Klinefelter syndrome is a genetic disorder caused by the presence of an extra X chromosome in males. It results in hypogonadism and infertility. Physical signs may include less facial/body hair, broader hips, larger breasts, and weaker bones/muscles. Cognitive effects like language/reading issues are also common. It occurs in around 1 in 500-1000 live male births. The extra chromosome is due to a nondisjunction event during meiosis. While symptoms vary, diagnosis is via karyotype showing 47,XXY. Treatment focuses on managing physical/developmental issues.

1. KLINEFELTE
R
SYNDROME

2. • Klinefelter syndrome or Klinefelter's
syndrome is the set of symptoms resulting
from additional X genetic material in males.
Also known as 47,XXY or XXY, Klinefelter
syndrome is a genetic disorder in which there
is at least one extra X chromosome to a
standard human male karyotype, for a total of
47 chromosomes rather than the 46 found in
genetically normal humans. While females
have an XX chromosomal makeup, and males
an XY, individuals with Klinefelter syndrome
have at least two X chromosomes and at least
one Y chromosome. Because of the extra
chromosome, individuals with the condition
are usually referred to as "XXY males", or
"47,XXY males".

3. • This chromosome
constitution (karyotype) exists
in roughly between 1:500 to
1:1000 live male birthsbut
many of these people may not
show symptoms. If the
physical traits associated with
the syndrome become
apparent, they normally
appear after the onset of
puberty.

4. • In humans, 47,XXY is the most
common sex chromosome aneuploidy
in males and the second most common
condition caused by the presence of
extra chromosomes. Other mammals
also have the XXY syndrome, including
mice.
• Principal effects include hypogonadism
and sterility. A variety of other physical
and behavioural differences and
problems are common, though severity
varies and many XXY boys have few
detectable symptoms.

5. Signs
and
symptoms

6. • There are many variances within the XXY
population, just as within the 46,XY
population. While it is possible to
characterise XXY males with certain body
types and physical characteristics, that in
itself should not be the method of
identification as to whether or not
someone has XXY. The only reliable
method of identification is karyotype
testing. The degree to which XXY males
are affected, both physically and
developmentally, differs widely from
person to person.

7. PHYSICAL
• As babies and children, XXY males may have
weaker muscles and reduced strength. As
they grow older, they tend to become taller
than average. They may have less muscle
control and coordination than other boys
their age.
• During puberty, the physical traits of the
syndrome become more evident; because
these boys do not produce as much
testosterone as other boys, they have a less
muscular body, less facial and body hair, and
broader hips. As teens, XXY males may have
larger breasts, weaker bones, and a lower
energy level than other boys.

8. • By adulthood, XXY males look similar to
males without the condition, although they
are often taller. In adults, possible
characteristics vary widely and include little
to no signs of affectedness, a lanky, youthful
build and facial appearance, or a rounded
body type with some degree of gynecomastia
(increased breast tissue).[Gynecomastia is
present to some extent in about a third of
affected individuals, a slightly higher
percentage than in the XY population. About
10% of XXY males have gynecomastia
noticeable enough that they may choose to
have cosmetic surgery.
• Affected males are often infertile, or may
have reduced fertility. Advanced reproductive
assistance is sometimes possible.

9. • The term hypogonadism in XXY
symptoms is often misinterpreted to
mean "small testicles" or "small penis". In
fact, it means decreased testicular
hormone/endocrine function. Because of
this (primary) hypogonadism, individuals
will often have a low serum testosterone
level but high serum follicle-stimulating
hormone (FSH) and luteinizing hormone
(LH) levels.Despite this
misunderstanding of the
term, however, it is true that XXY men
may also have microorchidism (i.e., small
testicles).

10. • XXY males are also more likely than
other men to have certain health
problems, which typically affect females,
such as autoimmune disorders, breast
cancer, venous thromboembolic disease,
and osteoporosis. In contrast to these
potentially increased risks, it is currently
thought that rare X-linked recessive
conditions occur less frequently in XXY
males than in normal XY males, since
these conditions are transmitted by
genes on the X chromosome, and people
with two X chromosomes are typically
only carriers rather than affected by
these X-linked recessive conditions.

12. Cognitive
and
developmen
tal

13. • Some degree of language learning or
reading impairment may be present,and
neuropsychological testing often reveals
deficits in executive functions, although
these deficits can often be overcome
through early intervention.There may also
be delays in motor development which
can be addressed through occupational
therapy and physical therapy. XXY males
may sit up, crawl, and walk later than
other infants; they may also struggle in
school, both academically and with
sports.

14. Cause

15. • The extra X chromosome is retained
because of a nondisjunction event during
meiosis I (gametogenesis).
Nondisjunction occurs when homologous
chromosomes, in this case the X and Y
sex chromosomes, fail to separate,
producing a sperm with an X and a Y
chromosome. Fertilizing a normal (X) egg
produces an XXY offspring. The XXY
chromosome arrangement is one of the
most common genetic variations from
the XY karyotype, occurring in about 1 in
500 live male births.

16. • Another mechanism for retaining
the extra X chromosome is
through a nondisjunction event
during meiosis II in the female.
Nondisjunction will occur when
sister chromatids on the sex
chromosome, in this case an X
and an X, fail to separate.
(meiosis) An XX egg is produced
which, when fertilized with a Y
sperm, yields XXY offspring.

17. • In mammals with more than one X
chromosome, the genes on all but one X
chromosome are not expressed; this is
known as X inactivation. This happens in
XXY males as well as normal XX
females.However, in XXY males, a few
genes located in the pseudoautosomal
regions of their X chromosomes, have
corresponding genes on their Y
chromosome and are capable of being
expressed.

18. Birth of a cell with karyotype XXY due to a non-disjunction
event of one X chromosome from a Y chromosome during
meiosis I in the male.

19. • The first published report of a man
with a 47,XXY karyotype was by
Patricia Jacobs and John Strong at
Western General Hospital in
Edinburgh, Scotland in 1959.This
karyotype was found in a 24-year-old
man who had signs of Klinefelter
syndrome. Jacobs described her
discovery of this first reported human
or mammalian chromosome
aneuploidy in her 1981 William Allan
Memorial Award address.

20. Birth of a cell with karyotype XXY due to a non-disjunction event
of one X chromosome during meiosis II in the female.

21. Variation
s

22. • 48,XXYY and 48,XXXY occur in 1 in 18,000–50,000 male
births. The incidence of 49,XXXXY is 1 in 85,000 to
100,000 male births.These variations are extremely rare.
Additional chromosomal material can contribute to
cardiac, neurological, orthopedic and other anomalies.
• Males with Klinefelter syndrome may have a mosaic
47,XXY/46,XY constitutional karyotype and varying
degrees of spermatogenic failure. Mosaicism
47,XXY/46,XX with clinical features suggestive of
Klinefelter syndrome is very rare. Thus far, only about
10 cases have been described in literature.
• Analogous XXY syndromes are known to occur in cats—
specifically, the presence of calico or tortoiseshell
markings in male cats is an indicator of the relevant
abnormal karyotype. As such, male cats with calico or
tortoiseshell markings are a model organism for
Klinefelter syndrome.

23. Diagnosis

24. • About 10% of Klinefelter cases are found by
prenatal diagnosis. The first clinical features may
appear in early childhood or, more frequently,
during puberty, such as lack of secondary sexual
characters and aspermatogenesis, while tall
stature as a symptom can be hard to diagnose
during puberty. Despite the presence of small
testes, only a quarter of the affected males are
recognized as having Klinefelter syndrome at
puberty and 25% received their diagnosis in late
adulthood: about 64% affected individuals are
not recognized as such.Often the diagnosis is
made accidentally as a result of examinations and
medical visits for reasons not linked to the
condition.

25. • The standard diagnostic method
is the analysis of the
chromosomes' karyotype on
lymphocytes. In the past, the
observation of the Barr body was
common practice as well.To
confirm mosaicism, it is also
possible to analyze the karyotype
using dermal fibroblasts or
testicular tissue.

26. • Other methods may be: research of
high serum levels of gonadotropins
(follicle-stimulating hormone and
luteinizing hormone), presence of
azoospermia, determination of the
sex chromatin,and prenatally via
chorionic villus sampling or
amniocentesis. A 2002 literature
review of elective abortion rates
found that approximately 58% of
pregnancies in the United States with
a diagnosis of Klinefelter syndrome
were terminated.

27. Percentages of Klinefelter's diagnosis divided by age groups,
with most diagnoses occurring in adulthood.

28. Differenti
al
diagnosis

29. • The symptoms of Klinefelter syndrome are
often variable; therefore, a karyotype analysis
should be ordered when small
testes, infertility, gynecomastia, long
legs/arms, developmental
delay, speech/language deficits, learning
disabilities/academic issues and/or
behavioral issues are present in an individual.
The differential diagnosis for the Klinefelter
syndrome can include the following
conditions: fragile X syndrome, Kallmann
syndrome and Marfan syndrome. The cause
of hypogonadism can be attributed to many
other different medical conditions.
• There have been some reports of individuals
with Klinefelter syndrome who also have
other chromosome abnormalities, such as
Down syndrome.

30. Treatment

31. • The genetic variation is irreversible. Often
individuals that have noticeable breast
tissue or hypogonadism experience
depression and/or social anxiety because
they are outside of social norms. This is
academically referred to as psychosocial
morbidity. At least one study indicates
that planned and timed support should
be provided for young men with
Klinefelter syndrome to ameliorate
current poor psychosocial outcomes.
• By 2010 over 100 successful pregnancies
have been reported using IVF technology
with surgically removed sperm material
from males with Klinefelter syndrome.

32. Prognosis

33. • Children with XXY differ little from other children.
Although they can face problems during adolescence, often
emotional and behavioural, and difficulties at school, most
of them can achieve full independence from their families
in adulthood. Most can lead a normal, healthy life.
• The results of a study carried out on 87 Australian adults
with the syndrome shows that those who have had a
diagnosis and appropriate treatment from a very young age
had a significant benefit with respect to those who had
been diagnosed in adulthood.
• There is research suggesting Klinefelter syndrome
substantially decreases life expectancy among affected
individuals, though the evidence is not definitive. A 1985
publication identified a greater mortality mainly due to
diseases of the aortic valve, development of tumors and
possible subarachnoid hemorrhages, reducing life
expectancy by about 5 years.Later studies have reduced
this estimated reduction to an average of 2.1 years. These
results are still questioned data, are not absolute, and will
need further testing.

34. Epidemiology

35. • This syndrome, evenly spread in all ethni
groups, has a prevalence of 1-2 subjects
every 1000 males in the general
population.3.1% of infertile males have
Klinefelter syndrome. The syndrome is
also the main cause of male
hypogonadism.
• According to a meta-analysis, the
prevalence of the syndrome has
increased over the past decades;
however, this does not appear to be
correlated with the increase of the age of
the mother at conception, as no increase
was observed in the prevalence of other
trisomies of sex chromosomes (XXX and
XYY).

36. History

37. • The syndrome was named after Harry
Klinefelter, who, in 1942, worked
with Fuller Albright at Massachusetts
General Hospital in
Boston, Massachusetts and first
described it in the same year. The
account given by Klinefelter came to
be known as Klinefelter syndrome as
his name appeared first on the
published paper, and seminiferous
tubule dysgenesis was no longer
used.

38. Interesting
facts about
Klinefelter
syndrome

40. • This disorder is named by Dr. Harry
Klinefelter, who first reported its
symptoms in 1942. Klinefelter
syndrome does not decrease the
longevity of males. Male with
Klinefelter syndrom are sterile. Before
puberty, there are no obvious
symptoms, symptoms become clear
until puberty. Half of patients with
breast development was gynecomastia.
Gynecomastia is a condition of
overdevelopment of a male's breasts.

41. KEY TERMS

42. • Chromosome— A microscopic thread-like structure
found within each cell of the body and consists of a
complex of proteins and DNA. Humans have 46
chromosomes arranged into 23 pairs. Changes in
either the total number of chromosomes or their
shape and size (structure) may lead to physical or
mental abnormalities.
• Gonadotrophin— Hormones that stimulate the ovary
and testicles.
• Gynecomastia— Excessive growth of breast tissue in
males.
• Leydig cells— Cells that make up the endocrine
tissue of the testis and produce testosterone. They
are named for Franz von Leydig (1821–1908), the
German professor of anatomy who first identified
them.
• Testosterone— Hormone produced in the testicles
that is involved in male secondary sex
characteristics.

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