I.

Title
Klinefelter Syndrome

II. Overview, History and Epidemiology

Overview
Genetic disorder is a disease that is caused by an abnormality in an
individual's DNA. Klinefelter syndrome is the most common disorder of sex
chromosomes in humans. Klinefelter syndrome is a disorder that affects only
males. Males normally have an X chromosome and a Y chromosome (XY). But
males who have Klinefelter syndrome have an extra X chromosome (XXY),
giving them a total of 47 instead of the normal 46 chromosomes. 1 Refer to
Plate no.1
History
In 1942, Dr. Harry Klinefelter and his coworkers at the Massachusetts
General Hospital in Boston published a report about 9 men who had enlarged
breasts, sparse facial and body hair, small testes, and an inability to produce
sperm. By the late 1950s, researchers discovered that men with Klinefelter
syndrome, as this group of symptoms came to be called, had an extra sex
chromosome, resulting in a chromosomal arrangement of XXY; the usual
male arrangement is XY.2 Infertility and gynecomastia are the 2 most
common symptoms that lead to diagnosis in patients with
Klinefeltersyndrome.Other symptoms include fatigue, weakness, erectile
dysfunction, osteoporosis, language impairment, academic difficulty,
subnormal libido, poor self-esteem, and behavioral problems.4
Based on these studies, the XXY chromosome arrangement appears to be
one of the most common genetic abnormalities known, XXY aneuploidy is the
most common disorder of sex chromosomes in humans, with a prevalence of
one in 500 males.3
Epidemiology
Frequency
United States
Klinefelter syndrome is the most common genetic form of male
hypogonadism.
Approximately 1 in 500-1,000 males is born with an extra sex chromosome;
more than 3,000 affected males are born yearly.
The prevalence rate is 5-20 times higher in individuals with mental
retardation than in the general newborn population.
Approximately 250,000 men in the United States have Klinefelter syndrome. 4
Mortality/Morbidity
About 40% of concepti with Klinefelter syndrome survive the fetal period.
In general, the severity of somatic malformations in Klinefelter syndrome is
proportional to the number of additional X chromosomes; mental retardation
and hypogonadism are more severe in patients with 49,XXXXY than in those
with 48,XXXY.
The mortality rate is not significantly higher than in healthy individuals.
 Race
Klinefelter syndrome does not have any racial predilection.
Sex
Because the syndrome is caused by an additional X chromosome on an XY
background, this condition affects only males.
Age
Klinefelter syndrome goes undiagnosed in most affected males; among
males with known Klinefelter syndrome, many do not receive the diagnosis
until they are adults. The most common indications for karyotyping are
hypogonadism and infertility.Refer to Plate no.2

III. Genomics
Most people have 46 chromosomes with the combination of 2 pairs
consisting of 23 chromosomes each from the egg cell and sperm cell during
meiosis. Chromosomes are threadlike gene-carrying structure found in the
nucleus. Each chromosome consists of one very long DNA molecule and
associate proteins.5 Two sex chromosomes determine the sex of an offspring
either a male or female. Specifically, the sex depends on whether the sperm
carries an X or a Y chromosome. Females (46,XX) normally have two XX
chromosomes, with the sperm carrying an X chromosome, while males
(46,XY) normally have an X and a Y chromosome, with the sperm carrying
the Y chromosome.6
Klinefelter syndrome is a condition related to the X and Y
chromosomes or the sex chromosomes. Most often, Klinefelter syndrome
results from the presence of one extra copy of the X chromosome in each cell
(47,XXY). Extra copies of genes on the X chromosome interfere with male
sexual development, often preventing the testes from functioning normally
and reducing the levels of testosterone.7Refer to Plate no.1

Etiology (Cause)
In 1959, Klinefelter syndrome was found to be caused by a
supernumerary X chromosome in a male. 8 The 47,XXY karyotype of
Klinefelter syndrome spontaneously arises when paired X chromosomes fail
to separate 9 An error in cell division called nondisjunction results in a
reproductive cell with an abnormal number of chromosomes. 5 Nondisjunction
is an occasional mishap wherein the members of a pair of homologous do not
move apart properly during meiosis I or sister chromatids fail to separate
during meiosis II. In these cases, one gamete receives two of the same type
of the chromosome and the other receives no copy. 1 An egg or sperm cell
may gain one or more extra copies of the X chromosome as a result of
nondisjunction. If one of these atypical reproductive cells contributes to the
genetic makeup of a child, the child will have one or more extra X
chromosomes in each of the body's cells.4
Maternal and paternal meiotic nondisjunction each account for approximately
50% of Klinefelter syndrome cases. Seventy-five percent of maternal
nondisjunction cases are caused by meiosis I errors, which are associated
with increased maternal age. Increased paternal age has been linked to a
possible increased risk of Klinefelter syndrome.10
Postfertilization nondisjunction is responsible for mosaicism, which is seen in
approximately 10% of Klinefelter syndrome patients. Men with mosaicism are
less affected and are often not diagnosed.11
The androgen receptor (AR) gene encodes the androgen receptor,
which is located on the X chromosome. The AR gene contains a highly
polymorphic trinucleotide (CAG) repeat sequence in exon 1, and the length of
this CAG repeat is inversely correlated with the functional response of the
androgen receptor to androgens. Thus, a short AR CAG repeat sequence
correlates with a marked effect of androgens.12
In individuals with Klinefelter syndrome, the X chromosome with the
shortest AR CAG repeat has been demonstrated to be preferentially
inactivated; this process is called skewed or nonrandom X-chromosome
inactivation.Individuals with short AR CAG repeats have been found to
respond better to androgen therapy, to form more stable partnerships, and
to achieve a higher level of education compared with individuals with long
CAG repeats.13
Conversely, long AR CAG repeat lengths are associated with increased
body height and arm span, decreased bone density, decreased testicular
volume, and gynecomastia.
Nonrandom X-chromosome inactivation, which preferentially leaves the allele
with the longest AR CAG repeat active, may actually contribute to the
hypogonadal phenotype found in Klinefelter syndrome and may also explain
some of the diverse physical appearances observed in affected individuals.
In boys with Klinefelter syndrome, the paternal origin of the
supernumerary X chromosome is associated with later onset of puberty and
longer CAG repeats of the androgen receptor, with later pubertal reactivation
of the pituitary-testicular axis.

Cellular Origin OfKlinefelters Syndrome

As said, the most frequent chromosomal complement associated with
Klinefelter syndrome is 47,XXY, which may result from a nondisjunction
during (1) meiosis I or meiosis II of oogenesis, or (2) meiosis I of
spermatogenesis. By using X-linked traits such as Xg blood type or color
blindness as markers, it is sometimes possible to determine whether the
nondisjunction is of maternal or paternal origin.14 Using polymorphic DNA
markers, several investigators have found that the extra X chromosome is of
paternal origin in 50% to 60% of cases and of maternal origin in the
remaining 40% to 50% of cases. 151617 Among the maternal cases,
nondisjunction is due to an error in meiosis I division in 70% of cases, an
error in meiosis II division in 20% of cases, and a postzygotic mitotic error in
10%.6 7 18 Increased maternal age has been demonstrated in approximately
75% of cases due to maternal meiosis I nondisjunction. 8 In the paternally
derived 47,XXY cases, the X-Y nondisjunction must always occur in the first
meiotic division. In a study of 41 paternally derived 47,XXY cases, Hassold
and colleagues found evidence of reduced recombination within the
pseudoautosomal region to be associated with X-Y nondisjunction.19

Molecular Mechanism
Studies on phenotype-genotype correlations in Klinefelter syndrome
patients have been limited. Although there appear to be no obvious
phenotypic differences between cases in which the extra X chromosome is of
paternal or maternal origin, a minority of Klinefelter syndrome patients are
clinically and intellectually much more adversely affected than the average
47,XXYpatients. Studies involving structurally abnormal X chromosomes
suggest that the Klinefelters phenotype is associated with genes mapping to
the long arm of the X chromosome. 20 Zanghypothesized that a
nondisjunction error in meiosis II or during postzygotic division leading to two
copies of the same X chromosome could induce a negative dosage effect of
some harmful recessive genes on the X chromosome. 21 Jacobs and
colleagues further postulated an imprinting effect on the phenotype of the
patients, depending on the parental origin of the extra chromosome. 22 In a
study of 80 females with Turners syndrome (45,X), Skuse and
colleagues demonstrated that the presence of an imprinted locus on the long
arm of the X chromosome plays a role in cognitive and social development. 23
Interestingly, as discussed below, Klinefelter syndrome patients display
behavior problems and impaired language skills, suggesting that imprinted
genes localized to the X chromosome are likely to be involved in the
observed phenotypic variability. However, no studies have yet demonstrated
a distinct difference in phenotype between the paternally and maternally
derived cases.

Klinefelters Syndrome: Variants

Some people with features of Klinefelter syndrome have more than one
extra sex chromosome in each cell (for example, 48,XXXY or 49,XXXXY).
These conditions, which are often called variants of Klinefelter syndrome,
tend to cause more severe signs and symptoms than classic Klinefelter
syndrome. In addition to affecting male sexual development, variants of
Klinefelter syndrome are associated with intellectual disability, distinctive
facial features, skeletal abnormalities, poor coordination, and severe
problems with speech. As the number of extra sex chromosomes increases,
so does the risk of these health problems.24
Some people with features of Klinefelter syndrome have the extra X
chromosome in only some of their cells; in these individuals, the condition is
described as mosaic Klinefelter syndrome (46,XY/47,XXY). Individuals with
mosaic Klinefelter syndrome may have milder signs and symptoms,
depending on how many cells have an additional X chromosome.25
Mosaicism of the karyotype 46,XY/47,XXY, which accounts for
approximately 15% of Klinefelter syndrome cases, probably arises by
nondisjunction or anaphase lag in the zygote or embryo. It is usually
assumed that such an error involved a 47,XXY embryo.7
Turning to less common forms of Klinefelter syndrome, the etiology of
49,XXXXY (more than 100 cases documented) is best explained by
successive nondisjunction at either meiosis I or II of oogenesis.7 Postzygotic
errors, however, may be equally important.
The etiology of the 48,XXYY chromosomal complement (more than 60
cases recorded) may best be explained by either successive nondisjunction
at both the first and second meiotic division during spermatogenesis and
syngamy of the resulting 25,XYY spermatozoon with a 23,X ovum, or
nondisjunction at the second meiotic division in both parents so that
syngamy occurs between a 24,XX ovum and a 24,YY sperm.
The most common karyotype is 47,XXY, which accounts for 80-90% of
all cases. Mosaicism (46,XY/47,XXY) is observed in about 10% of cases. Other
variant karyotypes, including 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY,
are rare.The mosaic forms of Klinefelter syndrome are due to mitotic
nondisjunction after fertilization of the zygote. These forms can arise from a
46,XY zygote or a 47,XXY zygote.Variant forms of Klinefelter syndrome
include 48,XXXY; 49,XXXXY; 48,XXYY; and 49,XXXYY.

Mode of Inheritance
Klinefelter syndrome and its variants are not inherited; these
chromosomal changes usually occur as random events during the formation
of reproductive cells (eggs and sperm) in a parent.5

IV. Pathophysiology
The X chromosome carries genes that play roles in many body systems,
including testis function, brain development, and growth. 26 The addition of
more than one extra X or Y chromosome to a male karyotype results in
variable physical and cognitive abnormalities. In general, the extent of
phenotypic abnormalities, including mental retardation, is directly related to
the number of supernumerary X chromosomes. As the number of X
chromosomes increases, somatic and cognitive development are more likely
to be affected.27
The major consequences of the extra sex chromosome, usually
acquired through an error of nondisjunction during parental gametogenesis,
include hypogonadism, gynecomastia, and psychosocial problems.Refer to
Plate no.3
Skeletal and cardiovascular abnormalities can become increasingly
severe. Gonadal development is particularly susceptible to each additional X
chromosome, resulting in seminiferous tubule dysgenesis and infertility, as
well as hypoplastic and malformed genitalia in polysomy X males.
Mental capacity diminishes with additional X chromosomes. The
intelligence quotient IQ) score is reduced by approximately 15 points for
each supernumerary X chromosome, but conclusions about reduced mental
capacity must be drawn cautiously. All major areas of development, including
expressive and receptive language and coordination, are affected by extra X
chromosome material.
Klinefelter syndrome is a form of primary testicular failure, with
elevated gonadotropin levels due to lack of feedback inhibition by the
pituitary gland. Androgen deficiency causes eunuchoid body proportions;
Refer to Plate no.4
o sparse or absent facial
o axillary
o pubic, or body hair
o decreased muscle mass and strength
o feminine distribution of adipose tissue
o gynecomastia
o small testes and penis
o diminished libido
o decreased physical endurance
o osteoporosis
The loss of functional seminiferous tubules and Sertoli cells results in a
marked decrease in inhibin B levels, which is presumably the hormone
regulator of the follicle-stimulating hormone (FSH) level. The hypothalamic-
pituitary-gonadal axis is altered in pubertal patients with Klinefelter
syndrome.
Presents with low serum testosterone levels, high luteinizing hormone
(LH) and FSH levels, and, often, elevated estradiol levels; however, the
decline in testosterone production is progressive over the life span, and not
all men suffer from hypogonadism.28
Men with Klinefelter syndrome are at a higher risk of autoimmune
diseases, diabetes mellitus, leg ulcers, osteopenia and osteoporosis, tumors
(breast and germ cells), systemic lupus erythematosus, rheumatoid arthritis,
and Sjgren syndrome and historically have increased mortality.2930
Whether the morbidity associated with Klinefelter syndrome is a result
of hypogonadism and hyperestrogenism or due to abnormal function of X
chromosome linked genes is unclear.31

V. Laboratory Diagnosis
Diagnosis of Klinefelter Syndrome can be made by examining
chromosomes or karyotyping for evidence of more than one chromosome
present in a male.32It can be prenatally diagnosed through cytogenetic
analysis of cells obtained through Amniocentesis and Chorionic villus
sampling. It may also be diagnosed through a physical exam when the male
is in his puberty.
Diagnosis of Klinefelter Syndrome can be done by karyotyping. Karyotyping
is a test to examine chromosomes in a sample of cells, which can help
identify genetic problems as the cause of a disorder or disease. 33This test can
help you count the number of chromosomes as well as look for structural
changes in the chromosomes. Under this test is Amniocentesis that is
sometimes done during the pregnancy stage and looks for birth defects and
genetic problems in the developing baby. This test removes a small amount
of the fluid from the sac that surrounds the baby in the womb. 35It is done
further along in pregnancy (approximately 16-18 weeks) to obtain the said
sample for testing. Another test is the Chorionic villus sampling (CVS) that is
like the Amniocentesis but is done in the early stage of pregnancy
(approximately 10-12 weeks) to obtain a small sample of the placenta for
testing. It is also done to detect genetic and chromosomal abnormalities of
the fetus. Fetal sex chromosomal abnormalities (47,XXX, 47,XXY, and
47,XYY) have been associated with increased nuchal translucency, which is
the accumulation of fluid in the back of the neck of the fetus which takes
place between 11 and 14 weeks. This measurement, combined with the
measurement of maternal serum levels of free beta-human chorionic
gonadotropin (hCG) and pregnancy-assisted plasma protein-A (PAPP-A) in the
first trimester often indicate when the fetus possesses a chromosomal
abnormality.3435Both these prenatal tests are not routinely done due to the
fact that it carries a higher risk for a miscarriage. It is only advised to use
either of the two prenatal tests when the pregnant woman is 35 years old
and older, a history of children born with birth defects and history of genetic
diseases. Klinefelter syndrome is not usually diagnosed until the time of
puberty. Doctors usually conduct physical examinations to look for
abnormalities. Males are usually seen with female characteristics such as
wide hips, breast development, fewer chest hairs and slow testicle growth.
Hormone tests or semen analysis is also done to diagnose this syndrome. It
is due to a fact that most males having Klinefelter syndrome may suffer from
infertility due to lack of sperms. A sperm analysis usually refers to the
amount of sperm per milliliter of semen collected. 36Anywhere from 20 million
to 150 million per milliliter is considered normal. This test evaluates how the
semen thickens into a solid and turns to liquid, its thickness, acidity and
sugar content, viscosity, motility, number and structure of the sperm as well
as the volume of the semen (Semen analysis).
Abramsky and Chappleestimated that about 10% of XXY aneuploidies
are diagnosed prenatally by amniocentesis; another 26% are diagnosed in
childhood or adulthood. Most men are not recognized and are never
diagnosed.37 Because of the varied clinical manifestations in men with
Klinefelter syndrome, physicians need to recognize potential features of
Klinefelter syndrome throughout the life span. Refer to Table 1.
In a systematic literature review, primarily comprising European and
American studies, prenatal diagnosis of XXY aneuploidy has beenassociated
with documented pregnancy termination rates of 92%. 38Pregnancy
termination rates are lowest when post-test counseling is provided by a
geneticist. There is evidence of great variation in health care professionals
knowledge regarding sex chromosome anomalies, such that some parents
receive outdated and incomplete information.39

Infancy
 Infancy and childhood Klinefeltersyndrome rarely can be identified in
infancy, after karyotyping is performed as part of a routine evaluation for
hypospadias, small phallus, or cryptorchidism. The genitals in infants with
Klinefelter syndrome are usually normal at birth. Affected toddlers often
manifest a delay in the first use of words and phrases compared with
siblings. Although motor development generally falls within the normal
range, some infants are slower to walk and lack coordination due to
hypotonia of the lower extremities and sensorimotor dysfunction. After age
5, boys with Klinefelter syndrome often show accelerated linear growth
velocity, owing to excessive leg length. This accelerated growth velocity is
the most uncommon growth abnormality a primary care physician
encounters in practice and always should prompt consideration of obtaining
a chromosome analysis to exclude Klinefelter syndrome. 40Most boys with
Klinefelter syndrome manifest learning disabilities. They typically have
difficulty with reading and language arts secondary to poor vocabulary skills,
limited abstract reasoning skills, poor auditory memory, and problems with
narrative formation. These speech and language deficits correlate with lower
verbal IQ scores. Although average IQ score may be 10 to 15 points below
that of siblings, most individuals with Klinefelter syndrome have average-
tosuperiorintelligence, with less than 20% scoring lower than 90. 41Suggested
educational accommodations may include the use of visual aids (pictures,
diagrams, and graphs), rather than verbal or written directions; computer,
typewriter, or tape recorder, rather than written communication; and
additional time for written assignments. Speech therapists can help advance
language development and communication skills. In boys with hand tremor
and impairments of fine motor coordination, occupational therapy may be
beneficial. Obesity may emerge in later childhood. Obesity combined with
poor coordination and poor muscle development may necessitate adapted
physical education.42

Endocrinologic and reproductive issues

Endocrinologic and reproductive issues Klinefelter syndrome is the
most common congenital abnormality responsible for testicular failure in
youth. Puberty often occurs at a normal age, but secondary sex changes do
not follow typical progression. The testes initially may enlarge normally, but
as the seminiferous tubules fibrose, the testes involute and become firm.
Ultimately the testes are typically less than 2.5 cm in greatest dimension
with volume of less than 5 cm3. Facial, axillary and pubic hair tends to be
sparse. Before adolescence, testosterone levels are within the normal range.
By early adulthood, testosterone levels decrease to low or low normal values.
Concomitantly, luteinizing hormone and FSH levels begin to increase around
age 11 or 12 and remain abnormally elevated.43
More than 50% of adolescents with Klinefelter syndrome develop
gynecomastia, owing to increased estradiol-to-testosterone ratio; this often
persists in adulthood. (Testosterone therapy does not improve or prevent
gynecomastia.) Eunuchoid proportions become evident, with lower body
segment (floor to pubis) exceeding upper body segment (pubis to crown) by
more than 2 cm and with arm span typically exceeding height by 7 cm or
more.39 Males with the XXY karyotype tend to have narrower shoulders and
wider hips. These physical and hormonal characteristics can present
significant psychosocial difficulties for adolescents with Klinefelter syndrome.
The gynecomastia, eunuchoid habitus, and lack of muscle strength, along
with difficulties with academic performance, can lead to low self-esteem,
insecurity, and withdrawal from peers. Although Klinefelter syndrome is not
associated with homosexuality or gender identity disorders, overall sexual
interest may be diminished. A young man with Klinefelter syndrome may find
it difficult to individuate and separate from his family.44
Men with Klinefelter syndrome first may come to diagnosis in the context of
evaluation for infertility. Although men who are mosaic 47,XXY/46,XY may be
fertile, men who are purely 47,XXY are considered infertile. There are a few
cases of confirmed paternity by men not found to have a mosaic phenotype.
Couples may consider assisted reproductive technologies, such as
intracytoplasmic sperm injection, after sperm are extracted through
testicular biopsy. Although healthy and karyotypically normal infants have
been born through this technique, there may be an increased risk of
autosomal aneuploidies.44 Most couples desiring children choose adoption or
artificial insemination with donor sperm. Testosterone replacement generally
is recommended at around age 11 or 12, when gonadotropin levels begin to
rise. The dosage should be titrated gradually to provide age-appropriate
normal levels of serum testosterone, luteinizing hormone, FSH, and estradiol
and to induce gradual virilization. This therapy typically requires consultation
with a pediatric endocrinologist. Testosterone replacement in adulthood is
less complicated and may be administered by the primary care clinician.

Associated medical conditions

The physician should be attentive to other medical conditions
associated with Klinefelter syndrome. Osteoporosis is more common,
particularly in patients who did not receive testosterone replacement during
adolescence and early adulthood. In addition to optimizing calcium, vitamin
D, and testosterone replacement, patients may benefit from antiresorptive
therapies.
Although autoimmune conditions, including rheumatoid
arthritis,systemic lupus erythematosus, and Sjo grens syndrome, seem to
be more common in males with Klinefelter syndrome compared with
karyotypicallynormal males, the absolute risk for these conditions is
unknown. Testosterone replacement may improve the clinical course of these
diseases.45
Endocrine conditions associated with Klinefelter syndrome include type 2
diabetes mellitus and chronic autoimmune thyroiditis. Some authors
recommend annual thyroid-stimulating hormone testing, beginning in
childhood.46Physicians should consider the diagnosis of Klinefelter syndrome
in young men with recurrent leg ulcers, whether or not obvious venous
disease is present.47Pulmonary conditions associated with Klinefelter
syndrome include chronic bronchitis, bronchiectasis, and emphysema.
Additional injury from cigarette use should be avoided.Men with Klinefelter
syndrome bear a risk of breast carcinoma thatapproximates that of similar-
aged women. This risk may exceed 20 fold that of karyotypically normal
men.48 Men should be instructed in breast selfexamination, and clinicians
should perform annual clinical breast examinations. There are no studies to
support routine screening mammography or prophylactic mastectomy.
Additionally, young adults with Klinefeltersyndrome bear an increased risk,
estimated around 1%, for the development of mediastinal germ cell tumors. 49

Complications
Complications may include the following:
Patients with Klinefelter syndrome have an increased risk of
extratesticular germ cell tumors and possibly increased risk of breast
cancer.50 The risk of breast carcinoma in men with the XXY variant may
approach 20 times that of healthy men. Other types of neoplasia occur in
1.6% of patients and includeacute leukemia, Hodgkin and non-Hodgkin
lymphomas, chronic myelogenous leukemia, and other myeloproliferative
diseases. Gonadal and extragonadal germ cell tumors (mediastinal germ cell
tumors, teratoma, teratocarcinoma, choriocarcinoma) may also occur.
Psychologic and psychiatric complications may occur in individuals with
lower-than-average intelligence, hypogonadism, or impotence.The results of
one study found that patients with Klinefelter syndrome are at elevated risk
for psychopathology such as autism and schizotypal traits, with schizotypal
traits increasing with age. Deficiencies in verbal abilities are associated with
increased autism traits, whereas deficiencies in visuospatial abilities are
more strongly associated with increased schizotypal traits.51
Vertebral collapse may result from osteoporosis.
All patients with Klinefelter syndrome should be informed about the
increased risk of deep vein thrombosis and should have their hematocrit
levels monitored to avoid increased viscosity.52
Development of varicose veins and leg ulcers may result from venous
stasis.
Associated endocrine diseases include diabetes mellitus,
hypothyroidism, empty sella syndrome, hypoparathyroidism, and precocious
puberty in association with human chorionic gonadotropin (hCG)-producing
germ cell tumors.
Benign prostatic hyperplasia may result from testosterone
supplementation. Adults undergoing such therapy should be screened for
prostatic enlargement starting at age 30 years.
In males with polysomic X Klinefelter syndrome, the mortality rate due to
cerebrovascular diseases such as aortic valvular disease and berry aneurysm
rupture is more than 6 times that in healthy males aged 25-84 years.
Enhanced platelet aggregation, thrombotic disease, and hypercoagulability
have been demonstrated and may be related to increased estrogen levels.
The results of one study found that prepubertal boys as young as 4-12 years
are at elevated risk for truncal obesity, insulin resistance, and childhood
metabolic syndrome. Reduced physical activity is associated with these risk
factors.53

Prognosis
Early studies of men with XXY Klinefelter syndrome produced
disturbing findings of an increased risk of psychiatric disturbance, criminality,
and mental retardation. These results are considered highly questionable
because of selection bias from institutionalized populations.
Babies with the XXY form differ little from healthy children. The results of one
cohort study on nonmosaic XXY infants younger than 2 years found that
most reported XXY neonates had normal external genitalia and height and
weight within the normal range and were not dysmorphic. Indications for
postnatal karyotyping included delayed ambulation and speech skills. These
findings along with previously reported clinical and biological features
suggest that early detection of Klinefelter syndrome is vital in monitoring
potential developmental problems.54
Although boys with the 47,XXY karyotype may struggle through
adolescence with limited academic success, many frustrations, and, in a few
instances, serious emotional or behavioral difficulties, most move toward full
independence from their families as they enter adulthood. Some have
completed graduate education and have a normal level of functioning.
The findings of a study including 87 Australian men with Klinefelter
syndrome suggest that adults diagnosed with this disease later in life
experienced similar personal and psychosocial difficulties compared with
those diagnosed at younger ages. These individuals would benefit from early
detection and intervention.55

VI. Treatment and Management

Medical Care
Early identification and anticipatory guidance are extremely helpful,
although Klinefelter syndrome is rarely diagnosed in prepubertal males.
Treatment should address 3 major facets of the disease: hypogonadism,
gynecomastia, and psychosocial problems.

Androgen therapy
Androgen therapy is the most important aspect of treatment.
Testosterone replacement should begin at puberty, around age 12 years, and
the dose should increase until it is sufficient to maintain age-appropriate
serum concentrations of testosterone, estradiol, follicle-stimulating hormone
(FSH), and luteinizing hormone (LH).
Androgen therapy is used to correct androgen deficiency, to provide
appropriate virilization, and to improve psychosocial status. Regular
testosterone injections can promote strength and facial hair growth; build a
more muscular body type; increase sexual desire; enlarge the testes;
improve mood, self-image, and behavior; and protect against precocious
osteoporosis.56

Speech and behavioral therapy

A multidisciplinary team approach can assist in improving speech
impairments, academic difficulties, and other psychosocial and behavioral
problems.
In children, early speech and language therapy is particularly helpful in
developing skills in the understanding and production of more complex
language.
Males with Klinefelter syndrome should receive a comprehensive
psychoeducational evaluation to assess their areas of strengths and
weaknesses. The information obtained from these evaluations may be
helpful in planning appropriate resources and classroom placement.57

Physical and occupational therapy

Physical therapy should be recommended in boys with hypotonia or
delayed gross motor skills that may affect muscle tone, balance, and
coordination.
Occupational therapy is advised in boys with motor dyspraxia.

Treatment for infertility

Men with Klinefelter syndrome were considered infertile until 1996.
Over the last decade, developments in microsurgical techniques and
advances in artificial reproductive technologies (ART) allowed more than 50%
of patients with Klinefelter syndrome to have their own children through the
combination of microsurgical testicular sperm extraction (TESE) and the use
of freshly retrieved sperm for in-vitro fertilization (IVF). 32 The fact that sperm
can be found in the testes of men with Klinefelter syndrome has challenged
the previous assumption that men with Klinefelter syndrome are always
sterile. Viable spermatozoa can now be extracted from the testes via surgical
biopsy, and a spermatozoon can be directly injected into an ovum.
More than 60 children have been born worldwide after successful
intracytoplasmic sperm injection (ICSI) in couples in which the male partner
has Klinefelter syndrome.
A minority of men with Klinefelter syndrome have viable sperm in their
ejaculate and are able to provide sperm for cryopreservation for future
pregnancies.
Microdissection testicular sperm extraction is an effective sperm retrieval
technique in men with Klinefelter syndrome. 58Men with hypogonadism who
respond to medical therapy may have a better chance of sperm retrieval.

Surgical Care
 Mastectomy may be indicated for gynecomastia, which places
considerable psychological strain on the patient and increases the risk of
breast cancer.
Consultations
Consultations may include the following:
o Clinical geneticist
o Endocrinologist
o Surgeon
o Psychologist
o Speech therapist
Diet
No special diet is needed.
Activity
No activity restrictions are required.
Further Inpatient and Outpatient Care
o Admission for supportive care is not necessary in patients with
Klinefelter syndrome.
o The patient should be monitored by an endocrinologist for testosterone
replacement therapy.

Genetic counseling
The recurrence risk is not increased above that in the general
population.
Physicians should provide parents with information from unbiased follow-up
studies of children with Klinefelter syndrome.
The best time to reveal the condition to an affected male is probably
mid-to-late adolescence, when he is old enough to understand his condition.
Reproductive genetic counseling.59
Sperm from patients with the nonmosaic 47,XXY karyotype has been
used successfully in assisted reproduction.
Origin of the meiotic products of patients with the nonmosaic 47,XXY
karyotype remains unclear. First, mosaicism cannot be excluded in the
nonmosaic 47,XXY karyotype.60 Indeed, the presence of a normal XY germ
cell line in the testis could explain the production of normal haploid sperm in
these apparently nonmosaic patients. Nevertheless, lymphocyte karyotyping
neither predicts the chromosomal constitution of the testis cells nor the
presence or absence of spermatogenesis.61
ICSI per se is also associated with an increased risk of producing a
chromosome anomaly in offspring.62 IVF is also associated with an increased
risk for de-novo chromosomal aberrations, especially those involving the sex
chromosomes.6364
Reproductive genetic counseling of patients with the 47,XXY karyotype
remains difficult. Some authors have recommended preimplantation or
prenatal diagnosis after ICSI using sperm cells from patients with the 47,XXY
karyotype.65 666768Arguments from authors who propose a preimplantation
genetic diagnosis (PGD) include the increased risk of producing sex
chromosomal-abnormal offspring (the unbalanced offsprings are 47,XXX or
47,XXY karyotypes).69 69707172
The genetic risk in the offspring of patients with 47,XXY karyotype
remains unknown but is presumably low. This risk concerns sex chromosomal
and autosomal aneuploidy. Genetic counseling should be reassuring, and
management of the pregnancy should proceed with caution.60
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