CHROMOSOMAL DESEASES.dox.pptx

CHROMOSOMAL
DISEASES
Lecturer Meerim Kurmanalieva

Lecture content
Clinical and cytogenetic characteristics of
the most common chromosomal
diseases:
◦ Down syndrome (Trisomy 21) ;
◦ Edwards syndrome (Trisomy 18)
◦ Patau syndrome (Trisomy 13)
◦ Klinefelter syndrome;
◦ Turner syndrome.
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Chromosomal diseases
◦ These are hereditary diseases that are caused by genomic and chromosomal
mutations. Chromosomal diseases, as a rule, are not transmitted to offspring
and occur in families as sporadic cases.
◦ The main reason for the occurrence of chromosomal diseases is that they arise
due to mutations in the gametes of one of the healthy parents or in the zygote
in the first stages of fragmentation.
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◦ Unlike gene mutations, chromosomal mutations cover a much larger volume of genetic
material and are characterized by multiple lesions.
◦ They cause about 45% of cases of fetal death and 60-70% - 2-4-week miscarriages.
◦ Patients with chromosomal diseases occupy almost 25% of hospitalized patients in the
world.
◦ Chromosomal abnormalities occur in 1% of newborns.
◦ They are the cause of 45-50% of multiple congenital malformations, about 36% of cases
of severe mental retardation, 50% of infertility in women, 10% in men.
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◦ There are chromosomal diseases caused by:
◦ 1) a change in the quantity and structure of autosomes (1-22 pairs);
◦ 2) a change in the quantity of sex chromosomes (XX/XY).
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Down syndrome (Trisomy 21)
The most common chromosome abnormality in humans
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Definition
◦ Down syndrome (DS or DNS), is a genetic disorder caused by the
presence of all or part of a third copy of chromosome 21.
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Down syndrome
◦ The clinical picture of the
syndrome was first described in
1866 by the English doctor
Langdon Down.
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Down syndrome
◦ In 1959, the French scientist I.
Lejeune found an extra
chromosome 21 in the karyotype
of patients.
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Etiology of Trisomy 21
◦ the cause of the chromosome abnormality is still poorly understood.
◦ The high percentage of all cases of trisomy 21 in which the abnormal gamete
originated during maternal meiosis I.
◦ Because of the increased risk of Down syndrome to older mothers, it has been
suggested theory, that the older the oocyte, the greater the chance that the
chromosomes will fail to disjoin correctly.
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Down Syndrome (Trisomy 21)
◦ Down syndrome, or trisomy 21, is by far the most common and best
known of the chromosome disorders and is the single most common
genetic cause of moderate mental retardation.
◦ The average IQ of a young adult with Down syndrome is 50,
equivalent to the mental ability of an 8- or 9-year-old child, but this
can vary widely.
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About 1 child in 800 is born with Down syndrome and among alive
newborns or fetuses of mothers 35 years of age or older, the
incidence rate is far higher.
◦DS is usually associated with:
◦ physical growth delays;
◦mild to moderate intellectual disability (mental retardation);
◦characteristic facial features.
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Signs and symptoms
◦ Those with Down syndrome nearly always have physical and
intellectual disabilities.
◦ They also typically have poor immune function and generally reach
developmental milestones at a later age.
◦ They have an increased risk of a number of other health problems,
including congenital heart defect, epilepsy, leukemia, thyroid
diseases, and mental disorders.
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Phenotype
◦ Down syndrome can usually be diagnosed at birth or shortly
thereafter by its dysmorphic features, which vary among patients but
nevertheless produce a distinctive phenotype.
◦ Hypotonia may be the first abnormality noticed in the newborn. The
patients are short in stature and have brachycephaly with a flat
occiput.
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Phenotype
◦ The neck is short, with loose skin on the nape.
◦ The nasal bridge is flat;
◦ the ears are low-set and have a characteristic folded appearance;
◦ the eyes have Brushfield spots around the margin of the iris;
◦ and the mouth is open, often showing a furrowed, protruding
tongue.
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◦ Characteristic epicanthal folds and upslanting palpebral fissures gave
rise to the term mongolism, once used to refer to this condition but
now considered inappropriate.
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Phenotype
◦ The hands are short and broad, often with a single transverse palmar
crease (“simian crease”) and incurved fifth digits, or clinodactyly. The
dermatoglyphics (patterns of the ridged skin) are highly
characteristic. The feet show a wide gap between the first and
second toes, with a furrow extending proximally on the plantar
surface.
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◦ Congenital heart disease is present in at least one third of all liveborn
Down syndrome infants and in a somewhat higher proportion of
abortuses with the syndrome.
◦ Certain malformations, such as duodenal atresia and
tracheoesophageal fistula, are much more common in Down
syndrome than in other disorders.
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The Chromosomes in Down Syndrome
◦ In about 95% of all patients, Down syndrome involves trisomy for
chromosome 21, resulting from meiotic nondisjunction of the
chromosome 21 pair. As noted earlier, the risk of having a child with
trisomy 21 increases with maternal age, especially after the age of 30
years. The meiotic error responsible for the trisomy usually occurs
during maternal meiosis (about 90% of cases), predominantly in
meiosis I, but about 10% of cases occur in paternal meiosis, usually
in meiosis II.
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Karyotype of Down Syndrome
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Translocation Down syndrome
◦ Translocation Down syndrome (about 4%) refers to the type of Down syndrome
that is caused by rearranged chromosome material. In this case, there are three
# 21 chromosomes, just like there are in trisomy 21, but one of the 21
chromosomes is attached to another chromosome, instead of being separate.
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Mosaic Down syndrome
◦ Mosaicism, or mosaic Down syndrome
(about 2%), is diagnosed when there is
a mixture of two types of cells. Some
have the usual 46 chromosomes, and
some have 47. Those cells with 47
chromosomes have an extra
chromosome 21. Mosaicism is usually
described as a percentage.
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◦ Ms Zambelli is pictured above with her
husband Taylor Doyle, 28, a restaurant worker.
He is holding their eldest daughter Lilian, two,
who has Down syndrome, their second child
Evelyn, one, who does not have the condition.
Ms Zambelli is holding their third child,
Katherine, who was born in February and has
the condition. Ms Zambelli also had a
miscarriage in 2019, with that fetus diagnosed
with Down syndrome as well
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Edwards syndrome / Trisomy 18
◦ Trisomy 18 (Edwards syndrome) is the most common autosomal anomaly among
live births after Down syndrome.
◦ In most cases, trisomy 18 is true, i.e. it is caused by nondisjunction of
chromosomes during meiosis.
◦ In a small number of cases (up to 10%), Edwards syndrome is mosaic caused by
postzygotic nondisjunction of chromosomes in anaphase - at an early stage of
development of the embryo.
◦ Partial trisomy is also possible like translocational form.
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Signs and symptoms
◦ low birth weight
◦ small head and jaw
◦ an unusual-looking face and head
◦ unusual hands and feet with
overlapping fingers and webbed toes
◦ problems with feeding, breathing,
seeing and hearing
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Mozaic Edwards syndrome
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Patau syndrome/ Trisomy 13
◦ Patau syndrome is a chromosomal disorder caused by an extra chromosome 13.
◦ This pathology was discovered in 1657 by the scientist Erasmus Bartholin , but
the chromosomal cause was only proven in 1960 by Dr. Klaus Patau .
◦ Patau's syndrome is a rare pathology (1:7000-1:10000 cases), with the same
frequency occurs in both sexes. The hereditary etiology of the disease has not
been proven, the incidence increases with the age of the parents.
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Signs of Patau Syndrome
◦ low body weight during full-term pregnancy
(less than 2500 grams);
◦ abnormal structure of the skull (small size,
narrowing of the forehead, expansion of the
occipital region) ;
◦ In pronounced deviations in physical and
mental development;
◦ malformations of brain structures;
◦ malformations of the eyes (lack of eyeballs,
small eyes, cataracts, retinal detachment, etc.);
◦ cleft lip;
◦ cleft palate;
◦ deformed ears;
◦ malformations of the hand (extra fingers,
improper formation of the thumb);
◦ local absence of skin, hair;
◦ deformed feet, extra toes;
◦ multiple defects of the urinary, cardiovascular ,
digestive and reproductive systems.
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Mosaic Patau syndrome
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Klinefelter Syndrome (47,XXY)
◦ The clinical picture of the
syndrome was described in 1942
in the works of Harry Kleinfelter
and Fuller Albright.
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CAUSE
◦ Maternal age is the only known risk factor. Women at 40 years have a four times
higher risk for a child with Klinefelter syndrome than women aged 24 years.
◦ The extra chromosome is retained because of a nondisjunction event during
paternal meiosis I, maternal meiosis I, or maternal meiosis II (gametogenesis).
The relevant nondisjunction in meiosis I occurs when homologous
chromosomes, in this case the X and Y or two X sex chromosomes, fail to
separate, producing a sperm with an X and a Y chromosome or an egg with two
X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY
offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also
produces an XXY offspring.
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Klinefelter Syndrome (47,XXY)
◦ The phenotype of Klinefelter syndrome:
◦ The patients are tall and thin and have relatively long legs. They
appear physically normal until puberty, when signs of hypogonadism
become obvious. Puberty occurs at a normal age, but the testes
remain small, and secondary sexual characteristics remain
underdeveloped.
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◦ Gynecomastia is a feature of some patients; because of this, the risk
of breast cancer is 20 to 50 times that of 46,XY males. Klinefelter
patients are almost always infertile because of the failure of germ
cell development, and patients are often identified clinically for the
first time because of infertility. Klinefelter syndrome is relatively
common among infertile males (about 3%) or males with
oligospermia or azoospermia (5% to 10%). In adulthood, persistent
androgen deficiency may result in decreased muscle tone, a loss of
libido, and decreased bone mineral density.
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Phenotype and karyotype
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KLINEFELTER'S SYNDROME SYMPTOMS IN NEWBORNS
◦ Testicles have not settled inside the scrotum (a condition known as
cryptorchidism)
◦ A hernia
◦ Weak muscles
◦ Delayed speech cognition, and slow in sitting, crawling or standing
◦ Taller than their peers at or after four years of age
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KLINEFELTER'S SYNDROME SYMPTOMS IN INFANTS
◦ Reduced energy levels
◦ Delayed cognitive development
◦ Low self-esteem
◦ Shyness
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KLINEFELTER'S SYNDROME SYMPTOMS IN
ADOLESCENTS
◦ Development of breasts like the
opposite sex
◦ Unusually tall, normally taller
than siblings, cousins or friends
◦ Firm and small testes
◦ Small penis
◦ Short torso, wide hips, and longer
limbs in proportion to the entire
body
◦ Retarded muscle growth and low
muscle tone
◦ Lesser hairs on the face, chest,
and other parts of the body
compared to other male
teenagers
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KLINEFELTER'S SYNDROME SYMPTOMS IN ADULTS
◦ Low sexual desire
◦ Infertility (low sperm count)
◦ Erectile dysfunction (Difficulty in having or maintaining an erection)
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VARIANTS:
48, XXYY or 48, XXXY occurs in one in 18,000–50,000 male births. The incidence of
49, XXXXY is one 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 KS 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 KS is very rare. Thus far, only about 10 cases have been
described in literature.
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Turner syndrome 45, X
◦ Turner syndrome (TS), also known 45,
X, or 45, X0, is a genetic condition in
which a female is partly or completely
missing an X chromosome. The
syndrome is named after Henry Turner,
an endocrinologist from Illinois, who
described it in 1938.
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TURNER SYNDROME CAUSES
◦ Mosaicism: In the early phases of fetal
development error it rarely occurs
during cell division. It results in an
improper distribution of cells, some
have complete X chromosomes (two
copies) while some have a single X
chromosome copy.
◦ Monosomy: In this condition, X
chromosome is entirely absent due to
an error in mother's egg or father's
sperm which results in only one X
chromosome in every cell.
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TURNER SYNDROME SYMPTOMS BEFORE BIRTH
Prenatally Turner's syndrome is assumed
based upon the cell-free DNA screening.
It is a procedure to check for some
chromosomal abnormalities in a growing
baby by prenatal ultrasound or by using
the mother's blood sample.
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TURNER SYNDROME SYMPTOMS BEFORE BIRTH
The Prenatal ultrasound of the baby
affected with this condition will show:
◦ Abnormal kidneys
◦ Abnormal heart
◦ Abnormal fluid collections (Edema)
◦ Immense collection of fluid on the back
of its neck
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DURING INFANCY OR AT BIRTH
◦ Low set ears
◦ Web-like or wide neck
◦ Broad chest with widely spaced nipples
◦ Slightly smaller than average height at
birth
◦ Receding or small lower jaw
◦ Swelling of the hands and feet,
particularly at birth
◦ Arms that turn outward at the elbows
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DURING INFANCY OR AT BIRTH
◦ Cardiac defects
◦ High, narrow roof of the mouth
(palate)
◦ Vile hairline at the back of the head
◦ Toenails and fingernails that are turned
upward and narrow
◦ Short fingers and toes
◦ Slowed growth
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IN TEENS & ADULTHOOD
◦ No growth as expected during
childhood
◦ Slowed growth
◦ No sexual changes as expected during
puberty
◦ Without fertility treatment unable to
conceive a child
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IN TEENS & ADULTHOOD
◦ Sexual development halts during
teenage
◦ Short height, less than what is
expected for the female member
◦ Early menstrual cycle ending, but not
due to pregnancy
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Karyotype of Terner Syndrome
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Prenatal diagnosis of chromosomal diseases
◦ 1) Invasive studies ( amniocentesis , chorionic
biopsy) are mainly prescribed for those women
who have an increased risk of having a baby
with Patau syndrome , for example, patients
whose age is over 35 years old or with poor
results of non-invasive tests: ultrasound and
tests. Invasive diagnostic methods are highly
accurate, however, given the risk of
complications, they are not suitable for mass
conduction by all pregnant women, but are
carried out only for special indications.
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◦ 2) Non-invasive technologies , the so-called screenings . Screening is a
comprehensive study of pregnant women for the presence of chromosomal
abnormalities in the fetus. Several signs have been identified that indicate a high
risk of the presence of the disease, which can be detected by ultrasound of the
fetus (absence of the nasal bone, increased thickness of the collar space,
insufficient length of the femur and humerus, and other features). In
combination with ultrasound, a biochemical test of the mother’s blood is
performed for hormones such as free beta-hCG and PAPP-A. The obtained data
on biochemical markers are analyzed in conjunction with the results of an
ultrasound examination, and the result of the entire screening is a calculation of
the risk of a chromosomal abnormality in the fetus.
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Thank you for attention!!!
14.12.2023

CHROMOSOMAL DESEASES.dox.pptx

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