Transcript Medical Genetics

Medical Genetics
14 畸变染色体引起的疾
病
chromosomal disorder
Medical Genetics
Any syndrome characterized by
malformations or malfunctions in any
of the body's systems, and caused
by abnormal chromosome number or
constitution.
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Medical Genetics
1. Down syndrome
A. A Brief History
The formal story began in 1866,
when a physician named John
Langdon Down published an essay in
England in which he described a set
of children with common features
who were distinct from other children
with mental retardation.
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Down was superintendent of
an asylum for children with mental
retardation in Surrey, England when
he made the first distinction between
children who were cretins (later to be
found to have hypothyroidism) and
what he referred to as "Mongoloids."
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Down based this unfortunate
name on his notion that these
children looked like people from
Mongolia, who were thought then to
have an arrested development.
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This ethnic insult came under fire in
the early 1960s from Asian genetic
researchers, and the term was dropped
from scientific use. Instead, the condition
became called "Down's syndrome." In the
1970s, an American revision of scientific
terms changed it simply to "Down
syndrome," while it still is called "Down's"
in the UK and some places in Europe.
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In the first part of the twentieth
century, there was much speculation
of the cause of Down syndrome. The
first people to speculate that it might
be due to chromosomal
abnormalities were Waardenburg and
Bleyer in the 1930s.
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But it wasn't until 1959 that
Jerome Lejeune and Patricia Jacobs,
working independently, first
determined the cause to be trisomy
(triplication) of the 21st chromosome.
Cases of Down syndrome due to
translocation and mosaicism were
described over the next three years.
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B. The Chromosomes
There are three different types of
Down syndrome: Standard Trisomy
21, Translocation, and Mosaicism.
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In Down syndrome, 95% of all
cases are caused by this event: one
cell has two 21st chromosomes
instead of one, so the resulting
fertilized egg has three 21st
chromosomes. Hence the scientific
name, trisomy 21. Recent research
has shown that in these cases,
approximately 90% of the abnormal
cells are the eggs.
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The cause of the nondisjunction
error isn't known, but there is
definitely connection with maternal
age. Research is currently aimed at
trying to determine the cause and
timing of the nondisjunction event.
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Three to four percent of all cases of
trisomy 21 are due to Robertsonian
Translocation. In this case, two breaks
occur in separate chromosomes, usually
the 14th and 21st or 21st and 22st
chromosomes. There is rearrangement of
the genetic material so that some of the
14th chromosome is replaced by extra
21st chromosome.
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So while the number of
chromosomes remain normal, there
is a triplication of the 21st
chromosome material. Some of these
children may only have triplication of
part of the 21st chromosome instead
of the whole chromosome, which is
called a partial trisomy 21.
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Translocations resulting in
trisomy 21 may be inherited, so it's
important to check the chromosomes
of the parents in these cases to see if
either may be a "carrier."
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Mosaicism is when a person has
a mix of cells, some containing 46
chromosomes and some containing
47 chromosomes.
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C. The 21st Chromosome and
Down Syndrome
In trisomy 21, the presence of an
extra set of genes leads to
overexpression of the involved genes,
leading to increased production of
certain products.
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For most genes, their
overexpression has little effect due
to the body's regulating mechanisms
of genes and their products. But the
genes that cause Down syndrome
appear to be exceptions.
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Which genes are involved? That's been
the question researchers have asked ever
since the third 21st chromosome was
found. From years of research, one popular
theory stated that only a small portion of
the 21st chromosome actually needed to
be triplicated to get the effects seen in
Down syndrome; this was called the Down
Syndrome Critical Region(DSCR).
Medical Genetics
However, this region is not one small
isolated spot, but most likely several areas
that are not necessarily side by side. The
21st chromosome may actually hold 200
to 250 genes (being the smallest
chromosome in the body in terms of total
number of genes); but it's estimated that
only a small percentage of those may
eventually be involved in producing the
features of Down syndrome.
Medical Genetics
Genes that may have input into Down syndrome include:
• Superoxide Dismutase (SOD1)-- overexpression may cause
premature aging and decreased function of the immune
system; its role in Senile Dementia of the Alzheimer's type or
decreased cognition is still speculative
• COL6A1 -- overexpression may be the cause of heart defects
• ETS2 -- overexpression may be the cause of skeletal
abnormalities
• CAF1A -- overexpression may be detrimental to DNA
synthesis
• Cystathione Beta Synthase (CBS) -- overexpression may
disrupt metabolism and DNA repair
• DYRK -- overexpression may be the cause of mental
retardation
• CRYA1 -- overexpression may be the cause of cataracts
• GART -- overexpression may disrupt DNA synthesis and repair
• IFNAR -- the gene for expression of Interferon,
overexpression may interfere with the immune system as well
as other organ systems
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Other genes that are also
suspects include APP, GLUR5, S100B,
TAM, PFKL, and a few others. Again,
it is important to note that no gene
has yet been fully linked to any
feature associated with Down
syndrome.
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One of the more notable
aspects of Down syndrome is the
wide variety of features and
characteristics of people with trisomy
21: There is a wide range of mental
retardation and developmental delay
noted among children with Down
syndrome.
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Some babies are born with
heart defects and others aren't.
Some children have associated
illnesses such as epilepsy,
hypothyroidism or celiac disease, and
others don't. The first possible
reason is the difference in the genes
that are triplicated.
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The effect of overexpression of genes
may depend on which allele is present in
the person with trisomy 21. The second
reason that might be involved is called
"penetrance," and that appears to be what
happens with trisomy 21: the alleles don't
do the same thing to every person who
has it. Both reasons may be why there is
such variation in children and adults with
Down syndrome.
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D. Clinical features
Growth: Short stature and obesity
occurs during adolescence.
CNS: Moderate-to-severe mental
retardation occurs, with an
intelligence quotient (IQ) of 20-85 .
Congenital heart defects
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Ears: The ears are small with an overfolded helix.
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Dermatoglyphics:
Distal axial
triradius in the
palms, transverse
palmar creases, a
single flexion
crease in the fifth
finger, ulnar loops
(often 10), a
pattern in
hypothenar, and
interdigital III
regions are
observed.
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E. Prenatal Testing
Maternal serum alpha fetoprotein (MSAFP) is measured by a
blood test in the pregnant woman at
15-18 weeks of gestation.
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AFP is made in the fetal liver, and
some escapes into the maternal circulation.
It is widely used as a screening test for a
DS fetus. MSAFP and at least 1 other
screening test are recommended for all
pregnancies not having amniocentesis by
the American College of Obstetrics, and
the American College of Medical Genetics.
Medical Genetics
MSAFP testing is based on the fact
that DS fetuses tend to be a little smaller
on average, have smaller placentas, and
thus secrete less MSAFP and other
materials, which are determined in the
serum of the pregnant woman. Factors
that affect this test include gestational age,
maternal weight, diabetes and ethnicity.
Medical Genetics
MSAFP screening is not a
definitive test. If the MSAFP test is
low it suggests the risk of a DS fetus
equal to the risk of a woman age 35,
and prenatal testing/chromosome
studies are suggested if the parents
want this information.
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If MSAFP alone is tested, 20 per cent
of DS fetuses will test low. If MSAFP and
human chorionic gonadotrophin (HCG) are
determined, 50 - 60 % of DS fetuses will
be identified. If MSAFP, HCG and estradiol
(E2) are tested, 60 -70 % of DS fetuses
will be identified. Some HCG testing
employs a beta subunit but this is not
widespread.
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A positive screening test suggests
only that the risk of DS is increased,
and the definitive testing of
amniocentesis is indicated.
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Some ultrasonographers can
determine suggestive findings of DS
by changes in the neck, or heart.
This is not yet confirmed or in wide
spread use. Ultrasounds can be
normal in a DS fetus.
Medical Genetics
Amniocentesis, a sampling of the
amniotic fluid surrounding the fetus,
is routinely done at 14-16 wks.
Amniocentesis testing for
chromosome disorders is 99.8 per
cent reliable for chromosome number,
and there is a risk of miscarriage
(usually 1/250 or less) after the
procedure.
Medical Genetics
2. Trisomy 18
Trisomy 18 was independently
described by Edwards et al and Smith et al
in 1960. Among liveborn children, trisomy
18 is the second most common autosomal
trisomy after trisomy 21. The disorder is
characterized by severe psychomotor and
growth retardation, microcephaly,
microphthalmia, malformed ears,
micrognathia or retrognathia, microstomia,
distinctively clenched fingers, and other
congenital malformations.
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Synonyms and related keywords:
Edwards syndrome
Edwards' syndrome
trisomy 18 syndrome
trisomy E syndrome
Medical Genetics
A. Pathophysiology
Trisomy 18 severely affects all
organ systems. In translocations that
result in partial trisomy or in cases of
mosaic trisomy 18, clinical
expression is less severe and longer
survival is usual.
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B. Frequency
In the US: Prevalence is
approximately 1 in 6000-8000 live
births.
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C. Mortality/Morbidity
• Approximately 95% of conceptuses with
trisomy 18 die in embryonic or fetal life;
5-10% of affected children survive beyond
the first year of life.
• The high mortality rate is usually due to
the presence of cardiac and renal
malformations, feeding difficulties, sepsis,
and apnea caused by CNS defects.
• Severe psychomotor and growth
retardation are invariably present for
those who survive beyond infancy.
Medical Genetics
D. Sex
Approximately 80% of cases
occur in females. The preponderance
of females with trisomy 18 in
liveborn infants (sex ratio 0.63)
compared to fetuses with prenatal
diagnoses (sex ratio 0.90) indicates
a prenatal selection against males
with trisomy 18 after the time of
amniocentesis.
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E. Cause
The cause of Edwards syndrome
is full trisomy 18 in 95% of cases.
Mosaicism and translocations cause
few cases. An extra chromosome 18
is responsible for the phenotype.
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Incidence increases with
advanced maternal age. In
approximately 90% of cases, the
extra chromosome is maternal in
origin, with meiosis II errors
occurring twice as frequently as
meiosis I errors.
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This is in contrast to other
human trisomies, which exhibit a
higher frequency of nondisjunction in
maternal meiosis I. Among cases
resulting from paternal
nondisjunction, most are the result
of postzygotic mitotic errors.
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F. Clinical features
Neurological
Cranial
Facial
Skeletal
Cardiac
Pulmonary
Gastrointestinal
Genitourinary
Endocrine
Dermal
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Thumb agenesis - Trisomy 18. 17 weeks.
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3. Patau syndrome
Trisomy 13 syndrome is a
disorder of human chromosomes
which occurs in approximately 1 in
10,000 live born infants.
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Synonyms:
Trisomy 13
Patau Syndrome
Trisomy 13-15
D Trisomy Syndrome
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Trisomy 13 is due to the presence
of an extra 13rd chromosome.
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Approximately 80% of infants
with Trisomy 13 syndrome will have
a full trisomy while the remainder
will have a trisomy due to a
rearrangement called a translocation
or have mosaicism (two different cell
lines).
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Findings of significance include
small head size (microcephaly);
small eyes (microphthalmia) or
sometimes absent eye or faulty
development of the retina. Cleft lip
or cleft palate or both occur in about
60% of children.
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In addition, there are a number of
less medically significant physical
findings that are helpful in diagnosis.
These include variations of ear shape,
changes on the palm of the hand,
and extra fingers and toes. Changes
in foot development, including
changes to the heel, the so-called
rocker bottom foot, can occur.
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Aplasia cutis congenita on the scalp (most common
location) shortly after birth.
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Triplet areas of aplasia cutis congenita are
common in infants with trisomy 13.
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4. cri du cat syndrome
In 1963, Lejeune et al described
a syndrome of multiple congenital
anomalies, mental retardation,
microcephaly, abnormal face, and a
mewing cry in infants with deletion
of a B group chromosome (Bp-),
later identified as 5p-.
Medical Genetics
Cri-du-chat syndrome is an
autosomal deletion syndrome caused
by a partial deletion of chromosome
5p. It is characterized by a
distinctive, high-pitched, catlike cry
in infancy with growth failure,
microcephaly, facial abnormalities,
and mental retardation throughout
life.
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Synonyms and related keywords
cat cry syndrome
chromosome deletion 5p syndrome
monosomy 5p syndrome
(Bp-)
5ppartial deletion of chromosome 5p
5p deletion
5p monosomy
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A. Pathophysiology
A partial deletion of the short
arm of chromosome 5 is responsible
for the characteristic phenotype. The
characteristic cry is perceptually and
acoustically similar to the mewing of
kittens.
Medical Genetics
This unusual cry is because of
structural abnormalities of the larynx
(such as laryngeal hypoplasia) and
CNS dysfunction. The laryngeal
appearance may be normal or may
exhibit marked anatomical
abnormalities such as floppy
epiglottis, small larynx, and
asymmetric vocal cords.
Medical Genetics
However, the cause of the
characteristic cry cannot be entirely
ascribed to the larynx. A developmental
field connecting the brain and the affected
clivus region of the cranial base with the
laryngeal region from which the
characteristic cry derives may exist. This
area of the brain is probably deformed in
patients with cri-du-chat syndrome. The
characteristic cry usually disappears with
time.
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B. Frequency
In the US: The estimated prevalence
is about 1 in 50,000 live births. The
prevalence among individuals with
mental retardation is about 1.5 in
1000.
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C. Mortality/Morbidity
With contemporary interventions,
the chance of survival to adulthood is
possible. Currently, death occurs in
6-8% of the overall population
affected with the syndrome.
Pneumonia, aspiration pneumonia,
congenital heart defects, and
respiratory distress syndrome are
the most common causes of death.
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D. Sex
A significant female
predominance exists in affected
newborns, with a male-to-female
ratio of 0.72.
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E. Causes
• Most cases (80-85%) are due to sporadic
de novo deletion of 5p (15.3->15.2).
• Approximately 10-15% of cases result
from the unequal segregation of a
parental balanced translocation where the
5p monosomy is often accompanied by a
trisomic portion of the genome. The
phenotypes in these individuals may be
more severe than in those with isolated
monosomy of 5p because of this additional
trisomic portion of the genome.
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• Most cases involve terminal deletions with
30-60% loss of 5p material. Fewer than
10% of cases have other rare cytogenetic
aberrations .
• The deleted chromosome 5 is paternal in
origin in about 80% of the cases.
• Loss of a small region in band 5p15.2 (cridu-chat critical region) correlates with all
the clinical features of the syndrome with
the exception of the catlike cry, which
maps to band 5p15.3 (catlike critical
region).
Medical Genetics
• High-resolution mapping of genotype-phenotype
relationships in cri-du-chat syndrome using array
comparative genomic hybridization (CGH)
– Localized the region associated with the cry to 1.5 Mb in
distal band 5p15.31, between bacterial artificial
chromosomes (BACs) containing markers D5S2054 and
D5S676.
– Localized the region associated with the speech delay to
3.2 Mb in band 5p15.32-15.33, between BACs
containing markers D5S417 and D5S635.
– Localized the region associated with the facial
dysmorphology to 2.4 Mb in band 5p15.2-15.31,
between BACs containing markers D5S208 and D5S2887.
Medical Genetics
F. Clinical features
History:
Characteristic cry
Developmental history: Early feeding problems are
present because of swallowing difficulties; poor
suck; failure to thrive; early ear infections; and
severe cognitive, speech, and motor delays.
Almost all patients have these problems.
Behavioral history
Physical:
Neonatal period
Childhood: Findings include severe mental
retardation; developmental delay; microcephaly;
Medical Genetics
Image is of an infant with cri-du-chat syndrome. Note
a round face with full cheeks, hypertelorism,
epicanthal folds, and apparently low-set ears.
Medical Genetics
Image is of a child with cri-du-chat syndrome.
Note hypertonicity, small and narrow face,
dropped jaw, and open-mouth expression
secondary to facial laxity.
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5. Klinefelter syndrome
In 1942, Klinefelter et al
published a report on 9 men who had
enlarged breasts, sparse facial and
body hair, small testes, and inability
to produce sperm.
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In 1959, these men with
Klinefelter syndrome were discovered
to have an extra sex chromosome
(genotype XXY) instead of the usual
male sex complement (genotype XY).
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Klinefelter syndrome is the most
common chromosomal disorder
associated with male hypogonadism
and infertility. It is defined classically
by a 47, XXY karyotype with variants
demonstrating additional X and Y
chromosomes.
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The syndrome is characterized
by hypogonadism (small testes,
azoospermia/oligospermia),
gynecomastia at late puberty,
psychosocial problems, hyalinization
and fibrosis of the seminiferous
tubules, and elevated urinary
gonadotropins.
Medical Genetics
A. Pathophysiology
The addition of more than 1 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 related directly to
the number of supernumerary X
chromosomes.
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As the number of X chromosomes
increases, somatic and cognitive
development are more likely to be
affected. 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.
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Moreover, mental capacity diminishes
with additional X chromosomes. The IQ 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.
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B. Frequency
In the US: Approximately 1 in 5001,000 males is born with an extra
sex chromosome; over 3,000
affected males are born yearly. The
prevalence is 5-20 times higher in
the mentally retarded than in the
general newborn population.
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C. Mortality/Morbidity
• About 40% of concepti with Klinefelter
syndrome survive the fetal period.
• In general, severity of somatic
malformations in Klinefelter syndrome is
proportional to the number of additional X
chromosomes; mental retardation and
hypogonadism are more severe in
49,XXXXY than in 48,XXXY.
• Mortality rate is not significantly higher
than in healthy individuals.
Medical Genetics
D. Causes
• Klinefelter syndrome is caused by the presence of
an additional X chromosome in a male.
• About 50-60% of cases are due to maternal
nondisjunction (75% meiosis I errors). In cases
in which these maternal meiosis I errors are
identified, maternal age is increased. The
remaining cases are due to paternal
nondisjunction.
• The most common karyotype is 47,XXY (about
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.
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• The mosaic forms of Klinefelter syndrome
– 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.
• The variant forms are as follows:
–
–
–
–
48,XXXY
49,XXXXY
48,XXYY
49,XXXYY
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E. Clinical features
Growth
Central nervous system
Dental
Sexual characteristics
Cardiac and circulatory problems
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Adolescent male with gynecomastia who has Klinefelter syndrome.
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Child with
Klinefelter
syndrome.
Other than a
thin build and
disproportionate
ly long arms
and legs, the
phenotype is
normal.
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Adolescent male with Klinefelter syndrome who
has female-type distribution of pubic hair and
testicular dysgenesis.
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6. Turner syndrome
In 1938, Henry Turner first
described Turner syndrome, which is
one of the most common
chromosomal abnormalities. More
than 95% of adult women with
Turner syndrome exhibit short
stature and infertility.
Medical Genetics
A. Pathophysiology
Turner syndrome is caused by
the absence of one set of genes from
the short arm of one X chromosome.
In patients with 45 X karyotype,
about two thirds are missing the
paternal X chromosome.
Medical Genetics
In addition to monosomy X, a
similar clinical picture is found with a
46 XXiq karyotype and in some
individuals with mosaic karyotypes. A
deletion of the SHOX gene can cause
a similar skeletal phenotype known
as Leri-Weill dyschondrosteosis.
Medical Genetics
B. Frequency
• In the US: Frequency is approximately 1
in 2000 live-born female infants. As many
as 15% of spontaneous abortions have a
45 X karyotype.
• Internationally: Incidence is the same
as for the United States. No known ethnic
or racial factors influence frequency.
Medical Genetics
C. Mortality/Morbidity
• Mortality may be increased in the neonatal
period because of coarctation of the aorta
and in adulthood because of
cardiovascular disease.
• Renal anomalies found in some individuals
may cause a predisposition to urinary
tract infections or hypertension. Even in
the absence of cardiac or renal anomalies,
patients are prone to develop
hypertension.
Medical Genetics
D. Causes
• Advanced maternal age is not associated
with an increased incidence.
• In patients with a single X chromosome,
the chromosome is of maternal origin in
two thirds of cases.
• Many of the features of Turner syndrome,
including the short stature, are due to the
lack of a second SHOX gene, which is on
the X chromosome.
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E. Clinical features
Approximately 95% of individuals
with Turner syndrome have both
short stature and signs of ovarian
failure on physical examination.
Medical Genetics
A patient with Turner syndrome is shown. This posterior view
shows a low hairline and a shield-shaped chest. Note the
narrow hip development.
Medical Genetics
Women and girls with TS tend to have a wide carrying angle
of the arms (Figure A).This means that when they hold their
arms at their sides, with their elbows touching their sides,
their hands stand away from their bodies. Girls with TS can
have low hairlines at the back of their heads (Figure B).
Medical Genetics
Their ears may be slightly lower than those of other girls and
their jawbones may be slightly less prominent (Figure A). The
nails on their hands and feet tend to turn up slightly (Figure
B).
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