Chromosomal

Disorders
By KYTE JURGEN M. BORINEZ
BSCE -2A

Objectives
Identify

the different types of genetic disorders.

Appreciate that malformations are a common
and significant health burden.
To be able to predict behavior for a purpose.
To be able to get the root cause of the
abnormalities.
Define malformations, the need to understand
and describe their behaviors.

Human Chromosomes

The human body is made up of billions of individual

CELLS.Each of these cells contains a structure
called the NUCLEUS, which is held within a thick
fluid called the CYTOPLASM. Inside the nucleus are
found the CHROMOSOMES, which contain the
GENES. Genes are the instructions that tell the
body how to develop and work properly.

The chromosome is that part of the material of

the nucleus which carries the genetic information.

Chromosomes are composed of deoxyribonucieic

acid (DNA) on framework of protein .

Segments of DNA molecules comprise the

genes; the units of heredity.

During cell division, the chromosome can

be seen to consist of 2 parallel strands;
the chromatids, held together at one
point,
the centromere.

Chromosomes

Short arm and long arm

Karyotype

It is the set of chromosomes of an

individual.

It is the systematized arrangement of the

chromosomes of a single cell.

Chromosomes are arranged according to

their shape & size.

The typical number of chromosomes in a human cell is

46: 23 pairs, holding an estimated total of 20,000 to
25,000 genes. One set of 23 chromosomes is inherited
from the biological mother (from the egg), and the
other set is inherited from the biological father (from
the sperm).
Of the 23 pairs of chromosomes, the first 22 pairs are
called "autosomes." The final pair is called the "sex
chromosomes." Sex chromosomes determine an
individual's sex: females have two X chromosomes
(XX), and males have an X and a Y chromosome (XY).
The mother and father each contribute one set of 22
autosomes and one sex chromosome.

The genotype is the set of genes the

individual carries.

The phenotype is the external

appearance of an individual as determined
by his genotype.

Karyotype of a normal
male

Karyotype of a normal
male

Karyotype of a normal
female

Karyotype of a female Down

syndrome

Chromosomal
Abnormalities

Chromosomal
Abnormalities
Chromosomal abnormalities are either
numerical or structural.
They are a very common cause of early
spontaneous miscarriage.
Usually, but not always, cause multiple
congenital anomalies and learning
difficulties.

How do chromosome abnormalities happen?

Most chromosome abnormalities occur as an accident

in the egg or sperm. In these cases, the abnormality is
present in every cell of the body. Some abnormalities,
however, happen after conception; then some cells
have the abnormality and some do not.

Chromosome abnormalities can be inherited from a

parent (such as a translocation) or be "de novo" (new
to the individual). This is why, when a child is found to
have an abnormality, chromosome studies are often
performed on the parents.

Chromosome abnormalities usually occur when there is an error in

cell division. There are two kinds of cell division, mitosis and
meiosis.

Mitosis results in two cells that are duplicates of the original cell.
One cell with 46 chromosomes divides and becomes two cells with
46 chromosomes each. This kind of cell division occurs throughout
the body, except in the reproductive organs. This is the way most of
the cells that make up our body are made and replaced.

Meiosis results in cells with half the number of chromosomes, 23,

instead of the normal 46. This is the type of cell division that occurs
in the reproductive organs, resulting in the eggs and sperm.
In both processes, the correct number of chromosomes is supposed
to end up in the resulting cells. However, errors in cell division can
result in cells with too few or too many copies of a chromosome.
Errors can also occur when the chromosomes are being duplicated.

Chromosomal Abnormalities

Numerical Aberrations (abnormalities)

o Polyploidy: Multiple of the haploid (> Diploid)
o Aneuploidy: Abnormal number
-Monosomy
-Trisomy
-Tetrasomy

Structural Abnormalities
o
o
o
o
o
o

Translocation
Deletion
Duplication
Inversion
Ring chromosomes
Isochromosomes

Numerical Aberration
(Aneuploidy)

Autosomal-aneuploidy
Trisomies: 1 ch extra (e.g. trisomy 21-13-18)
Monosomies: 1 ch is missing
Sex chromosome-aneuploidy
Klinefilter syndrome (47, XXY male)
Turner syndrome (45, XO female)

Cause of Aneuploidy
Alterations in chromosome number
Nondisjunction occurs when either homologues fail to separate
during anaphase I of meiosis, or sister chromatids fail to separate
during anaphase II. The result is that one gamete has 2 copies of
one chromosome and the other has no copy of that chromosome.
(The other chromosomes are distributed normally.)

If either of these gametes unites with another during fertilization,

the result is aneuploidy (abnormal chromosome number)
The frequency of nondisjunction is quite high in humans, but the
results are usually so devastating to the growing zygote that
miscarriage occurs very early in the pregnancy.

If the individual survives, he or she usually has a set of symptoms

- a syndrome - caused by the abnormal dose of each gene
product from that chromosome.

Non-disjunction during Meiosis.

These abnormal gametes are formed when a

spindle fibre fails and one of the pair of
homologous chromosomes fail to become
separated

Non-disjunction

Sex Chromosome
Aneuploidy

The majority of known types of chromosomal

abnormalities involve sex chromosomes. In
frequency of occurrence, they are only slightly less
common than autosomal abnormalities. However,
they are usually much less severe in their effects.
The high frequency of people with sex chromosome
aberrations is partly due to the fact that they are
rarely lethal conditions. Like Down syndrome and
other autosomal problems, sex chromosome gross
abnormalities can be diagnosed before birth by
amniocentesis and chorionic villi sampling.

Female Sex Chromosome Abnormalities

Turners Syndrome- (monosomy X)

Genotype is XO
Individuals are always female and short in stature, averaging 4
foot 7 inches as adults, and often have distinctive webbed necks
(i.e., extra folds of skin), small jaws, and high arched palates.
Their ovaries do not develop so they are infertile and fail to
develop secondary sexual characteristics. e.g. breast
development and menstruation. Their ovaries do not develop
normally and they do not ovulate.
Happens 1:2500 live births
Women with Turner syndrome have a higher than average
incidence of thyroid disease, vision and hearing problems, heart
defects, diabetes, and other autoimmune disorders. In a few
individuals, there is slight mental retardation.

Turner syndrome Treatment

Growth hormone therapy
Oestrogen replacement for development of
secondary sexual characteristics at the
time of puberty (but infertility persists).

 Triple-X

syndrome- (Trisomy X)

Genotype is XXX or rarely XXXX,XXXXX

As adults, these "super-females" or "metafemales" generally
are an inch or so taller than average with unusually long legs
and slender torsos but otherwise appear normal.
They usually have normal development of sexual
characteristics and are fertile but tend to have some ovary
abnormalities that can lead to premature ovarian failure.
They may have slight learning difficulties, especially in speech
and language skills, and are usually in the low range of normal
intelligence (especially the XXXX and XXXXX individuals).
They frequently are very tall in childhood and tend to be
emotionally immature for their size. This sometimes results in
teachers and other adults labeling them as troublemakers
because they expect more maturity from bigger girls.
Triple-X syndrome is less rare than Turner syndrome, but little
is known about it. The frequency is approximately 1 in 1,000
female infants and it occurs more commonly when the mother
is older.

Male Sex Chromosome Abnormalities

Klinefelter syndrome (trisomy/tetrasomy)
genotype is XXY or more rarely XXXY or XY/XXY.
Individuals are always male and possess male sex organs
However they are infertile since their testes only develop
to half the normal size and fail to produce sperm
Testes produce low levels of testosterone so facial hair,
deepening of voice are only weakly expressed. Some
sufferers develop small breasts.
. In severe cases, they have relatively high-pitched voices,
asexual to feminine body contours as well as breast
enlargement, and comparatively little facial and body hair.
They are sterile or nearly so, and their testes and prostate
gland are small. As a result, they produce relatively small
amounts of testosterone. Causing feminizing effect.
Occurs in 1:1000 live male births.

-Like triple-X females (described above), many

Klinefelter syndrome men are an inch or so above
average height. They also are likely to be overweight.
They usually have learning difficulties as children,
especially with language and short-term memory. If
not given extra help in early childhood, this often
leads to poor school grades and a subsequent low self
esteem. However, most men who have Klinefelter
syndrome are sufficiently ordinary in appearance and
mental ability to live in society without notice.
-They have a higher than average risk of developing
osteoporosis, diabetes, and other autoimmune
disorders that are more common in women. This may
be connected to low testosterone production.
-Males with Down syndrome sometimes also have
Klinefelter syndrome. Both syndromes are more likely
to occur in babies of older mothers.

XYY syndrome ( Jacobs Syndrome)

their genotype is XYY.
As adults, these "super-males" are usually tall (above 6 feet)
and generally appear and act normal. However, they produce
high levels of testosterone.
During adolescence, they often are slender, have severe facial
acne, and are poorly coordinated. They are usually fertile and
lead ordinary lives as adults. Many, if not most, are unaware
that they have a chromosomal abnormality.
may be as common as 1 in 900 male births to as rare as 1 in
1500.
XYY men were genetically predisposed to antisocial, more of
aggressive behavior, below average intelligence, short
tempered and sometimes homosexuality. Contributing to having
serious personality disorders.
Some researchers suggest that the high testosterone levels of
XYY men can make them somewhat more prone to violence and
that this may cause higher rates of wife beating.

Autosomal Aneuploidy
Human

disorders due to chromosome

alterations in autosomes
(Chromosomes 1-22). There are only
3 trisomies that result in a baby that
can survive for a time after birth; the
others are too devastating and the
baby usually dies in uterus.

1. . Edward syndrome (Trisomy

18):
almost every organ system affected
1:10,000 live births.
Children with full Trisomy 18
generally do not live more than a
few months.
30% of these children die within
the first month and only 10%
survive one year.
There is severe mental retardation.
Other characteristics:

elongated skull, a very narrow pelvis.

the ears are often low set and the
mouth and teeth are small.
nearly all babies born with this
condition die in early infancy.

Trisomy 18, Edward Syndrome

Overlapping of the fingers in

Edwards' syndrome

 2. Patau Syndrome
(Trisomy 13):
-serious eye, brain,
circulatory defects as
well as cleft palate.
-Children rarely live more
than a few months.
Only 1 in 15,000 live
births. (most aborted
naturally)

Survival:

Forty five percent die

within the first month
90% by six months
Less than 5% reach 3
years.

A. Down Syndrome
(Trisomy 21):
- The result of an extra copy
of chromosome 21. People
with Down syndrome are
47, 21+. -Down syndrome
affects 1:700 children and
alters the child's phenotype
either moderately or
severely.

Trisomy 21 is one of the most

common causes of mental
retardation (IQ between 2574).
An average person has an IQ
between 90-110.
Survival rate is very high for
this non-disjunction.

Clinical Features
1) Mental retardation
Moderate - severe range except in mosaic
Manifested by delayed smiling, laughing &
recognition of mother.
2) Delayed motor development
(Hypotonia)
Delayed head support, sitting & standing

3) Characteristic physical features

(in the absence of mental retardation, they
should NEVER be considered diagnostic)
Head
Flat occiput
Upward slanting of palpebral fissure
Epicanthal folds
Flat nasal bridge
Malformed ears
Protruded tongue

Hands
Simian crease (transverse palmar crease)
Clinodactly (incurved little finger)
Short broad hand
Feet
Big space between the first and second toes

Clinical Features
Associated congenital anomalies
1 - Congenital heart disease: (40% of cases)
Common atrioventricular canal or VSD
2 - GIT anomalies: Duodenal atresia
3 - Renal anomalies
Complications
1 - Recurrent chest infections: due to
hypotonia and CHD
2 - Leukemia : 20 times commoner in
trisomy 21.

Down syndrome, child

Down Syndrome

Gap between first and

second toes

Short broad hand

Simian Crease, Trisomy

21

Cytogenetics

Structural abnormalities
1)
2)
3)
4)
5)
6)

Translocation
Deletion
Ring chromosome
Duplication
Inversion
Isochromosomes

1. Deletion
: a portion of one
chromosome is lost
during cell division.
That chromosome is
now missing certain
genes. When this
chromosome is passed
on to offspring the
result is usually lethal
due to missing genes.

Example 1. - Cri du chat (cry of

the cat): A specific deletion of a
small portion of chromosome
5(DISTAL DELETION); these children
have severe mental retardation, a
small head with unusual facial
features, and a cry that sounds like
a distressed cat.
Cri-du-chat babies have round face,
low set ears, heart disease, and have a
small cranium.
Occurrence:

1/1,000,000 live births.

Karyotype:
46XX or 46 XY with chromosome
#5 upper arm deletion.

Exampl 2-Prader-Willi Syndrome

1 per 10,000-25,000 births
A deletion from a gene segment on
chromosome 15 is inherited from the father.
Children with this syndrome tend to become
obese and show mental retardation; they
also have small hands and feet and are
short in stature. They may develop
maladaptive behaviors such as throwing
frequent temper tantrums and picking at
their own skin. Beginning at ages 1-6,
children may eat excessively, hoard food,
and eat unappealing substances.

Example3-Angelman Syndrome
1 per 10,000-30,000 births
A deletion from a gene segment on
chromosome 15 is inherited from the
mother. Children with this syndrome show
mental retardation, a small head, seizures,
and jerky movements. They have unusual,
recurrent bouts of laughter not associated
with happiness.

2. Duplication
if the fragment
joins the
homologous
chromosome, then
that region is
repeated
when an extra copy
of a segment of a
chromosome is
present.

Example - Fragile X:

One the most common form of mental

retardation. The X chromosome of some people is
unusually fragile at one tip - seen "hanging by a
thread" under a microscope.
Most people have 29 "repeats" at this end of their
X-chromosome, those with Fragile X have over
700 repeats due to duplications.
Affects 1:1500 males, 1:2500 females.
These unusual findings are explained by the
nature of the mutation, which occurs in 'premutation' and 'full mutation' forms.

Child with fragile

X syndrome. At
this age, the main
physical feature is
often the prominent
ears.

Fragile X syndrome
Clinical findings in males in fragile X syndrome

Moderate-severe learning difficulty (IQ 20-80, mean 50)

Macrocephaly
Macro-orchidism - postpubertal
Characteristic facies - long face, large everted ears,
prominent mandible and broad forehead, most evident
in affected adults.
Other features - mitral valve prolapse, joint laxity,
scoliosis, autism, hyperactivity
Fragile

X syndrome is the second most common genetic

cause of severe learning difficulties after Down's
syndrome.

Structural abnormalities

3. Translocation
A translocation happens when DNA is
transferred from one non-homologous
chromosome to another. They include :
Balanced reciprocal translocations
Unbalanced reciprocal translocations
or Robertsonian translocations
Insertional translocations.

A.)Reciprocal
translocations
An exchange of material between two
different chromosomes is called a reciprocal
translocation. When this exchange involves
no loss or gain of chromosomal material, the
translocation is 'balanced' and has no
phenotypic effect. Mostly have no symptoms.

Balanced reciprocal translocations are

relatively common, occurring in 1 in 500 of
the general population.

Reciprocal Translocation

Unbalanced reciprocal translocations

or Robertsonian translocations
The problems with balanced reciprocal
translocations arise because carriers are at
risk of producing offspring with part of one
chromosome missing and part of another
extra. Such translocations are unbalanced
and may lead to miscarriage or the birth of
children with symptoms including learning
difficulties and physical disabilities.

Robertsonian Translocation

Structural abnormalities
Robertsonian Translocation

Reciprocal Translocation

Robertsonian Translocation

4. Inversion

Inversions occur when there are two breaks in a single

chromosome. The segment between the breakpoints turns
through 180 degrees and reinserts itself into the "gap" left
in the chromosome. If both breaks occur in the same arm
of the chromosome, this is called a PARACENTRIC
INVERSION. If one break occurs in the short arm and the
other in the long arm of the chromosome, then this is
called a PERICENTRIC INVERSION. Usually, inversions do
not cause problems in the carrier (unless important genes
are disrupted) but there is a risk of producing sperm or
eggs with unbalanced chromosomes. Carriers of
paracentric inversions very rarely give birth to children
with abnormalities. On the other hand, carriers of
pericentric inversions more frequently give birth to
children with abnormalities.

Structural Abnormalities

5. Isochromosomes

Division of chromosome at
centromere transversely
instead of longitudinally
Sometimes people carry
an extra or
supernumerary
chromosome made up of
parts of one or more
chromosomes. They will
effectively carry a
duplication or triplication
of the material forming
this extra

6. Ring chromosome
A RING chromosome usually forms when the
ends of both arms of the same chromosome
are deleted. The remaining broken ends of
the chromosome are "sticky" and join
together to make a ring shape.
Some geneticists believe that there can also
be a general effect caused by any ring
chromosome, poor growth and
developmental delay being the outcome.

Structural abnormalities

Structural Abnormalities

Ring chromosome

Other factors that can increase

the risk of chromosome
abnormalities are:
Maternal Age:

Environment:

Chorionic villous
sampling

Amniocentesis

Management

Supportive care :
1- Proper nutrition & medical care to
diagnose and manage possible
complications.

2- Special social & educational care in

specialized institutes like speech therapy
aiming to make the child as independent
as possible.

THANK YOU..

THE END