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Medical Genetics-Lecture
#2
November 14, 2011
Genetic Disorder
• A genetic disorder is an illness caused by
abnormalities in genes or chromosomes. While
some diseases, such as cancer, are due in part to
a genetic disorders, they can also be caused by
environmental factors. Most disorders are quite
rare and affect one person in every several
thousands or millions. Some types of recessive
gene disorders confer an advantage in the
heterozygous state in certain environments
Chromosomal Abnormalities:
• Chromosomal abnormalities can be divided
firstly into those which affect the autosomes
and those which affect the sex chromosomes .
• Secondly, the chromosomal abnormalities can
be divided into:
• 1- Numerical abnormalities.
• 2- Structural abnormalities.
Numerical Abnormalities:
• Numerical abnormalities involve :
• 1- Euploidy or polyploidy : the addition of one or more
complete haploid complements . Like, Triploidy (3N)
and Tetraploidy (4N) in man are incompatible with life
unless they occur in mosaic form with a normal cell
lines.
• A small number of live born infants with pure triploidy
have been reported but they have survived for only a
matter of hours.
• Cytogenetic studies on a spontaneous abortions
indicates that triploidy is relatively common in man,
perhaps as high as 1% of all conceptions, but the
embryonic mortality probably exceeds 99%.
Numerical Abnormalities:
• A variety of congenital malformations
associated with the condition have been
described , the common anomalies :
• - Genetalia
• - fusion of the digits ( syndactyly)
• - mental retardation.
Numerical Abnormalities:
• 2- Aneuploidy : the gain or loss of one or more
chromosomes.
• a- Aneuploidy in Autosomal chromosomes
• Many types of autosomal aneuploidy have been found in
spontaneously aborted embryos , but only trisomic
conditions of some of the smaller autosomes are
compatible with post-natal life, in which the abnormal
cell line occurs in mosaic form with a normal cell lines.
• Three autosomal trisomes are well established in
man:
• 1- Trisomy 21
• 2- Trisomy 18
• 3- Trisomy 13
• All the three types show an increased mean maternal age
at birth.
A- Trisomy 21 (47,XX,+21 or
47,Xy,+21) Down’s syndrome:
Down’s Syndrome
• 1- This is the most common autosomal abnormality in
man, occurring with a frequency of about 1 per 800 live
births.
• 2- It is the result from the presence of chromosome
number 21 in three copies rather than two due to the
phenomenon of non-disjunction.
• 3. The most facial features of children with Down’s
syndrome are familiar to most people .It is characterized
by a combinations of several morphological features.
The most common one are:
Down’s Syndrome-cont’d
•
•
•
•
•
•
•
•
•
a- Flat broad face.
b- epicanthus ( a skin fold in the medial angle of the eye)
c- The nose has a low bridge.
d- The tongue usually protrudes and is furrowed, lacking
a central fissure e- Small ears.
f- The hands are short and broad, usually with single
palmar crease and clinodactyly ( incurving ) of the fifth
finger.
g- There may be a single crease on the fifth finger.
h- On the feet, there is often a wide gap between the first
and second toe. i- About one-third of the patients have
congenital malformation of the heart.
years, from an estimated 9 years to over 18 years.
O: The increased incidence of Down’s syndrome with
increasing maternal age is quite dramatic.
Down’s Syndrome-cont’d
•
•
•
•
j- Hyper flexibility of the joint.
k- Irregular and abnormal sets of teeth.
L: Mental retardation With I.Q between 25-50
m: Down’s syndrome children are credited with being
good natured and affectionate , with having a sense of
rhythm.
• n: They tend to have a shorter life expectancy than
average , due to largely to their increased susceptibility
to chest infections or bronchial pneumonia, The
increased effectiveness of modem drugs, however ,has
• increased their life expectancy considerably over recent
Incidence of Down’s syndrome in relation to
maternal age
Maternal age at delivery
20
25
30
40
41
42
43
44
45
Incidence of DS
I in l500
1350
900
l in l00
85
65
l in 50
l in 40
l in 30
Down’s Syndrome-cont’d
• P: Clearly, not all cases of Down’s syndrome
can be related to maternal effect. Some may be
the result of non-disjunction in the father, a
genetic predisposition for non-disjunction,
environmental influences causing non-disjunction (e.g. X-ray) or unbalanced
translocation involving chromosome 21.
• Q: It is found in pure form, mosaic and
translocation form
Chromosome abnormalities in Down’s syndrome
Abnormality
Frequency %
Pure Trisorny
Translocation
Mosaicism
95
3
2
Down’s Syndrome
An infant with Down syndrome,
illustrating typical features of this
disorder: upslanting palpebral
fissures, redundant skin of the
inner eyelid (epicanthic fold),
protruding tongue, and low nasal
bridge.
Down syndrome
A 7-year-old girl with
Down syndrome,
illustrating upslanting
palpebral fissures,
redundant skin of the
inner eyelid
(epicanthic fold), and
low nasal bridge.
This is an example of
trisomy 21 (47, XY, +21)
also known as Down
syndrome. Additions or
deletions of genetic material
are generally lethal in utero,
but Trisomy 21 is an
example of one form of
addition in which the fetus
may occasionally survive to
term and beyond. The
overall incidence is 1 in
1000 livebirths, but the
non-dysjunctional event in
meiosis that produces this
anomaly increases in
Down’s Syndrome
This baby demonstrates
the typical features of
Down syndrome with
down slanting palpebral
fissures and a slightly
protruding tongue.
Down’s Syndrome
The prominent
epicanthal fold of a child
with Down syndrome is
shown here. The pupil
also demonstrate a light
smudgy opacity called a
Brushfield spot.
A simian crease is seen
on the hand of this child
with Down syndrome. A
single crease extends
transversely across the
palm.
B- Trisomy 18 (47,XX,+ 18 or
47,Xy,+18) Edwards syndrome:
• 1- The syndrome caused by trisorny 18 was first
described by Edward et.al. in 1960 . Its incidence is
about one in 8000 new born although there have
been a number of reports of clustering of the disease
suggesting that environmental factors, such as
epidemic viral infections may be causally related to
sudden localized increases in the incidence of this
trisomy.
• 2- A significantly greater proportion of females are
born with the disease than males, the ratio being
approximately 3:1
B- Trisomy 18 (47,XX,+ 18 or
47,Xy,+18) Edwards syndrome:
• 3- Some of the more congenital malformations
associated with trisomy 18 include:
• a- Elongated occiput
• b- small Jaw ( micrognathia)
• c- small mouth ( microstomia)
B- Trisomy 18 (47,XX,+ 18 or 47,Xy,+18)
Edwards syndrome:
• d- Widely spaced eyes (hypertelorism)
• e-Low-set and pointed ears.
• f- Tightly flexed fingers with a characteristic grasp in
which the index
• finger overlaps the third and the fifth overlap the fourth.
• g- heart defects and malformations of the kidney are also
common.
• h- Apparent mental retardation and a failure of infants to
thrive (grow).
• i- Few survive beyond six months, and only about 1%
beyond one year.
• J- It is found in pure form, mosaic, and translocation
form.
Edwards syndrome (Trisomy 18)
An infant with trisomy 18 (Edwards syndrome),
exhibiting characteristic facial features, short
sternum, overlapping fingers with clenched fists,
and a left-sided clubfoot.
Edward's syndrome-Trisomy 18
(47,XY,+18)
• This karyotype demonstrates
trisomy 18 (47, XY, +18)
also known as Edward's
syndrome. It is uncommon
for fetuses with this
condition to survive, so the
incidence is only 1 in 8000
live births. It is rare for
babies to survive for very
long if live born because of
the multitude of anomalies
that are usually present.
The characteristic
overlapping fingers
(clenched fist) of a
fetus with trisomy 18
is shown here
This appearance is
highly suggestive of
trisomy 18. Note that
digits 2 and 5 overlap
3 and 4.
Patau Syndrome- trisomy 13.
• A newborn male with full trisomy 13. This baby
has a cleft palate, atrial septal defect, inguinal
hernia, and postaxial polydactyly of the left hand.
•
Patau Syndrome (Trisomy 13)
An individual with
full trisomy 13 at age
7 years (survival
beyond the first year
is uncommon). He is
deaf and legally blind.
Patau Syndrome (Trisomy 13)
This is a prominent
bilateral cleft lip
associated with trisomy 13.
Patau Syndrome (Trisomy 13)
Polydactyly, particularly of all extremities,
strongly suggests trisomy 13. Extra toes are
seen here on each foot.
Patau Syndrome (Trisomy 13)
An extra finger (polydactyly) is present on this
hand of an infant with trisomy 13.
SCID-Bubble Boy
• David Phillip
Vetter suffered from a
rare genetic disease now
known as severe
combined immune
deficiency
syndrome (SCID).
Forced to live in a
sterile environment, he
became popular with the
media as the boy in the
plastic bubble.
SCID-Cont’d
• The baby boy had been
born with a
defective thymus, a gland
which is important in the
functioning of
the immune system, due
to a genetic condition,
SCID. Also a defect in
the adenosine deaminase
(ADA) gene
• Water, air, food, diapers,
and clothes were
disinfected. the product
would be placed in a
chamber filled
with ethylene oxide gas
for four hours at 140
degrees Fahrenheit
(60˚C), and then aerated
for a period of one to
seven days before it could
finally go in the bubble
• David received bone
marrow from his sister
Katherine. Her bone
marrow contained
traces of a dormant
virus, Epstein-Barr,
which had been
undetectable in the pretransplant screening.
David developed
Burkitt’s lymphoma