Types of Chromosomal aberrations in man are of two general types: variation in the number of chromosomes and alteration in structure. Cells containing multiples of the normal chromosome number are called polyploid, those with irregular numbers aneuploid. Trisomy, in which a particular chromosome is represented in the somatic cells in triplicate, may cause clinical disease. Complete monosomy, in which there is one chromosome less than normal, has been found only in connection with the sex chromosomes.
Etiology.
Abnormal segregation of human chromosomes may take place during mitosis or during the first or second meiotic divisions. Abnormal segregation is known as nondisjunction. When nondisjunction takes place the chromatids or homologous chromosomes fail to separate, but remain attached at the centromere instead of one going to each of the two daughter cells.
Thus when the cell divides, one daughter cell receives both chromosomes, and the other acquires none . Meiotic nondisjunction produces an ovum containing 24 chromosomes, which is usually viable on fertilization, and one with 22, which is usually invisible except for the XO individual with Turner’s syndrome (see under Human Sex Anomalies in section on Diseases of the Endocrine System). The phenomenon of anaphase lag, which results in the loss of a chromosome during mitosis or meiosis, gives rise to two daughter cells, only one of which has an abnormal chromosome number.
If nondisjunction occurs at the first mitotic division of the fertilized ovum, the zygote develops into a mosaic individual, half of whose cells contain ’45 chromosomes and half 47. If nondisjunction occurred at the second division or later, and all cell lines were equally viable, a mosaic of 45, 46, and 47 chromosomes would result. If the monosomic cell line of 45 chromosomes were in viable, as is usually the case, a chromosomal mosaic of 46/47 would result. To detect mosaicism it is important to examine the karyotype of the skin as well as that derived from lymphocyte cultures.
Mosaicism may be suspected when the clinical manifestations of a disease, known to be caused by chromosomal aberrations, appear relatively mild. Thus the presence of a nearly normal intelligence in a child with mongolism would suggest the presence of a population of cells with a normal chromosomal constitution as well as some with 47 chromosomes. An increased liability to nondisjunction with increasing maternal age appears well established. Moreover, in some families an unusual concentration of chromosomal abnormalities strongly suggests the possibility that genetic factors may predispose to chromosomal aberrations. Consanguinity in one of the parents would strengthen such a supposition.
Types of Chromosomal Aberrations Complete Guide Every Doctor Must Know
Mongolism (Down’s Syndrome, Trisomy 21).
In 1866 Langdon Down described this syndrome, which is characterized by mental retardation, congenital abnormalities, and a pathognomonic facies. Cardinal features include an upward, outward slant of the palpebral fissures, epicanthic folds, flat nose bridge, downward slant of the mouth, microcephaly, flattened occiput, high arched palate, micrognathia, low set ears, short stature, incurved little fingers, and characteristic dermatoglyphic patterns. Mild skeletal anomalies, particularly a shallow acetabulum, are common, and approximately 25 per cent of mongols have a congenital heart defect, frequently affecting the atrioventricular septum.
There is delayed growth, and mental retardation is almost universal. Approximately 15 per cent of all institutionalized retardates are mongols. There is a familial recurrence in approximately 3 per cent of the cases. Increased maternal age is noteworthy; the average age of mothers at birth of the mongol child is about 33 years compared with 26 years for mothers of normal children. There is a slight excess of males. Some female mongols are fertile, and half their offspring are mongols. Male mongols, however, are sterile. Their testes are small, and spermatogenesis is absent or incomplete.All but 3 per cent of mongols have 47 chromosomes in each of their body cells —the extra chromosome is No.’ 21- The remainder result from mosaicism or translocations (vide infra).
Trisomy 13
Clinically this rare syndrome, which has a frequency of approximately 1 per 5000 live births, is characterized by severe central nervous system defects, anophthalmia (rarely, cyclopia), harelip, cleft palate, congenital heart disease, polydactyly, microcephaly, and mental retardation. Arhinencephaly and clubbed feet with prominent elongated heels are common. Over 100 cases have been described; the patients die before six months of age unless they are chromosomal mosaics. There is a strong maternal age effect.
Trisomy 18
This chromosomal abnormality has a frequency of approximately 1 per 3000 live births. The condition is characterized by severe mental retardation, low-set malformed ears, and congenital heart disease. The hands are held in a flexed position with the index and little fingers overlapping the central digits; in the first few months of life this sign in invariably found. The great toes are usually short. Instead of the usual whorls or loops, the fingerprints show several arches, usually more than six. The chin and pelvis are characteristically small. All patients die before one year of age. There is a strong maternal age effect. Confusion with Turner’s syndrome must be avoided.
Sex Chromosome Variation
Turner’s syndrome (45, XO), Klinefelter’s syndrome (47, XXY), and the double Y male (47, XYY) are discussed elsewhere. Many other numerical variants of the X chromosome have been described, including 49 XXXXX females and 49 XXXXY or 49 XXXYY males. The Y chromosome is strongly male-determining; without a Y chromosome the individual is a phenotypic female. Mosaicism is especially common in individuals with sex chromosome anomalies.
Predictably, sex chromosome variations are accompanied by malformations of the urogenital system.
Frequently growth disturbances, skeletal malformations, and endocrine defects occur. With increasing numbers of sex chromosomes mental retardation is common. Infertility accompanies the XO and XXY conditions, but XXX and XYY individuals are fertile. The latter produce only children with normal karyotype.
Nomenclature
During meiotic crossing over, homologous chromosomes break and rejoin. Normally, however, the exchange is exact since the breakage point on the two chromatids is the same. Thus, although exchange of genetic material has taken place between the two homologous chromosomes, the total amount of genetic information is unaltered. If, however, the break occurs at different points of the chromosome, one chromosome‘will have excess genetic material (duplication), and the other chromosome will have less {deletion).
Terminal deletions may be difficult to distinguish from translocations vide infra). If a chromosome is broken in two places and the interstitial segment rotates 180 degrees and rejoins, an inversion occurs. When the inverted segment includes the centromere region, it is called a pericentric inversion, when it is confined to one arm of the chromosome, it is termed a parametric inversion. All these structural rearrangements are stable and may be inherited.
Etiology
Chromosome breads may be spontaneous or induced by physical, chemical, or biologic agents. Physical agents include temperature shock, gravity changes, electromagnetic disturbances, and various forms of radiation, e.g., x- rays, gamma rays, and ultraviolet light. Over 200 chemicals are known to alter chromosome structure. These chemicals fall into many classes, but the^ largest number are nucleic acid analogues and alkylating agents. There is increasing concern that an unidentifiable number of drugs may affect chromosome structure. Antimicrobials and drugs affecting the central nervous system are under particular scrutiny.
There is growing evidence that certain viral infections may cause chromosomal aberrations. Three types of morphologic change have been noted: chromosomal breakage, complete fragmentation and polarization of the chromosomes, and cell fusion with abnormal spindle formation. Abnormalities can be detected in vitro with measles virus, herpes virus, and certain oncogenic viruses, and have been reported in vivo in certain epidemics of measles, infectious hepatitis, and infectious mononucleosis. The single chromosome breaks, and dicentric chromosomes following viral infection are similar to those that may follow diagnostic or therapeutic irradiation.
Deletion in the Short Arm of Chromosome 5 (Cri du Chat Syndrome).
This syndrome is characterized by hypertelorism, microcephaly, severe mental deficiency, and a characteristic plaintive “catlike” cry. This sign, which disappears after the age of two, has given the syndrome its descriptive name. Approximately 10 per cent of patients suffer from congenital heart disease, and the patients usually die in childhood.
Deletion in the Long Arm of Chromosome 18.
Fewer than,ten cases of this syndrome have been described. Symmetrical dimples on the shoulders, fusiform fingers, and severe mental deficiency are common.
Deletion in the Long Arm of Chromosome 21 (Philadelphia Chromosome).
A partial deletion of the long arm of chromosome 21 has been a constant finding in chronic myelogenous leukemia. The abnormal chromosome is confined to the erythrocytic, thrombocytic, and granulocytic series of hematopoietic cells. During remission the deleted chromosome may disappear from the circulation to reappear during relapse (see Chronic Myelogenous Leukemia).
Rings
A ring configuration results if breaks occur at both ends of one chromosome and the proximal broken ends join. This results in loss of genetic material (deletion) distal to the breaks. Since any chromosome can undergo ring formation, there is no simple phenotype associated with rings.- One outstanding characteristic is the absence of the thumbs in some patients with a ring chromosome in the 13-14-15 group. Rings are unstable during cell division. They are variable in size and may be lost entirely in some cells.
Translocations
The chromosomal aberration in which a fragment of one chromosome becomes attached to a homologous chromosome is termed a translocation. Translocations occur when two chromosomes break and are followed by mistaken reunion of the broken ends.
In order for the homologous segments to pair at meiosis, translocated chromosomes assume cruciform configurations. When the chromosomes separate, six possible gametes are produced. One of these gametes is entirely normal, one has essentially the same amount of genetic information as a normal gamete, but the genetic material is abnormally distributed between the two chromosomes (balanced translocation), and four gametes are unbalanced
It is apparent that a normal person with a balanced translocation may be phenotypically normal and yet have 45 chromosomes. A person with a balanced translocation may transmit the abnormal chromosomes to his offspring. Only three of the six types of offspring have been observed: normal persons, persons with the balanced translocation who are similar to the parents, and affected persons with 46 chromosomes who are essentially trisomic and have an abnormal phenotype. Individuals who are monosomic and lack the translocation chromosome are not seen; it is presumed that the condition is lethal.
It is evident that a concentration of abnormal persons may occur in families in which there is a translocation chromosome. Patients with mongolism who have a chromosomal complement of 46 and possess a translocation chromosome are relatively common. The translocation is usually a 14:21 translocation (2 per cent of Mongols), or, more rarely, 21:22 translocation (1 per cent of Mongols). In 14:21 translocations the condition is usually transmitted through the mother, whereas the 21:22 translocation is transmitted equally by both sexes.
