CHROMOSOMAL ABNORMALITIES

Chromosomal aberrations are surprisingly frequent events. About 20% of all human conceptions have them. It is likely that as many as 1 in 118 newborn infants inherit such an abnormality. Many, if not most, abnormal chromosomes are the result of a failure of meiosis in the production of sperm and ova. It has been estimated that 1 out of 5 sperm cells produced by healthy men is grossly defective. Similarly, as many as half of all spontaneous miscarriages may result from gross chromosomal errors. The vast majority of chromosomal abnormalities are so severe as to cause spontaneous abortions early in pregnancies.

There are two major categories of chromosomal abnormalities:

1. irregular number of chromosomes
2. structural modification in a chromosome

Both kinds of abnormalities usually result from nondisjunction errors. These are mechanical errors during meiosis. Specifically, members of a pair of homologous chromosomes move to the same pole rather than the opposite ones.

Irregular Number of Chromosomes
The most obvious kind of error that shows up in karyotypes of human embryonic and fetal cells is a variation in the number of chromosomes from the normal 46. Both the mother and the father normally each contribute 23 chromosomes, resulting in 23 homologous pairs or sets in their child. The error can be complete multiples of sets (e.g., 23 + 23 + 23). This is known as polyploidy . Instead, there can be an addition or loss of chromosomes within a set (e.g., 23 + 22). This is aneuploidy.

Structural Modification of a Chromosome
A slightly less obvious but potentially still devastating kind of error is a structural modification of a chromosome. This usually occurs when there is a breakage of a chromatid arm and subsequent reunion at a different location on the same chromosome or on a different chromosome (i.e., crossing-over). In most cases, the actual cause of a breakage is unknown. However, breaks can be created experimentally with radiation, some chemicals, and viruses. A chromosome structural modification can also result when extra sections of chromatids are produced.

Mosaicism
Chromosomal abnormalities do not always show up in every cell. Sometimes there is a mosaic pattern--that is, only some cells and some tissues carry the abnormality. In these cases, the symptoms are generally less severe for the individual than if all cells are abnormal. It is thought that mosaicism usually results from mutations that occur during mitosis, early in the development of an embryo. The later the mutations occur in the embryonic stage, the fewer cells are likely to ultimately become abnormal.

It is now possible to link specific medical syndromes , or groups of related symptoms, to particular chromosomal errors.


Autosomal Abnormalities (Monosomies and Trisomies)

The majority of human chromosomal abnormalities occur in the autosomes. Most of these abnormalities are monosomies or trisomies. In the case of a monosomy, there is only one copy of each kind of chromosome instead of the usual pair of homologous chromosomes. With trisomy, there are three of each type of chromosome. All fetuses with autosomal monosomies spontaneously abort early in pregnancy. Likewise, almost all fetuses with trisomies die before birth. Those that survive usually have multiple physical malformations, mental retardation, and relatively short lives.

Trisomy is a chromosomal anomaly that is characterized by the presence of an extra chromosome in the cells of a person's body. Under normal circumstances everyone has 46 chromosomes in each cell. A Trisomy occurs when there are 47 chromosomes instead of the usual 46. A partial Trisomy occurs when part of an extra chromosome, as opposed to a whole extra chromosome, attaches itself to one of the other chromosomes. Mosaic Trisomy is where not every cell contains the extra chromosomal material.

The most commonly known Trisomies are: Trisomy 21, Trisomy 18 and Trisomy 13

Trisomy 21

The most well known and most common autosomal abnormality is Down syndrome . This is a mild to severe form of mental retardation accompanied by distinctive physical traits. People with Down syndrome have an irregularity with autosome pair 21. In most cases, there is an extra chromosome (i.e., trisomy). More rarely (3-5%), there is a structural modification in this chromosome. Specifically, there is a translocation of all or part of chromosome 21 to chromosome 14 or 15. The actual gene or genes on chromosome 21 that are responsible for Down syndrome are now being identified in a critical region of 20-40 genes. About 2-4% of Down syndrome people are genetically mosaic. That is, some of their cells have chromosome 21 trisomy while others do not, resulting in generally milder symptoms. The translocational type of Down syndrome also usually has less severe symptoms.

According to the National Down Syndrome Society, one in every 800 to 1,000 live-born infants has Down syndrome. Approximately 5,000 babies with Down syndrome are born each year in the U.S. alone. Down syndrome is a non-hereditary congenital condition usually caused by an extra copy of chromosome 21. Down syndrome is associated with moderate to severe mental retardation, characteristic facial appearance, short stature, hypotonia (low muscle tone), and heart and lung defects. Studies also have indicated that individuals with Down syndrome have a higher incidence of leukemia.

The Occurrence of Down syndrome: Most of the time, the occurrence of Down syndrome is due to a random event that occurred during formation of the reproductive cells, the ovum or sperm. Down syndrome is not attributable to any behavioral activity of the parents or environmental factors.
For parents of a child with Down syndrome, there may be an increased likelihood of Down syndrome in future pregnancies.


Trisomy 18

Trisomy 18 is a syndrome associated with the presence of a third (extra) number 18 chromosome. Trisomy 18 is a relatively common syndrome affecting approximately 1 out of 3,000 live births. Multiple abnormalities are associated with the presence of an extra number 18 chromosome, many which are not compatible with more than a few months of life. Few infants survive beyond the first year. Common findings include low birth weight, mental retardation, low-set ears, malformed ears, small jaw (micrognathia) hand abnormalities, congenital heart disease, hernia, and cryptorchidism.

Trisomy 13

Trisomy 13 is associated with the presence of a third (extra) chromosome 13. Trisomy 13 occurs in about 1 out of every 5,000 live births. It is a syndrome with multiple abnormalities, many of which are not compatible with more than a few months of life. Almost half of the affected infants do not survive beyond the first month, and about three quarters die within 6 months. Trisomy 13 is associated with multiple abnormalities, including severe mental defects and defects of the brain that lead to seizures, apnea, deafness, and ocular (relating to the eye) abnormalities. Most infants have a cleft lip and cleft palate, and low-set ears. Congenital heart disease is present in approximately 80% of affected infants. Hernias and genital abnormalities are common.


Sex Chromosome Abnormalities

The majority of known types of chromosomal abnormalities involve sex chromosomes. In frequency of occurrence, they are only slightly less common than autosomal abnormalities. However, they are usually much less severe in their effects. The high frequency of people with sex chromosome aberrations is partly due to the fact that they are rarely lethal conditions. Like Down syndrome and other autosomal problems, sex chromosome gross abnormalities can be diagnosed before birth by amniocentesis and chorionic villi sampling.

Sex chromosome abnormalities are gender specific. Normal males inherit an X and a Y chromosome while females have two X's. A single Y chromosome is sufficient to produce maleness while its absence is necessary for femaleness. Female abnormalities are due to variations in the number of X chromosomes. Male abnormalities are the result of irregular numbers of either the X or the Y chromosome or both.


Female Sex Chromosome Abnormalities

Turner syndrome

Turner syndrome occurs when females inherit only one X chromosome--their genotype is X0. If they survive to birth, these girls have abnormal growth patterns. They are short in stature, averaging 4 foot 7 inches as adults, and often have distinctive webbed necks (i.e., extra folds of skin), small jaws, and high arched palates. They generally lack prominent female secondary sexual characteristics. They have exceptionally small, widely spaced breasts, broad shield-shaped chests, and turned-out elbows. Their ovaries do not develop normally and they do not ovulate. The few oöcytes that they produce are destroyed by the time they are two. They are in a sense postmenopausal from early childhood and are sterile. They also have a higher than average incidence of thyroid disease. In some individuals, there is slight mental retardation. Turner syndrome is rare. Current estimates of its frequency range from 1 in 3,000 female infants to 1 in 5,000. If diagnosed in early childhood, regular injections of human growth hormones can increase their stature by a few inches. Beginning around the normal age of puberty, estrogen replacement therapy can result in some breast development and menstruation. These treatments allow Turner syndrome women to appear relatively normal.

Metafemales , or triple-X females, inherit three X chromosomes--their genotype is XXX or more rarely XXXX or XXXXX. As adults, these "super-females" are usually an inch or so taller than average with unusually long legs and slender torsos, but otherwise appear normal. They have normal development of sexual characteristics and are fertile. They may have slight learning difficulties and are usually in the low range of normal intelligence (especially the XXXX and XXXXX individuals). They tend to be emotionally immature for their size during childhood. This sometimes results in teachers and other adults labeling them as troublemakers. None of these traits prevent them from being socially accepted as ordinary adult women. This type of chromosomal abnormality is apparently rare and little is known about it. However, the frequency is approximately 1 in 1,000 female infants and it occurs more commonly when the mother is older.


Male Sex Chromosome Abnormalities

Klinefelter syndrome
Klinefelter syndrome males inherit one or more extra X chromosomes--their genotype is XXY or more rarely XXXY, XXXXY, or XY/XXY mosaic. They have relatively high-pitched voices, asexual to feminine body contours as well as breast enlargement, and comparatively little facial and body hair. They are sterile or nearly so, and their testes and prostate gland are small. As a result, they produce relatively small amounts of testosterone. The feminizing effects of this hormonal imbalance can be significantly diminished if Klinefelter syndrome boys are regularly given testosterone from the age of puberty on. Like metafemales (described above), many Klinefelter syndrome men are an inch or so above average height. They also are likely to be overweight. They usually have learning difficulties as children, especially with language and short-term memory. If not given extra help in early childhood, this often leads to poor school grades and a subsequent low self esteem. However, most are sufficiently ordinary in appearance and mental ability to live in society without notice. It is not unusual for Klinefelter syndrome adults with slight symptoms to be unaware that they have it until they are tested for infertility. They are usually capable of normal sexual function, including erection and ejaculation, but many, if not most, are unable to produce sufficient amounts of sperm for conception. Klinefelter syndrome males with more than two X chromosomes usually have extreme symptoms and are often mentally retarded. Men who are mosaic (XY/XXY) generally have the least problems. There is no evidence that Klinefelter syndrome boys and men are more inclined to be homosexual, but they are more likely to be less interested in sex. They have a higher than average risk of developing osteoporosis, diabetes and other autoimmune disorders. This may be connected to low testosterone production. The frequency of Klinefelter syndrome has been reported to be between 1 in 500 and 1 in 1000 male births. This makes it one of the most common chromosomal abnormalities. Males with Down syndrome sometimes also have Klinefelter syndrome. Both syndromes are more likely to occur in babies of older mothers.

XYY syndrome males inherit an extra Y chromosome--their genotype is XYY. As adults, these "super-males" are usually tall (above 6 feet) and generally appear and act normal. However, they produce high levels of testosterone. During adolescence, they often are slender, have severe facial acne, and are poorly coordinated. They are usually fertile and lead ordinary lives as adults. Many, if not most, are unaware that they have a chromosomal abnormality. The frequency of XYY syndrome is not certain due to statistical differences between different studies of this condition. It may be as common as 1 in 900 male births to as rare as 1 in 1500 or even 1 in 2,000.

Early studies of XYY syndrome done in European prisons initially led to the erroneous conclusion that these men were genetically predisposed to antisocial, aggressive behavior, below average intelligence, and homosexuality. Contributing to the early view that XYY syndrome men have serious personality disorders was the case of Richard Speck. In 1966, he coldly murdered 8 nurses in a Chicago dormitory. At his trial, his lawyer claimed that he was innocent due to uncontrollable urges caused by his XYY genotype. This novel appeal was akin to claiming insanity or severely diminished mental competence. The jury was not convinced and found him guilty of murder. He was sentenced to life in prison where he eventually died. In fact, Richard Speck did not have an XYY genotype. However, some researchers suggest that the high testosterone levels of XYY men can make them somewhat more prone to violence.


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