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Failure of development of a primitive organ anlage in the embryo results in agenesis—complete absence of the organ. Agenesis of a vital organ such as the heart or brain leads to death of the fetus in utero. If the tissue is not vital or is one of a pair of organs, such as a kidney, the remainder of the embryo may develop normally.
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Abnormal differentiation of the anlage leads to a structurally abnormal organ. For example, in renal dysgenesis, a mass of tissue composed of abnormal epithelium-lined cysts and mesenchymal tissues such as cartilage is found instead of a normal kidney (Figure 15-2). Dysgenesis sometimes affects only part of an organ.
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Hypoplasia and Aplasia
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When the anlage differentiates normally but growth or development ends prematurely, a structurally normal but small organ results (hypoplasia). In aplasia, the organ is completely absent. Aplasia can be distinguished from agenesis only if an undeveloped anlage or its vascular connections can be identified. In agenesis, there is no anlage or vascular pedicle.
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Causes of Fetal Abnormalities
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In most instances, the exact cause of fetal abnormalities is unknown. Known causes fall into two major groups: those affecting the genome and those acting mainly on the proliferating cells of the embryo or fetus. Almost any cause of injury to a child or adult (Table 15-1) may also act on the fetus. Although the fetus is in a sheltered environment, it is particularly susceptible to injury during times of rapid cell multiplication and primary differentiation of organs. In addition, normal growth of the fetus is critically dependent upon normal expression of genetic information and the integrity of the placenta and maternal blood flow. The most severe fetal abnormality is death, termed spontaneous abortion in the first 14 weeks and intrauterine death thereafter.
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Fetal Abnormalities Caused by Genetic Disorders
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The term mutation is used broadly to denote any stable heritable genetic change, whether or not it is associated with detectable structural abnormalities of the chromosomes.
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Peripheral blood lymphocytes or skin fibroblasts are induced to divide and then arrested in metaphase with colchicine. The individual chromosomes, which become separated at metaphase, can then be identified by special staining techniques (banding with Giemsa stain or fluorescent dyes). The arrangement of an individual's chromosomes in the proper sequence is known as the karyotype (Figure 15-3). Cytogenetic methods can only detect changes in chromosomal number or major structural changes (chromosomal aberrations) that are sufficiently large to be seen by banding techniques (Figure 15-3; see also Figure 15-9). Such visible changes involve at least 1 million base pairs and may affect multiple genes. The clinical effects of such changes are therefore usually severe.
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This term embraces a number of related methods that incorporate recombinant deoxyribonucleic acid (DNA) technology and are able to detect a mutation (substitution or deletion) of even a single base pair. The classic approach commences with isolation of the gene product, followed by determination of the amino acid sequence and hence the messenger ribonucleic acid (mRNA), following which the gene is cloned and its chromosomal location identified. In the reverse approach, a disease locus (abnormal gene) is identified by mapping its location in relation to known marker genes (such as blood groups or various enzymes) through family linkage studies. Synthetic DNA probes can then be prepared. Under suitable conditions, these will bind with complementary DNA sequences on the chromosomes and can be visualized by labeling techniques (in situ hybridization, using radiographic, fluorescent, or enzymatic labels). Suitably configured probes permit visualization of whole chromosomes by targeting multiple repeat sequences (chromosome painting), or translocations, or even mutations involving a single nucleotide change following amplification of the region of interest by the polymerase chain reaction (PCR). An alternative simpler method of detecting mutations involves cutting the chromosomes into numerous fragments by the use of restriction enzymes. The resulting DNA fragments can then be displayed on a Southern blot. Changes in nucleotide sequence yield differently sized fragments (restriction fragment length polymorphism [RFLP]).
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Chromosomal Aberrations
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Normal Chromosomal Complement
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The normal human cell has 46 chromosomes: 22 pairs of autosomes and two sex chromosomes (Figure 15-3). One of each of these homologous pairs of chromosomes is derived from each parent.
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The autosomes are divided into seven groups (A–G) on the basis of the size and position of the centromeres (Figure 15-3).
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The sex chromosomes are a pair of X chromosomes in the female and an X and a Y chromosome in the male. The genetic sex of an individual may be ascertained by examination of the karyotype, which is very accurate, or by examination of cells for the presence of a Barr body. When two X chromosomes are present in a cell, as in a normal female, one of them—the Barr body—becomes inactivated and condensed on the nuclear membrane. Absence of Barr bodies indicates that the cell has only one X chromosome (normal male: XY; Turner syndrome: XO). Barr bodies are most easily seen in a smear of squamous epithelial cells obtained by scraping the buccal mucosa. The Y chromosome can be identified in interphase nuclei by its strong fluorescence in ultraviolet light after it has been stained with quinacrine, and this is another means of establishing genetic sex.
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Mechanisms of Chromosomal Aberrations
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Nondisjunction in Meiosis
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Nondisjunction is failure of paired homologous chromosomes to separate during the first meiotic division that leads to the production of gametes (ova and spermatozoa) (Figure 15-4). Thus, some gametes receive two and others receive none of the involved chromosome pair. After the second meiotic division, the resulting gametes will have 24 and 22 chromosomes. Such gametes are aneuploid (ie, the number of their chromosomes is not an exact multiple of 23, the haploid chromosome number for humans).
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Union of an aneuploid gamete with a normal gamete leads to an aneuploid zygote that has either three of the involved chromosomes (trisomy) or only one (monosomy) (Figure 15-5).
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Trisomy and monosomy involving the sex chromosomes are generally compatible with life, eg, Klinefelter syndrome (XXY) and Turner syndrome (XO). Autosomal monosomy, on the other hand, is associated with a profound loss of genetic material and is usually lethal. A few autosomal trisomies (21, 13, and 18) may be compatible with survival but are associated with severe abnormalities.
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Nondisjunction in Mitosis
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Nondisjunction of the early zygote during mitotic division produces mosaicism: the presence in an individual of two or more genetically different cell populations (Figure 15-5). In this type of nondisjunction (which may also occur during the second meiotic division), the two chromatids of a duplicated chromosome fail to divide. Mosaic individuals manifest phenotypic abnormalities that are intermediate between those associated with the two cell populations; eg, 45,X/46,XX is a Turner syndrome mosaic karyotype, and the individual's appearance will be somewhere between that of a normal female and those of an individual with classic Turner syndrome (45,XO).
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Deletion is loss of part of a chromosome after chromosomal breakage. Most deletions are lethal because a great deal of genetic material is lost. Deletions of the short arms of chromosomes 4 and 5 produce well-defined clinical syndromes (Wolf's syndrome and cri du chat syndrome, respectively). Partial deletions are common in malignant neoplastic cells (Chapters 18: Neoplasia: II. Mechanisms & Causes of Neoplasia and Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms).
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Translocation is the transfer of a broken segment of one chromosome to another chromosome. In balanced translocations, all genetic material is present and functional, and the individual is phenotypically normal.
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The most common balanced translocation is transfer of the entire 21 chromosome to chromosome 14. Such an individual has 45 chromosomes, with absence of one each of chromosomes 14 and 21 and the presence of an abnormal, large chromosome containing the material of both chromosomes 14 and 21; assuming the patient is male, the karyotypic designation is 45,XY,t(14;21). The gametes produced by such an individual may be abnormal (Figure 15-6); offspring with monosomy 21 (incompatible with life) and translocation-type Down syndrome may result.
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Other balanced translocations are being recognized as an important cause of habitual or repeated abortion. Still others occur in malignant tumors (Table 19-2). The Philadelphia chromosome (t[9;22]) in chronic granulocytic leukemia is the best-known example (Figure 19-3).
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Other Chromosomal Rearrangements
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Inversion and ring chromosome formation may occur after breakage or abnormal division of the centromere.
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In addition, single changes (additions or deletions) in the composition of DNA bases result in misreading of the triplet code but cause no detectable structural changes in the chromosomes. These abnormalities constitute single gene disorders and are considered in a later section.
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Note that an abnormality present in the germ line (gamete) will affect all of the cells of the body. This is typical of the major inherited disorders that will be described here and occurs also in some inherited tumors (eg, loss of a tumor suppressor gene in retinoblastoma; see Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia).
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Genetic abnormalities that occur in other types of cancer are much more restricted in terms of the cells affected. These are discussed in Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia.
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Causes of Chromosomal Aberrations
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Most chromosomal defects occur at random without known cause, but in some cases a cause can be identified.
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Increasing Maternal Age
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Nondisjunction is associated with increasing maternal age, as is clearly shown in trisomy 21 (Down syndrome). The risk of trisomy 21, which is 1:1500 live births in women under 30 years of age, increases to 1:30 for women over 45 years of age. For this reason, routine chromosomal analysis of fetal cells obtained by amniocentesis is recommended for pregnancies occurring in women older than age 35 years. Increasing maternal age is also associated with other nondisjunction syndromes, eg, Klinefelter syndrome.
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The incidence of chromosomal abnormalities is high in the survivors of the Nagasaki and Hiroshima atomic blasts. A safe low dose of ionizing radiation has not been established. Diagnostic abdominal x-rays should be avoided whenever possible in women who are pregnant or suspect they may be.
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Drugs and other chemical agents are an uncommon cause of structural chromosomal abnormalities. When used in early pregnancy, anticancer agents that interfere with DNA synthesis may cause chromosomal abnormalities that lead to fetal death. Many commonly used drugs, including aspirin, have been shown to cause karyotypic abnormalities in tissue culture; whether these drugs have this effect in vivo is unknown.
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Common Autosomal Abnormalities
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Down Syndrome (Trisomy 21)
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Down syndrome is the most common autosomal disorder (1:700 live births overall). It results from the presence of three chromosome 21s, producing a characteristic clinical appearance (Figure 15-7). The infant has oblique palpebral fissures with a flat profile, upward-slanting eyes, and prominent epicanthal folds (a purported resemblance to Asian facial features, accounting for the older term mongolism). Severe mental retardation is a constant feature. Thirty percent of patients have congenital heart anomalies, most commonly ventricular septal defect. These children also have an increased susceptibility to infections, duodenal ulcers, and acute leukemia. Patients surviving into adulthood (50% or more) frequently develop presenile dementia with features of Alzheimer's disease. Beta amyloid protein is deposited in the lesions; interestingly, the beta amyloid gene is on chromosome 21.
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Men with Down syndrome are generally infertile; women with the disease have borne children. The offspring of mothers with Down syndrome may be normal because the extra 21 chromosome is not transmitted to all gametes.
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Three types of Down syndrome are recognized:
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Nondisjunction Down Syndrome
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Most cases (95%) of Down syndrome are due to this mechanism. These cases are associated with increasing maternal age (over age 35 years). The child has an extra 21 chromosome (47,XX,+21 or 47,XY,+21); the parents have normal karyotypes.
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Translocation Down Syndrome
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A few cases of Down syndrome (5%) are due to inheritance of a balanced translocation from one of the parents—commonly a 14,21 translocation (Figure 15-6), more rarely a 21,22 translocation. One parent carries the abnormal chromosome. The infant with Down syndrome has 46 chromosomes, one of which has the genetic material of both chromosomes 14 and 21. Translocation Down syndrome is not associated with increased maternal age but is familial.
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In this very rare type of Down syndrome, nondisjunction occurs during an early mitotic division in the developing embryo. Only one of two cell lines in the body shows trisomy for chromosome 21.
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Edwards' Syndrome (Trisomy 18)
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Trisomy 18 (47,XX/XY,+18) is rare. It produces severe defects, and few children survive beyond 1 year of age. Clinically, failure to thrive and severe mental retardation are accompanied by characteristic physical abnormalities such as rocker-bottom feet and clenched hands with overlapping fingers.
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Patau's Syndrome (Trisomy 13)
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Trisomy 13 (47,XX/XY,+13) is also rare. Most affected infants die soon after birth. Trisomy 13 is characterized by abnormal development of the forebrain (absent olfactory bulbs, fused frontal lobes, single ventricle) and midline facial structures (cleft lip, cleft palate, nasal defects, single central eye [cyclops]).
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Cri Du Chat (Cat Cry) Syndrome
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This disorder is caused by deletion of the short arm of chromosome 5. A mewing, cat-like cry is typical. Severe mental retardation and cardiac anomalies are common. Survival rates are slightly higher than those of patients with trisomy 18 or 13.
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Microdeletions of 13q14 (retinoblastoma gene) or 11p13 (Wilms tumor gene) are associated with a high incidence of specific childhood tumors (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia). Other genes are also often deleted, leading to mental retardation and other changes in these patients.
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Acquired Chromosomal Abnormalities
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These occur quite commonly as somatic mutations in children and adults and are associated with a variety of neoplasms (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia). The germ cells are usually not involved, and these anomalies are therefore not heritable.
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Common Sex Chromosomal Abnormalities
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Klinefelter Syndrome (Testicular Dysgenesis)
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Klinefelter syndrome is common, with an incidence of 1:600 live male births. It is usually caused by nondisjunction of the X chromosome in the mother of the affected male child, resulting in an extra X chromosome (47,XXY) (Figures 15-8 and 15-9). More rarely, patients with Klinefelter syndrome have more than two X chromosomes (48,XXXY or 49,XXXXY).
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The Y chromosome dictates testicular differentiation of the primitive gonad that results in a male phenotype. No abnormality is usually noted until puberty. The extra X chromosome interferes with normal development of the testis at puberty in some unknown manner. The testes remain small and typically do not produce spermatozoa (Figure 15-10). Patients are usually infertile. Testosterone levels are low, leading to failure of normal development of male secondary sexual characteristics. Patients tend to be tall (testosterone induces fusion of epiphyses) and of eunuchoid habitus with a high-pitched voice, small penis, and female distribution of hair (Figure 15-11). Gynecomastia (enlargement of breasts) may occur. Intelligence may be affected in a minority of cases.
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The diagnosis of Klinefelter syndrome may be made by finding Barr bodies in a buccal scraping of a phenotypic male or by performing karyotypic analysis (Figure 15-9).
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Turner Syndrome (Ovarian Dysgenesis)
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Turner syndrome occurs in 1:2500 live female births. It is caused by nondisjunction of the X chromosome in either parent of an affected female, leading to absence of one X chromosome (45,XO; Figure 15-8). About half of patients with Turner syndrome show mosaicism (45,X/46,XX) owing to nondisjunction occurring in a postzygotic mitotic division. In a minority of cases, the second X chromosome is present but is grossly abnormal (isochromosome, partial deletion, etc).
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Loss of the second X chromosome frequently causes fetal death, and many affected fetuses are aborted. Liveborn infants show lymphedema of the neck that persists into adulthood as a characteristic webbing of the neck (Figure 15-12). Congenital cardiac anomalies (most commonly coarctation of the aorta), short stature, obesity, and skeletal abnormalities (most typically an increase in the carrying angle of the forearm) are common. Intelligence is usually not affected.
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In the presence of one X chromosome (and no Y chromosome), the primitive gonad develops as an ovary; the baby is phenotypically female but fails to develop at puberty. The absence of the second X chromosome causes failure of ovarian development at puberty. The ovaries remain small and lack primordial follicles (streak ovaries). Failure of estrogen secretion causes failure of the endometrial cycle (amenorrhea) and poor development of female secondary sex characteristics.
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The diagnosis may be established by absence of Barr bodies in the buccal smear of a female and by karyotypic analysis.
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XXX Syndrome (Superfemale)
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The presence of a third X chromosome in a female causes the triple X disorder. Most patients are normal. A few show mental retardation, menstrual problems, and decreased fertility.
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The presence of an extra Y chromosome in a male causes XYY syndrome. Most patients appear normal. A minority may show aggressive behavior and mild mental retardation. The incidence is 1:1000 male births.
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This syndrome is associated with mental retardation in 80% of males who carry the abnormal chromosome but only 30% of females (perhaps due to preferential inactivation of the abnormal X chromosome). The abnormality consists of an unusually large number of repeat nucleotide triplets close to the tip of the long arm of the X chromosome (Xq27). Growth abnormalities may occur in addition to severe retardation. The frequency may be as high as 1:1000 in males and 1:2000 in females (see Table 15-4).
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Single-Gene (Mendelian) Disorders
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Dominant and Recessive Disorders
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Diseases caused by a single abnormal gene are inherited in a manner predicted by mendelian laws. The pattern of inheritance depends on whether the abnormal gene is on a sex chromosome or an autosome and whether it is dominant or recessive.
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If a gene has two alleles (alternative forms of the gene) A and a, three genotypes (AA, Aa, and aa) are possible. In homozygous genotypes (AA and aa) the two alleles are identical. In heterozygous genotypes (Aa), the alleles are different. The terms dominant and recessive denote the degree of expression of an allele. The mode of inheritance is dominant if only one abnormal allele is required for phenotypic expression of the disease (genotypes Aa, AA; Figure 15-13). A recessive trait, on the other hand, requires the presence of two abnormal alleles for expression of disease (genotype aa; Figure 15-14).
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Analysis of the family history (pedigree) of an individual affected with a single-gene disease (proband; propositus or index case) is helpful in establishing the inheritance pattern of the disease.
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If the A allele is abnormal, the disease is expressed in both the AA and the Aa genotypes (Figure 15-13). In diseases with dominant inheritance patterns, patients with the aa genotype are normal.
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Recessive Inheritance
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If the a allele is abnormal, however, the disease will occur only in the aa genotype (Figure 15-14). The person who is an Aa heterozygote for a recessive trait carries the abnormal gene but does not express the disease (heterozygous carrier of the trait). If the gene products of both the A and the a alleles can be detected in the Aa heterozygote, the disease is said to have a codominant mode of inheritance (ie, both alleles are expressed).
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Autosomal Dominant Diseases
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(Table 15-2.) Diseases with an autosomal dominant mode of inheritance have a characteristic family history (Figure 15-13; Table 15-3).
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Many autosomal dominant diseases permit survival to adulthood. Transmission of the abnormal gene to the next generation only occurs following reproduction by affected individuals. Sporadic (nonfamilial) cases occur with varying frequency due to new mutations.
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A characteristic of many autosomal dominant disorders is the variation in frequency with which the abnormal gene is manifested clinically as a disease (penetrance) and the degree of abnormality seen in different individuals (expressivity).
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Autosomal Recessive Diseases
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(Table 15-2.) Diseases with an autosomal recessive mode of inheritance also have a characteristic family history (Figure 15-14; Table 15-3).
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Most autosomal recessive disorders are characterized by enzyme deficiency leading to biochemical defects that have come to be called inborn errors of metabolism. In the heterozygote (carrier), the level of a critical enzyme or other normal protein may be reduced, but not to the level where disease occurs (one gene still functions). In the homozygote, disease results from lack of a critical protein (eg, hemoglobin A in thalassemia), presence of an abnormal product (eg, sickle-cell hemoglobin (HbS) in sickle cell anemia), or accumulation of toxic metabolites in an enzymatic pathway due to absence of a critical enzyme (eg, the storage diseases). These disorders are often fatal in early life, although with treatment some patients survive to adulthood, eg, people with phenylketonuria can lead normal lives if phenylalanine is abolished from the diet.
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Autosomal recessive traits are rare, and there is little chance of encountering the gene in an asymptomatic carrier in the general population. Many autosomal recessive diseases occur with greatest frequency in societies that discourage interracial mating. Tay-Sachs disease, for example, is virtually restricted to those of Ashkenazic Jewish ancestry. Very rare autosomal recessive diseases tend to occur in offspring of consanguineous matings when the parents have a common ancestor who carried the abnormal gene.
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Sex Chromosome-Linked Diseases
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(Table 15-4.) All sex chromosome-linked diseases are linked to the X chromosome and are characterized by an unequal incidence of the disease in the two sexes, in contrast to diseases linked to autosomes.
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X-linked recessive diseases are common. The abnormal gene is usually expressed only in the male, who has only one X chromosome (Figure 15-15). X-linked recessive disorders are transmitted by asymptomatic female heterozygous carriers of the abnormal gene. On average, half of the male offspring of a mating between a carrier female and a normal male will manifest the disease. If an affected male mates with a normal female, all of the daughters will be carriers and the sons will be unaffected. If an affected male mates with a heterozygous carrier female, half of the sons and half of the daughters (homozygotes) on average will be affected. X-linked recessive diseases are often severe and commonly cause death early in life. Modern treatment, such as is available for hemophilia, has permitted survival of affected individuals to adult reproductive life.
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X-linked dominant diseases are uncommon. Pseudohypoparathyroidism and hypophosphatemic rickets are the main examples. Because females have two X chromosomes, X-linked dominant diseases are more common in females.
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Inborn Errors of Metabolism
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These diseases are caused by an inherited single-gene abnormality that causes failure of synthesis of an enzyme and a subsequent block in a metabolic pathway. Enzyme deficiency results in abnormal amino acid, lipid, carbohydrate, or mucopolysaccharide metabolism with accumulation of the substrate and deficiency of the product of the enzymatic reaction. Cell damage may result from either mechanism. These diseases are all rare. As noted above (Table 15-2), most have an autosomal recessive mode of inheritance; a few are X-linked recessive diseases.
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Abnormal Amino Acid Metabolism
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The inherited diseases associated with deficiency of enzymes involved in phenylalanine and tyrosine metabolism are good examples of inborn errors of metabolism (Figure 15-16). In phenylketonuria, the absence of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine. This produces a tyrosine deficiency in the cell (with deficient melanin production and lack of pigmentation), as well as accumulation of phenylalanine, which is toxic to nerve cells (producing mental retardation). Phenylketonuria is an example of a biochemical abnormality that produces no specific morphologic change in affected cells. Diagnosis is made by detection of high levels of phenylalanine in the urine or serum. Treatment consists of removal of phenylalanine from the diet.
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Abnormal Lipid Metabolism (Lipid Storage Diseases)
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The enzyme deficiencies listed in Table 15-6 all involve closely related pathways in the metabolism of sphingolipids. These deficiencies cause metabolic blocks that lead to accumulation of abnormal amounts of complex lipids in cells. Most of these enzymes are lysosomal, and abnormal lipid storage occurs within secondary lysosomes—hence the term lysosomal storage diseases. Except for Fabry's disease, which has an X-linked recessive inheritance pattern, these diseases are autosomal recessive in inheritance.
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Storage of lipid occurs in different cells in the various diseases. Involvement of parenchymal cells causes degeneration and necrosis of these cells. When neurons are involved, as in Tay-Sachs disease and the infantile forms of Gaucher's disease and Niemann-Pick disease, severe mental retardation and death occur. Kidney failure occurs with renal involvement in Fabry's disease. In the milder adult forms of Gaucher's disease and Niemann-Pick disease, accumulation of lipid occurs in reticuloendothelial cells, producing enlargement of liver and spleen.
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The diagnosis can be made in several ways.
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In Tay-Sachs disease, lipid deposition in the macula of the retina produces a cherry-red spot visible on ophthalmoscopy. Diffuse skin lesions occur in Fabry's disease. Hepatosplenomegaly occurs in Gaucher's disease.
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Microscopic Examination
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Light microscopic examination of affected tissues such as brain, bone marrow, liver, and spleen (Figure 15-17) permits identification of the abnormal, lipid-distended cells. The affected cells in Tay-Sachs and Niemann-Pick disease have foamy cytoplasm. Gaucher's cells have a characteristic fibrillary (crinkled paper) cytoplasm.
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Characteristic inclusions in the greatly distended lysosomes are demonstrated on electron microscopy. In Tay-Sachs disease, these are whorled; in Niemann-Pick disease, they appear as parallel lamellas (zebra bodies); and in Gaucher's disease the stored lipid is arranged in linear stacks.
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Demonstration of the Enzyme Deficiency
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The definitive diagnostic test is demonstration of the enzyme deficiency in cultured skin fibro-blasts.
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Prevention and Treatment
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Lipid storage diseases have no treatment. Prevention is achieved by genetic counseling.
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Heterozygous carriers of Tay-Sachs disease can be identified by serum enzyme assay. Screening of high-risk populations such as Ashkenazi Jews, with a carrier rate of 1:30 for the abnormal Tay-Sachs gene, enables identification of heterozygous carriers.
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In high-risk pregnancies, amniocentesis permits identification of affected fetuses by demonstrating the enzyme deficiency in fetal fibroblasts.
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Abnormal Glycogen Metabolism (Glycogen Storage Disease)
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(Table 15-7.) Glycogen storage diseases are caused by deficiency of an enzyme involved in the metabolism of glycogen. Most of these diseases have an autosomal recessive mode of inheritance, with onset of disease in infancy or childhood. Interference with glycogen metabolism produces a variety of effects.
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Accumulation of Glycogen
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Glycogen accumulates in the cytoplasm and appears as granules that can be recognized on electron microscopy. In routinely fixed tissues, glycogen is dissolved by the aqueous formalin fixative; affected cells in routine slides appear distended and empty on examination by light microscopy (Figure 15-18). Demonstration of glycogen in cells requires fixation in alcohol and staining with Best's carmine or periodic acid-Schiff (PAS) reagent.
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Dysfunction of Involved Cells
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Hepatic involvement causes hepatomegaly, fibrosis, and liver failure; myocardial involvement causes heart failure.
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Abnormal Glucose Delivery
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With liver involvement (eg, type I), hypoglycemia occurs because breakdown of liver glycogen is the main source of blood glucose. With skeletal muscle involvement, lack of glucose in the cell causes muscle cramps and weakness.
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Abnormal Mucopolysaccharide Metabolism (Mucopolysaccharidoses)
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(Table 15-8.) The mucopolysaccharidoses are rare inherited lysosomal storage diseases in which deficiency of a lysosomal enzyme leads to the accumulation of mucopolysaccharides (glycosaminoglycans) in lysosomes in a variety of cells. All have an autosomal recessive pattern of inheritance except Hunter's syndrome, which is an X-linked recessive disease.
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Accumulation of glycosaminoglycans in cells results in great enlargement of affected cells. Involvement of macrophages and endothelial cells leads to hepatosplenomegaly and deformities due to changes in skin and bones. Grotesque facial deformities occur (gargoylism is the alternative name for Hurler's syndrome). Affected cells are distended and, in routine preparations, demonstrate clear cytoplasm (balloon cells). Peripheral blood cells show glycosaminoglycan deposits as large purple cytoplasmic granules (Alder-Reilly bodies).
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Dysfunction of affected parenchymal cells also occurs. Degeneration of involved neurons causes mental retardation; myocardial involvement causes heart failure.
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Detection of Heterozygous Carrier State in Recessive Traits
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Heterozygous carriers of a recessive trait, whether autosomal or X-linked, do not show evidence of clinical disease. In many disorders, however, biochemical abnormalities are present, permitting detection of the carrier state, which in turn makes possible genetic counseling and early diagnosis of affected offspring.
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Hemophilia A is a good example of how heterozygous carriers are detected. Patients with hemophilia have low levels of factor VIII in the plasma. Female heterozygous carriers have plasma levels of factor VIII that fall between those of normal individuals and hemophiliac patients. The ratio between factor VIII clotting activity (low in hemophilia A) and factor VIII-related antigen (normal in hemophilia A) permits detection of over 90% of heterozygous carriers (see Chapter 27: Blood: IV. Bleeding Disorders).
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Carrier detection is now possible in a large number of autosomal recessive diseases. Screening of populations for carriers is cost-effective only in families known to have the abnormal gene and in ethnic groups with a high incidence of the disease, eg, Tay-Sachs disease in individuals of Ashkenazi Jewish ancestry.
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Polygenic (Multifactorial) Inheritance
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Familial diseases such as atherosclerosis, high blood pressure, and diabetes mellitus are believed to be due at least in part to the presence of several abnormal genes. In atherosclerosis, two or more of the genes causing the different hyperlipidoses may interact to predispose to the disease (Chapter 20: The Blood Vessels). It is thought that this inherited predisposition for development of disease has an additive effect on environmental factors. A number of congenital disorders also show a familial but not strictly mendelian pattern. These include anencephaly, cleft palate, and Hirschsprung's disease.
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Fetal Abnormalities Caused by External Agents (Teratogens)
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Congenital anomalies (Table 15-9) due to abnormal development of the fetus affect about 2% of newborns and represent an important cause of neonatal morbidity and death. Most anomalies have no detectable chromosomal abnormality and are not inherited. Although a few teratogenic (monster-producing) agents have been identified, the cause of most congenital anomalies is unknown.
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In addition to its action on DNA and the genetic apparatus of the cell, ionizing radiation has direct toxic effects on other components of the developing fetus, and various congenital anomalies have been reported following irradiation during pregnancy. Because it is not known whether there is a safe low dose of radiation during pregnancy, abdominal x-rays should be avoided except when essential for diagnosis of diseases threatening the life of the mother or fetus.
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Teratogenic Viral Infections
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Rubella is the best-recognized teratogenic virus, ie, one that causes developmental defects. Transplacental infection of the fetus by the virus during the first trimester of pregnancy, when the fetal organs are developing, is associated with a high incidence of congenital anomalies. The risk is greatest (about 70%) in the first 8 weeks of pregnancy. Rubella virus interferes with protein synthesis in tissue culture. Rubella syndrome denotes the triad of congenital heart disease, deafness, and cataracts that is common in affected infants. Many other anomalies, including microcephaly, mental retardation, and microphthalmia, have been reported. The risk of rubella infection of fetuses has decreased dramatically since the introduction of rubella antibody testing and immunization.
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The teratogenic effect of other viral infections in early pregnancy is uncertain. Congenital anomalies have been reported following many infections, including influenza, mumps, and varicella, but whether this is incidental or represents a teratogenic effect of these viruses is unknown.
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As with irradiation, the use of drugs of any sort during pregnancy should be discouraged except to save the life of the mother or when the benefits outweigh the risk to the fetus. No drug can be considered totally safe, especially during early pregnancy, and well-established drugs are preferred to newer ones. Although all drugs approved for use in the United States have undergone rigorous testing in pregnant animals, their safety in humans can be established only after many years of use. The significant congenital damage associated with use of thalidomide and diethylstilbestrol (now both discontinued) exemplify the risks of using newly approved drugs during pregnancy.
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Thalidomide is a mild sedative that was commonly used in Europe in the 1960s until it was shown by epidemiologic evidence to cause a distinctive fetal anomaly (phocomelia) when used in pregnancy. Failure of development of the limbs resulted in hands and feet that resemble the flippers of seals—short stumps closely attached to the trunk.
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Diethylstilbestrol (DES)
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Diethylstilbestrol is a synthetic estrogen used extensively between 1950 and 1960 to treat threatened abortion (miscarriage). Female offspring of women who took DES in pregnancy develop epithelial abnormalities of the vagina, including collections of mucous glands (vaginal adenosis) and, more seriously, clear cell adenocarcinoma.
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Exposure of the fetus to alcohol during organogenesis in early pregnancy leads to congenital abnormalities, the extent of which correlates with the amount of alcohol consumed by the mother, who may not even know she is pregnant. Fetal alcohol syndrome occurs in one of every 1000 live births in the United States and in 30–50% of infants born to women who consume over 125 g of alcohol (about 450 mL of whisky) per day. Fetal alcohol syndrome is characterized by growth retardation, a characteristic abnormal facial appearance (short palpebral fissures, epicanthal folds, micrognathia, a thin upper lip), cardiac defects (commonly septal defects), vertebral anomalies (including spina bifida), and mental retardation with microcephaly and brain malformation.
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Heavy smoking during pregnancy is associated with fetal growth retardation. To date, no teratogenic effects have been reported.
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Normal Postnatal Development
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The organs of the body vary considerably in degree of development and maturity at birth.
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Most tissues (eg, skeletal muscle, bone, skin, gastrointestinal tract, endocrine glands) are fully developed and functional at birth and show growth during childhood. Liver and kidney are immature but sufficiently developed to function adequately after delivery, although many newborn infants develop transient mild jaundice as a result of immaturity of liver enzyme systems.
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The lungs mature late in fetal life and are immature in premature infants—especially those born before 34 weeks of gestation. Maturity of the lungs is critical for survival in premature infants. Lung maturity of the fetus may be assessed by estimating the lecithin, sphingomyelin, and phosphatidylglycerol levels in amniotic fluid (eg, lipids associated with surfactant). As the lung matures—normally after 34 weeks—lecithin and phosphatidylglycerol appear in increasing amounts in amniotic fluid. Problems related to lung immaturity are very uncommon if the amniotic fluid lecithin:sphingomyelin ratio is over 2:1 or when significant amounts of phosphatidylglycerol are present.
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The brain shows rapid growth and development after delivery, reaching full size and development in early childhood. Brain development after birth includes migration of primitive neuroectodermal cells and myelination in the central nervous system.
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Lymphoid tissues show maximal growth during childhood, after which involution occurs.
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Genital tissues (gonads, reproductive organs, and secondary sexual characteristics) reach full maturity during puberty.
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Diseases of Infancy & Childhood
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Postnatal growth and development may be interrupted by many disease processes. The frequency and nature of these diseases vary greatly during the different age groups recognized by physicians and statisticians (Table 15-10). Of the 10 leading causes of death in American infants (children under 1 year of age), 7 are complications of pregnancy, labor, or neonatal period (ie, the first 4 weeks of life). By far the most common cause of death for this age group is congenital anomalies. Overall, infant mortality rates are regarded as an indicator of the quality of medical care. Infant death rates are much higher in developing countries, and a significantly higher proportion of these deaths is due to infectious disease, malnutrition, and other largely preventable factors.
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After the first year of life, the major causes of death change (Table 15-10). Infectious disease becomes more prominent: acquired immune deficiency syndrome (AIDS) was not recognized until 1981, but within a decade it had become one of the leading causes of death in American children. (AIDS is discussed in Chapter 7: Deficiencies of the Host Response and infectious diseases as a group in Chapters 13 and 14.) Benign and malignant neoplasms also become increasingly frequent causes of death in older children. For public-health officials, some of the most important information in Table 15-10 does not pertain to disease. For children aged 5 years and older, at least 2 of the top 4 causes of death are due to unintentional injury or violence (homicide or suicide). The leading cause of death for all American children older than 1 years in unintentional injury.
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Disorders Associated with Low Birth Weight
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The average American infant born at term (ie, between 38 and 42 weeks of gestation) weighs 2500–3999 g. Any infant with a birth weight of less than 2500 g is considered a low-birth-weight newborn. Term newborns who weigh less than 2500 g are considered small-for-gestational-age. Infants born prematurely are often low-birth-weight newborns. Factors other than prematurity that may compromise birth weight may be fetal, placental, or maternal in origin. Fetal factors include congenital anomalies and fetal infections. Placental insufficiency may be due to placental problems such as vascular lesions or infection. Placental insufficiency may also be due to numerous maternal factors—hypertension, cigarette smoking, narcotic and cocaine abuse, or alcohol abuse.
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Disorders associated with low birth weight are generally the result of nutritional deprivation in utero (eg, placental insufficiency) or immaturity of organs. Such disorders are most common in infants born before 34 weeks of gestation. The risks increase as birth weight decreases and as gestational age decreases. Mortality and long-term outcome correlate with Apgar score. Apgar testing is performed at 1 and 5 minutes after delivery, and it assesses five key physiologic parameters (heart rate, respiratory effort, muscle tone, skin color, and reflex irritability). A low Apgar score (≤ 3) at 5 minutes suggests severe depression and correlates with a poor prognosis if the infant survives.
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Respiratory Distress Syndrome (RDS)
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Despite significant gains in the medical care of premature and low-birth-weight infants, RDS remains a leading cause of death in infants (Table 15-10). It most commonly affects infants under 34 weeks of gestational age and is caused by immaturity of type II pneumocytes, which fail to secrete adequate surfactant. Surfactant is a surface tension-reducing agent that performs the vital function of keeping alveoli expanded. Deficiency of surfactant causes alveolar collapse in the first hour after delivery following reasonably normal initial expansion of the lung, because the alveoli cannot remain expanded without the surface tension-reducing factor. Progressive respiratory distress, hypoxemia, and cyanosis occur. Alveolar collapse is associated with hypoxic necrosis of alveolar epithelium and exudation of protein-rich fluid into dilated alveolar ducts. This fluid forms eosinophilic hyaline membranes—a microscopic hallmark of the disease (see Chapter 34: The Lung: I. Structure & Function; Infections). RDS was once called hyaline membrane disease.
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Treatment with artificial ventilation and oxygen has improved survival in RDS, but the overall mortality rate remains around 30%. Prolonged high-concentration oxygen therapy must be used with extreme caution because it is toxic to the lung (permanent interstitial fibrosis) and eyes (retrolental fibroplasia and blindness).
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Intraventricular Hemorrhage
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Intraventricular hemorrhage may occur in preterm infants with or without RDS. Hemorrhage begins in the periventricular region of the cerebral hemispheres and extends into the ventricular cavity. The cause of hemorrhage is unknown, but immaturity of the brain, poor support of the fragile vessels in this region by the subependymal tissue, increased fibrinolytic activity, and hypoxia are believed to contribute. Severe intraventricular hemorrhage carries a mortality rate of about 75%.
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Necrotizing Enterocolitis
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This is a dangerous complication of premature infants treated in neonatal intensive care units. It is characterized by extensive mucosal necrosis and ulceration involving the ileum and colon. The cause is unknown, although hypoxia and bacterial infection—notably Escherichia coli—probably contribute. Treatment commonly includes surgical resection of the involved intestine.
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In contrast to teratogenic infections such as rubella, which occur in early pregnancy, perinatal infections are caused by transplacental infection in late pregnancy or infection of the fetus by contagion during delivery. They present as infectious diseases in the neonatal period. TORCH complex is a general term for infections acquired in this way and is an acronym for toxoplasmosis, other (viruses), rubella, cytomegalovirus, and herpes simplex. To this list some would add syphilis (TORCHS).
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Toxoplasma gondii and Cytomegalovirus Infections
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These third-trimester fetal infections involve chiefly the brain and eyes. Extensive necrosis of the brain, most prominent in the periventricular region, is accompanied by dystrophic calcification and leads to microcephaly and mental retardation. The eyes show chorioretinitis, frequently associated with visual impairment.
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Treponema pallidum Infection (Congenital Syphilis)
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Syphilis is also a third-trimester transplacental infection of the fetus born to a mother with early active syphilis. When infection is severe, intrauterine death occurs. With lesser infections, congenital syphilis occurs (see Figure 54-2).
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Rubella Virus Infection
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Rubella infection in late pregnancy leads to severe infection of the fetus characterized by fever, petechial skin rash, and liver enlargement. The infantile immune system responds poorly to the virus, and affected infants frequently have prolonged infection with excretion of virus for several months after delivery.
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Infections Acquired in the Birth Canal
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Herpes simplex represents the most significant birth canal infection and occurs when the mother has active infection at the time of delivery. Fetal infection results either in severe viremia or encephalitis. The mortality rate is very high. Infants who recover commonly have severe permanent neurologic deficits. Active genital herpes infection of the mother is an absolute indication for cesarean section.
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Other infections acquired during passage through an infected birth canal include gonorrhea and lymphogranuloma venereum, both of which cause severe conjunctivitis.
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Sudden Infant Death Syndrome (SIDS; Crib Death)
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The number of infant deaths due to SIDS has decreased significantly since parents were advised to place healthy babies on their side or back instead of on their abdomen. However, SIDS remains a major cause of death in infants (Table 15-10). SIDS is the sudden and unexpected death of a previously well infant in whom no cause of death is found at autopsy. SIDS occurs predominantly during sleep and has a maximum incidence in the age group from 2 to 4 months. While new hypotheses are put forward almost monthly, the cause is still unknown. An abnormality of the respiratory center that causes cessation of respiration during sleep appears the most likely cause.
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Congenital Anomalies, Inborn Errors of Metabolism, & Hemolytic Disease of the Newborn
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These are common problems during early childhood. The first two have been considered earlier in this chapter. Hemolytic disease of the newborn is discussed in Chapter 25: Blood: II. Hemolytic Anemias; Polycythemia.
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Malignant neoplasms, although much less common overall in children than in adults, account for over 10% of deaths in the age group from 5 to 14 years and 7% of deaths in children 1–4 years of age. Malignant neoplasms in children are primarily those of the lymphoid and hematopoietic cells (lymphomas and leukemias) and mesenchymal cells (sarcomas) (see Table 17-6).
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Aging is the final phase of human development and may be defined as the aggregate of structural changes that occur with the passage of time; it is characterized by progressive inability to sustain vital functions, with death the eventual result. The life expectancy of humans varies from country to country (it is high in countries with well-developed systems of medicine and health care delivery, as in the Scandinavian countries, and lower in developing nations). It is generally higher in females than males. In the United States, the average male life expectancy at birth is between 70 and 75 years; for females, between 75 and 80 years.
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There is a steady loss of function in various critical organs with age. Extrapolation from such observations would indicate that humans have a finite biologic life span of 90–110 years, so that even if cardiovascular diseases and cancer were eradicated, the current average life expectancy would increase by only a few years.
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Several different hypotheses have been proposed to explain aging, but no one of them is entirely satisfactory, and it is probable that aging is due to a combination of several processes.
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Programmed Aging Hypothesis
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According to this hypothesis, the genome of every cell is programmed at conception to cease mitotic division after a certain time. This has been demonstrated by normal fibroblasts and other cells in tissue culture, which undergo a finite number (40–60) of divisions. Programmed cessation of mitotic division does not explain the attrition in permanent (irreversibly postmitotic) cells such as neurons and muscle cells. To explain loss of these cells, proponents suggest that such cells are also programmed to make errors in transcription of nucleic acid that lead to cell death.
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Evidence supporting the theory of programmed aging derives from observations of identical twins, who show remakably similar life spans, and from rare diseases that are characterized by acceleration of the aging process. These include Down syndrome and progeria. In infantile progeria, a young child resembles a wizened old person, with loss of hair, fusion of epiphyses, atherosclerosis, and arterial calcification. The life span in Down syndrome and progeria is variable but always shortened.
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DNA Damage Hypothesis
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According to this hypothesis, aging is the result of DNA damage, due either to somatic mutations or to failure of DNA repair mechanisms in aging cells. DNA changes lead to errors in ribonucleic acid (RNA) transcription and in that way cause defects in cellular synthesis of protein. Although these changes undoubtedly occur in aging cells, they could just as easily be the result of the aging process rather than the cause.
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Neuroendocrine Hypothesis
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This hypothesis holds that the aging process is programmed into brain cells at birth and that these cells direct the process by means of hormonal and neural influences. Proponents point to the control of puberty, which is initiated by the hypothalamus via pituitary hormones, as evidence that the brain can be programmed to function in this manner. Experiments in rats provide some supportive evidence in that removal of the pituitary increases life span.
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A decline in immunologic reactivity occurs with increasing age, which predisposes to development of infections, autoimmune diseases, and neoplasia in elderly persons. This hypothesis postulates that such progressive immunologic dysfunction is inevitable and that it is responsible for limitations on life span. In experimental animals, immunologic manipulations such as thymic transplants have been shown to increase life span. On the other hand, if they are kept in a microbe-free environment, mice with thymic aplasia and marked immune deficiency live as long as normal mice.
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Free Radical Hypothesis
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Aging is accompanied by the accumulation of lipofuscin in cells—mainly in the heart, liver, and brain. Lipofuscin is derived from the action of oxygen-based free radicals on plasma membranes of cellular organelles by lipid peroxidation. While lipofuscin itself is harmless, it provides evidence for a general increase in free radical injury of cells as the individual ages. This is due probably to decreased activity of enzymes such as superoxide dismutase that normally inactivate free radicals. Because free radicals can cause cell death, increasing free radical injury as the individual ages may contribute to increasing cell loss and the aging process.
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Cumulative Injury Hypothesis
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It has been suggested that aging may merely represent the aggregate effect of pathologic insults sustained during the life of the individual. If this were true, eradication of disease would lead to a greatly increased life expectancy. All available evidence suggests, however, that it is not true, and maximum life expectancy (90–100 years) is not greatly different now from what it was 100 years ago.
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Changes Associated with Aging
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As life expectancy increases, the study of aging (gerontology) becomes increasingly important. It is crucial to distinguish changes that are part of the aging process from diseases that are common in older individuals. Changes associated with aging are inevitable; on the other hand, diseases associated with aging should be aggressively treated to permit the individual to function at the highest possible level.
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Changes in metabolism lead to decreased cell size and number and to atrophy of organs. Cell loss occurs in all tissues but is most evident in organs composed of permanent (irreversibly postmitotic) cells such as the brain and heart, in which replacement of lost cells does not occur. Cell loss in the brain is selective, with the greatest loss occurring in the basal ganglia, substantia nigra, and hippocampus.
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The endoplasmic reticulum of aged cells is often disorganized, and its usual close relationship with ribosomes is lost. Free ribosomes are present in greater numbers than normal, with resulting abnormalities of protein synthesis. The activity of many enzymes is decreased.
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Mitochondria of aged cells show abnormalities in size, shape, and cristae. These, coupled with decreased levels of cytochrome C reductase, decrease the efficiency of energy production.
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An increased rate of organelle breakdown in aged cells is associated with the presence of increased numbers of phagolysosomal vacuoles in the cells and the deposition of lipofuscin (Chapter 1: Cell Degeneration & Necrosis)—a brown pigment believed to be derived from degraded organelle membranes—particularly evident in the heart, brain, and liver.
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Specialized cytoplasmic structures are often abnormal in aged cells. Myofibrils in muscle cells show decreased contractility. Nerve cells show decreased synthesis of acetylcholine. Poor function of cytoskeletal microfilaments in macrophages leads to decreased efficiency of phagocytosis. Hormone receptors on the cell surface become abnormal, resulting in inefficient action of hormones such as insulin.
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DNA abnormalities are mainly the result of a progressive failure of cellular DNA repair mechanisms. Failure of DNA repair can potentially affect any cellular function and frequently leads to cell death.
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Connective Tissue Changes
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Weakening of fibrous tissues, in association with intermittent muscle spasm, may increase the incidence of diverticula in the colon. Weakening of the abdominal and pelvic walls leads to abdominal hernias (inguinal, umbilical, diaphragmatic) and prolapse of organs (uterus, rectum) through the pelvic floor.
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Deposition of abnormal substances in connective tissue is common in old age and makes the line between disease and simple aging difficult to define. Calcification of the media of muscular arteries is common and usually without clinical significance. Deposition of amyloid (senile amyloidosis) may occur in the heart, brain, and many other organs; clinical disease may result.
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Elastic Tissue Changes
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Changes in elastic tissue of the body result in loss of elasticity and wrinkling of the skin. This occurs first in the sun-exposed regions of the body. Loss of elasticity in large arteries such as the aorta leads to decreased distensibility. The systolic pressure increases with age because of the aorta's decreased ability to accommodate cardiac output. Loss of elastic tissue in the lungs is associated with destruction and dilation of alveoli (senile emphysema).
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Ground Substance Changes
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Changes in the ground substance of tissues result in various abnormalities. In the lens, for example, these changes are associated with the development of opacities (cataracts), which usually impair vision. Cataract formation may be accelerated by disease, eg, diabetes mellitus. The lens also loses its accommodative power with age, so that visual changes—most commonly presbyopia (far-sightedness)—occur, and the individual cannot see objects in the near distance.
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Cartilage and Bone Changes
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Changes in articular cartilage lead to erosions and fibrillations. The end result is osteoarthrosis (Chapter 68: Diseases of Joints & Connective Tissue). Osteoarthrosis is most common in weight-bearing joints of the spine and the lower extremities, suggesting that wear and tear is an aggravating factor.
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Loss of bone (osteoporosis) is also a manifestation of aging. It is characterized by loss of both bone matrix and mineral, with resulting thinning of bones. Compression of vertebrae causes a decrease in total height. If collapse of vertebral bodies occurs, abnormal curvature (kyphosis) results. Elderly people are therefore often represented in caricature as short and bent over. Osteoporosis in the long bones predisposes to fractures, particularly in the neck of the femur. Osteoporosis is more common in postmenopausal women because of lack of the anabolic effects of estrogens, and estrogen replacement therapy delays onset of the disease. Lack of physical exercise (especially weight-bearing exercise) accelerates the onset and progression of osteoporosis.
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In elderly people, the hair becomes thin and sparse and loses its pigment. These characteristic changes are due to progressive failure of hair follicles to produce both keratin-like hair protein and pigment.
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Reproductive System Changes
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Menopause signifies the end of reproductive life in women. Cessation of ovulation results in decreased ovarian hormone levels, endometrial atrophy, cessation of menses, atrophy of the reproductive system, and increased secretion of pituitary gonadotropins by removal of feedback inhibition. Increased follicle-stimulating hormone (FSH) levels are thought to be responsible for some menopausal symptoms, eg, hot flushes. Menopause usually occurs between age 40 and 50 years.
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Although testicular function declines with age, the existence of a corresponding climacteric in men (so-called male menopause) is controversial.
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Changes in Host Defense Mechanisms
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The thymus begins to atrophy even in childhood. Some authorities maintain that this is the earliest form of aging or even a direct cause of aging—a belief that may account for the use of injections of embryonic thymus extracts in an attempt to retard the aging process.
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Abnormal immune function in the elderly predisposes to development of infections (Figure 15-20). Viral infections of the respiratory tract and bacterial infections of the respiratory and urinary tracts and skin are common. The incidence of tuberculosis is increased and the disease is more virulent in the elderly. Pneumonia is a common cause of death. Older individuals frequently develop autoantibodies and show an increased incidence of autoimmune diseases such as pernicious anemia, Hashimoto's thyroiditis, and Addison's disease. Cancer is predominantly a disease of older individuals and may in part be related to the decreased ability of the immune system to rid the body of cancer cells.
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Diseases Associated with Aging
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Older individuals are susceptible to many different diseases that affect virtually every organ of the body (Table 15-12). It is important to identify diseases responsible for clinical symptoms in elderly patients in order to maximize personal independence and quality of life.