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‫هبة تمرجان‬
‫مرح تيّم‬

‫علي الحياري‬
‫إياس أبو حجلة‬

‫‪9th, March, 2016‬‬

‫مكتبة تالع العلــي – ‪ABC Books‬‬

‫شارع الجامعة األردنية – جسر كلية الزراعة‬

‫عمارة العساف – ‪ 235‬داخــــل المج ّمع‬

‫هاتـــف ‪:‬‬
‫‪0797121818‬‬
‫‪06/5336475‬‬

‫‪LjnehAsnan‬‬ ‫‪Dental Correctionn‬‬

‫‪Dental.c2013@gmail.com‬‬ ‫‪D.correction2013 @gmail.com‬‬
*Chromosomal Disorders

We’ve talked about abnormalities in number of chromosomes, today we’ll talk about other
abnormalities; the structural abnormalities,i.e. the structure of the chromosome is not normal, not
the number.

*You know that abnormalities in chromosomes are variable according to the age of the patient.

- If we look during the pregnancyperiod, most abnormalities are chromosomal, & generally they
have abortion early in pregnancy.Sometimes, at first 2-3 weeks, most of those chromosomal
abnormalities will end up with abortion, some of them will be seen after birth, but with time the
prevalence of the diseases will go down & down, so the chromosomal abnormalities will not
increase with age.

While if we look at the single gene diseases, generally at birth we don’t see them much, but at
the first year of age we can see them increasing then decreasing; because patients with single
gene diseases don’t survive for a long period. There are some diseases, which are single gene,
they start to be seen later in age like; Alzheimer disease, muscular dystrophy & others, so we can
see slight increase in the number of single gene abnormalities.

When we look at multifactorial diseases, the common diseases at birth are very low & some
would be increased, but with age they are increasing very much like; hypertension, dyslipidemia,
diabetes or cancer, we can see them later with age.

These abnormal chromosomes have high frequency in humans; generally they will end up with
abortion& most important imbalance in the regulatory molecules; if we have deletion; segment
is lost or we have something increasing in an area, the function of that gene will be abnormal…

If we have deletion, this means that gene is not there, so the function of that gene is not there at all.
If we have for example duplication the gene will produce double what we have, so that also will be
abnormal.

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Some of these diseases are tolerable; if we have thalassemia for example, we can survive & live
with it, but there should be certain treatment to prevent the complications; we don’t have
enough RBCs or Hemoglobin, so there should be blood transfusion. Some others in certain
conditions can't survive the unbalance; we’ll talk about it later.

So all those abnormalities are caused of;

1) The material is not produced at all,

2) There is extra material produced,

-Or combination of both.

We can see in multiple myeloma, there are a lot of proteins, while in immunodeficiency we don’t
have lot of proteins.

These abnormalities, some of them we call them balanced while some others are unbalanced;
this is due to rearrangement of the chromosomes.

*When we talk about balanced, this means a segment of the chromosome moved from
one area & went to another area, but still functioning whether it’s in chromosome A or
B, that exchange between chromosomes did not cause loss of any part of the genetic
material, so functionally they are working, this is why we call it balanced, there is no
problem, but it will affect the offspring; because that chromosome should contain

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 certain contents & the other also should contain its contents, so one of them is deficient
& the other is with extra if it passed to children

will make problem, but in the same person there would be no problem, because there is
balance between them.
The unbalanced can cause diseases; if we have segment that moved from one area to
another, but it’s not functional segment, as we can see in certain tumors; gene from
chromosome X goes to Y, the gene is cut from the middle not the whole gene is
translocated or transferred to another chromosome, there is no complete gene transfer,
here it’s not balanced so we would have some diseases due to these types of
characteristics.

*Let us look at the abnormalities which we can see between chromosomes:

1)Translocations; transfer of one segment from chromosome #1 to #2, if we are talking
about chromosomes, we’re considering reciprocal translocation, except acrocentric
chromosomes where we don’t have reciprocal translocations, we'll talk about them later.
2)Inversions.
3)Insertions.
4)Deletions.
5)Rings.
6)Duplication.
7)Isochromosomes.

*We mean by translocation, if we have chromosomes A & B, segment from A will move to B
or segment from B will go to A.

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 **As we can see here**

-After translocation, HIJ sequence from chromosome #1 went to #2,& N segment from #2 to
#1.
-This what we call reciprocal translocation; if the segments containing the whole genes, it
could be a balanced translocation & there will be no problem in the patient who have that
translocation, but if it’s cut in the middle for example then we’ll have abnormalities in
offspring.

*We saw this when we talked about chromosomes 14 & 21, we have translocation between
them, there is no loss of the genetic material the patient is completely normal, then during
meiosis chromosomes will segregate;
-Option #1; cell containing normal chromosome 14 & 21; normal gametes.
-Option #2; translocated chromosomes; balanced translocation, no loss of genetic materials.
-Option #3; normal 21 but translocation in 14, having small segment of 14 with extra
segment from 21.
-Option #4; normal 14 but translocation in 21.
-Both options #3 & #4 when they are segregated, we’ll have partial trisomy &monosomy;
depending on where is the extra or deletion of segments in each chromosome.

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*If we look to the acrocentric chromosomes; we’ll have
Robertsonian Translocations, where here there is no p
arm, we have satellites, if translocation happen, we’ll
have a complete chromosome which consists of 2
chromosomes, if you do counting for this you’ll get 45
chromosomes. These translocations can be seen in
chromosomes (13, 14, 15, 21, 22).

Here, if we have translocation in

chromosomes 14 & 21, & segregation
happen;

 Option #1; normal 14 & 21 // 14 & 21

are translocated.
 Option #2; translocated 21 with
normal 14 // normal 21 alone.
 Option #3; translocated 14 with
normal 21 // normal 14 alone.
After fertilization we’ll end up with;

 Option #1; normal cell // balanced

translocation.
 Option #2; trisomy 14 //
monosomy14 .
 Option #3; trisomy 21 // monosomy 21.
& that what we’ll get in Robertsonian Translocations.

Paracentric

Pericentric

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*Secondly, we’ll look for what we call inversion; if we have A B C D sequence on a
chromosome, it will change its orientation to A C B D for example. We have 2
types:pericentric&paracentric.
-Pericentric; changing segments between p & q.
-Paracentric; in the same area changing happened, in p OR q. The inversion could be
completely normal, but sometimes it could be abnormal.
*The third one is deletion; segment is completely
lost. As we can see here segment C from this
chromosome is completely lost.
*As you remember when we said when
chromosome has deletions;
-If it at Terminal; the end of the arm 46,XY,del(5)(p13) >> we only mention the
segment’s number; here the deletion is in chromosome 5, at p arm, at the end of
segment 13.
-When it’s Interstitial; in-between the arm 46,XY,del(13)(q12q21)>> we should clarify
the segment’s borders; from where to where; here the deletion is in chromosome 13, at
q arm, at segment between 12 & 21.
*The fourth is duplication; one segment will be
duplicated, as you can see here D E isduplicated &
we have another D E, so we have an extra
segment of that chromosome. We can see this in
tumors & in diseases very much. This duplication
could be in the same direction, or it could be in the opposite; D E will be D E E D.

& here is another example;

-In duplication; if it happened in single
gene we might have a pseudodominance;
if we took sickle cell anemia as an example,
the carrier has only one chromosome, if
duplication happened to that segment
which has the deficient gene, we’ll have 2 genes of the same chromosome as if we have
dominance, & that what we call pseudodominance. It’s not original dominance, but
because of this duplication wehad that dominance. “pseudo”dominance

P a g e 6 | 17
 *The other thing, if we lose a segment, this means that the amount which will be
produced will go to half when we have duplication; LDL receptors as an example, we
have 2 alleles to produce enough receptors to transport cholesterol, if one is deficient it
will give us half of the amount of receptors, which is not enough to transport cholesterol
then we’ll end up with hypercholesterolemia, & this is what we call haploinsufficiency.
*The fifth is insertion; it’s not like translocation,
here one segment of one chromosomewill go to
another chromosome, so the original
chromosome will lose that segment.
Like here; segment of chromosome 4 went to 20,
so chromosome 4 became shorter & 20 longer.
Again also, if the insertion is balanced; no loss of genetic material, the patient will be
normal, but his children will have problem, because there will not be complete 4 or 20.
*The sixth is the ring formation; sometimes to one reason or another, the ends of the
chromosome will be chopped out, so they will turn & produce a ring, the nucleotides
could be complementary to each other at the telomeres, so they could bind to each
other& produce a ring formation. This thing will happen during anaphase in the division
area.
We can nomenclature it as: 46,XY,r(5)(p15q23) >> ring at chromosome 5,
at the ends there is no interstitial, generally it happens DE novo, we don’t
know what is the reason of it

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Isochromosomes
Normally , when the two sister chromatids segregate from each other , the centromere
is cut vertically. The result will be: P-arm with q-arm together in one pole and p-arm
with q-arm together in the other pole.

So we said in cell division, it starts from the centromere and the kinetoplast will be
pulled to the poles of the cell so one chromatid will go to one pole and the other
chromatid will go to the other side.And these will be duplicated in the S phase and
you will get a complete chromosome. That is the normal division that happens.

When we talk about Isochromosomes, the

cut will be horizontally, the result will be
two p-arms together in one pole and two q-
arms in the other pole.These will be
duplicated in the S-phase as well.
When each goes to a cell, there will be a
missing material in both cells . (Imagine you
cut the chromosome horizontally and you get
2 p-arms together and 2 q-arms together then
duplication happens and you get
complementary half with missing p-arms or
q-arms in each case)

From thatwe conclude that an

isochromosome is a chromosome that
consists of two copies of one chromosome
arm with the absence of the other arm.
It is called an isochromosome because both
segments are the same.

It may result from :

1. Misdivision of the centromere at mitosis or meiosis.
2. Through misrepair of chromatid breaks near the centromere.
3. Through crossing over in a small pericentric inversion.

It could be a translocation between similar arms from different chromosomes. An

example on that is : Pallister-Killian 47,XY, +i(12)(p10)

Isochromosome can be seen in Turner's syndrome,45, X0, a condition in which a

female is partly or completely missing an X chromosome.

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Note: Isochromosomes could happen (originate) from any chromosome as for
acrocentric ones, although they only have one type of arms horizontal cut will give
rise to 2 q-arms but no p-arms because they don’t have them.

** This is a summary or different chromosomal abnormalities and their potential

causes:
Causes of chromosomal abnormalities
Cause A Brief definition
Error in cell division in which all chromatids fail to separate at
Polyploidy
anaphase. Multiple fertilizations.
Aneuploidy Nondisjunction leading to extra or lost chromosomes
Deletions and Translocations.
duplications Crossover between a pericentric inversion and normal homologue
Translocation Recombination between nonhomologous chromosomes
Inversion Breakage and reunion with wrong orientation
Dicentric or
acentric Crossover between paracentric inversion and normal homologue.
fragments
Isochromosome Division of centromeres on wrong plane
Ring
Loss of telomeres and fusion of ends
chromosome

Chromosomal Deletion Syndromes:

They are of two types:
1. Large deletion: where a large segment of the chromosome is deleted
Examples: ( We see them by normal cytogenetics "G- banding" )
1. Cri du Chat Syndrome
2. Wolf-Hirschorn Syndrome
3. DiGeorge Syndrome (DGS)
2. Micro deletion: where a small segment is deleted Examples:
- Deletion 1p36  Chromosome 1
- Williams  Chromosome 7
- Langer Giedion  Chromosome 8
- Neurofibromatosis NF-1  Chromosome 17
- Prader-Willi Syndrome (PWS)  Chromosome 15
- Angelman Syndrome (AS)  Chromosome 15
- Rubinstein – Taybi  Chromosome 16

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- Miller – Dieker  Chromosome 17
- Smith-Magenis  Chromosome 17
( Only the ones we are going to talk about are required )

We can see the large deletions by normal cytogenetics (can be detected by normal G-
banding only) not high resolution banding (we do not use FISH technique to see them
for example.) Actually, they are large enough that we can see these chromosomes
normally by cytogenetics. On the other hand, micro deletions can’t be detected by G-
banding and they need special tests to detect them ( high resolution banding ) FISH
for example.

Large deletion abnormalities

1. Cri du Chat (Cat-cry) Syndrome:
Abnormality: Large deletion in chromosome 5 at the distal part of the p- arm;
many genes are deleted.

Karyotype : 46,XX,p-5 46,XY,p-5

Incidence : 1 in 50,000 births
Maternal age : Normal

Main characteristics: The face will be similar to

a kitten, the meowing-cry (the voice is actually
like a new born kitten).

Other clinical features

• Mental retardation
• Microcephaly and round facies
• Meowing cry
• Epicanthic folds ( around the eyes )
• Hypertelorism
• Retrognathia.
Diagnosis: we can do chromosomal analysis and we
will notice that there is a large deletion in chromosome
(5).

2. Wolf – Hirschhorn Syndrome:

Abnormality:
 Deletions of certain segments of
Chromosome 4. Terminal parts of P-arms
(short arms) could be large or small
segment.

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  9 different genes in that region are missing.
 Critical region at 4p16.3 – 165 kb segment located at the short arm of chromosome 4

Main Characteristics: the patient has (Greek helmet) face.

Incidence: 1/50,000 live birth

 Clinical features:
• Distinctive “Greek helmet” facies
• Cardiac defects in 50%
• Mental retardation, Microcephaly
• Most are stillborn or die in infancy
• Frequent seizures
• 85-90% de novo deletions not inherited (the defect occurred during development).
• Abnormal facies. Cardiac, renal, and genital abnormalities.

De novo deletion (WHSC1, WHSC2) ----- 87% Wide-spaced eyes and

WHSC1=Wolf-Hirschhorn syndrome repaired cleft lip
candidate 1
Translocation of 4p ------ 13%

Diagnosis: we can detect the abnormal chromosome in the lab

by doing normal chromosomal analysis or by FISH
(Florescence in situ hybridization) technique.

3. DiGeorge Symdrome:
Also called Velo(lips)-cardio(heart)-facial(face) Syndrome (VCFS)

We talked about it in immunology last semester as an immunodeficiency

characterized by cellular ( t-cells ) deficiency. As part of the developmental defect ,
the thymus gland may be affected and t-lymphocytes production may be impaired
resulting in low T-lymphocyte number and frequent infection.

P a g e 11 | 17
Abnormality: It occurs due to deletion in chromosome
22 (so it is called as 22q11deletion syndrome).

Disease characteristics:
 Congenital heart disease (74%)
 Palatal abnormalities (unilateral or bilateral
clifts) (69%)
 Characteristic facial features
 Learning difficulties (70 - 90%)

Diagnosis: either by normal chromosomal analysis or

by FISH technique.

Micro deletion abnormalities

Prader-Willi and Angelman syndromes (PWS/AS):

Parder-Willi or Angelman syndrome are caused by the same deletion (micro deletion
in 15 , q11-q13 ), the difference between them is that Parder-Willi’s deletion is
inherited from the father, while Angelman syndrome’s deletion is inherited from the
mother.

This is called Genomic imprinting, which is the epigenetic phenomenon by which

certain genes are expressed in each parent in a specific manner. If the allele inherited
from the father is imprinted, it is thereby silenced, and only the allele from the mother
is expressed. If the allele from the mother is imprinted, then only the allele from the
father is expressed. (imprinting generally means that if same abnormality same area
and same segment was inherited from the father it will be different that if inherited
from the mother)

InParder-Willi, the patients are mentally retarded with short stature, obese, with small
hands and feet and small eyes while in Angelman syndrome, the patient is happy and
his posture is typical.

“As you can see although PWS/AS happen due to a deletion from the same gene
except that one from the father and the other is from the mother” the clinical features
are completely different”.
1.Prader - Willi Syndrome :
Phenotype:
 Mild to moderate MR
 Hypotonia, poor feeding in infancy
 Short stature, small hands and feet, small external genitalia

P a g e 12 | 17
  Hyperphagia (compulsive overeating), obesity
 Developmental delay, hypogonadism,
 Hyperphagia and obesity,
 Dysmorphic face,
 Hypopigmentation, intellectual disability,
 Short status

Can be diagnosed by normal cytogenetics or FISH.

Documented cases of PWS go back to
the 17th Century.

That portrait is found in a French museum, but back then, this was just a
portrait of a fat girl. They didn’t know it was Prader-Willi Syndrome.

2.Angelman Syndrome :
Phenotype:
• Severe MR, absence of speech
• Jerky movements
• Inappropriate laughter
• Developmental delay,
• Mental retardation,
• Happy and puppet syndrome,
• Easily provoked laughter

Further explanation for PWS/AS :

You receive your genes from your parents, one copy from yourmother (maternal
copy) and another one from your father(paternal copy). Your cells typically use
information from both copies, but in a small number of genes, only one copy is active.
Now look at the figure in the next page.

• Case (A) represents a normal individual, the maternal allele of the certain gene (gene
number 4) of chromosome 15 is expressed (turned on) and the paternal allele is
specifically silenced (turned off). The maternal allele is almost exclusively the active
one.

• If the maternal is lost or mutated, the result is Angelmansyndrome (case C in the

figure). Some other genes on chromosome 15 are maternally imprinted (turn off), and
when the paternal contribution is lost, by deletion, the result is Prader-Willi syndrome
(case B in the figure).

P a g e 13 | 17
 Chromosome 15

A B C
Gene No.4
A B C

Duplication
Syndromes:
( The dr said just be familiar with them – have a look at slides  -)

• Beckwith-Wiedemann
 Duplication - 11p15 (Paternal)
• Duplication 17p11.2p12
• Cat-Eye Syndrome
 Duplication of 22q
• Velo-cardio-facial syndrome – features (VCF)
 Duplication – 22q11.21-q11.22
• PWS/AS Duplication – 15q11-q13

Note that here we present a patient with typical 15q11-q13 deletion who also
carried a familial duplication of centromerically located in 15q11-q13.

Marker Chromosomes
 Chromosomes of unidentifiable origin (except now chromosomal origin can be
identified using SKY, although specific bands cannot yet be identified). In
other words, a marker chromosome is defined as a structurally abnormal
chromosome that cannot be identified by routine cytogenetics. This is usually
observed in tumor cells.

 Occasionally occur as supernumerary (they are extra) chromosomes with or

without phenotypic effect (range from NORMAL to SEVERELY
ABNORMAL).

 Parental chromosomes should be analyzed to understand the

karyotype‐phenotype relationship of supernumerary marker chromosomes.

P a g e 14 | 17
Other abnormalities
1- Chromosome breaks:
o Once chromosome is broken by some means
o Unstable situation as telomeres are not at end
o Usually join up to other piece

Chromosome breakage syndrome: are a group of inherited conditions associated

with chromosomal instability and breakage leading to chromosomal rearrangements
encompassing several different classes of events: deletions, duplications, inversions;
and translocations. Each of theseevents can be caused by breakage of DNA double
helices in thegenome at two different locations, followed by a rejoining ofthe broken
ends to produce a new chromosomal arrangement ofgenes, different from the gene
order of the chromosomes beforethey were broken.

2-Dicentric Chromosomes:
Chromosomes with two centromeres from differentchromosome or from the two
chromatids of a singlechromosome (centromere is duplicated without segregation).

3- Double minutes:
o Are small fragments of extrachromosomal DNA
o A minute is an acentric fragment smaller than the width of a chromatid
o Double minutes (dmin) are seen in tumor cells as double dots.

These conditions cause a bunch of diseases in which DNA repair mechanism do not
work. Thus, there will be no ability to correct the faults ( deletion, insertion, …. )
resultant from those abnormalities. So once the chromosome is broken by some

Some of those diseases: (instability of chromosomes)

1- Xeroderma Pigmentosum:
Just know the name.
2- Ataxia Telangiectasia:
It is an autosomal recessive disease, chromosomes is not stable, There is
increases vascularization of the sclera and its patients are susceptible to have
lymphoma , leukemia , conjunctivitis and extremely sensitive for radiation.

3- Bloom Syndrome:
It is also an autosomal recessive disease. It is characterized by short stature, a
skin rash that develops after exposure to the sun, and a greatly increased risk of
cancer. Its patients are very sensitive to light and they have hypo and hyper-
pigmentations on their skin.

P a g e 15 | 17
 4- Fanconi Anemia:
It is also autosomal recessive, abnormality in DNA Repair. In addition to the
previous problems of light sensitivity and pigmentation, the patients have
skeletal and kidney abnormalities.

5- Cockayne Syndrome.
6- Werner Syndrome.
 We can almost see the same problems in all these syndromes.
 Many genes are responsible for them.
 Always remember that the age of the pregnant lady always plays a big
role in the occurrence of the diseases we have mentioned in this sheet
or inherited diseases in general because a women’s age resembles the
ovum age.

How Can We Check for the stability/ instability of the

chromosomes ?
We can check for that by Sister chromatid
exchanges (SCEs) that involve breakage of
both DNA strands, followed by an exchange
of whole DNA duplexes. This occurs during S
phase and is efficiently induced by mutagens
that form DNA adducts or that interfere with
DNA replication. The formation of SCEs has
been correlated with recombinational repair
and the induction of point mutations, gene
amplification and cytotoxicity.

The researcher distinguishes both chromatids

by differential staining ( adding stains/ dyes/
colors to the culture medium).

Normally, if we culture cells from the patients

in the diseases we’ve mentioned
(lymphocytes), the chromosome will be
duplicated. But for that duplication to be
completed, it needs nucleotides to be found in the media. We can add these
nucleotides from outside ( but we add colors that won’t interfere with the interaction
as well ). It is usually BrdU (bromo-deoxy-uridine) that is used. During duplication
those colored nucleotides will be used.
If no breakage happened (chromosomes are stable)  one strand will appear
labeled and the other strand appears unlabeled.
If they were unstable Each starnd will be mixed.

P a g e 16 | 17
Check this video if you couldn’t get it :
https://www.youtube.com/watch?v=Zig58akltjs

The sequence of events in diagnosis of chromosomal

abnormalities:
First you see the phenotype (outer characteristics) If the results of the basic
cytogenetic chromosomal analysis does not satisfy you, you use the FISH and the
same thing applied to FISH (if the results ofthe FISH does not satisfy you, you use the
molecular biological analysis).

! Done !
~ Another long sheet ... 
~ Although most of it is a memorizing material ..
~ Hope you got to understand it 

Excuse us guys as we were all studying microbiology while doing this

sheet.

Good Luck for All.

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