Chromosomal abnormalities figure prominently in assessments of the impact of genetic disease, accounting for 50 percent of embryonic deaths, 5 to 7 percent of fetal losses, 6 to 11 percent of stillbirths and neonatal deaths, and 0.9 percent of live births. The number of chromosomes as well as the structure of individual chromosomes may be abnormal.
An individual’s chromosome makeup or karyotype is described using the international system for human cytogenetic nomenclature. When reporting a karyotype, the total number of chromosomes is listed first, followed by the sex chromosomes and then by a description of any structural variation or abnormality. Specific abnormalities are indicated by standard abbreviations, such as del (deletion) and t (translocation), along with the region of the short (p) or long (q) arms affected. Examples are shown in Table 5-1.
TABLE 5-1. Examples of Chromosome Karyotype Designations Using the International System for Human Cytogenetic Nomenclature (2009)
ABNORMALITIES OF CHROMOSOME NUMBER
Aneuploidy is the inheritance of an extra chromosome, trisomy, or loss of a chromosome, monosomy. Aneuploidy differs from polyploidy, which is characterized by an abnormal number of sets of haploid chromosomes, for example, triploidy.
Autosomal trisomy usually results from meiotic nondisjunction, in which chromosomes fail to pair up, pair up properly but separate prematurely, or fail to separate. The risk of autosomal trisomy increases with maternal age, as shown in Figure 5-1. Only trisomies 21, 18, and 13 can result in a term pregnancy, and many pregnancies with these common trisomies will be lost before term. With trisomy 21, the fetal loss rate is 30 percent between 12 and 40 weeks. Other trisomies have even higher rates of pregnancy loss. For example, Trisomy 16 accounts for 16 percent of all first-trimester losses but is never seen later in pregnancy.
FIGURE 5-1 Maternal age-related risk for selected aneuploidies. (Redrawn, with permission, from Nicolaides KH: The 11 to 13 + 6 weeks Scan. London: Fetal Medicine Foundation; 2004.)
Trisomy 21, also called Down syndrome, is present in approximately 1 in 800 to 1000 newborns. Infants with Down syndrome have a characteristic phenotype, shown in Figure 5-2. Features include epicanthal folds, a flat nasal bridge, a small head with flattened occiput, loose skin at the nape of the neck, hypotonia with tongue protrusion, a single palmar crease, hypoplasia of the middle phalynx of the fifth finger, and a prominent space or “sandal-gap” between the first and second toes. Major malformations include heart defects (30 to 40 percent) and gastrointestinal atresias. Affected individuals are also at increased risk for childhood leukemia and thyroid disease. The intelligence quotient ranges from 25 to 50, with a few individuals testing higher, and most affected children have social skills averaging 3 to 4 years ahead of their mental age.
FIGURE 5-2 Trisomy 21—Down syndrome. A. Characteristic facial appearance. B. Redundant nuchal tissue. C. Single transverse palmar crease. (Photographs courtesy of Dr. Charles Read and Dr. Lewis Weber.)
Approximately 95 percent of Down syndrome cases result from maternal nondisjunction for chromosome 21, with the remaining 5 percent resulting from a chromosomal rearrangement, such as a translocation, or from mosaicism. If a pregnancy has been complicated by trisomy 21, the recurrence risk is 1 percent until the woman’s age-related risk exceeds this (see Chapter 3). Females who have Down syndrome are fertile, and approximately one-third of their offspring will have Down syndrome. Males with Down syndrome are almost always sterile.
Trisomy 18 is known as Edwards syndrome and occurs in 1 in 8000 newborns. Approximately 85 percent of conceptuses with trisomy 18 die between 10 weeks and term. Of liveborn infants, the median survival is only 14 days, though 10 percent may survive to 1 year. Infants are usually growth restricted. Abnormalities occur in virtually every organ system, with cardiac defects in almost 95 percent. Striking features include prominent occiput, rotated and malformed ears, short palpebral fissures, a small mouth, and clenched fists with overlapping digits. Fetuses surviving to term commonly have heart rate abnormalities in labor.
Trisomy 13 is known as Patau syndrome and occurs in approximately 1 in 20,000 births. Of liveborn infants, the median survival is only 7 days, with 10 percent surviving up to 1 year. Similar to trisomy 18, abnormalities may occur in virtually every organ system. Common abnormalities include cardiac defects in 80 to 90 percent and holoprosencephaly in 70 percent, as well as ear abnormalities, omphalocele, cystic kidneys, areas of skin aplasia (such as the scalp), and polydactyly. Trisomy 13 is the only aneuploidy associated with an increased risk for preeclampsia.
Monosomy is almost universally incompatible with life, the exception being monosomy X which is also called 45,X or Turner syndrome. Turner syndrome is the most common aneuploidy in abortuses and accounts for 20 percent of first trimester losses. At least 98 percent of cases abort in the first trimester. Of the remainder, the majority develop cystic hygromas and hydrops, usually followed by a fetal demise. The prevalence in liveborn neonates is only about 1 in 5000, and as many as half of these are mosaic (two populations of cells, one normal, one monosomy X). Survivors generally have intelligence in the normal range, though difficulties with visual–spatial organization and nonverbal problem solving are common. Between 30 and 50 percent have a major cardiac malformation such as aortic coarctation or bicuspid aortic valve. Features include short stature, broad chest with widely spaced nipples, congenital lymphedema with puffy fingers and toes, low hairline with webbed posterior neck, and minor bone and cartilage abnormalities. Ovarian dysgenesis and infertility are found in over 90 percent, and these women require lifelong hormone therapy beginning just before adolescence.
Extra sets of chromosomes account for about 20 percent of early losses and are rarely seen in later pregnancies. Triploidy is the most common polyploidy. Two-thirds of triploidy cases result from fertilization of one egg by two sperms. The extra set of chromosomes is paternal, and the result is usually a partial hydatidi-form mole with abnormal fetal structures. In one-third of cases, failure of one of the meiotic divisions results in an extra set of maternal chromosomes, and the fetus and placenta develop but the fetus is severely growth restricted and also frequently dysmorphic. If a woman has a triploidy fetus that survived past the first trimester, the recurrence risk is 1 to 1.5 percent.
Extra Sex Chromosomes
An additional X chromosome is present in approximately 1 in 1000 female infants—47,XXX, and in 1 in 600 male infants—47,XXY or Klinefelter syndrome. An additional Y chromosome, 47,XYY is present in about 1 in 1000 male infants. None of these sex chromosome abnormalities is associated with an increased incidence of anomalies or unusual phenotypic features. With XXX, XXY, or XYY, tall stature is common and IQ scores fall within the normal range. However, affected children may have delays in speech and motor skills. For XXX and XYY, pubertal development is normal and fertility is typically normal. Males with Klinefelter syndrome do not virilize at puberty, require testosterone therapy, and are infertile as a result of gonadal dysgenesis. When more than one extra sex chromosome is present (resulting in 48 or more chromosomes), there are likely to be obvious physical abnormalities and mental retardation.
ABNORMALITIES OF CHROMOSOME STRUCTURE
Deletions and Duplications
A deletion means that a portion of a chromosome is missing, and a duplication means that a portion of a chromosome has been included twice. Both are described by the location of the two break points within the chromosome. Most deletions and duplications result from malalignment or mismatched pairing of homologous chromosomes during meiosis, as shown in Figure 5-3. If a deletion or duplication is identified in a fetus or child, the parents should be tested to find if either carries a balanced translocation, which would increase the recurrence risk.
FIGURE 5-3 A mismatch during pairing of homologous chromosomes may lead to a deletion in one chromosome and a duplication in the other. del, deletion; dup, duplication. (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, et al (eds). Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Some deletions and duplications are not large enough to be recognized by traditional karyotyping. These are termed microdeletion and microduplication syndromes, and their diagnosis requires molecular cytogenetic techniques such as fluorescence in-situ hybridization. Table 5-2 lists some common microdeletion syndromes and their features.
TABLE 5-2. Some Microdeletion Syndromes Detectable by Fluorescence In-Situ Hybridization
Translocations are DNA rearrangements in which a segment of DNA breaks away from one chromosome and attaches to another chromosome. The rearranged chromosomes are called derivative (der) chromosomes. There are two types of translocations—reciprocal and Robertsonian.
A reciprocal translocation is a rearrangement in which breaks occur in two different chromosomes, and chromosomal material is exchanged before the breaks are repaired. If no chromosomal material is gained or lost in this process, it is a balanced translocation, and the phenotype is usually normal. The incidence of a major anomaly, among balanced translocation, carriers is 6 percent. However, carriers of a balanced translocation can produce unbalanced gametes that result in abnormal offspring (Figure 5-4). In general, translocation carriers identified after the birth of an abnormal child have a 5 to 30 percent risk of having liveborn offspring with unbalanced chromosomes. Carriers identified for other reasons, for example, during an infertility workup, have a 5 percent risk.
FIGURE 5-4 A carrier of a balanced translocation may produce offspring who are also carriers of the balanced rearrangement (B), offspring with unbalanced translocations (C, D), or offspring with normal chromosomal complements (A). (Reproduced, with permission, from Cunningham FG, Leveno KJ, Bloom SL, et al (eds). Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010.)
Robertsonian translocations result when the long arms of two acrocentric chromosomes—chromosomes 13, 14, 15, 21, and 22—fuse at the centromere to form one derivative chromosome. Because the centromere number determines the chromosome count, a carrier of a Robertsonian translocation has only 45 chromosomes. Robertsonian translocations occur in approximately 1 in 1000 newborns. Chromosome studies should be obtained on both parents if their offspring is found to have a Robertsonian translocation. In general, the recurrence risk is 15 percent if carried by the mother and 2 percent if carried by the father.
Isochromosomes are composed of either two p arms or two q arms of one chromosome fused together. An isochromosome made of the q arms of an acrocentric chromosome behaves like a homologous Robertsonian translocation. Such a carrier can produce only unbalanced gametes. When an isochromosome involves nonacrocentric chromosomes that have p arms containing functional genetic material, the carrier is usually phenotypically abnormal and produces abnormal gametes. An example is isochromosome X, which causes the full Turner syndrome phenotype.
Inversions result when two breaks occur in the same chromosome, and the intervening genetic material is inverted before the breaks are repaired. Although no genetic material is lost or duplicated, the rearrangement may alter gene function. Paracentric inversions are those in which the inverted material is from only one arm, and the centromere is not within the inverted segment. The carrier makes either normal balanced gametes or gametes that are so abnormal as to preclude fertilization. Although infertility may be a problem, the risk of abnormal off-spring is extremely low. Pericentric inversions occur when the breaks are in each arm of the chromosome, and the inversion includes the centromere. Because of the problems in chromosomal alignment during meiosis, the carrier is at high risk to produce abnormal offspring. In general, the observed risk is 5 to 10 percent if the couple has had an abnormal child, and 1 to 3 percent if ascertainment was prompted by another reason.
When there are deletions from both ends of a chromosome, the ends may unite, forming a ring chromosome. If the deletions are substantial, the carrier is pheno-typically abnormal. If only the telomeres are lost, all important genetic material is retained, and the carrier is essentially balanced. However, the ring prevents normal chromosome alignment during meiosis and thus produces abnormal gametes. It also disrupts cell division, which may cause abnormal growth of many tissues and lead to short stature, mental deficiency, and minor dysmorphisms.
An individual with mosaicism has two or more cytogenetically distinct cell lines derived from a single zygote. The phenotypic expression depends on factors such as whether the abnormal cells involve the placenta, the fetus, part of the fetus, or some combination. Mosaicism encountered in amniotic fluid culture may or may not reflect the actual fetal chromosomal complement, as discussed in Table 5-3.
TABLE 5-3. Mosaicism Encountered in Amniotic Fluid Culture
While true mosaicism is rarely encountered in a fetus, confined placental mosaicism is relatively common, occurring in approximately 2 percent. Confined placental mosaicism may have either positive or negative effects. It may play a role in survival of cytogenetically abnormal fetuses, such as fetuses with trisomy 13 or 18 who survive to term only because of “trisomic correction” in cells that become trophoblasts. Conversely, cytogenetically normal fetuses may have severe growth restriction because the placenta contains a population of aneuploidy cells that impair its function.
Gonadal mosaicism is confined to the gonads. It may explain de-novo autosomal dominant mutations in the offspring of normal parents, leading to such diseases as achondroplasia or osteogenesis imperfecta. It is because of the potential for gonadal mosaicism that the recurrence risk after the birth of a child with a disease caused by a “new” mutation is approximately 6 percent.
For further reading in Williams Obstetrics, 23rd ed.,
see Chapters 12, “Genetics,” and 13, “Prenatal Diagnosis and Fetal Therapy.”