The 46 chromosomes exist in 23 homologous pairs in the normal individual; one chromosome of each pair is from the mother, the other is from the father and one of each pair is transmitted to each child. Twenty-two pairs of chromosomes are alike in males and females and are, hence, called the autosomes; the two sex chromosomes, the remaining pair, differ in males and females. The members of the homologous pair carry the same genetic information; they have the same gene loci in the same sequence, although at any one locus they may have either the same or different alleles. Each of the human genes is, therefore, paired, and the total expression of any particular gene is the sum of the products coded for by both the maternal and paternal copies, or alleles, of that gene. Chromosomal abnormalities will, as a rule, involve only one of the two chromosomes in any pair. When a chromosome or part of chromosome is missing, the impaired alleles on the other chromosomes are expressed without modification. In the case of genes that code for enzymatic proteins, total activity will be reduced by 50% if the enzyme activity is gene dose dependent. On the other hand, when an entire chromosome or a position of one is duplicated, the genes in that segment have three alleles, and the gene product is present in 150% of normal amounts.

The abnormal dose effect of multiple genes in chromosomal disorders may have widespread effects on the developing organism. In Drosophila, mutations or deletions involving as many as 41 loci on all four chromosomes produced a similar phenotype consisting of slow development, small body size, large rough eyes, thin wings, and low fertility. These 41 loci represent sites of synthesis of transfer DNA, deficiency of which results in a generalized decreased rate of protein synthesis.² Many of the human chromosomal abnormalities share common features: mental retardation, low fertility, growth retardation, and coarse and abnormal facial features, among others. In humans, as in Drosophila, the recurrent and overlapping phenotypes seen with many of the chromosomal abnormalities can be explained on the basis of a generalized decreased rate of protein synthesis.

Table 1, which summarizes the ocular features of some of the partial trisomies and partial deletion chromosomal syndromes, demonstrates the considerable phenotypic overlap among the various chromosomal disorders. It is believed that abnormal rates of cell division at critical times in embryogenesis, likely the result of abnormal gene dose effect, result in the generalized growth retardation and the congenital anomalies noted at birth.² For example, closure of the fetal choroidal fissure takes place between the fifth and seventh week of gestation. If an embryo has an abnormal karyotype that causes retardation of localized cell division, the result may be that closure of the fetal choroidal fissure will not occur. Uveal coloboma is a feature of chromosomal disorders involving many different chromosomes.

Many of the ocular abnormalities noted in the chromosomal disorders are not chromosome specific; rather, they are secondary phenotypes. Orbital hypotelorism is found in many chromosomal disorders. In trisomy 21, the abnormally narrow space between the orbits is a result of primary hypoplasia of the central facial structures, whereas in the 13q+ and the 18p- syndromes the hypotelorism is associated with some degree of holoprosencephaly and trigonocephaly. In both situations, however, the end result is a phenotypic anomaly that results secondarily from a more basic defect in development as well. The ocular pathology in embryos with chromosomal abnormalities demonstrated that not only does retardation of development occur but also that various forms of dysgenesis of ocular structures occur. Specific findings included microphthalmia, cataract, subluxation of the lens, staphyloma of the optic nerve, retinal dysplasia, and cyclopia.³

Microphthalmia is an ocular abnormality seen in several chromosomal syndromes. The microphthalmia in trisomy 13 is probably related to the presence of holoprosencephaly. However, because microphthalmia is seen in other syndromes in which holoprosencephaly is not present, the defect must be nonspecific or related to some other specific gene locus. It is known, for example, that mutations on all four chromosomes of Drosophilia may produce small eyes or anophthalmia. In the mouse, genes on three separate chromosomes may result in the same ocular anomalies. Deletion or duplication of different portions of the human karyotype can result in microphthalmia. Hypertelorism, antimongoloid lid slant, epicanthal folds, highly arched eyebrows, strabismus, and colobomas are abnormalities that are frequently found among the chromosomal disorders (see Table 1).

Before 1956 there were believed to be 48 human chromosomes; however, in that year Tjio and Levan⁴ showed that 46 was the correct number. In 1979, Hsu published a book reviewing the history of human cytogenetics in which he divided the subject into four eras: the dark ages before 1952, the hypotonic period from 1952 to 1958, the trisomy period between 1959 and 1969, and the current chromosome banding era that started in 1970.

In the dark ages, Painter, in 1923, was studying slides of paraffin-sectioned testes and suggested 48 as the number of chromosomes in humans. Because his paper was cited repeatedly that number was eventually repeated as fact. During this era, the squash technique for separating human metaphase chromosomes was developed, and the chemical prefixation technique and the use of colchicine to block cell division metaphase were also introduced. In 1952, Hsu introduced the hypotonic technique, which leads to control of swelling of the cells and separation of individual chromosomes. It was this technique that allowed Tjio and Levan to determine the correct number of human chromosomes. The techniques introduced during the hypotonic era were applied to the analysis of chromosomes from individuals who were mentally retarded or who had other congenital anomalies. In 1959, Lejeune and associates described the first known human trisomy, Down syndrome. In that same year, Ford and associates reported that patients with Turner’s syndrome had only one of the two X chromosomes, for a total of 45 chromosomes instead of 46. Rapidly thereafter, additional chromosomal defects were defined, and the cataloguing of human trisomies compatible with life was exhausted. Attention was then turned to structural aberrations and their phenotypic consequences.

Most human chromosomes could not be identified individually before 1970. In that year, Caspersson and associates⁵ applied fluorescence microscopy to human chromosomes. It was found that chromosomes, when stained with quinacrine, exhibited fluorescent cross bands of different widths. Subsequently, nonfluorescent banding was achieved through a number of different techniques, including various ways of partially denaturing chromosomal DNA. With several of these partial denaturation techniques, subsequent Giemsa staining resulted in reproducible banding patterns that were unique for each chromosome. The technique of banding prophase chromosomes made it possible to define chromosomal segments and break points even more accurately. Through banding techniques, small deletions or duplications of segments of DNA within the chromosome can be precisely identified. This advance made possible the description of a whole new class of chromosomal diseases, the partial trisomy and partial deletion syndromes.

The incidence of chromosomal abnormalities among newborn infants has been studied extensively. Pooled data shows that karyotypic abnormalities are found in approximately 5.7/1000 newborns and congenital ocular malformations occur in approximately 6.0/10,000.^6,7,8,9,10

The abbreviations and terminology commonly used in describing chromosomal rearrangement are as follows. The letter p is used to represent the short arm of a chromosome and the letter q the long arm. The letters are used after the number of the chromosome under discussion. A plus sign (+) after the letter indicates duplication or partial trisomy for the portion of the arm indicated. A minus sign (-) indicates a partial deletion for a portion of that arm. For example, the 5q+ syndrome is the name used to refer to the clinical entity resulting from any partial duplication of the long arm of chromosome 5. More precise localization along a chromosome arm is provided by a numbering system based on prominent bands beginning at the centromere. Each arm of a chromosome is divided into three to five regions, and these are again subdivided into three or more subunits. Using this system, a single band can be named.