Numerical Abnormalities

Virtually all types of numerical abnormalities are eliminated prenatally, so that only those involving small, gene-poor autosomes or the sex chromosomes are identified with any frequency among live-borns. Clinically, the most important of these is trisomy 21, the most frequent cause of Down syndrome. Depending on the maternal age structure of the population and the utilization of prenatal testing, the incidence of trisomy 21 ranges from 1/600 to 1/1000 live births, making it the most common chromosome abnormality in live-born individuals. Like most trisomies, the incidence of trisomy 21 is highly correlated with maternal age, increasing from about 1/1500 live births for women 20 years of age to 1/30 for women 45 years.

In addition to trisomy 21, only two other autosomal trisomies, 13 and 18, occur with any frequency in livebirths. Incidence rates for trisomies 13 and 18 in livebirths are 1/20,000 and 1/10,000, respectively. Unlike trisomy 21, which is associated with near-normal life expectancy, both trisomies 13 and 18 are associated with death in infancy, typically occurring during the first year of life.

Three sex chromosome trisomies—the 47,XXX, 47,XXY (Klinefelter syndrome), and 47,XYY conditions—are quite common, with each occurring in about 1/2000 newborns. Of all the trisomic conditions, these three have the fewest phenotypic complications. In fact, with the exception of infertility in Klinefelter syndrome (Chap. 343), it is likely that most individuals with such trisomic conditions would go undetected. The additional Y chromosome in the 47,XYY condition is small and contains only a few genes. Most Y-linked genes are involved in testicular development or spermatogenesis. Thus, dosage imbalance of Y-linked genes has relatively little effect on other developmental processes. The 47,XYY genotype is associated with increased height. Its role in antisocial behavior, postulated initially because of an increased prevalence among some penalized populations, is unclear.

For the 47,XXX and 47,XXY conditions, the situation is different—the X chromosome contains >1000 genes, many of them essential for normal development. How, then, are 47,XXX and 47,XXY individuals spared from the catastrophic consequences of dosage imbalance? The answer lies in the biology of X chromosome gene expression. In normal females, one of the chromosomes undergoes X inactivation in somatic cells. The inactivation of the paternal or maternal X chromosome occurs randomly in each somatic cell and thereby serves as a mechanism of dosage compensation, ensuring that males and females have equal expression of most X-linked genes. The inactivation process occurs at the blastocyst stage of development; prior to this, both X chromosomes are active. In addition, not all X-linked genes are inactivated. Some genes on the X chromosome "escape" the inactivating mechanism and are expressed from both X chromosomes. In disorders such as Klinefelter syndrome, some genes may be expressed from both X chromosomes, resulting in its phenotypic features.

As a rule, monosomic conditions are incompatible with fetal development and, consequently, autosomal monosomies are only rarely identified in spontaneous abortions and are not found among live-born individuals. In fact, the only monosomy compatible with live birth is the 45,X condition, which causes Turner syndrome. The 45,X chromosome constitution occurs with surprisingly high frequency, present in at least 1–2% of all pregnancies. More than 99% of all 45,X conceptions are spontaneously aborted. Thus, live-born individuals with a 45,X chromosome constitution represent a rare group of survivors. The 45,X phenotype is mild, presumably because the second copy of many X chromosomal genes is normally inactivated. Nonetheless, Turner syndrome causes gonadal dysgenesis, resulting in infertility and failure to undergo secondary sexual development, along with a number of other phenotypic features (Chap. 343). Several other structural abnormalities of the X chromosome such as deletions, isochromosome X, or ring chromosomes can cause Turner syndrome. Mosaicism, including 45,X/45,XX, 45X/45,XXX, 45,X/45,XY, and others, also occurs (see below) and contributes to the phenotypic spectrum in Turner syndrome.

Because numerical abnormalities originate in meiosis (Table 63-3), affected individuals have missing or extra chromosomes in all cells. In a small proportion of cases, a mitotic nondisjunctional event occurs at an early stage in an individual with an initially normal chromosome constitution. Alternatively, a "normalizing" mitotic nondisjunctional event may result in a normal chromosome complement in some cells of an embryo. In either case, the embryo is a mosaic, with some cells bearing a normal chromosome constitution and others an aneuploid number of chromosomes. The phenotypic consequences are difficult to predict because they depend on the timing of nondisjunction and the distribution of normal and abnormal cells in different tissues. Nevertheless, mosaicism may lead to clinical abnormalities indistinguishable from those of nonmosaic individuals; for example, nearly 5% of all cases of Down syndrome involve individuals with mosaic trisomy 21, and about 15% of individuals with Turner syndrome are mosaic for various sex chromosomal constitutions as described above.

Table 63-3 Studies of the Parent and Meiotic/Mitotic Stage of Origin of Human Trisomies and Sex Chromosome Monosomy

Origin, % Paternal Maternal I II I II Mitotic Trisomy 2 28 — 54 13 6 7 — — 17 26 57 15 — 15 76 9 — 16 — 1 96 3 — 18 — — 33 56 11 21 3 5 67 22 2 22 3 — 94 3 — XXY 46 — 38 14 3 XXX — 6 60 16 18 Monosomy Xa   80 20

aResults pertain to nonmosaic 45,X individuals.

Reff:

Harrison's Internal Medicine > Chapter 63. Chromosome Disorders >