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Official reprint from UpToDate®

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Clinical features, diagnosis, and management of

Klinefelter syndrome
Authors: Alvin M Matsumoto, MD, Bradley D Anawalt, MD
Section Editor: Peter J Snyder, MD
Deputy Editor: Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2022. | This topic last updated: Dec 03, 2019.

INTRODUCTION

Klinefelter syndrome is the most common cause of primary hypogonadism. The majority of
men with Klinefelter syndrome are not diagnosed. Many of these missed diagnoses are likely
due to the failure of clinicians to recognize the symptoms and signs of hypogonadism and the
distinctive phenotype (eg, small, very firm testes) of classic Klinefelter syndrome. Recognition
and treatment of Klinefelter syndrome is important for prevention or treatment of its
consequences, such as micropenis, learning disabilities, delayed puberty, infertility, and
osteoporosis.

The epidemiology, pathogenesis, clinical features, diagnosis, and management of Klinefelter

syndrome are reviewed here. The use of advanced reproductive technologies for men with
Klinefelter syndrome and reviews of other male hypogonadal disorders are found separately.
(See "Treatments for male infertility", section on 'Retrieval of sperm' and "Clinical features and
diagnosis of male hypogonadism".)

EPIDEMIOLOGY

The prevalence of Klinefelter syndrome is approximately 1 to 2.5 per 1000 boys and men (0.1 to
0.25 percent) [1-4]. Only 25 to 50 percent of patients with Klinefelter syndrome are diagnosed
during their lifetimes [1,3,4].

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PATHOGENESIS

Klinefelter syndrome results from supernumerary X chromosomes in an XY male (X1+nY).

Approximately 80 to 90 percent of men with Klinefelter syndrome are 47,XXY (47 chromosomes
with an extra X) [1,5]. The extra X chromosome is due to maternal or paternal meiotic
nondisjunction of the X chromosome during gametogenesis (ova or sperm production) [1,5].
Maternal and paternal nondisjunction occurs equally in Klinefelter syndrome [1,5].

Approximately 10 percent of men with Klinefelter syndrome have mosaicism (47,XXY/46XY) with
47,XXY present in some tissues and the normal karyotype in other tissues [1,5]. Mosaic
Klinefelter syndrome is due to post-fertilization mitotic nondisjunction during early fetal
development. Men with mosaic Klinefelter syndrome have a milder phenotype. Very rarely, men
may have more than two X chromosomes (eg, 48,XXXY) [5]. Men with three or more X
chromosomes have a more severe phenotype of Klinefelter syndrome than those with 47,XXY
karyotypes [5].

The phenotype of Klinefelter is also affected by androgen responsiveness [1,6,7]. Androgen

sensitivity is related partly to polymorphic variations in the number and length of cytosine,
adenine, and guanine (CAG) trinucleotide repeats in the noncoding region of the androgen
receptor gene. Longer CAG repeats in the androgen receptor gene correlates with decreased
responsiveness to testosterone and are associated with small variations in phenotype (eg,
modest differences in body height and limb length) [1].

The genetic abnormality results in progressive fibrosis and destruction of both the seminiferous
tubules and the Leydig cells, causing decreased sperm production and decreased testosterone
production. Abnormalities of spermatogenesis generally precede and are more severe than
abnormalities in testosterone production.

CLINICAL FEATURES

The clinical features of Klinefelter syndrome differ by developmental stage and severity of the
phenotype ( figure 1). Because of the variability of phenotype severity and the failure of many
clinicians to recognize the clinical features of Klinefelter syndrome, the majority of diagnoses
are made in adulthood; the mean age at diagnosis of Klinefelter syndrome is approximately 30
years [1]. The diagnosis of Klinefelter syndrome should be suspected in any neonatal boy with
micropenis, hypospadias, or cryptorchidism, in teenage boys with delayed puberty, or men who
present with small testes and androgen deficiency or infertility.

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Neonates and prepubertal boys — Only the most severe phenotypes of Klinefelter syndrome
are recognized before puberty. Neonates with Klinefelter syndrome may present with
micropenis (<1.9 cm for neonate) or clinodactyly, hypospadias, or cryptorchidism. Prepubertal
boys with Klinefelter syndrome may present with behavioral abnormalities, language delay,
learning disabilities, or hypertelorism.

Puberty — Many males with Klinefelter syndrome are often recognized and diagnosed at the
usual age of puberty because they do not begin or complete pubertal development (including
failure of testes to grow normally, incomplete virilization [eg, scant pubic and facial hair]) and
gynecomastia. Boys of pubertal age with Klinefelter syndrome tend to be taller than expected
based on mid-parental height and have legs that grow out of proportion to arm length. Their
leg length is, on average, 4 to 8 cm greater than men without Klinefelter syndrome. This
difference varies by the severity of the Klinefelter syndrome phenotype as well as genetic
background. We do not recommend measuring leg length, as there is no consensus on how the
measurement should be performed [7].

Adults

Typical presentation — Less severe phenotypes of Klinefelter syndrome are recognized and
diagnosed in adulthood. Adult men with Klinefelter syndrome may present with infertility due
to azoospermia or symptoms and signs of androgen deficiency (gynecomastia, sexual
dysfunction, or osteoporosis). Men with classic Klinefelter syndrome have very small, firm testes
(≤4 cc each). The small testicular volume is due to progressive fibrosis and destruction of both
functional (steroidogenic and spermatogenic) compartments of the testes. Men with nonclassic
Klinefelter syndrome (including men with mosaic Klinefelter syndrome) may have testes that
are larger (and even normal-sized) [8-10]. Abnormalities of spermatogenesis generally precede
and are more severe than abnormalities in testosterone production ( figure 1).

Biochemical findings — The characteristic laboratory findings in men and boys older than
pubertal age are the following: low serum total and free testosterone and high follicle-
stimulating hormone (FSH) and luteinizing hormone (LH) concentrations. Because serum sex
hormone-binding globulin (SHBG) concentrations are also higher in Klinefelter syndrome,
serum free testosterone concentrations are disproportionately lower than serum total
testosterone concentrations. We do not measure serum estradiol (E2) in these men, but they
tend to be high-normal to slightly high. (See "Clinical features and diagnosis of male
hypogonadism", section on 'Diagnosis'.)

Some men with Klinefelter syndrome may present with normal serum total testosterone
concentrations and low serum free testosterone concentrations. Rarely, men with Klinefelter

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syndrome will have normal serum total and free testosterone concentrations at the initial
evaluation; over time, serum testosterone concentrations fall as progressive fibrosis destroys
the normal testicular tissue. Serum FSH concentrations are uniformly elevated and are always
higher than serum LH concentrations. Most men with Klinefelter syndrome have high serum LH
concentrations, but men with Klinefelter syndrome may initially present with normal serum
testosterone concentrations and high-normal serum LH concentrations that rise as serum
testosterone concentrations decline. Karyotype results are described below. (See 'Diagnosis'
below.)

Mortality and comorbidities — In addition to gynecomastia, infertility, osteoporosis, genital

abnormalities, and variable androgen deficiency, males with classic Klinefelter syndrome report
to have an increased risk of other potential adverse health consequences ( table 1) [1,11-14].
Any conclusions about the mortality and morbidity of Klinefelter syndrome must be tempered
by the fact that the many men with Klinefelter syndrome are not recognized and diagnosed; the
published reports are biased by more severe phenotypes and other factors. The effects on
mortality have been established in several epidemiologic studies of national health registries
worldwide. Although these epidemiologic studies have demonstrated an increased relative risk
of a broad range of morbidities and Klinefelter syndrome, the absolute increased risk of these
morbidities is uncertain, but it is generally small [1,11].

Longevity — Lifespan is reduced by five to six years; younger age at diagnosis is associated
with a greater reduction in longevity [1]. It is likely that younger age of diagnosis is associated
with a more severe phenotype that explains that greater effect on mortality.

Psychosocial and cognitive abnormalities — Learning and developmental disabilities are

common (present in >50 percent diagnosed with classic Klinefelter syndrome) [1]. Personality
disorders and behavioral problems occur commonly in all males with Klinefelter syndrome after
the neonatal period. These effects might be due to psychosocial consequences of learning
disabilities and in later in life due to untreated androgen deficiency. Neuropsychiatric illness
such as anxiety, attention deficit disorder, major depression, autism spectrum disorder, and
schizophrenia appears to be more common in men with classic Klinefelter syndrome [1,15-17].

Other comorbidities

● Dentofacial abnormalities – Certain dentofacial abnormalities have been associated with

Klinefelter syndrome including taurodontism (an enlargement of the pulp of molars on
dental radiography that might be associated with increased risk of caries), mandibular
prognathism, and the absence of permanent teeth [18]. The causal relationship and the
absolute and relative risk of these dentofacial abnormalities is being studied [18].

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● Cardiovascular – Klinefelter syndrome has been associated with an increased relative risk
of ischemic heart disease, mitral valve prolapse, lower extremity varicose veins and
venous stasis ulcers, and deep venous thrombosis and pulmonary embolism [1,11].

● Pulmonary – Chronic obstructive pulmonary disease and pneumonia are more likely to be
diagnosed in men with Klinefelter syndrome [11].

● Musculoskeletal – In addition to an increased lifetime risk of osteoporotic fracture,

osteoarthritis appears to be more common [1]. Men with Klinefelter syndrome also may
have persistently decreased muscle mass and weakness (even after testosterone therapy)
that is at least partially due to congenital and peripubertal hypogonadism.

● Neurologic – There is an increased prevalence of essential tremor and a Parkinson-like

syndrome with tremor in men with classic Klinefelter syndrome. More than 25 percent of
patients with Klinefelter syndrome may have a tremor [1].

● Cancer – The risk of breast cancer is up 50-fold higher in men with Klinefelter syndrome,
but the absolute lifetime risk of breast cancer in these men is <1 percent [1,12]. Men with
Klinefelter syndrome account for 4 percent of all cases of male breast cancer.
Extragonadal germ cell cancer and non-Hodgkin lymphoma also appear to occur at higher
frequency, but the absolute risk is small [1]. The lifetime risk of prostate cancer appears to
be lower than the general adult male population [1].

● Autoimmune disorders – Autoimmune diseases such as rheumatoid arthritis, systemic

lupus erythematosus, and autoimmune endocrinopathies (eg, Hashimoto's thyroiditis and
type 1 diabetes mellitus) are relatively more common in men with Klinefelter syndrome
[1]. However, the absolute risk appears to be small [11].

DIAGNOSIS

Klinefelter syndrome is diagnosed definitively by sex chromosome karyotyping of serum white

blood cells that demonstrates a supernumerary X chromosome plus a Y chromosome.
Klinefelter syndrome is generally diagnosed based on clinical presentation and confirmatory
laboratory testing, including karyotype [1,19]. However, the diagnosis may also be made
presumptively based on clinical presentation in adults [1].

Age at diagnosis — The diagnostic approach differs according to the age of the patient and the
patient's clinical presentation.

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Prenatal and newborn diagnosis — Diagnosis in the prenatal or newborn boy requires
karyotyping. Routine prenatal and newborn screening for Klinefelter syndrome are not
recommended, although some experts have advocated for screening newborns [4]. Prenatal
screening is not offered routinely, because this syndrome is not severe enough to justify
abortion. Newborn screening is not being performed, because it has not been established that
the benefit of early diagnosis and reduction of missed diagnoses justifies the cost.

Prenatal screening is done on a maternal blood sample with karyotyping of fetal DNA that
circulates in an unbound, cell-free state [19]. The diagnosis must be confirmed with karyotyping
of cells from prenatal amniocentesis or chorionic villous sampling or postnatal testing of cells
from the infant boy's blood sample. Although elective termination based on prenatal diagnosis
was common in the past, the largest study indicates that a minority of couples elect to
terminate a male fetus with an XXY karyotype [20,21]. The clinician plays a large role in this
decision-making process because couples are influenced by the perception of the
consequences of this syndrome that are generally less severe than other common trisomies,
such as Down syndrome.

Prepubertal and peripubertal diagnosis — Karyotyping must be done to make a definitive

diagnosis of Klinefelter syndrome in prepubertal boys or boys of peripubertal age.

Adult diagnosis — The authors and some other experts believe that it is reasonable to make a
presumptive diagnosis of Klinefelter syndrome without confirmatory sex chromosomal
karyotyping in adult men with classic phenotypic features (including small firm testes) of
Klinefelter syndrome and primary hypogonadism if the man is not interested in conceiving. (See
'Karyotype' below.)

Karyotype — Karyotype analysis of sex chromosomes is expensive and should be done by

experienced personnel in a laboratory that performs such testing frequently. If traditional
cytogenetic testing is performed, at least 20 cells in metaphase should be examined to reduce
the likelihood of false negative results [22]. The addition of fluorescence in situ hybridization
(FISH) is superior to cytogenetic testing alone [23]. Barr body cytology is too insensitive and
nonspecific, and this test is no longer used routinely in clinical practice. Cytogenetic testing is
usually performed on cultured circulating blood lymphocytes, but in cases of suspected
mosaicism, additional testing of cultured cells from skin and testicular tissue is required.
Quantitative polymerase chain reaction (PCR) assays are less expensive and may be as accurate
as cytogenetic test with FISH, but this technique has not been fully validated [24].

We recommend sex chromosome karyotype analysis when Klinefelter syndrome is suspected

prepubertally or at the time of puberty. We also recommend karyotype analysis for all men with

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primary hypogonadism that are seeking fertility treatment with assisted reproductive
technology such as intracytoplasmic injection and for men who want to definitive confirmation.
There is controversy about whether men with classic Klinefelter syndrome (eg, very small testes
and primary hypogonadism) benefit from sex chromosome karyotyping unless they are seeking
fertility treatment. Some experts recommend sex chromosome karyotype analysis for all men
with primary hypogonadism without an obvious cause. This recommendation is based on the
potential added value of knowing whether the patient is at increased risk for the morbidities
that have been associated with Klinefelter syndrome. (See 'Mortality and comorbidities' above.)

MANAGEMENT

There are no clinical practice guidelines on the management of Klinefelter syndrome. Most of
the recommendations are based on clinical experience of experts and small clinical trials.
Patients with a severe phenotype of Klinefelter syndrome may benefit from care from a
multidisciplinary group that might include primary care physicians, endocrinologists, mental
health professionals, and infertility specialists.

Informing the patient and family about the diagnosis — The first step in treatment is to
inform the patient of the diagnosis. The diagnosis must be provided in a gentle, sensitive
manner that openly discloses the genetic basis and the potential consequences. The clinician
must explain that Klinefelter syndrome is not inherited per se and that there is no fault to be
assigned to either parent or to the patient.

When initially discussing the potential consequences, it is important to stress the broad range
of variability of the phenotype and focus on the features that are universal: a very high
likelihood of eventual permanent androgen deficiency and infertility. Because the increased
absolute risk of other consequences of Klinefelter syndrome is generally low, we typically review
those at a later date.

Informing a boy (under 18 years old) of the diagnosis requires prior discussion and
collaboration with the parents. There is no best way to disclose the diagnosis to a boy although
the following principles are useful [23]. The clinician should inform the parents of the diagnosis
and answer questions related to prognosis and treatment. Then, ask the parents to describe
the syndrome in their words and educate them about any misconceptions that they might
express. The clinician should discuss the options for informing the boy: (1) by the clinician
without the parents present; (2) by the clinician in the presence of the parents; or (3) by the
clinician and the parents as a team.

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For a younger boy (5 to 10 years), the key information to convey is that he does not have a
condition that is deadly or contagious. He should also be informed that there is nothing that he
or his parents could have done to prevent the condition. We sometimes present information
about Klinefelter syndrome in stages. An adolescent needs to be informed that this syndrome
does not affect gender or sexual orientation. It may be useful to inform an adolescent that the
X chromosome is partially inactivated ("just like the other boys that they know") [25].

Clinicians must respect the wishes of parents who want to delay disclosure, but clinicians
should gently inquire periodically about whether the boy and parents might be ready for
disclosure. When a boy begins to ask specific questions about his health, that is an indication of
readiness. Limited evidence suggests that more children with sex chromosome abnormalities
such as Klinefelter syndrome experience positive (eg, relief) or neutral reactions than negative
reactions (eg, anger or anxiety) when informed of their diagnosis [26].

Informing an adult of the diagnosis of Klinefelter syndrome might also require staging of
information. Many men (particularly those with prominent gynecomastia) might be concerned
that they are "partially female," and they should be told that they are male (if they self-identify
as male). Virtually all men who are diagnosed with Klinefelter syndrome as adults have initially
presented with androgen deficiency and/or infertility. The initial focus of disclosure of the
diagnosis in an adult should be on the lifelong benefit of testosterone therapy and the options
for androgen replacement therapy (see 'Testosterone therapy' below and "Testosterone
treatment of male hypogonadism", section on 'General approach to treatment'). The clinician
should also discuss the permanent damage to spermatogenesis. For a man who expresses
interest in conceiving children in the future, the clinician should be prepared to discuss the
options: adoption, insemination with sperm from a donor, or an attempt at extraction of sperm
from the testes. The low success rate of assisted reproductive techniques should be discussed
(see 'Options for male infertility' below and "Treatments for male infertility", section on 'Assisted
reproductive technologies'). Some adult men with newly diagnosed Klinefelter syndrome and a
history of significant learning disabilities or behavioral problems will be relieved to learn that
these might be due to Klinefelter syndrome. Describing the other extragonadal effects of
Klinefelter generally should be delayed until questions arise.

Preventive and routine health care — Although there are many adverse health consequences
associated with Klinefelter syndrome, there is no evidence that specific preventive or screening
measures should differ from the general population. The absolute risks of adverse effects of
Klinefelter syndrome appear to be low, and these risks do not justify a divergence from
published guidelines for preventive health care in boys and men.

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We suggest a periodic breast examination (eg, every one to two years) because of the increased
risk of breast cancer (see 'Other comorbidities' above). Clinicians should be familiar with the
nongonadal disorders associated with Klinefelter syndrome. For example, the clinician should
be more attentive to the possibility of autoimmune disease and psychiatric disease in these
boys and men; a man with Klinefelter syndrome and unexplained arthritis is more likely to have
rheumatoid arthritis or systemic lupus than the average man.

The treatment of Klinefelter syndrome varies based on the age of the patient at diagnosis, the
severity of the phenotype, and the specific clinical endpoint ( figure 2).

Testosterone therapy — Testosterone therapy is the most important component of long-term

management of pubertal boys and adult men with Klinefelter syndrome. The principles, goals,
and dosing of testosterone are the same as for other men with hypogonadism; these are
discussed in detail separately. (See "Testosterone treatment of male hypogonadism".)

Neonates and prepubertal boys — We suggest a short course of testosterone cypionate or

enanthate (eg, 25 mg injected monthly for three doses) to treat micropenis in neonatal boys
and infants (up to age 1) with Klinefelter syndrome. This treatment may modestly increase
penile length and girth [27,28]. Although some evidence suggests that androgen therapy may
benefit specific aspects of behavioral, social, and cognitive function in prepubertal boys (ages 1
to 12) with Klinefelter syndrome [29,30], the authors of this topic recommend against this
treatment because of the potential risks of early onset of puberty and decreased adult height (
figure 2) [31].

Boys of pubertal age — Testosterone treatment options for boys ≥13 years old and men with
Klinefelter syndrome are the same as those for any man with primary hypogonadism (see
"Testosterone treatment of male hypogonadism", section on 'General approach to treatment').
For boys 13 to 18 years, the goal of testosterone therapy is to cause gradual virilization (eg,
facial and pubic hair, muscle development) without inducing early closure of bony epiphyses
and decreased growth and height. We recommend low doses (50 to 100 mg) of monthly
intramuscular testosterone enanthate or cypionate until growth ceases or until age 18 to 19
years. Transdermal testosterone products have not been approved for use in boys, but they can
be used off-label at low doses (eg, one-half the usual daily adult dose) for teenage boys.
Although transdermal testosterone application obviates the need for injections, adherence to
monthly injections might be better. We do not recommend very long-acting testosterone
formulations (such as intramuscular testosterone undecanoate or testosterone pellets) in
teenage boys, because it is not possible to deliver low doses of these preparations reliably.

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Adults — For adult men, full doses of testosterone replacement should be used ( figure 2).
Serum gonadotropin concentrations should not be used to determine the testosterone dose,
because this approach results in nonphysiologic doses in many men [32,33]. Instead, the
testosterone dose should be based on the usual adult replacement regimens for male
hypogonadism. (See "Testosterone treatment of male hypogonadism", section on 'Choice of
testosterone regimen'.)

We suggest initiation of testosterone therapy at typical adult replacement doses for adult men
with hypogonadism (see "Testosterone treatment of male hypogonadism"). Men with very low
serum testosterone concentrations might experience behavioral and mood changes (eg, due to
increased libido) with immediate initiation of typical adult replacement doses of testosterone. In
this setting, it may be prudent to initiate one-quarter to one-half of the usual replacement dose
of testosterone with gradual escalation to a full adult replacement dose over a few months. For
men who experience mood symptoms with full dose testosterone, we typically reduce the dose
of testosterone temporarily.

Although some men with Klinefelter syndrome have normal serum testosterone
concentrations, we suggest treating with testosterone if the serum luteinizing hormone (LH)
concentration is elevated. Elevation of serum LH indicates that the serum testosterone is low
enough to activate the hypothalamic-pituitary-testicular axis.

In general, men with Klinefelter syndrome and low serum testosterone concentrations report
improved sense of well-being and sexual function with testosterone replacement therapy [1].
However, many aspects of Klinefelter syndrome persist or do not completely remit. For
example, certain aspects of cognition might improve, but overall cognition is not improved in
boys and men with Klinefelter syndrome who are treated with an androgen [1]. Bone density
increases with testosterone, but it generally does not normalize compared with peers, and the
quality of bone might remain below average in patients with Klinefelter syndrome [1].

Options for male infertility

Assisted reproductive technologies — The two most effective treatments for infertility in
men with Klinefelter syndrome remain adoption and the use of donor sperm. However, patients
with Klinefelter syndrome who are interested in having children should be informed about the
development of microscopic testicular extraction of sperm (microTESE). Between 45 to 50
percent of men with Klinefelter syndrome have sperm that can be extracted by microTESE for
use in assisted reproductive techniques such as intracytoplasmic injection of sperm into an
ovum [34-36] (see "Treatments for male infertility", section on 'Retrieval of sperm').
Approximately one-half of these men will conceive with assisted reproductive techniques. The

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reported rates of microTESE extraction of sperm reflect the experience of highly specialized
centers; the rates of successful sperm extraction with microTESE are lower for less experienced
specialists.

Although there are no data to support the practice, testosterone therapy is often withheld for
six months prior to an attempt to harvest sperm. Normal or high serum and intratesticular
gonadotropin concentrations are required for optimal spermatogenesis so exogenous
testosterone therapy is discontinued to ensure that elevated serum gonadotropins that might
stimulate sperm production are not suppressed. Because spermatogenesis takes three months
from initiation to release of mature sperm, testosterone therapy is withheld for at least three
months and usually six months.

Extraction and cryopreservation of sperm in boys and men — The natural history of
Klinefelter syndrome is progressive testicular fibrosis. An area of uncertainty is whether to
harvest and freeze sperm in teenage boys and men soon after the diagnosis. It is difficult to
persuade peripubertal boys to submit a seminal fluid sample, and rarely will peripubertal boys
(or men) with Klinefelter syndrome have sperm in their ejaculate [34,35]. Based on very limited
data, it appears that peripubertal boys with Klinefelter syndrome are not more likely than men
with Klinefelter syndrome to have sperm found during attempted surgical extraction [34-36].

We suggest against surgical extraction and cryopreservation of sperm before desired

conception. The rationale for this recommendation is that it is storage of cryopreserved sperm
is expensive (approximately USD $1000 to $3000 per year), with some risk of degradation of
sperm viability. In addition, there is no good evidence of better outcomes (conception or live
births) compared with waiting to do sperm extraction when conception is desired.

Males with mosaic Klinefelter syndrome, normal or slightly elevated serum LH concentrations,
or testes with total volume 8 cc or larger are more likely to have sperm in the ejaculate [10]. We
recommend that seminal fluid analysis be performed promptly in such patients because it is
likely cost effective to cryopreserve sperm for them. As noted above, sperm can be extracted
from approximately one-half of men with Klinefelter syndrome using microTESE; sperm can
then be used for assisted reproductive techniques. (See 'Assisted reproductive technologies'
above and "Treatments for male infertility", section on 'Retrieval of sperm'.)

Ineffective therapies — We do not recommend the use of gonadotropins, aromatase

inhibitors, or selective estrogen receptor modulators to increase spermatogenesis. Although
some experts postulate that gonadotropin therapy or treatments that further increase serum
gonadotropins (eg, aromatase inhibitors, selective estrogen receptor modulators) might
increase residual spermatogenesis, this hypothesis has little supportive evidence.

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Behavioral abnormalities and cognitive and learning disabilities — Many boys with
Klinefelter syndrome have behavioral abnormalities and learning disabilities. Most individuals
with Klinefelter syndrome have normal or slightly low overall cognitive function, but good
overall health. Specific education such as speech and reading therapy might be beneficial.
Counseling might be useful to address anxiety about their cognition and health [1].

Gynecomastia — For adolescents and men with cosmetically bothersome gynecomastia,

reduction mammoplasty is beneficial. This surgery should be delayed until several months after
testosterone therapy has been initiated because untreated hypogonadism will cause recurrent
breast tissue growth. (See "Management of gynecomastia", section on 'Surgery'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Testosterone therapy in
men" and "Society guideline links: Male infertility or hypogonadism" and "Society guideline
links: Male sexual dysfunction".)

SUMMARY AND RECOMMENDATIONS

● Klinefelter syndrome (47,XXY) is the most common cause of primary hypogonadism. The
majority of men with Klinefelter syndrome are never diagnosed because clinicians fail to
recognize the phenotypic features. (See 'Epidemiology' above.)

● Klinefelter syndrome should be suspected in infants with hypospadias or micropenis,

teenage boys with delayed puberty, and adult men with primary hypogonadism or
infertility and small testes ( table 1 and figure 1). (See 'Clinical features' above.)

● The definitive diagnostic test for Klinefelter syndrome is sex chromosome karyotyping that
reveals at least one supernumerary X chromosome with a Y chromosome. (See 'Diagnosis'
above.)

● The majority of men with Klinefelter syndrome have small testes (≤4 cc each), low or low-
normal serum testosterone concentrations and high serum gonadotropin concentrations
(follicle-stimulating hormone [FSH] greater than luteinizing hormone [LH]). (See 'Adults'
above.)

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● In addition to infertility and the complications associated with androgen deficiency,

Klinefelter syndrome increases the risk of learning and language disorders, metabolic
syndrome and diabetes mellitus, cardiovascular events, thromboembolic disease,
autoimmune disease, as well as certain cancers ( table 1 and figure 1). (See 'Clinical
features' above.)

● Speech and reading therapy and counseling are important for many boys and men with
Klinefelter syndrome ( figure 2). (See 'Behavioral abnormalities and cognitive and
learning disabilities' above.)

● We suggest against the use of testosterone therapy in prepubertal boys as the potential
benefits on behavioral, social, and cognitive function are outweighed by the risks of early
onset of puberty and decreased adult height (Grade 2C). (See 'Neonates and prepubertal
boys' above.)

● Testosterone therapy is the most important component of long-term management of

pubertal boys and adult men with Klinefelter syndrome. The principles, goals, and dosing
of testosterone are the same as for other men with hypogonadism. (See "Testosterone
treatment of male hypogonadism".)

● We suggest low doses (50 to 100 mg) of monthly intramuscular testosterone enanthate or
cypionate for pubertal boys starting at age 13 years until either growth ceases or until age
18 to 19 years (Grade 2C). The goal of testosterone therapy in this age group is to cause
gradual virilization (eg, facial and pubic hair, muscle development) without inducing early
closure of bony epiphyses and decreased growth and height. (See 'Boys of pubertal age'
above.)

● For adult men with Klinefelter syndrome, we suggest full doses of testosterone
replacement ( figure 2) (Grade 2B). (See 'Adults' above and "Testosterone treatment of
male hypogonadism".)

● Options for men who are infertile due to Klinefelter syndrome include adoption,
insemination of the female partner with donor sperm, or sperm harvesting with
microscopic testicular sperm extraction (microTESE) and use of assisted reproductive
techniques for insemination ( figure 2). (See 'Options for male infertility' above.)

● Males with mosaic Klinefelter syndrome, normal or slightly elevated serum LH

concentrations, or testes with total volume 8 cc or larger are more likely to have sperm in
the ejaculate. Seminal fluid analysis should be performed promptly in such patients

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because it is likely cost effective to cryopreserve sperm for these individuals. (See
'Extraction and cryopreservation of sperm in boys and men' above.)

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as compared with non-mosaic Klinefelter patients. Fertil Steril 2014; 101:950.
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13. Bojesen A, Juul S, Birkebaek N, Gravholt CH. Increased mortality in Klinefelter syndrome. J
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syndrome: The impact of personality and social engagement. PLoS One 2018; 13:e0206932.
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28. Hatipoğlu N, Kurtoğlu S. Micropenis: etiology, diagnosis and treatment approaches. J Clin
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29. Flannigan R, Patel P, Paduch DA. Klinefelter Syndrome. The Effects of Early Androgen
Therapy on Competence and Behavioral Phenotype. Sex Med Rev 2018; 6:595.
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31. Davis SM, Lahlou N, Cox-Martin M, et al. Oxandrolone Treatment Results in an Increased
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32. Matsumoto AM, Bremner WJ. Modulation of pulsatile gonadotropin secretion by

testosterone in man. J Clin Endocrinol Metab 1984; 58:609.
33. Amory JK, Anawalt BD, Bremner WJ, Matsumoto AM. Daily testosterone and gonadotropin
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testosterone: implications for male contraceptive development. J Androl 2001; 22:1053.
34. Gies I, Oates R, De Schepper J, Tournaye H. Testicular biopsy and cryopreservation for
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Fertil Steril 2016; 105:249.
35. Franik S, Hoeijmakers Y, D'Hauwers K, et al. Klinefelter syndrome and fertility: sperm
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36. Corona G, Pizzocaro A, Lanfranco F, et al. Sperm recovery and ICSI outcomes in Klinefelter
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Topic 13921 Version 2.0

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GRAPHICS

Developmental stages and most common clinical presentation(s) at time of dia

Darker shades of blue correspond to greater likelihood of diagnosis during that time band. The most comm
is between ages 20 to 40 years when men with Klinefelter syndrome typically present with infertility (or and
deficiency). The mean age of diagnosis of Klinefelter syndrome is approximately 30 years. Prepubertal, perip
and adult males with Klinefelter syndrome often have behavioral abnormalities and learning disabilities.

Courtesy of Bradley D Anawalt, MD and Alvin M Matsumoto, MD.

Graphic 122872 Version 1.0

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The most common morbidities in Klinefelter syndrome

Morbidity Frequency (%) Comments

Children

Learning disability >75

Delayed speech development >40

Autism spectrum disorder 30 to 50 Most patients are diagnosed as

children

Psychiatric disorder >25 Anxiety and depressed mood are most

common

Decreased penis size 10 to 25 May not meet strict criteria for

micropenis

Cryptorchidism 25 to 40 Cryptorchidism is typically detected

during childhood

Adults

Testosterone deficiency and 99 to 100 A few men with Klinefelter syndrome

infertility with azoospermia and (particularly mosaic Klinefelter
small testes syndrome) have normal serum
testosterone concentrations and
sperm in the ejaculate at time of
diagnosis

Metabolic syndrome 40 to 50 Prevalence increases with age

Type 2 diabetes mellitus 10 to 40 Prevalence increases with age

Osteoporosis 40 Prevalence increases with age

Tremor >25 Prevalence increases with age

Psychiatric disorder >25 Anxiety and depressed mood are most

common

Courtesy of Bradley D Anawalt, MD and Alvin M Matsumoto, MD.

Graphic 122875 Version 1.0

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Recommended management of Klinefelter syndrome based on common seque

developmental stage

Each therapy should be considered at the respective stage of development of a male with known Klinefelter
syndrome. For example, if the diagnosis is made prenatally, then the clinician would educate the parents ab
Klinefelter syndrome and its prognosis. An 8-year-old boy with Klinefelter syndrome who presented with
micropenis as a neonate might be doing well at school and does not need speech and language therapy, or
counseling. An older man who is diagnosed with Klinefelter syndrome during an evaluation of severe osteop
might need treatment with calcium and vitamin D supplements and an approved drug for osteoporosis in a
to testosterone replacement therapy.

ART: assisted reproductive technologies.

Courtesy of Bradley D Anawalt, MD and Alvin M Matsumoto, MD.

Graphic 122874 Version 1.0

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Contributor Disclosures
Alvin M Matsumoto, MD Consultant/Advisory Boards: AbbVie [Testosterone];Partnership for Clean
Competition [Anabolic steroid doping and testing];US Anti-Doping Agency [Board of Directors,
performance enhancing drug doping and testing]. All of the relevant financial relationships listed have
been mitigated. Bradley D Anawalt, MD No relevant financial relationship(s) with ineligible companies to
disclose. Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism];Crinetics
[Acromegaly];Novartis [Cushing's];Recordati [Cushing's]. Consultant/Advisory Boards: AbbVie
[Hypogonadism];Novartis [Cushing's];Pfizer [Acromegaly];Teva Pharmaceuticals [Cushing's]. All of the
relevant financial relationships listed have been mitigated. Kathryn A Martin, MD No relevant financial
relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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