Chromosomal Abnormalities

Chromosomes carry genetic material or genes. The normal number of chromosomes in human beings is forty-six, made up of twenty-three pairs. Twenty-two pairs, the autosomes, carry the genes that encode the information necessary to develop a person from a single-celled ovum (egg). The autosomes are numbered in order of size, the largest labeled number 1 and the smallest, number 22. The additional pair of chromosomes is the pair of sex chromosomes. This pair determines the individual's genetic sex. Each sex chromosome is designated X or Y. A female has two X chromosomes and is designated XX. A male has an X and a Y chromosome and is designated XY. The sex chromosomes also contain genes, but most traits are carried on the autosomes.

The chromosomes consist of short arms and long arms, with relatively inactive material at the point where the arms cross each other, the centromere. The short arms, designated as q, and the long arms, designated as q, are always on the same side of the centromere-the short arms are uppermost.

Every cell in the human body undergoes division into "daughter" cells at some time in its life-mitosis. During mitosis, the chromosomes divide into two equal sets of twenty-three pairs. This process gives rise to two new cells with genetic makeup identical to that of the parent cell. In the formation of reproductive cells, however, the process of division produces a sperm or egg cell equipped with only one of each pair of chromosomes. This process is called meiosis. Because of meiosis, egg and sperm merge in fertilization to form a potential human being consisting of twenty-three chromosomes from one parent and twenty-three from the other.

During the ordinary working life of a cell, when it is not in the process of division, the material of the chromosomes is not visible even under the microscope. At the time of cell division the chromosomes be­come thicker and more easily take up a chemical stain for visualization. At this time the chromosomes can be analyzed. A complete picture of the chromosomes is taken and they are mapped in order. This is called a karyotype.

Defects in Chromosome Number

Chromosomal defects may be the result of either abnormal chromo­some number or structure. Abnormal chromosome number, called aneuploidy, can result from a missing chromosome or one or more extra chromosomes. Extra chromosomes may occur in either the autosomes or sex chromosomes. A fetus cannot survive the loss of an autosome­each autosome carries too much genetic material. A fetus can form and develop, however, lacking one sex chromosome, but only if it has an X but no Y chromosome. Not even an embryo will form if there is a Y but no X.

Embryos with one X, designated as 45X (previously denoted as 45XO), have a high rate of miscarriage in the first trimester and of fetal death in the second. Some do develop to full term, however. Their condition is called Turner syndrome. They ordinarily look like females but have rudimentary sex organs. They are commonly short in stature. There is an increase in heart and kidney problems among individuals with Turner syndrome. Deficiencies in sexual development can be corrected with hormone therapy, but 45X individuals cannot reproduce.

Occasionally when sperm or ova form during cell division they ac­quire excess numbers of chromosomes, either autosomes or the sex chromosomes. Trisomy is the addition of an extra autosome for a total of forty-seven chromosomes. Trisomy occurs because of non disjunction-when the chromosomes fail to separate (disjoin) or to separate completely­during the formation of a sperm or ovum. Rarely, this can happen during early cell division of the fertilized egg, explaining why it is possible for only one of a pair of identical twins to have a trisomy.

There are also individuals with extra sex chromosomes, as many as two or three extras, for a total of forty-eight or forty-nine chromosomes. Individuals with forty-seven chromosomes who are 47XXY are said to have Klinefelter syndrome. They tend to be tall, gangly males with small genitalia and even smaller testes who cannot produce sperm. The individuals who are 47XXX are externally normal females with normal fertility; a small proportion of these suffer from a mild degree of mental retardation. The even rarer individuals with forty-eight and forty-nine chromosomes all manifest minor degrees of mental retardation and are infertile. They may be externally male or female.

Trisomy of the larger chromosomes ordinarily results in a fertilized ovum that cannot survive embryonic life. The pregnancy miscarries. When trisomy of the chromosomes having very short arms occurs, a live birth is possible, although these fetuses and infants tend to be smaller than usual. The most common trisomy involves chromosome number twenty-one and is responsible for Down syndrome.

An abnormal chromosome number may occur simply by accident, as an inherited characteristic, as a consequence of advanced maternal age, and rarely as a consequence of advanced paternal age. Most forms of non disjunction become more frequent as the mother's age increases. The accompanying table will give you some idea of the likelihood of having a baby with Trisomy 21, a baby with anyone of the three trisomies compatible with life, and a baby with any chromosomal abnormality at given maternal ages. Although older mothers are more likely than younger ones to conceive an infant with a trisomy, the actual number of such babies is greater in women under 30 today. This is because there are so many more babies born to women under 30 and because mothers over 35 are offered routine testing for the condition and, on its discovery, often choose not to carry the fetus to term.

Lower than the number of trisomies found by first trimester chorionic villus sampling because some of the affected fetuses do not survive to be born alive. Trisomies 13 and 18 are compatible with live birth, but the children have serious problems and do not survive early childhood.

The likelihood of Down syndrome reaches approximately 1 in 100 at about age 39 and the likelihood of all trisomies reach 1 in 100 slightly earlier than this. Women with Down syndrome, since they have an extra chromosome 21, can be expected to have many more children with the chromosome abnormality than will women without it, and indeed that is the case.

Defects in Chromosome Structure

Chromosomes can be changed in a number of ways during pregnancy. A part of one chromosome can switch over with a part of another chromosome. This is called a translocation. There can be an inversion, where there is a break in two places on a single chromosome with a resulting rearrangement of the genetic material. There can be a deletion, loss of a segment of a chromosome, or a duplication, an extra segment within a chromosome. The ends of the chromosomes can come together to form a ring, which usually involves a deletion.

Changes in chromosomes mayor may not cause problems. For example, a translocation may be balanced, when there is no loss or gain of genetic material. In this case, the person with the translocation will be unaffected by it. If an amniocentesis shows a child with a balanced translocation, the blood of the parents will be drawn for a karyotype. If either parent shows the same balanced translocation, the child can be assumed to be similarly unaffected by the chromosomal change.

In the formation of the sex cells, however, the translocation will not always remain balanced in the daughter cells. Genetic material can be lost. This is called an unbalanced translocation. A child of a parent with a balanced translocation can then be born with a chromosomal abnormality that can cause difficulties. Sometimes, the unbalanced translocation may be incompatible with life, causing a miscarriage. Recurrent miscarriage is a cause to perform chromosomal analysis of the parents.

One form of translocation is called a Robertsonian translocation and involves chromosomes 14 and 21. In cell division, this may result in a trisomy of chromosome 21, causing Down syndrome. Approximately 5 percent of the incidence of Down syndrome is caused by a Robertson­ian translocation. The risk of conceiving a child with Down syndrome if either parent has a Robertsonian translocation is about 33 percent, but many of these will spontaneously miscarry. Such a parent has a 33 percent chance of having a child without the translocation, and a 33 percent chance of having a child with a balanced translocation-in short, a 66 percent chance of a pregnancy occurring without a problem caused by this chromosomal change.

Among the other structural changes in chromosomes, inversions usually cause no problems. Persons who carry inversions have normal offspring or, if abnormal, the changes are incompatible with life and result in miscarriage. Deletions usually result in problems while duplications are highly variable in their effects.

Amniocentesis, the withdrawal of amniotic fluid from the uterine cavity, or CVS, the sampling of early placental structures, are the tests currently used to verify the presence or absence of trisomy and other chromosomal abnormalities in the fetus. After growing the cells in culture, which allows them to be harvested in the dividing state, the investigator takes a photograph through a microscope of a dividing cell. The individual chromosomes are identified and arranged in order. In skilled hands this forms a reliable chromosomal map or karyotype. A firm diagnosis of a chromosomal abnormality can be made.