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Birth Defects and Spontaneous Abortions: Chromosomal and Genetic Factors

Chromosomal abnormalities, which may be numerical or structural, are important causes of birth defects and spontaneous abortions. It is estimated that 50% of conceptions end in spontaneous abortion and that 50% of these

Primary Oocyte
Figure 1.4 Events occurring during the first and second maturation divisions. A. The primitive female germ cell (primary oocyte) produces only one mature gamete, the mature oocyte. B. The primitive male germ cell (primary spermatocyte) produces four spermatids, all of which develop into spermatozoa.

abortuses have major chromosomal abnormalities. Thus approximately 25% of conceptuses have a major chromosomal defect. The most common chromosomal abnormalities in abortuses are 45,X (Turner syndrome), triploidy, and trisomy 16. Chromosomal abnormalities account for 7% of major birth defects, and gene mutations account for an additional 8%.

Numerical Abnormalities

The normal human somatic cell contains 46 chromosomes; the normal gamete contains 23. Normal somatic cells are diploid, or 2n; normal gametes are haploid, or n. Euploid refers to any exact multiple of n, e.g., diploid or triploid. Aneuploid refers to any chromosome number that is not euploid; it is usually applied when an extra chromosome is present (trisomy) or when one is missing (monosomy). Abnormalities in chromosome number may originate during meiotic or mitotic divisions. In meiosis, two members of a pair of homologous chromosomes normally separate during the first meiotic division so that each daughter cell receives one member of each pair (Fig. 1.5 A). Sometimes, however, separation does not occur (nondisjunction), and both members of a pair move into one cell (Fig. 1.5, B and C). As a result of nondisjunction of the chromosomes, one cell receives 24 chromosomes, and the other receives 22 instead of the normal 23. When, at fertilization, a gamete having 23 chromosomes fuses with a gamete having 24 or

Visualizing Nondisjunction
Figure 1.5 A. Normal maturation divisions. B. Nondisjunction in the first meiotic division. C. Nondisjunction in the second meiotic division.

22 chromosomes, the result is an individual with either 47 chromosomes (trisomy) or 45 chromosomes (monosomy). Nondisjunction, which occurs during either the first or the second meiotic division of the germ cells, may involve the autosomes or sex chromosomes. In women, the incidence of chromosomal abnormalities, including nondisjunction, increases with age, especially at 35 years and older.

Occasionally nondisjunction occurs during mitosis (mitotic nondisjunction) in an embryonic cell during the earliest cell divisions. Such conditions produce mosaicism, with some cells having an abnormal chromosome number and others being normal. Affected individuals may exhibit few or many of the characteristics of a particular syndrome, depending on the number of cells involved and their distribution.

Sometimes chromosomes break, and pieces of one chromosome attach to another. Such translocations may be balanced, in which case breakage and reunion occur between two chromosomes but no critical genetic material is lost and individuals are normal; or they may be unbalanced, in which case part of one chromosome is lost and an altered phenotype is produced. For example, unbalanced translocations between the long arms of chromosomes 14 and 21 during meiosis I or II produce gametes with an extra copy of chromosome 21, one of the causes of Down syndrome (Fig. 1.6). Translocations

Steps Karyotyping Down SyndromeAlzheimer Chromosome

Figure 1.6 A. Translocation of the long arms of chromosomes 14 and 21 at the centromere. Loss of the short arms is not clinically significant, and these individuals are clinically normal, although they are at risk for producing offspring with unbalanced translocations. B. Karyotype of translocation of chromosome 21 onto 14, resulting in Down syndrome.

Figure 1.6 A. Translocation of the long arms of chromosomes 14 and 21 at the centromere. Loss of the short arms is not clinically significant, and these individuals are clinically normal, although they are at risk for producing offspring with unbalanced translocations. B. Karyotype of translocation of chromosome 21 onto 14, resulting in Down syndrome.

Galactosemia Karyotype

are particularly common between chromosomes 13, 14, 15, 21, and 22 because they cluster during meiosis.

trisomy 21 (down syndrome)

Down syndrome is usually caused by an extra copy of chromosome 21 (trisomy 21, Fig. 1.7). Features of children with Down syndrome include growth retardation; varying degrees of mental retardation; craniofacial abnormalities, including upward slanting eyes, epicanthal folds (extra skin folds at the medial corners of the eyes), flat facies, and small ears; cardiac defects; and hypotonia (Fig. 1.8). These individuals also have relatively high incidences of leukemia, infections, thyroid dysfunction, and premature aging. Furthermore, nearly all develop signs of Alzheimer's disease after age 35. In 95% of cases, the syndrome is caused by trisomy 21 resulting from meiotic nondisjunction, and in 75% of these instances, nondisjunction occurs during oocyte formation. The incidence of Down syndrome is approximately 1 in 2000 conceptuses for women under age 25. This risk increases with maternal age to 1 in 300 at age 35 and 1 in 100 at age 40.

In approximately 4% of cases of Down syndrome, there is an unbalanced translocation between chromosome 21 and chromosome 13, 14, or 15 (Fig. 1.6). The final 1% are caused by mosaicism resulting from mitotic

Chromosome Syndrome

Figure 1.8 A and B. Children with Down syndrome, which is characterized by a flat, broad face, oblique palpebral fissures, epicanthus, and furrowed lower lip. C. Another characteristic of Down syndrome is a broad hand with single transverse or simian crease. Many children with Down syndrome are mentally retarded and have congenital heart abnormalities.

Figure 1.8 A and B. Children with Down syndrome, which is characterized by a flat, broad face, oblique palpebral fissures, epicanthus, and furrowed lower lip. C. Another characteristic of Down syndrome is a broad hand with single transverse or simian crease. Many children with Down syndrome are mentally retarded and have congenital heart abnormalities.

nondisjunction. These individuals have some cells with a normal chromosome number and some that are aneuploid. They may exhibit few or many of the characteristics of Down syndrome.

trisomy 18

Patients with trisomy 18 show the following features: mental retardation, congenital heart defects, low-set ears, and flexion of fingers and hands (Fig. 1.9). In addition, patients frequently show micrognathia, renal anomalies, syndactyly, and malformations of the skeletal system. The incidence of this condition is approximately 1 in 5000 newborns. Eighty-five percent are lost between 10 weeks of gestation and term, whereas those born alive usually die by age 2 months.

trisomy 13

The main abnormalities of trisomy 13 are mental retardation, holo-prosencephaly, congenital heart defects, deafness, cleft lip and palate, and eye defects, such as microphthalmia, anophthalmia, and coloboma (Fig. 1.10). The incidence of this abnormality is approximately 1 in 20,000 live births, and over 90% of the infants die in the first month after birth.

Klinefelter Syndrome Birth Defects

klinefelter syndrome

The clinical features of Klinefelter syndrome, found only in males and usually detected at puberty, are sterility, testicular atrophy, hyalinization of the seminiferous tubules, and usually gynecomastia. The cells have 47 chromosomes with a sex chromosomal complement of the XXY type, and a sex chromatin body (Barr body: formed by condensation of an inactivated sex chromosome; a Barr body is also present in normal females) is found in 80% of cases (Fig. 1.11). The incidence is approximately 1 in 500 males. Nondisjunction of the XX homologues is the most common causative event. Occasionally, patients with Klinefelter syndrome have 48 chromosomes: 44 autosomes and four sex chromosomes (XXXY). Although mental retardation is not generally

Figure 1.11 Patient with Klinefelter syndrome showing normal phallus development but gynecomastia (enlarged breasts).

part of the syndrome, the more X chromosomes there are, the more likely there will be some degree of mental impairment.

turner syndrome

Turner syndrome, with a 45,X karyotype, is the only monosomy compatible with life. Even then, 98% of all fetuses with the syndrome are spontaneously aborted. The few that survive are unmistakably female in appearance (Fig. 1.12) and are characterized by the absence of ovaries (gonadal dysgen-esis) and short stature. Other common associated abnormalities are webbed neck, lymphedema of the extremities, skeletal deformities, and a broad chest with widely spaced nipples. Approximately 55% of affected women are mono-somic for the X and chromatin body negative because of nondisjunction. In 80% of these women, nondisjunction in the male gamete is the cause. In the remainder of women, structural abnormalities of the X chromosome or mitotic nondisjunction resulting in mosaicism are the cause.

Figure 1.12 Patient with Turner syndrome. The main characteristics are webbed neck, short stature, broad chest, and absence of sexual maturation.

triple x syndrome

Patients with triple X syndrome are infantite, with scanty menses and some degree of mental retardation. They have two sex chromatin bodies in their cells.

Structural Abnormalities

Structural chromosome abnormalities, which involve one or more chromosomes, usually result from chromosome breakage. Breaks are caused by environmental factors, such as viruses, radiation, and drugs. The result of breakage depends on what happens to the broken pieces. In some cases, the broken piece of a chromosome is lost, and the infant with partial deletion of a chromosome is abnormal. A well-known syndrome, caused by partial deletion of the short arm of chromosome 5, is the cri-du-chat syndrome. Such children have a catlike cry, microcephaly, mental retardation, and congenital heart disease. Many other relatively rare syndromes are known to result from a partial chromosome loss.

Microdeletions, spanning only a few contiguous genes, may result in microdeletion syndrome or contiguous gene syndrome. Sites where these deletions occur, called contiguous gene complexes, can be identified by high-resolution chromosome banding. An example of a microdeletion

Prader Willi Syndrome
Figure 1.13 Patient with Angelman syndrome resulting from a microdeletion on maternal chromosome 15. If the defect is inherited on the paternal chromosome, Prader-Willi syndrome occurs (Fig. 1.14).

occurs on the long arm of chromosome 15 (15q11-15q13). Inheriting the deletion on the maternal chromosome results in Angelman syndrome, and the children are mentally retarded, cannot speak, exhibit poor motor development, and are prone to unprovoked and prolonged periods of laughter (Fig. 1.13). If the defect is inherited on the paternal chromosome, Prader-Willi syndrome is produced; affected individuals are characterized by hypotonia, obesity, mental retardation, hypogonadism, and cryptorchidism (Fig. 1.14). Characteristics that are differentially expressed depending upon whether the genetic material is inherited from the mother or the father are examples of genomic imprinting. Other contiguous gene syndromes may be inherited from either parent, including Miller-Dieker syndrome (lissencephaly, developmental delay, seizures, and cardiac and facial abnormalities resulting from a deletion at 17p13) and most cases of velocardiofacial (Shprintzen) syndrome (palatal defects, conotruncal heart defects, speech delay, learning disorders, and schizophrenia-like disorder resulting from a deletion in 22q11).

Fragile sites are regions of chromosomes that demonstrate a propensity to separate or break under certain cell manipulations. For example, fragile sites can be revealed by culturing lymphocytes in folate-deficient medium. Although numerous fragile sites have been defined and consist of CGG repeats, only the site on the long arm of the X chromosome (Xq27) has been

Prader Willi Leukemia
Figure 1.14 Patientwith Prader-Willi syndrome resulting from a microdeletion on paternal chromosome 15. If the defect is inherited on the maternal chromosome, Angelman syndrome occurs (Fig. 1.13).

correlated with an altered phenotype and is called the fragile X syndrome. Fragile X syndrome is characterized by mental retardation, large ears, prominent jaw, and pale blue irides. Males are affected more often than females (1/1000 versus 1/2000), which may account for the preponderance of males among the mentally retarded. Fragile X syndrome is second only to Down syndrome as a cause of mental retardation because of chromosomal abnormalities.

Gene Mutations

Many congenital formations in humans are inherited, and some show a clear mendelian pattern of inheritance. Many birth defects are directly attributable to a change in the structure or function of a single gene, hence the name single gene mutation. This type of defect is estimated to account for approximately 8% of all human malformations.

With the exception of the X and Y chromosomes in the male, genes exist as pairs, or alleles, so that there are two doses for each genetic determinant, one from the mother and one from the father. If a mutant gene produces an abnormality in a single dose, despite the presence of a normal allele, it is a dominant mutation. If both alleles must be abnormal (double dose) or if the mutation is X-linked in the male, it is a recessive mutation. Gradations in the effects of mutant genes may be a result of modifying factors.

The application of molecular biological techniques has increased our knowledge of genes responsible for normal development. In turn, genetic analysis of human syndromes has shown that mutations in many of these same genes are responsible for some congenital abnormalities and childhood diseases. Thus, the link between key genes in development and their role in clinical syndromes is becoming clearer.

In addition to causing congenital malformations, mutations can result in inborn errors of metabolism. These diseases, among which phenylketonuria, homocystinuria, and galactosemia are the best known, are frequently accompanied by or cause various degrees of mental retardation.

Diagnostic Techniques for Identifying Genetic Abnormalities

Cytogenetic analysis is used to assess chromosome number and integrity. The technique requires dividing cells, which usually means establishing cell cultures that are arrested in metaphase by chemical treatment. Chromosomes are stained with Giemsa stain to reveal light and dark banding patterns (G-bands; Fig. 1.6) unique for each chromosome. Each band represents 5 to 10 x 106 base pairs of DNA, which may include a few to several hundred genes. Recently, high resolution metaphase banding techniques have been developed that demonstrate greater numbers of bands representing even smaller pieces of DNA, thereby facilitating diagnosis of small deletions.

New molecular techniques, such as fluorescence in situ hybridization (FISH), use specific DNA probes to identify ploidy for a few selected chromosomes. Fluorescent probes are hybridized to chromosomes or genetic loci using cells on a slide, and the results are visualized with a fluorescence microscope (Fig.1.15). Spectral karyotype analysis is a technique in which every chromosome is hybridized to a unique fluorescent probe of a different color. Results are then analyzed by a computer.

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  • gennaro
    What chromosome is damaged with galactosemia?
    8 years ago
  • Naomi
    8 years ago
  • tiina
    What chromosome is affected by galactosemia?
    8 years ago
  • lauchlan
    Does praderwilli syndrome occur in mitosis or meiosis?
    8 years ago
  • agata genovese
    What chromosomes does galactosemia effects?
    8 years ago
  • Sara
    What chromosome is galactosemia found on?
    8 years ago
  • edward
    What does Klinefelter's syndrome affect?
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  • lily
    What is the diploid chromosome number for a karyotype with klinefelter's syndrome?
    8 years ago
  • reagan henderson
    What does it mean when the fetus chromosomes 13 and 14 are attached together?
    8 years ago
  • arthur
    Can klinefelter's syndrome be detected before birth?
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  • wolfgang
    How may spermatozoa form from a primary spermatocyte?
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  • saradoc
    What is prader willi syndrome?
    8 years ago
  • ayla
    Is galactosemia nondisjunction?
    7 years ago
  • lilly
    Is galactosemia involve nondisjunction?
    5 years ago
  • yolanda
    What are clinical correlates of meiosis?
    4 years ago
  • antonia
    What is the clinical correlate of meiosis?
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  • wilma
    What are the clinical correlates of mitosis and meiosis?
    4 years ago
  • Robert Busch
    What is the clinical correlation of mitosis and mieosis?
    3 years ago
    What is the clinical correlation in meiosis and mitosis?
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