klinefelter syndrome

2. Individuals with Klinefelter
syndrome have at least
two X chromosome and at
least one Y chromosome.
So it is a trisomic
syndrome.
47,XXY is the most
common sex
chromosome aneuploidy
in males and the second
most common condition
caused by the presence
of extra chromosomes.

3. First indentified in 1942 and by the
late 1950s the cause of
Klinefelter syndrome was
discovered.
and his
coworkers at the Massachusetts
General Hospital in Boston
published a report about 9 men
who had enlarged breasts, sparse
body and facial hairs , small testes
and an inability to produce sperm.

4. • The extra X
chromosome is
retained because of a
nondisjunction event
during:
As it is a random event
during reproduction so it
is not a inherited type of
disorder.

5. • Nondisjunction occurs when homologous
chromosomes ( X and Y sex chromosomes) fail to
separate, producing a sperm with an X and 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, occuring in about 1 in 500 live male
births.

6. • In nondisjunction during
meiosis 1, the homozygous
chromosome fail to pair and
exchange genetic material
during the metaphase plate.
The homozygous
chromosomes then enter the
same cell. When the cell
further divides in meiosis 2,
the resulting gamete (sperm in
nondisjunction during meiosis
1) will have a XY chromosome
configuration.

7. • Nondisjunction will occur when sister
chromatids on the sex chromosome , in
this case a X and a X , fail to separate.
• A XX egg is produced which , when
fertilized with a Y sperm yields XXY
offspring.

8. In nondisjunction during meiosis 2,
the homozygous chromosomes do
pair and swap genetic material
during the metaphase plate. They
then separate again during
meiosis 2. During meiosis 2, one
of the chromosome pairs
separates successfully. The result
is a gamete with only one
chromatid. The other chromosome
pair does not further separate into
a chromatid. Instead, the
chromosome enters one gamete
(the egg in nondisjunction during
meiosis 2). The resulting gamete
will have an XX chromosome
configuration.

9. • This syndrome is evenly spread in all ethnic
groups , has a prevalence of 1-2 subjects
every 1000 males in general population.
• 3.1% of infertile males have Klinefelter
syndrome.

10. • 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.
• 48,XXYY and 48 XXXY occur in 1
in 18000-50,000 male births.
• They are mostly azospermic and
oligospermic.

11. BABIES
 Weak muscles
 Slow motor
development
 Delay in speaking
 Quiet and docile
personality
 Problems at birth ,
such as testicles that
haven't descended
into scrotum

12. BOYS AND TEENAGERS:
 Taller than average stature
 Longer legs , shorter torso and
broader hips compared with
other boys
 absent, delayed or incomplete
puberty
 Small and firm testicles(
hypogonadotropism)
 Lower sperm count and low sex
drive
 Small penis
 Enlarged breast tissue (
gynecomastia)
 Weak bones
 Problems with reading , writting
and spelling
 Also have attention problems

13. Adulthood
 Tall body stature
 Decreased facial and body hairs( low tesrosterone)
 Increased LH and FSH
 increased of fatty tissue especially in abdomen and
pelvis
 Osteoporosis
 Increased risk of breast cancer, autoimmune
diseases and hypothyroidism

14. Typical testicular histology
in KS is with hyalinization of
seminiferous tubules with
loss of germ cells and
Leydig cell hyperplasia. The
hyalinization of the
seminiferous tubules
probably occurs at
midpuberty
At the beginning of puberty,
the levels of FSH, LH, and
testosterone are normal,
but FSH and LH start to
increase and testosterone
to decline compared with
normal boys .
In adult KS patients, levels
of testosterone, insulin-like
factor 3 , inhibin B, and
anti-Müllerian hormone are
decreased, whereas FSH
and LH are elevated and
17β-estradiol and SHBG
are comparable to controls.
Sexual dysfunction in KS is
probably high, but it seems
to be linked to low
testosterone

15. • Andrew R. Zinn, Purita
Ramos, Frederick F. Elder, Karen
Kowal, Carole Samango-
Sprouse, Judith L. Ross
• The Journal of Clinical
Endocrinology & Metabolism,
Volume 90, Issue 9, 1 September
2005, Pages 5041–
5046, https://doi.org/10.1210/jc.20
05-0432
The AR gene encodes a ligand-
dependent transcription factor and
has a highly polymorphic
CAGn trinucleotide repeat in the
coding sequence of the first exon. AR
CAGn repeat length variation has
been associated in vivo with
Dysregulation of X-Linked Gene
Expression in Klinefelter’s Syndrome
and Association With Verbal Cognitio
Marquis P. Vawter, Philip D. Harvey,
and Lynn E. DeLisi
Am J Med Genet B Neuropsychiatr
Genet. 2007 Sep 5; 144(6): 728–734.
doi: 10.1002/ajmg.b.30454
PMCID: PMC2094046
KS individuals often show language
impairment and the phenotype might be
due to overexpression of genes on the
extra X chromosome(s). There were 129
differentially expressed genes (DEGs) in
KS group The DEGs included 14 X
chromosome genes which were
significantly over-represented. The Y
chromosome had zero
DEGs.Overexpression of XIST was
found in KS compared to XY controls
suggesting that silencing of many genes
on the X chromosome might occur in KS
similar to XX females.

16. • FGFR3-Fibroblast growth factor receptor 3 on chr 4
{MIM134934} alleviate the destruction of Seminiferous
tubules.
• GH1-Growth hormone 1 on chr 17 {MIM 139250}
• IKBKG-Inhibitor of nuclear factor kappa B kinase on chr
X {MIM 300248} cells succeptible to apoptosis leading to
incontinentia pigmenti.
• GPER1-G protein coupled estrogen 1 on chr 7 {MIM
601805} regulate testis development and
spermatogenesis.
• INHBA-Inhibin subunit beta A on chr 7 {MIM 147290}
regulate FSH secretion in males.
• GAS5- Growth arrest specific 5 on chr1 , development of
imflammatory and autoimmune diseases.

17. • INSL3- Insulin like 3 on chr.19 {MIM 146738}
secreted by Leydig cells and role in bone health.
• AZF1- Azospermia factor 1 {MIM 415000}
• ESR1- Estogen receptor 1 on chr 6 {MIM
133430}
• SERPINE1-Serpin family E member 1 on chr7
{MIM 173360} Play role in thromboembolism
and lead to leg ulcers in KS patients
• ESR2- Estrogen receptor 2 on chr14 {MIM
601663}
And many more like NPPC , FSHB, AURKC,MT-
ND6 and LDOC1.

18. • The greatest chances to make Klinefelter's
diagnosing are in following times of life:
• Before or shorty after birth
• Early childhood 5%
• Adolescence 15%
• Adulthood

19. • This is the standard
diagnostic method for
the analysis of the
chromosomes's
karyotype on
lymphocytes.
• To confirm mosaicism
, it is possible to
analyze the karyotype
using dermal
fibroblasts and
testicular tissue.

21. • Blood or urine samples
can reveal abnormal
hormone levels that
are a sign of Klinefelter
syndrome.
In patients with
Klinefelter’s
syndrome, blood
tests
characteristically
show a low
testosterone level,
high sex hormone
binding globulin
(SHBG) and raised
gonadotrophins.

22. • Many males have been
diagnosed through
Aminocentesis or
Chorionic villus
sampling(CVS).
• In aminocentesis , a
sample of the fluid
surrounding the fetus is
withdrawn
• CVS is similar to
aminocentesis. The
procedure is done in the
first trimester and the fetal
cells needed for
examination are taken
from the placenta.

24. • Testosterone treatment
should begin at puberty.
Can normalize body proportions
and promote development of
normal secondary sex
characteristics changes such as
developing a deeper voice ,
growing facial and body hair and
increasing muscle mass and
penis size.
but does not treat infertility,
gynecomastia and small testes.

25. • Over 100 to many successful
pregnancies hace been reported
using IVF technology with
surgically removed sperm material
from men with Klinefelter
syndrome.
• ICSI is for minimal sperm
production patient. During ICSI ,
Sperm is removed from testicle
with a biopsy needle and injected
directly into egg.
A family
therapist, counsellor or psychologist
can help work through emotional
issues.

26. excess breast tissue can be removed by
surgeon, leaving a normal looking chest.

27. TO DETEMINE TRAIL STATUS

28. • KS may be associated with widespread changes in the methylome of both
blood and brain tissue. These genome-wide alterations in DNA methylation
may play a role in the biological mechanisms underlying the clinical KS
phenotype by affecting chromatin structure and gene expression and
thereby potentially be responsible for the development of phenotypical traits
and diseases.
• The only gene associated with the KS phenotype is SHOX5. It is localized in
the pseudoautosomal region of the sex chromosomes and likely causes the
tall stature in KS due to the presence of a third copy.
• The systems biology approaches together pointed to novel aspects of KS
disease phenotypes including perturbed Jak-STAT pathway, dysregulated
genes important for disturbed immune system (IL4), energy balance (POMC
and LEP) and erythropoietin signalling in KS

29. • A new assessment tool is being developed by
researchers at Columbia University Medical
Center (CUMC) to help pediatricians detect
the physical traits of the syndrome. The tool
could pave the way for early interventions that
prevent and treat a range of physical,
psychological, social, and cognitive
impairments. The study was published in The
Journal of Pediatrics.
• The development of the Klinefelter Physical
Phenotype Index (KSPHI) made it possible
for this study to be the first to link the physical
traits of Klinefelter syndrome with
psychosocial function in children," says study
co-author Dr. Fennoy. "This new assessment
tool will help primary care providers identify
those who are at greatest risk for neuro-
developmental problems."
Journal Reference:
Sharron Close, Ilene
Fennoy, Arlene
Smaldone, Nancy
Reame. Phenotype and
Adverse Quality of Life in
Boys
with Klinefelter Syndrome.
The Journal of Pediatrics,
2015; 167 (3): 650
DOI: 10.1016/j.jpeds.2015
.06.037

30. • Thyroid function in Klinefelter
syndrome: a multicentre study
from KING group
• G. Balercia,
• M. Bonomi,
• […]
• KING group
• Journal of Endocrinological
Investigation volume 42, pages
1199–1204(2019)
• DOIhttps://doi.org/10.1007/s406
18-019-01037-2
Conclusions
• We demonstrated in KS no
etiopathogenic link to
hypogonadism or change in the set
point of thyrotrophic control in the
altered FT4 production. The
prevalence of HT in KS was similar
to normal male population, showing
absence of increased risk of HT
associated with the XXY karyotype.

31. • American Journal of Medical Genetics Part C: Seminars in Medical
Genetics
• Volume 184, Issue 2
• RESEARCH REVIEW
• Morbidity in Klinefelter syndrome and the effect of testosterone
treatment
• Simon Chang
• Anne Skakkebæk
• Shanlee M Davis
• Claus H Gravholt
• First published: 04 June 2020
• https://doi.org/10.1002/ajmg.c.31798