Virtual Hospital: Clinical Genetics: A Self Study for Health Care Providers?
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Clinical Genetics: A Self Study for Health Care Providers: Lesson 1
Abnormalities in Chromosome Number
Virginia P. Johnson, MD
Carol Christianson, MS
University of South Dakota, School of Medicine
Peer Review Status: Internally Peer Reviewed
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
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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 inci dence 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 Gl 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
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(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 reaming 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:
Maternal Age Risk for Down Syndrome Total Risk for Chromosomal Abnormalities
20-24
1/1490
1/500
25-29
1/1120
1/450
30
1/952
1/417
31
1/909
1/385
32
1/769
1/322
33
1/602
1/286
34
35
36
37
38
39
40
41
42
43
44
45
1/485
1/378
1/289
1/224
1/173
1/136
1/106
1/82
1/63
1/49
1/38
1/30
1/238
1/192
1/156
1/127
1/102
1/83
1/66
1/53
1/42
1/33
1/26
1/21
46
1/23
1/16
47
1/18
1/13
48
1/14
1/10
49
1/11
1/8
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
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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.
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