Chromosomal abnormalities occur quite commonly. Most are not compatible with life and are aborted spontaneously. Over 50% of early SABs have an abnormal karyotype (21). The attrition rate of fetuses with chromosomal abnormality decreases as pregnancy progresses, and about 5% of stillbirths (21) and a smaller percentage of term deliveries are chromosomally abnormal. Chromosomal abnormality is a significant cause of major birth defects. Abnormalities of the sex chromosomes are generally better tolerated than abnormalities of the autosomes and often show a milder phenotype.
Chromosomal abnormalities fall into two broad categories: numerical and structural. Numerical abnormalities include ane-uploidy (the presence or absence of entire whole chromosomes) and polyploidy (the presence of entire additional sets of chromosomes).
4.1. ANEUPLOIDY Human chromosomal aneuploidy is seen in about 0.5% of term pregnancies, but it represents about 75% of abnormal karyotypes in SABs (22). In early embryologic development, it has been estimated that 20% of human conceptuses are aneuploid (23). Monosomy is the absence of an entire chromosome, whereas trisomy is the presence of an additional chromosome. Both result from chromosomal nondisjunction during meiosis. Although nondisjunction can occur in either spermatogenesis or oogenesis and in either meiosis I or II, it occurs most commonly in maternal meiosis I. Double trisomies are rare, but they are seen in products of conception.
4.1.1. Monosomy Autosomal monosomies are almost invariably lethal very early in embryonic development and are seldom seen, even in SABs. Rare cases of liveborns with monosomy 21 and 22 have been reported, often in mosaic form (22). Mosaicism is the presence of two or more genetic cell lines. The presence of a normal karyotype in addition to an abnormal one often results in a milder phenotype and, in some cases, the potential for survival. Aneuploid/diploid mosaicism occurs postzygotically as a result of mitotic nondisjunction or from trisomy rescue (loss of one of the extra chromosomes) of a tri-somic fetus. Monosomy Y is also lethal; the presence of at least one X chromosome is necessary for survival.
Monosomy X, or Turner syndrome, is the only human monosomy compatible with life. Even so, as many as 99% of cases are aborted spontaneously, and 45,X is the most common karyotype seen in SABs (21). Ironically, the phenotype of Turner syndrome is relatively mild (Table 1) as far a chromosomal abnormalities are concerned. It is postulated that liveborns with a 45,X karyotype could have undetected mosaicism or confined placental mosaicism, which allows their survival.
The 45,X karyotype is seen in somewhat greater than 50% of Turner patients. The remainder have variant karyotypes. Mosaicism involving a 46,XX and/or 47,XXX karyotype or a structurally abnormal X chromosome is common. Structural abnormalities of an X chromosome such as isochromosomes of the long arm, ring chromosomes, and various deletions of the X chromosome are also fairly frequent. Of particular importance are karyotypes involving a Y chromosome, such as 45,X/46,XY mosaics. Females with a Y chromosome or even particular Y sequences are at increased risk of developing gonadoblastomas (24).
Nearly three-quarters of 45,X individuals receive their sole X chromosome from their mother (25). Of interest, those with a paternally derived X have higher levels of social cognition than those with a maternally derived X. There is apparently a gene for social cognitive functioning that is active on the paternal X, but not on the maternal one (26).
4.1.2. Additional Sex Chromosomes Trisomy of the X chromosome (47,XXX) occurs fairly frequently, being seen in about 1 in 1000 live births. This chromosomal abnormality does not form a well-defined syndrome. Women with this condition are usually phenotypically normal but might be mentally deficient or psychotic or have serious learning deficits. They are fertile and overwhelmingly produce chromosomally normal offspring rather than the one-half XXX females and XXY males that might be expected.
The presence of more than three X chromosomes in females (48,XXXX and 49,XXXXX) is associated mental deficiency and a variety of rather nonspecific physical anomalies. As the number of X chromosomes increases, so does the degree of abnormality. Tetra-X women have menstrual irregularities and reduced fertility, whereas penta-X women appear to be infertile.
Klinefelter syndrome is also present in about 1 in 1000 births. The vast majority of patients have a 47,XXY karyotype, but 46,XX/47,XXY mosaics and Klinefelter variants with a 48,XXYY karyotype also occur. Affected individuals tend to be tall and slim in childhood, but have a tendency toward obesity as adults if not given testosterone replacement therapy. They have testicular atrophy with azoospermia and are infertile. Some develop gynecomastia and have an increased incidence of breast cancer. Intelligence quotients (IQs) are generally somewhat lower than normal, but the range is wide.
As in females, the phenotypic abnormality increases as the number of additional X chromosomes increases in males. Males with 48,XXXY and 49,XXXXY show a variety of physical anomalies and mental deficiency. Infertility is the norm.
A 47,XYY karyotype is seen in about 1 in 1000 male births, but it is usually found incidentally while looking for something else (amniocentesis for advanced maternal age, as part of a family study after detection of a familially transmitted structural abnormality, as part of a cancer study, etc.). This is because most individuals with 47,XYY are not dysmorphic. They tend to have tall stature and large tooth size, and some do show minor anomalies and have a severe type of acne in adolescence. IQs are near normal, although somewhat lower than siblings. Fertility is normal and 47,XYY individuals do not produce an increased incidence of offspring with sex chromosome abnormalities. Several decades ago the question was raised as to whether the presence of an extra Y chromosome predisposed males to violence, criminality, or aggressive behavior. This has not proved to be the case.
4.1.3. Autosomal Aneuploidy Human chromosomal trisomy is very common. Just over one-half of all pregnancy losses with a chromosomal abnormality are trisomic 21. Although trisomy of all chromosomes has been reported in spontaneous abortions, only a few survive to term, and only three of these (trisomies 21, 18, and 13) occur in liveborns with any frequency. Trisomies 8, 9, 14, 15, 21, and 22 have been reported in live births, but usually in mosaic form with a normal cell line. Trisomy 14 has only been reported as a mosaic. Common features of the viable autosomal trisomies are listed in Table 2. Trisomy 16 is the most commonly seen trisomy in spontaneous abortions, but none survive to term (Fig. 2).
Trisomy 21 (Down syndrome) is the most common of all autosomal trisomies to survive to term and is seen in 1 in 700 live births. Even so, 60% of cases of trisomy 21 abort spontaneously. About 94% of cases of trisomy 21 are the sporadic, noninherited type that result from meiotic nondisjunction, whereas 4-5 % result from inherited Robertsonian translocations or isochromosomes of the long arm of chromosome 21, and 1-2 % are mosaic, resulting from mitotic nondisjunction early in embryogenesis. A very small portion of full trisomy 21s are the result of gonadal mosaicism of a parent. This phenomenon accounts for the rare cases of recurrent complete tri-somy 21 reported in some families. Mosaicism usually results in a milder phenotype. Life expectancy for individuals with Down syndrome is greater than 45 yr (27).
There are dozens of relatively minor abnormalities seen in trisomy 21 and no patient exhibits all of them. Most of these findings are not particularly abnormal by themselves, but together, they result in a very characteristic appearance. There are a few major abnormalities as well. These include mental retardation, which is fairly universal, heart defects that affect 40-45% of patients, and gastrointestinal abnormalities seen in 10-12% of cases (27).
Trisomy 18 (Edward syndrome) has an incidence of about 1 in 5000-8000 live births. The vast majority of trisomy 18 conceptuses die prenatally, and 90% of liveborns die within the first year of life. A few have survived into their teens. Although most cases are complete trisomy 18 resulting from meiotic nondisjunction, a small percentage are mosaic and typically have a milder phenotype and longer survival. Trisomy 18 is characterized by intrauterine and postnatal growth retardation, profound mental retardation, and a variety of physical anomalies (Table 2).
Trisomy 13 (Pateau syndrome) is seen in 1 in 12,000 live births. Most cases result in SAB and those that continue to term usually have a limited survival. Only 5-10% live to 1-yr and long-term survival is rare. At least 10% of cases result from structural rearrangements such as translocations. Mosaicism does occur, and as with other mosaic conditions, mosaic tri-somy 13 can show a broad spectrum of abnormality and longer survival. There appears to be two critical regions on chromosome 13, one proximal and one distal, and both need to be present an extra time for full expression of the syndrome. Profound mental deficiency, midline face defects, cardiac anomalies, and a variety of phenotypic abnormalities (Table 2) are characteristic of trisomy 13.
4.2. POLYPLOIDY Polyploidy can take two forms in humans: triploidy (three sets of chromosomes) and tetraploidy (four sets of chromosomes). Triploidy (3n = 69) occurs in about 1% of conceptuses and as many as 20% of spontaneous abortions with a chromosomal abnormality (27). Few triploids survive to term, and those that do usually have a quick demise. Diploid/triploid mosaics have had a longer survival.
Meiotic errors in both oogenesis and spermatogenesis can result in eggs or sperm with an unreduced chromosome number. If normal fertilization occurs, a triploid chromosome complement results. Other possible causes of triploidy include
Table 2 Autosomal Aneuploidies
Trisomy 21 (Down syndrome) Mental retardation Cardiac anomalies GI tract anomalies Hypotonia Hyperflexible joints
Tendency to keep mouth open and protrude tongue
Flat occiput and facial profile
Upward slant to eyes
Small, low-set, abnormally shaped ears
Short neck with loose folds of skin, especially in infancy
Fine, soft, sparse hair
Single palmar crease
Increased incidence of leukemia
Decreased incidence of solid tumors, except testicular cancer
Trisomy 18 (Edward syndrome) Mental retardation Heart defects Prominent occiput Micrognathia
Clinched fist and overlapping fingers Absent digital crease on fifth finger Hypoplastic nails Short sternum Rocker bottom feet
Trisomy 13 (Pateau syndrome) Mental retardation Holoprosencephaly Cleft lip and palate Small eyes or cyclopia Coloboma iridium Cardiac anomalies Polydactyly
Persistence of fetal hemoglobin GU tract abnormalities Scalp defects
Trisomy 8 (usually mosaic)
Mild to severe mental retardation
Unusual creasing of the palms of hands and soles of feet Camptodactyly
Slender body habitus and narrow pelvis Widely spaced nipples
Trisomy 9 (usually mosaic) Mental retardation
Intrauterine and postnatal growth delay
Low-set, malformed ears and other facial anomalies Joint anomalies
Trisomy 22 (usually mosaic) Microcephaly Holoprosencephaly Hypertelorism Hypoplastic, low-set ears Limb anomalies Genital anomalies
Trisomy 15 (usually mosaic) Growth delay Developmental delay Various craniofacial anomalies Limb anomalies
Trisomy 14 (always mosaic) Growth retardation Psychomotor retardation Central nervous system abnormalities Limb abnormalities, including limb asymmetry Abnormal skin pigmentation reunion of a polar body with the egg nucleus or fertilization of a single oocyte by two sperm. Most triploids have a 69,XXX or 69,XXY karyotype. A 69,XYY karyotype is very uncommon, but it does occur.
The origin of the extra set of chromosomes could be maternal or paternal, and the presentation is very different depending on the origin. If the extra set of chromosomes is paternally derived, the placenta is large and overgrown and the fetus is underdeveloped or undeveloped. If the extra set is maternally derived, the placenta is small and underdeveloped and the fetus is large.
Tetraploidy (4n = 92) is much less common and is extremely rare in liveborns, but it is seen in 6-7% of spontaneous abortions with a chromosomal abnormality (28). All reported tetraploids have been 92,XXXX or 92,XXYY. No 92,XXXY or 92,XYYY karyotypes have been described, even in SABs (28).
Most nonmosaic tetraploids probably result from chromosomal duplication without cytoplasmic division in the first postzygotic mitotic division. Other less likely possibilities include the fertilization of a diploid oocyte by a diploid sperm or fertilization of a normal diploid oocyte by three sperm's. Diploid/tetraploid mosaicism has been reported with longer survival.
4.3. STRUCTURAL ABNORMALITIES Structural abnormalities occur much less frequently than numerical ones. Whereas numerical abnormalities are always genetically unbalanced, structural rearrangements might be balanced or unbalanced. A balanced rearrangement is one in which all of the genetic material is present; it is just moved around within the karyotype. In unbalanced rearrangements, parts of the genome are represented too few or too many times. Carriers of balanced chromosomal abnormalities are usually phenotypically normal, but they are at risk of producing unbalanced gametes and therefore genetically unbalanced conceptuses, resulting in high rates of spontaneous abortion and/or abnormal offspring.
Translocations (t in cytogenetic nomenclature) are the most commonly occurring structural abnormalities in humans. A
translocation is an exchange of material between nonhomologous chromosomes. Although balanced translocation carriers are usually phenotypically normal, the translocation chromosomes can malsegregate during meiosis, resulting in genetically unbalanced gametes.
Robertsonian translocations (rob) are a special type of translocation between two acrocentric chromosomes. The result is a single chromosome consisting of the long arms of the two chromosomes involved. This is also referred to as centric fusion. The satellited short-arm material is lost, but this does not result in a genetic imbalance because the short arms of all the acrocentric chromosomes contain redundant copies of the same genetic material. Balanced carriers of Robertsonian translocations have 45 chromosomes instead of the usual 46 but are phe-notypically normal. Malsegregation can occur during meiosis, however, and this can result in nullisomic and disomic gametes.
Nonhomologous Robertsonian translocations are the most common recurrent constitutional rearrangements in humans. The most frequently encountered Robertsonian translocations involve chromosomes 13 and 14 and chromosomes 14 and 21.
A deletion (del) is a loss of material from a chromosome. Deletions can be terminal (involving the end of a chromosome arm) or interstitial (involving material within a chromosome arm). Deletions result in the individual being hemizygous for the genes of the deleted region. Not all deletions are visible cytogenetically, even with high- resolution banding techniques. FISH can be helpful in detecting many deletions that are below the level of resolution of light microscopy.
A ring chromosome (r) is a special type of deletion chromosome in which breaks occur in both chromosome arms. The telomeric segments are lost and the broken ends of the piece with the centromere join together to form a donut-shaped chromosome. Ring chromosomes are very unstable and have difficulty accomplishing normal cell division. If crossing-over occurs, the homolog can become tangled or a large dicentric ring could be formed. These might break as cell division progresses. Because of this instability, rings are sometimes lost, giving rise to cells that are monosomic for the chromosome in question.
Duplication chromosomes (dup) contain a chromosomal segment that is represented a second time and that lies adjacent to the original segment. Duplications are referred to as being direct or inverted, depending on the orientation of the duplicated region. If the repeated segment occurs in the same order relative to the centromere as it did in the original chromosome, it is a direct duplication. If the order is reversed relative to the centromere, it is an inverted duplication. Individuals with chromosomal duplications are trisomic for the genes in the duplicated portion.
Inversions (inv) are structural abnormalities involving two breaks in a single chromosome. The region between the breaks rotates 180° and reattaches. If the breaks occur in the same chromosome arm, it is referred to as a paracentric inversion. If the breaks occur in different arms, it is referred to as a pericentric inversion. There are a few inversions that occur frequently enough in the population to be considered polymorphic variants. These are specific inversions of chromosomes 9, Y, and 2.
Duplication and Deletion Syndromes
Wolf-Hirschhorn syndrome Type of abnormality: deletion Critical region: 4p16.3 Mental deficiency Ocular hypertelorism Dull expression Strabismus
Cleft lip and/or palate Microcephaly and/or cranial asymmetry Turned-down corners of mouth "Greek warrior helmet" face
Large, simple, low-set ears with preauricular pits or tags
Type of abnormality: deletion Critical region: 5p15.2 Mental deficiency High-pitched catlike cry in infancy Microcephaly Round, moonlike face Wide-set, downward-slanting eyes Strabismus Epicanthal folds
Type of abnormality: deletion Critical region: 7q11.23
Mental retardation/developmental delay
Short, up-turned nose
Full lips and wide mouth Long philtrum Stellate pattern to iris Hoarse voice
Premature graying and wrinkling Congenital heart defects Hypercalcemia
Langer-Giedion syndrome Type of abnormality: deletion Critical region: 8q24.11-q24.13 Mental retardation Fine, sparse scalp hair Large, bulbous nose Long, simple philtrum Thin upper lip
Large, laterally protruding ears Loose, redundant skin in infancy Multiple exostoses Epiphyseal coning Tendency toward bone fractures
Aniridia-Wilms' tumor association (WAGR) Type of abnormality: deletion Critical region: 11p13 Wilms' tumor Aniridia
Genitourinary defects Mental retardation
Type of abnormality: Duplication of paternal 11 and other mechanisms Critical region: 11p15.5
Linear ears creases
Increased incidence of a number of embryonal tumors (Wilms' tumor, adrenocortical carcinoma, embryonal rhabdomyosarcoma, hepatoblastoma) Pancreatic hyperplasia Abdominal wall defects Fairly normal growth No mental impairment
Type of abnormality: mosaic tetrasomy Critical region: 12 short arm Mental retardation Sparse hair, eyebrows, and eyelashes Long philtrum
Cupid-bow shape to upper lip Protruding lower lip Deafness
Minimal speech development Hypotonia
Contractures that develop with age
Type of abnormality: deletion of paternal 15 and other mechanisms Critical region: 15p12 Mental retardation
Type of abnormality: deletion of maternal 15 and other mechanisms Critical region: 15p12 Mental retardation "Marionette like" gait
Open mouth and seemingly inappropriate laughter
No language development
Smith-Magenis syndrome Type of abnormality: deletion Critical Region: 17p11.2 Mental retardation Brachycephaly Low-set, malformed ears Broad nasal bridge Prognathism Cleft lip and/or palate Short fingers Delayed dentition Hoarse voice Sleep disorders Behavior problems
Table 3 (Continued)
Hyperactivity Self-destructive behavior Attention-seeking behavior
Type of abnormality: deletion Critical region: 17p13.3 Lissencephaly Mental retardation Microcephaly
Short nose with anteverted nostrils
Vertical ridging of central forehead when crying
Type of abnormality: trisomy or tetrasomy of 22q
(could be mosaic) Critical Region: 22q11 Coloboma of the iris Anal atresia
Down-slanting palpebral fissures Misshapen ears with preauricular pits or tags Most have mild mental deficiency
As with other balanced rearrangements, individuals with inversion chromosomes are usually phenotypically normal, but inverted chromosomes can encounter mechanical problems during meiosis. If the inverted segment is large enough, an inversion loop forms as the chromosomes attempt to pair. If crossing-over occurs within the inversion loop, abnormal gametes with duplicated and deleted chromosomes result.
Insertions (ins) involve the movement of a piece of one chromosome into another or the same chromosome. An insertion requires three breaks: two to create the insertion segment and one in the recipient chromosome. Because of the number of breaks required, insertions are rather rare events.
Isochromosomes (i) are structurally abnormal chromosomes comprised of two identical arms: either two short arms are two long arms. Individuals with isochromosomes will be hemizy-gous for the genes on the arm missing and trisomic for genes on the arm represented twice.
All of these unbalanced structural abnormalities have their effect by rendering the individual who possesses them genetically imbalanced for specific segments of chromosomes. Some of these are viable and give rise to duplication and deletion syndromes. Although a complete discussion of these is beyond the scope of this chapter, some of the more common duplication and deletion syndromes are described in Table 3. Although most of these syndromes occur sporadically, some are inherited from parents who are carriers of balanced chromosomal abnormalities. Thus, chromosomal study of the biologic parents to rule out carrier status is indicated whenever a structural abnormality is detected in a prenatal sample or in a child.
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