CYTOLOGY
FINALS
Cytogenetic Disorders
Nomenclature
• The standard for cytogenetic nomenclature is the
International System of Cytogenetic
Nomenclature (ISCN)
• The nomenclature describing a chromosome
complement can be broken down into three basic
parts: the total number of chromosomes, the sex
chromosome complement, and any chromosome
abnormalities
• These units are listed in order, separated by
commas.
• A normal female would be 46,XX
• A normal male would be 46,XY
• If two or more cell lines are present, they are
listed sequentially, separated by a slash, with a
normal diploid clone, if present, always listed last
(45,X/46,XX)
• For numerical anomalies, the total number of
chromosomes would be increased or decreased
to indicated the overall change, and the specific
chromosome gained or lost would be noted at the
end
• A trisomy 13 in female would be written as
47,XX,+13
• A monosomy 8 in a male would be written as
45,XY,-8
• However, it is not necessary to use a + or – sign
when sex chromosome variation is known to be
constitutional or inherent, because the change in
the chromosome complement can be noted
directly
• Monosomy X becomes 45,X, and gain of a sex
chromosome would be 47,XXY, 47,XXX, or
47,XYY
• If the sex chromosome change is acquired, a + or
– indicating this would be required (45,X-Y for a
male whose Y chromosome has been lost as a
result of his disease)
• A series of abbreviations for common structural
anomalies has been generated (t for
translocation, rob for Robertsonian translocation,
dup for duplication, inv for inversion, and del for
deletion)
• A structural abnormality is indicated by the
abbreviation of the abnormality, followed by the
chromosome involved and breakpoints of the
chromosome
• For rearrangements in which two chromosomes
are involved, a first set of parentheses gives the
chromosomes (lowest numbered or sex
chromosome first), followed by the breakpoints of
the rearrangement in the same relative order
• t(4;9)(q21.2;p22) is a translocation between
chromosomes 4 and 9 with breakpoints 4q21.2
and 9p22
Disorders Associated with Variations in Chromosome
Number
Autosomal Monosomy
• Autosomal monosomies are observed only rarely
among spontaneous abortions and live births
• The likely explanation is that the majority if
autosomal monosomic embryos are lost very
early, even before pregnancy is recognized
Autosomal Trisomy
• Autosomal trisomy is found in 30% to 50% of all
cases of chromosomal abnormalities in fetal
death
• Only few autosomal trisomies result in live births
(trisomy 8, 13, and 18)
• Trisomy 21 (Down syndrome) is the only
autosomal trisomy that allows survival into
adulthood
Trisomy 21 (Down syndrome) is the only autosomal
trisomy that allows survival into adulthood
• 47 chromosomes, and the extra chromosome
was identified as chromosome 13
• Only 1 in 15,000 live births involves trisomy 13,
and the condition is lethal
• Half of all affected individuals die in the first
month, and the mean survival time is 6 months
• Abnormalities include facial malformations, eye
defects, extra fingers or toes, and feet with large
protruding heels
• There is usually severe malformations of the
brain and nervous system, as well as congenital
heart defects
• Parental age is the only factor known to be related
to trisomy 13
Trisomy 18: Edwards Syndrome (47,+18)
• Infants with this condition are small at birth, grow
very slowly, and are mentally retarded
• Occurs in 1 in 11,000 live births, average survival
time is 2 to 4 months
• For unknown reasons, 80% of all trisomy 18 births
are female
• Clenched fists, with the second and fifth fingers
overlapping the third and fourth fingers, and
malformed feet are characteristic
• Heart malformations are almost always present,
and heart failure or pneumonia usually causes
death
• Advanced maternal age is predisposing factor
Trisomy 21: Down Syndrome (47,+21)
• Described by John Langdon Down in 1866
• The only human autosomal trisomy in which a
significant number of individuals survive longer
than a year past birth
• Found in 1 in every 800 births
• Leading cause of childhood mental retardation
and heart defects in the US
• Characterized by prominent epicanthic fold in
each eye, and individuals usually have a wide, flat
skull, and spots on the iris
• They may have furrowed, large tongues that
cause the mouth to remain partially open
Trisomy 21: Down Syndrome (47,+21)
• Physical growth, behavior, and mental
development are retarded, and approximately
40% of all Down syndrome children have
congenital heart defects
• They are susceptible to respiratory infections and
contract leukemia at a rate far above that of the
normal population
• It is observed that death in older adults with Down
syndrome is frequently due to Alzheimer disease
Maternal Age
• Maternal age is a leading risk factor for trisomy
• Young mothers have a low probability of having
trisomy 21 children, but the risk increases rapidly
after age 35 years
• It is also a risk factor for other autosomal
aneuplodies
• Maternal age as a risk factor is supported by
studies on the parental origin of nondisjunction
• For trisomy 21, nondisjunction occurs about 94%
of the time in the mother and about 6% of the time
in the father, and the great majority of these
nondisjunction events take place at meiosis I in
oocytes
• The relationship between maternal age and
nondisjunction focuses on the duration of meiosis
in females
• Primary oocytes are formed early in embryonic
development and enter the first meiotic prophase
well before birth
• Meiosis I is not completed until ovulation, so that
eggs produced at age 40 have been in meiosis I
for more than 40 years
• During this time, intracellular events or
environmental agents may damage the cell so
that aneuploidy results when meiosis resumes at
ovulation
• Another idea focuses on the interaction between
implanting embryo and the uterine environment
• According to this idea, the embryo-uterine
interaction normally results in the spontaneous
abortion of chromosomally abnormal embryos, a
process called maternal selection
• As women age, maternal selection may become
less effective, allowing more chromosomally
abnormal embryos to implant and develop
Aneuploidy of the Sex Chromosomes
• Aneuploidy of the X and Y chromosomes is more
common than autosomal aneuploidy
• Overall incidence of sex chromosome anomalies
in live births is 1 in 400 for males and 1 in 650 for
females
• These abnormalities include both monosomy and
trisomy
Turner Syndrome (45,X)
• Females with this condition are short and wide-
chested with rudimentary ovaries
• At birth, puffiness of the hands and feet is
prominent, but that disappears in infancy
• Many turner patients also have a narrow
constriction of the aorta
• There is no mental retardation associated with
this syndrome
• Characterized by short stature (usually under 5
feet), skin flaps on the back of the neck, and
underdeveloped breasts
• Occurs with a frequency of 1 in 10,000 female
births

• Two X chromosomes are needed for normal
development of the ovary, normal growth
patterns, and development of the nervous system
in females
• Complete absence of an X chromosome in the
absence or presence of a Y chromosome is
always lethal
Klinefelter Syndrome (47,XXY)
• Occurs in approximately 1 in 1,000 male births
• The features of this syndrome do not develop until
puberty
• Affected individuals are male but have very low
fertility
• Some Klinefelter individuals have learning
disabilities or subnormal intelligence, but most do
not show cognitive reduction
• A significant number of Klinefelter males are
mosaics, with some cells having an XY
chromosome combination and others having an
XXY set of chromosomes
• In these cases, nondisjunction occurred during
mitosis of embryonic cells
• Individuals with this condition are generally tall
and often have long arms and legs
• They have genitalia and internal ducts that are
male, but their testes are reduced in size
• Although 50% of affected individuals do produce
sperm, a low sperm count renders most
individuals sterile
• Gynecomastia is common, and hips are often
rounded
XYY Syndrome (47,XYY)
• Presence of an additional Y chromosome in an
otherwise male karyotype
• Patricia Jacobs discovered that 9 of 315 males in
a Scottish maximumsecurity prison had the
47,XYY karyotype
• The males were significantly above average in
height and had been incarcerated as a result of
dangerous, violent, or criminal propensities
• Of the 9 males studied, seven were of subnormal
intelligence, and all suffered personality disorders
• Occurs in about 1 in 1,000 male births, and the
frequency of XYY individuals in penal and mental
institutions is significantly higher than it is in the
population at large
• There is no strong evidence to support the linkage
between XYY condition and criminal behavior
• The vast majority of XYY males lead socially
normal lives
Triplo-X (47,XXX)
• Occurs in about 1 of 1000 female births
• Frequently, 47,XXX women are perfectly normal
and may remain unaware of their abnormality in
chromosome number unless a karyotype is done
• In other cases, underdeveloped secondary sex
characteristics, sterility, delayed development of
language and motor skills, and intellectual
disability may occur
Tetra-X (48,XXXX) and Penta-X (49,XXXXX)
• Syndromes that are similar to but more
pronounced than the 47,XXX syndrome
• The presence of additional X chromosomes
appears to disrupt the delicate balance of genetic
information essential to normal female
development
Polyploidy
• Abnormalities in the number of chromosomal sets
• Can result from errors in mitosis or meiosis
• Can be produced in the fusion of diploid gamete
and a normal haploid gamete (triploid zygote)
• Can result from dispermy (triploid zygote)
Triploidy
• The most common form of polyploidy in humans,
which is found in 15% to 18% of all spontaneous
abortions
• Three types of triploid chromosome sets are
observed: 69,XXY, 69,XXX, and 69,XYY
• Approximately 75% of all cases of triploidy have
two sets of paternal chromosomes

• Only 1 in 10,000 live births is triploid
• Triploid infants do not survive; most die within a
month
• Multiple abnormalities includes an enlarged head,
fusion of fingers and toes (syndactyly), and
malformations of the mouth, eyes and genitals
• The high rate of embryonic death and failure to
survive after birth indicates that triploidy is a lethal
condition
• In this translocation, centromeres of two
chromosomes fuse, and chromosomal material is
lost from the short arms
• This individual is phenotypically normal, even
though he or she has only 45 chromosomes
• Such individuals have a normal 14, a normal 21,
and a translocated 14/21
• At meiosis, such carriers produces 6 types of
gametes
• Three of these result in lethal conditions
• Of the remaining three, one will produce a Down
syndrome child, one is a translocation carrier, and
one is chromosomally normal

Tetraploidy
• Found in 5% of all spontaneous abortions and is
extremely uncommon in live births
• Can result from a failure of cytokinesis in the first
mitotic division after fertilization

Disorders Associated with Variations in Chromosome

Composition and Arrangement

Cri du Chat Syndrome (46,5p-)

• It results from the deletion of a small terminal
portion of chromosome 5
• Occurs in 1 in 100,000 births
• Infants with this syndrome exhibits intellectual
disability, delayed development, small head size,
and abnormalities in the glottis and larynx,
leading to the characteristic crying sound
(meowing of a cat)
• Loss of chromosome segment in 5p15.3 results
in abnormal larynx development; deletions in
5p15.2 are associated with mental retardation
and other phenotypic features of this syndrome

Familial Down Syndrome

• Some cases of Down Syndrome run in families
• About 5% of all cases of Down syndrome involve
a Robertsonian translocation
• In the cytogenetic studies of parents and their
offspring, it is revealed that one of the parents
contain a 14/21 translocation
• One parent has the majority of chromosome 21
translocated to one end of chromosome 14