1.

Chromosomal aberrations
2. sex determination
Dr. Bheem Prasad

vEach cell (except RBO) contain all of the

chromosomes from both parents in the
nucleus
v23 pairs of chromosomes come from each
parent
vAutosome: one of the 22 pairs of
chromosomes that is not responsible for
determining the sex of the child
vSex Chromosome: X and Y chromosomes
responsible for sex determination
2

Chromosomal Defects
Abnormal Number
Monosomy: one less than the diploid number (45)
Trisomy: one more than the diploid number (47)

Mosaicism: some cells have the correct number of

chromosomes and some have more or less than the
correct number of chromosomes
Abnormal Structure
Deletion: loss of a chromosomal segment
Translocation: the occurrence of a chromosomal segment at an
abnormal site either on another chromosome or in the wrong
position on the same chromosome
3

Trisomy 21
Incidence

1 : 650 1000 live births, parental age related

75 % abort spontaneously
Sex ratio: 3 males / 2 females
Most common autosomal chromosomal disorder causing mental
retardation

Risk Factors

maternal age
Parental carrier of translocation

Prenatal Testing

Triple screen (alpha-fetal protein decreased, estriol decreased, betaHCG increased)

If positive, amnio or CVS may be indicated
4

Clinical Presentation
Size: small, 20% are
premature
Skull: short and round with a
flat occiput, separated sutures
Eyes: slant upward and
outward
Prominent epicanthal fold
Moon-shaped face
Brushfields spots
Cheeks: red
Palate: narrow and short
Nose: short with flat bridge

Tongue: protrudes, tongue

thrusting
Skin loose around lateral and
dorsal aspects of neck
Hands: fingers are short,
hands are square, thumbs are
low set, separated more than
usual from second finger, 5th
finger is short and curves
inward, single/bilateral simean
crease
Ears: low-set, posteriorly
rotated ears

Clinical Presentation
Umbilicus: herniated
Feet: wide space between
great toe and 2nd toe, deep
crease between great toe
and the 2nd toe, flat feet
Heart: VSD
Duodenal atresia
Muscular hypotonia
Retarded psychomotor
development
Hyperlaxity of ligaments

Velvety, loose
adhering mottled skin
in infancy, coarse skin
in adolescence
Mouth frequently
open/frequently open
mouth
Visual and/or hearing
impairment
6

Trisomy 21

Trisomy 18
Edwards Syndrome, Trisomy E, Trisomy 16
18
Caused by an extra chromosome 18

Normal Karyotype

Edwards Syndrome (47,XY, +18)

Trisomy 18
Incidence
1 : 6000 8000 live births
F > M (4 : 1)
Most die in embryonic or fetal life

Risk factors
Increased paternal and maternal age

Prenatal screening
Good indicator is if in maternal serum during mid trimester have
low human chorionic gonadotrophin and low unconjugated
estriol
Ultrasound
If anomalies seen, amnio or CVS may be indicated
9

Types of Trisomy 18
Full Form
Every cell in the body has 3 chromosome 18 instead of
2
Severe form

Mosaic Form
Some cells have 3 chromosome 18 and others have 2
Less severe form

Partial Form
In some cells there may be an extra copy of part of
chromosome 18
Severity dependent on anomalies
10

Clinical Presentation
Prenatal hx: feeble fetal
activity, polyhydramnios, small
placenta, single umbilical
artery
Post-dates
SGA
Weight: low birth weight in
term infant
Weak cry
Response to sound decreased
Ears: low set and/or abnormal
shape

Mouth: micrognathia,
microstomia, cleft lip, cleft palate
Mental retardation
Heart: VSD, PDA, ASD
Feet: rocker bottom, big toe
shortened and dorsiflexed,
clubfeet
Crossed legs
Diastasis recti
Pectus carinatum
GU defects: horseshoe kidneys,
hydronephrosis, polycystic
kidneys
11

Clinical Presentation
Hands: clenched and with
flexed fingers (usually where
index finger overlaps 3rd and
4th fingers),flexion contraction
of the two middle digits,
underdeveloped or absent
thumb, simian crease, arches
on seven or more fingers, nails
underdeveloped
Syndactyly
Eyes: ptosis of one or both
eyelids, epicanthal folds

Head: abnormally
prominent occiput,
microcephaly
Hernias: umbilical,
inguinal
Redundant skin folds
esp. over the back of
the neck
Males: cryptorchidism
12

Trisomy 18

13

Trisomy 13
Pataus Syndrome, 13+ Syndrome, 13 15 D
Syndrome, Trisomy Syndrome
Caused by an extra chromosome 13

Normal Karyotype

Trisomy 13 (47,XX,+13)
14

 Incidence
1 : 5000 live births
Male = Female

Risk Factors
Increases with maternal and paternal age
Increases with increased parity
Parental carrier of balanced translocation

Prenatal Screening
Ultrasound
If anomalies seen, amnio or CVS may be indicated

15

Clinical Presentation
Severe mental and
psychomotor retardation
Ears: malformed, low-set
Hands: flexion deformities;
polydactyly, simian crease,
clenched hands
Heart: VSD, PDA, ASD,
rotational anomalies
(dextrocardia)
Eyes: microphthalmos,
colobomas of iris, cataracts,
retinal dysplasia, close set
(may fuse into one)

Nose: broad and flattened

Mouth: cleft lip and palate
Hernias: umbilical hernia,
inguinal hernia
Kidneys: polycystic
Skin: cutaneous hemangiomas
Head: dermal sinus on scalp,
microcephaly
Brain: gross defects, grand
mal seizures, myoclonic jerks,
seizures, holoprosencephaly

16

17

Turners Syndrome
Turners Syndrome, Monosomy X, Gonadal Dysgenesis,
Bonnevie-Ullrich Syndrome, XO Syndrome Is the absence of
one set of genes from the short arm of one X chromosome

Normal Karyotype

Turners Syndrome (45,X)

18

 Incidence

1 : 2000-3000 live-born females

Females only affected
98% of pregnancies with TS spontaneously abort
10% of pregnancies that spontaneously abort have TS

Risk Factors
Increased paternal age
Mother with mosaic or deletional Turners Syndrome

SHOX gene association

SHOX gene provides instructions for making a protein that
regulates activity of other genes

19

Clinical Presentation
Short stature; mean birth weight
2.9 kg; average height: 47
Webbed neck
Low posterior hairline
Micrognathia
Ears: low-set, sometimes
malformed, prone to otitis media
Widely spaced hypoplastic
nipples on a shield-shaped chest
Increased carrying angle at the
elbow

Heart: coarctation of the

aorta, aortic vavular stenosis,
bicuspid aortic valve, aortic
dissection
Eye: ptosis, strabismus,
amblyopia, cataracts,
epicanthal folds, dry eyes, redgreen color blindness
Congenital hip dislocation
Abnormal growth patterns
Congenital lymphedema of
hands and feet
20

Clinical Presentation
Absent or retarded
development of
secondary sexual
characteristics that
normally appear at
puberty
Absent menstruation
Absence of normal
vaginal moisture
infertility

Gonadal dysplasia
Horseshoe kidney
Unilateral renal
agenesis
Intelligence: not at risk
for mental retardation,
better verbal then
visuospatial abilities
Broad nasal bridge
21

22

Klinefelter Syndrome

Incidence = 1/1000
Usually taller than average
Disproportionately long limbs
30-50% gynaecomastia
Infertility / Azoospermia
I.Q may be reduced relative to sibs

Example karyotypes = 47,XXY

47,XXY/46,XY

23

Klinefelter Syndrome
Phenotype very variable some patients are not
diagnosed until they try for a family
Mosaics 47,XXY/46,XY may have milder phenotype
and may be fertile
Therefore always carry out mosaicism check as
infertility is the main clinical problem

24

Cri-du-chat
Syndrome

25

Fragile X Syndrome
Moderate to sever mental retardation
Speech delay, short attention, hyperactivity
Poor motor coordination and mouthing
objects
Poor socialization, temper tantrum
Mood disorder (bipolar), schizophrenia

26

Fragile X syndrome

Long protruding ears

Long face and prominent jaw
Flattened nasal bridge
High arch palate
Macroorchidism
Genetic is complex, 80% penetration in male
and 30% penetration in female
27

Fragile X syndrome

28

Angelman syndrome
Sever mental retardation
Inappropriate laughter
Decrease pigmentation of choroid or iris (pale blue
eyes)
Ataxia and jerky eye movement
Sever speech proplem
Deletion of b15q11q13, maternal in origin
Paternal uniparental disomy

29

30

Prader-willi syndrome
(A fat red faced boy in state of somnolency) Charles
Diickens
Early hypotonia
Obesity
Short stature as adult
Almond shaped blue eyes
Mental retardation (mild to moderate)
Narrow hands

31

Prader Willi Facial Features

32

Chromosome abnormalities and maternal age

% trisomic

clinically recognized pregnancies

35
30
25
20
15
10
5
0
-20

20-24

25-29

30-34

35-39

40+

maternal age
33

Sex determination

34

 The Y chromosome contains far fewer genes

than the X chromosome.

35

 Pseudoautosomal Regions (PARs)

regions on Y chromosome that share homology
with regions on the X chromosome
synapse and recombine with it during meiosis
Presence of such a pairing region is critical to
segregation of the X and Y chromosomes during
male gametogenesis

36

 Y chromosome
contains:
the male-specific
region of the Y
(MSY)
a sex-determining
region of the Y
(SRY)

37

 Testis-determining factor (TDF)

a protein encoded by a gene in the SRY that
triggers testes formation.

The MSY consists of three regions:

X-transposed region
X-degenerative region
ampliconic region
38

 Dosage Compensation Prevents Excessive

Expression of X-Linked Genes in Humans and
Other Mammals
Dosage compensation balances the dose of X
chromosome gene expression in females and
males.

39

 The inactive X is highly condensed, can be

observed in stained interphase cells, and are
referred to as Barr bodies.

40

 The Lyon hypothesis states that

X-inactivation occurs randomly in somatic cells.
This is evident in the calico cat.

41

 The X-inactivation center (Xic) is active on the

inactive X.
It consists of the X-inactive specific transcript
(XIST) gene.

42

THANK YOU
43