Lesson 1- Table of Contents)
( Next) (Glossary)
It is important to clarify at the outset the difference
between chromosome abnormalities and single gene disorders. Chromosome
abnormalities are errors that result in an abnormal chromosome
number or an abnormal chromosome structure. These abnormalities
lead to the loss or gain of chromosome material. All the genes
within these chromosomes, however, are normal. Most chromosome
abnormalities are sporadic with a small to negligible risk of
recurrence. Of those that are familial, the risk of recurrence
is usually less than 15%.
In the case of single gene disorders, the error lies
in a mutation or change within the DNA sequence. Errors that occur
within a gene can result in absent, deficient or abnormal protein
products. The chromosomes, or karyotype, of a patient with a single
gene disorder are expected to be normal, 46,XX or 46,XY. Therefore,
chromosome studies are not recommended for patients who are thought
to have a single gene disorder such as cystic fibrosis or muscular
dystrophy.
ABNORMALITIES IN CHROMOSOME NUMBER
Most chromosomal abnormalities result in spontaneous
abortion. As many as 50-60% of spontaneous abortions are shown
to have an underlying chromosomal abnormality. These abnormalities
are numerical (aneuploidy) or structural (rearrangement).
Haploid is the normal
number of chromosomes in the mature egg and sperm (23 or n). Diploid
is the normal number of chromosomes in a cell following fertilization
(46 or 2n). On occasion, a fetus is born triploid (69 or
3n) or tetraploid (92 or 4n); these cases are rare and
not compatible with survival.
Aneuploidy is the term
used when there are more than, or less than, the normal 46 chromosomes.
The most common form of aneuploidy is trisomy or three
copies of a chromosome. Most trisomy fetuses are spontaneously
aborted. For practical purposes, the only ones that come to term
are trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome), trisomy
18 (Edward syndrome), and trisomies of the sex chromosomes (XXX
female, XYY male, or XXY Klinefelter male).
Another form of aneuploidy is monosomy, or
one copy of a chromosome instead of two. Monosomy can involve
any chromosome; however, only monosomy X (Turner syndrome) is
compatible with survival. The vast majority of fetuses with 45,X
are also spontaneously aborted (95%) with only a few that come
to term.
Aneuploidy is due to nondisjunction, or failure
of normal separation of a chromosome pair when the eggs or sperm
are formed during meiosis. Normally the 46 chromosomes present
in a cell are copied (replication) and pair up. The pairs of chromosomes
are separated (segregation) during meiosis 1. During meiosis 2,
a second division of the chromosomes occurs resulting in the formation
of four sperm, or one egg and three polar bodies, each with 23
chromosomes. In the normal situation, the mature eggs and sperm
are monosomic (one copy) for each chromosome. This leads to disomy
(two copies of each chromosome) following fertilization. Nondisjunction
can occur in meiosis 1 or meiosis 2.
Fig. 1.2. Nondisjunction
at meiosis 1
Fig. 1.3. Nondisjunction at meiosis 2
Nondisjunction leads to the formation of two chromosomally
different eggs or sperm; one has a pair of chromosomes (disomic),
and the other is missing a chromosome (nullisomic). The former,
when fertilized by a normal egg or sperm, with one copy of each
chromosome (monosomic), leads to a trisomy fetus; and the latter
leads to a monosomy fetus.
Finally, a much less common form of aneuploidy is
mosaicism. The mechanism is virtually the same; however,
nondisjunction occurs post-fertilization during mitosis. The zygote
starts with the normal complement of 46 chromosomes then, sometime
in early embryonic development, a misdivision occurs in a cell
leading to two daughter cells; one with 47 chromosomes (trisomy)
and one with 45 chromosomes (monosomy). The monosomic cell line
is often lost so that at birth only two cell types are identified,
the normal and the trisomic cells. The clinical effect of mosaicism
is highly variable depending on the degree of mosaicism (the percentage
of abnormal trisomic cells), and the tissues and organs involved
(with a trisomic cell line).
The following are examples of common chromosome abnormalities:
Trisomy 13 has an incidence
of 1 in 5,000. Forty-four percent of affected newborns succumb
in the first month of life and 69% by six months. Only 18% of
the babies born with trisomy 13 survive the first year. The clinical
manifestations include microcephaly, scalp defects, microophthalmia
(small eyes), coloboma of the iris (keyhole pupil), cleft lip
or cleft palate, polydactyly (extra fingers), congenital heart
defects, urogenital defects, brain malformations, and severe to
profound mental retardation.
Trisomy 18 has an incidence
of about 1 in 3,000 newborns. There is a 3:1 preponderance of
females to males. Thirty percent of affected newborns die within
the first month, 50% by two months, and 90% by one year. Affected
individuals have severe mental retardation, microcephaly, a prominent
occiput, receding chin, short sternum, clenched fist with overlapping
fingers, and rocker bottom feet. Neurologically they are hypertonic
and may have frequent episodes of apnea. Other common malformations
include congenital heart, kidney, or GI abnormalities.
Trisomy 21 has an incidence
of 1 in 660 and is by far the most common chromosomal abnormality.
Facial features are highly suggestive of the diagnosis, with brachycephaly
(a short front to back measurement of the head), a flat facial
profile, short nose, low nasal bridge, epicanthic folds, upslanting
eyes, Brushfield spots (white spots on the iris), low set ears,
open mouth with protruding tongue, high palate, and small chin.
Hands show brachydactyly (short fingers), clinodactyly (curved
fifth fingers), and a single palmar crease. About a third of the
children with Down syndrome have congenital heart disease, and
about 2% have duodenal atresia (obstruction of the small intestine).
Down syndrome is associated with moderate mental retardation.
About 95% of individuals with Down syndrome have
trisomy 21 (47,XX,+21). A smaller subset, 4 to 5%, have a chromosomal
rearrangement, usually a translocation involving chromosomes 14
and 21 (46,XY,t(14;21)). A few individuals, 0.5%, have a mosaicism
with two chromosomally distinct cell lines (46,XX/47,XX,+21).
For this reason, all patients suspected of having Down syndrome,
even if the diagnosis is not in question, should have chromosome
studies. If the Down syndrome is due to an extra chromosome 21,
then the risk of recurrence in future sibs is small. Population
studies of couples who have had a child with trisomy 21 suggest
that the risk of recurrence is around 1%. However, if the Down
syndrome is secondary to a translocation abnormality and one of
the parents is a balanced translocation carrier, the risk of recurrence
is much greater, theoretically, up to a third. This will be further
discussed under the section on chromosomal rearrangements.
Turner syndrome has an
incidence of 1 in 5,000 newborns. It is caused by the loss of
an X chromosome (45,X). The clinical manifestations include short
stature, failure to feminize, amenorrhea (absent menstruation),
infertility and other malformations such as a webbed neck, short
4th and 5th digits, coarctation of the aorta and kidney abnormalities.
Females with Turner syndrome are, as a rule, intellectually normal.
Klinefelter syndrome has
an incidence of 1 in 500 males. In Klinefelter syndrome there
is an extra X chromosome (47,XXY). The presence of this extra
chromosome results in failure to masculinize, small testes and
sterility. It may also cause behavior problems and a learning
disability.
It is common knowledge that chromosome abnormalities
are more likely to occur with advanced maternal age. Based on
data by Ernest Hook the incidence of chromosome abnormalities
in newborn infants based upon maternal age is:
Hook EB. Rates of chromosomal abnormalities at different maternal
ages. Obstet Gynecol 1981;58:282.
A number of hypotheses have been proposed to explain why older
women are more likely to have babies with chromosome abnormalities.
One hypothesis takes into consideration the fact that, in females,
the eggs are present in the ovaries at birth. The eggs remain
in meiosis 1 until ovulation between 15-50 years. Presumably,
in older mothers the eggs will have been exposed longer to adverse
factors that may result in nondisjunction. Another hypothesis
is that in the late 30's or early 40's, when women may be actively
avoiding pregnancy, an "old" egg (relative to when it
was ovulated) or an "old" sperm (relative to when it
was deposited) is likely to be fertilized, and this may increase
the chance of nondisjunction.
SUMMARY
Eggs and sperm are formed following meiosis. This
is a two step process resulting in the replication and segregation
of each chromosome pair, and the formation of four gametes from
the original cell. Normally, the eggs and sperm contain a set
of each of the 23 chromosomes. At fertilization, the total chromosome
count of 46 chromosomes is restored. Following mitosis, all somatic
cells will have 46 chromosomes.
Nondisjunction occurs when a pair of chromosomes
fails to separate during meiosis. This results in the formation
of eggs or sperm with too many or too few chromosomes. When these
chromosomally abnormal gametes are fertilized the resulting fetus
is most often miscarried. Infants with chromosome abnormalities
who do survive have physical abnormalities and intellectual delays.
The incidence of nondisjunction increases with
maternal age. For instance, women in their early 20's have a 1
in 500 chance of having a child with a chromosome abnormality,
increasing in the mid 40's to 1 in 21.
PRACTICE ACTIVITY 2
1. What is the difference between a chromosome abnormality
and a genetic disorder?
2. Chromosome abnormalities account for what percent of miscarriages?
3. Describe meiosis.
4. Describe nondisjunction.
PRACTICE ACTIVITY 2: ANSWERS
1. A chromosome abnormality is caused by the presence
of extra or missing chromosome material. The genes in a person
with a chromosome abnormality are normal. It is the number of
genes (increased or decreased) that is abnormal. A genetic disorder
is caused by a change in a single gene, or genetic message, coding
for a particular trait.
2. 50-60%
3. Meiosis is a special process of cell division
which results in the formation of eggs and sperm. During meiosis,
the pairs of chromosomes are replicated and separated, and the
resulting gametes contain a set of 23 chromosomes.