primary pediatri-
cian. Clin Pediatr (Phila) 40:639651.
Visootsak J, Graham JM. Jr. 2006. Klinefelter syndrome and other
sex chromosomal aneuploidies. Orphanet J Rare Dis 24:42
lkl TM, Langer T, Aigner T, Greess H, Beck JD, Rauch AM, Do
Vo rr HG.
2006. Klinefelter syndrome and mediastinal germ cell tumors.
Am J Med Genet A 140:471481.
Wallentin M, Nielsen AH, Vuust P, Dohn A, Roepstorff A, Lund TE.
2011. Amygdala and heart rate variability responses from listen-
ing to emotionally intense parts of a story. Neuroimage 58:963
973.
Wang C, Baker HW, Burger HG, De Kretser DM, Hudson B. 1975.
Hormonal studies in Klinefelters syndrome. Clin Endocrinol (Oxf)
4:399411.
Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM,
Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. 2004. Long-
term testosterone gel (AndroGEl) treatment maintains benecial
effects on sexual function and mood, lean and fat mass, and
bone mineral density in hypogonadal men. J Clini Endocrinol
Metab 89:20852098.
Warwick MM, Doody GA, Lawrie SM, Kestelman JN, Best JJ,
Johnstone EC. 1999. Volumetric magnetic resonance imaging
study of the brain in subjects with sex chromosome aneuploidies.
J Neurol Neurosurg Psych 66:628632.
Warwick MM, Lawrie SM, Beveridge A, Johnstone EC. 2003. Abnor-
mal cerebral asymmetry and schizophrenia in a subject with Kli-
nefelters syndrome (XXY). Biol Psych 53:627629.
Wikstro m AM, Bay K, Hero M, Andersson AM, Dunkel L. 2006. Serum
insulin-like factor 3 levels during puberty in healthy boys and boys
with Klinefelter syndrome. J Clin Endocrinol Metab 91:47054608.
m AM, Dunkel L, Wickman S, Norjavaara E, Ankarberg-
Wikstro
Lindgren C, Raivio T. 2006. Are adolescent boys with Klinefelter
syndrome androgen decient? A longitudinal study of Finnish
47,XXY boys. Pediatr Res 59:854859.
Wikstro m AM, Dunkel L. 2011. Klinefelter syndrome. Best Pract Res
Clin Endocrinol Metab 25:239250.
Wikstro m AM, Raivio T, Hadziselimovic F, Wikstro m S, Tuuri T,
Dunkel L. 2004. Klinefelter syndrome in adolescence: onset of
puberty is associated with accelerated germ cell depletion. J Clin
Endocrinol Metab 89:22632270.
Witelson SF. 1989. Hand and sex differences in the isthmus and
genu of the human corpus callosum. A post-mortem morphologi-
cal study. Brain 112:799835.
Yan JB, Xu M, Xiong C, Zhou DW, Ren ZR, Huang Y, Mommersteeg
M, van Beuningen R, Wang YT, Liao SX, Zeng F, Wu Y, Zeng YT.
2011. Rapid screening for chromosomal aneuploidies using
array-MLPA. BMC Medical Genetics 12:68
Zeger MP, Zinn AR, Lahloun N, Ramos P, Kowal K, Samango-Sprouse
C, Ross JL. 2008. Effect of ascertainment and genetic features
on the phenotype of Klinefelter syndrome. J Pediatr 152:716
722.
Zeitoun O, Ketelsen UP, Wolff G, Mu ller CR, Korinthenberg R. 1997.
Rare combination of Becker muscular dystrophy and Klinefelters
syndrome in one patient. Brain Dev 19:359361.
Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. 2004. X-chro-
mosome inactivation patterns and androgen receptor functional-
ity inuence phenotype and social characteristics as well as
pharmacogenetics of testosterone therapy in Klinefelter patients.
J Clin Endocrinol Metab 89:62086217.
Zoppi MA, Ibba RM, Floris M, Monni G. 2001. Fetal nuchal translu-
cency screening in 12 495 pregnancies in Sardinia. Ultrasound
Obstet Gynecol 18:649651.