Chromosomal disorders form a major category of genetic disease, accounting for a large proportion of reproductive wastage (early gestational abortions), congenital malformations, and intellectual disability. Cytogenetics is the term given to chromosome disorders, and they are classified using the International System for Human Cytogenetic Nomenclature. During cell division in non–germ cells, the chromosomes replicate so that each cell receives a full diploid number. In germ cells, a different form of division called meiosis takes place. During meiosis, the double sets of 22 autosomes and the 2 sex chromosomes (normal diploid number) are reduced to single sets (haploid number) in each gamete. At the time of conception, the haploid number in the ovum and that in the sperm join and restore the diploid number of chromosomes.
Chromosomal abnormalities are commonly described according to the shorthand description of the karyotype. In this system, the total number of chromosomes is given first, followed by the sex chromosome complement, and then the description of any abnormality. For example, a male with trisomy 21 is designated 47,XY,+21.
The aberrations underlying chromosomal disorders may take the form of alterations in the structure of one or more chromosomes or an abnormal number of chromosomes. Occasionally, mitotic errors in early development give rise to two or more cell lines characterized by distinctive karyotypes, a condition referred to as mosaicism. Mosaicism can result from mitotic errors during cleavage of the fertilized ovum or in somatic cells. Sometimes, mosaicism consists of an abnormal karyotype and a normal one, in which case the physical deformities caused by the abnormal cell line usually are less severe.
Structural Chromosomal Abnormalities Structural changes in chromosomes usually result from breakage in one or more of the chromosomes followed by rearrangement or deletion of the chromosome parts. Among the factors believed to cause chromosome breakage are exposure to radiation sources, such as x-rays; influence of certain chemicals; extreme changes in the cellular environment; and viral infections.
Several patterns of chromosome breakage and rearrangement can occur (Fig. 7.7). There can be a deletion of the broken portion of the chromosome. When one chromosome is involved, the broken parts may be inverted. Isochromosome formation occurs when the centromere, or central portion, of the chromosome separates horizontally instead of vertically. Ring formation results when deletion is followed by uniting of the chromatids to form a ring. Translocation occurs when there are simultaneous breaks in two chromosomes from different pairs, with exchange of chromosome parts. With a balanced reciprocal translocation, no genetic information is lost; therefore, persons with translocations usually are normal. However, these people are translocation carriers and may have normal or abnormal children.
A special form of translocation called a centric fusion or robertsonian translocation involves two acrocentric chromosomes in which the centromere is near the end, most commonly chromosomes 13 and 14 or 14 and 21. Typically, the break occurs near the centromere affecting the short arm in one chromosome and the long arm in the other. Transfer of the chromosome fragments leads to one long and one extremely short fragment. The short fragment is usually lost during sub- sequent divisions. In this case, the person has only 45 chromosomes, but the amount of genetic material that is lost is so small that it often goes unnoticed. Difficulty, however, arises during meiosis; the result is gametes with an unbalanced number of chromosomes. The chief clinical importance of this type of translocation is that carriers of a robertsonian translocation involving chromosome 21 are at risk for producing a child with Down syndrome.
The manifestations of aberrations in chromosome structure depend to a great extent on the amount of genetic material that is lost or displaced. Many cells sustaining unrestored breaks are eliminated within the next few mitoses because of deficiencies that may in themselves be fatal. This is beneficial because it prevents the damaged cells from becoming a permanent part of the organism or, if it occurs in the gametes, from giving rise to grossly defective zygotes. Some altered chromosomes, such as those that occur with translocations, are passed on to the next generation.
Numeric Disorders Involving Autosomes
Having an abnormal number of chromosomes is referred to as aneuploidy. Among the causes of aneuploidy is a failure of the chromosomes to separate during oogenesis or spermatogenesis. This can occur in either the autosomes or the sex chromosomes and is called nondisjunction (Fig. 7.8). Nondisjunction gives rise to germ cells that have an even number of chromosomes (22 or 24). The products of conception formed from this even number of chromosomes have an uneven number of chromosomes, 45 or 47. Monosomy refers to the presence of only one member of a chromosome pair. The defects associated with monosomy of the autosomes are severe and usually cause abortion. Monosomy of the X chromosome (45,X), or Turner syndrome, causes less severe defects.
Polysomy, or the presence of more than two chromosomes to a set, occurs when a germ cell containing more than 23 chromosomes is involved in conception. Trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome) share several karyotypic and clinical features with trisomy 21 (Down syndrome). In contrast to Down syndrome, however, the malformations are much more severe and wide-ranging. As a result, these infants rarely survive beyond the first years of life.
Down Syndrome. First described in 1866 by John Langdon Down, trisomy 21, or Down syndrome, causes a combination of birth defects including some degree of intellectual disability, characteristic facial features, and other health problems. It is the most common chromosomal disorder.
Approximately 95% of cases of Down syndrome are caused by nondisjunction or an error in cell division during meiosis, resulting in a trisomy of chromosome 21. A rare form of Down syndrome can occur in the offspring of people in whom there has been a robertsonian translocation (see Fig. 7.7) involving the long arm of chromosome 21q and the long arm of one of the acrocentric chromosomes (most often 14 or 22). The translocation adds to the normal long arm of chromosome 21. Therefore, the person with this type of Down syndrome has 46 chromosomes, but essentially a trisomy of 21q.
The risk of having a child with Down syndrome increases with maternal age. The reason for the correlation between maternal age and nondisjunction is unknown, but is thought to reflect some aspect of aging of the oocyte. Although men continue to produce sperm throughout their reproductive life, women are born with all the oocytes they ever will have. These oocytes may change as a result of the aging process. With increasing age, there is a greater chance of a woman having been exposed to damaging environmental agents such as drugs, chemicals, and radiation. Unlike trisomy 21, Down syndrome due to a chromosome (21;14) translocation shows no relation to maternal age but has a relatively high recurrence risk in families when a parent, particularly the mother, is a carrier.
A child with Down syndrome has specific physical characteristics that are classically evident at birth. These features include a small and rather square head. There is a flat facial profile, with a small nose and somewhat depressed nasal bridge; small folds on the inner corners of the eyes (epicanthal folds) and upward slanting of the eyes; small, low-set, and malformed ears; a fat pad at the back of the neck; an open mouth; and a large, protruding tongue (Fig. 7.9). The child’s hands usually are short and stubby, with fingers that curl inward, and there usually is only a single palmar (i.e., simian) crease. There is excessive space between the large and second toes. Hypotonia and joint laxity also are present in infants and young children. There often are accompanying congenital heart defects and an increased risk of gastrointestinal malformations. Approximately 1% of people with trisomy 21 Down syndrome have mosaicism (i.e., cell populations with the normal chromosome number and trisomy 21). These people may be less severely affected. There is a high correlation of the development of acute leukemia, both myeloid and lymphoblastic, among children with Down syndrome. In addition, there is an increased risk of Alzheimer disease among older people with Down syndrome, and many of these children have a higher chance of acquiring cardiovascular disease.
There are several prenatal screening tests that can be done to determine the risk of having a child with Down syndrome.18 The most commonly used are blood tests that measure maternal serum levels of α-fetoprotein (AFP), human chorionic gonadotropin (hCG), unconjugated estriol, inhibin A, and pregnancy-associated plasma protein A (PAPP-A) (see section on Diagnosis and Counseling). The results of three or four of these tests, together with the woman’s age, often are used to determine the probability of a pregnant woman having a child with Down syndrome. Nuchal translucency (sonolucent space on the back of the fetal neck) is another test that can be done to assess this aspect of the fetus by uses ultrasonography and can be performed between 10 and 13 weeks’ gestation. The fetus with Down syndrome tends to have a greater area of translucency compared with a chromosomally normal infant. The nuchal transparency test is usually used in combination with other screening tests. The only way to accurately determine the presence of Down syndrome in the fetus is through chromosome analysis using chorionic villus sampling, amniocentesis, or percutaneous umbilical blood sampling, which is discussed later in this chapter.
Numeric Disorders Involving Sex Chromosomes
Chromosomal disorders associated with the sex chromosomes are much more common than those related to the autosomes, except for trisomy 21. Furthermore, imbalances (excess or deletions) are much better tolerated than those involving the autosomes. This is related in a large part to two factors that are peculiar to the sex chromosomes:
• The inactivation of all but one X chromosome
• The modest amount of genetic material that is carried on the Y chromosome
Although girls normally receive both a paternal and a maternal X chromosome, the clinical manifestations of X chromosome abnormalities can be quite variable because of the process of X inactivation (previously discussed in Chapter 6). In somatic cells of females, only one X chromosome is transcriptionally active. The other chromosome is inactive. The process of X inactivation, which is random, occurs early in embryonic life and is usually complete at about the end of the first week of development. After one X chromosome has become inactivated in a cell, all cells descended from that cell have the same inactivated X chromosome. Although much of one X chromo- some is inactivated in females, several regions contain genes that escape inactivation and continue to be expressed by both X chromosomes. These genes may explain some of the variations in clinical symptoms seen in cases of numeric abnormalities of the X chromosome, such as Turner syndrome.
It is well known that the Y chromosome determines the male sex. The gene that dictates testicular development (Sry: sex-determining region Y gene) has been located on its distal short arm. Recent studies of the Y chromosome have yielded additional information about gene families in the so-called “male-specific Y” or MSY region. All of these are believed to be involved in spermatogenesis. A few additional genes with homologs on the X chromosome have been mapped to the Y chromosome, but to date, no disorders resulting from mutations in these genes have been described.
Turner Syndrome. Turner syndrome describes an absence of all (45,X/0) or part of the X chromosome. Some women with Turner syndrome may have part of the X chromosome, and some may display a mosaicism with one or more additional cells lines. This disorder affects approximately 1 of every 2500 live births and is the most frequent occurring genetic disorder in women.
Characteristically, the girl with Turner syndrome is short in stature, but her body proportions are normal (Fig. 7.10). Females with Tuner syndrome lose the majority of their oocytes by the age of 2 years. Therefore, they do not menstruate and shows no signs of secondary sex characteristics. There are variations in the syndrome, with abnormalities ranging from essentially none to cardiac abnormalities such as bicuspid aortic valve and coarctation of the aorta, problems with hearing and vision, a small size mandible, a horseshoe kidney, and a small webbed neck. Women with Turner syndrome have been found to develop autoimmune disorders associated with male predominance, such as type 1 diabetes mellitus and Hashimoto thyroiditis.
Although most women with Turner syndrome have normal intelligence, they may have problems with visuospatial organization (e.g., difficulty in driving, nonverbal problem-solving tasks such as mathematics, and psychomotor skills) and attention deficit disorders.
The diagnosis of Turner syndrome often is delayed until late childhood or early adolescence in girls who do not present with the classic features of the syndrome. Only about 20% to 33% of affected girls receive a diagnosis as a new-born because of puffy hands and feet or redundant nuchal skin. Another 33% are diagnosed in mid-childhood because of short stature. The remainder of the girls are mainly diagnosed in adolescence when they fail to enter puberty. It is important to diagnose girls with Turner syndrome as early as possible so treatment plans could be implemented and managed throughout their lives.
The management of Turner syndrome begins during childhood and requires ongoing assessment and treatment. Growth hormone therapy generally can result in a gain of 6 to 10 cm in final height. Estrogen therapy, which is instituted around the normal age of puberty, is used to promote development and maintenance of secondary sexual characteristics.
Klinefelter Syndrome. Klinefelter syndrome is a condition of testicular dysgenesis accompanied by the presence of one or more extra X chromosomes in excess of the normal male XY complement. Most males with Klinefelter syndrome have one extra X chromosome (47,XXY). In rare cases, there may be more than one extra X chromosome (48,XXXY). The presence of the extra X chromosome in the 47,XXY male results from nondisjunction during meiotic division in one of the parents. The extra X chromosome is usually of maternal origin, but approximately 1/3 of the time, it is of paternal origin. The cause of the nondisjunction is unknown. Advanced maternal age increases the risk, but only slightly. Klinefelter syndrome occurs in approximately 1 per 1000 newborn male infants.
Although the presence of the extra chromosome is fairly common, the syndrome with its accompanying signs and symptoms that may result from the extra chromosome is uncommon. Many men live their lives without being aware that they have an additional chromosome. For this reason, it has been suggested that the term Klinefelter syndrome be replaced with 47,XXY male.
Klinefelter syndrome is characterized by enlarged breasts, sparse facial and body hair, small testes, and the inability to produce sperm (Fig. 7.11). Regardless of the number of X chromosomes present, the male phenotype is retained. The condition often goes undetected at birth. The infant usually has normal male genitalia, with a small penis and small, firm testicles. At puberty, the intrinsically abnormal testes do not respond to stimulation from the gonadotropins and undergo degeneration. This leads to a tall stature with abnormal body proportions in which the lower part of the body is longer than the upper part. Later in life, the body build may become heavy, with a female distribution of subcutaneous fat and variable degrees of breast enlargement. There may be deficient secondary male sex characteristics, such as a voice that remains feminine in pitch and sparse beard and pubic hair. Although the intellect usually is normal, most 47,XXY males have some degree of language impairment.
Adequate management of Klinefelter syndrome requires a comprehensive neurodevelopmental evaluation. In infancy and early childhood, this often includes a multidisciplinary approach to determine appropriate treatments such as physical therapy, infant stimulation programs, and speech therapy. Men with Klinefelter syndrome have congenital hypogonadism, which results in an inability to produce normal amounts of testosterone accompanied by an increase in hypothalamic gonadotrophic hormones. Androgen therapy is usually initiated when there is evidence of a testosterone deficit. Infertility is common in men with Klinefelter syndrome because of a decreased sperm count. If sperm are present, cryopreservation may be useful for future family planning. However, genetic counseling is advised because of the increased risk of autosomal and sex chromosomal abnormalities. Men with Klinefelter syndrome also experience increased risk for osteoporosis and need to be educated on prevention management.