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The following points highlight the four main types of chromosomal anomalies. The types are: 1. Autosomal Anomalies 2. Sex Chromosome Anomalies 3. Chromosomes and Spontaneous Abortions 4. Chromosomes in Disorders with DNA Repair Defects.
Type # 1. Autosomal Anomalies:
The first known case of a chromosomal anomaly associated with a clinical disorder was described by Lejeune. Gautier and Turpin in 1959 in Down’s syndrome or mongolism.
Characterised by mental retardation and a few other clinical symptoms, the condition is due to trisomy (presence of an extra chromosome so that a certain pair is represented by three homologues instead of two) of an autosomal chromosome. So far three clinical syndromes have been found to be associated with trisomy of autosomal chromosomes.
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A few genetic disorders are related to some other aberrations of the autosomes and are described below:
i. Down’s Syndrome:
This is frequently due to trisomy of the G group chromosome 21 arising from non-disjunction during meiosis in one of the parents. The karyotype thus shows 47 chromosomes. G trisomy is the most common of all autosomal trisomies.
Sometimes a translocation between a D group chromosome and 21, or between two G group chromosomes is associated with the syndrome (Fig. 21.2). Some patients of Down’s syndrome show mosaicism. Metaphase spreads of such patients show two cell lines in peripheral blood, one cell line with normal chromosomes, another with 21 trisomy.
About one in 700 births of both sexes could show Down’s syndrome. The disorder is characterised by a typical mongoloid facial appearance, webbed neck, a flat nasal bridge, epicanthal fold (small folds of skin over inner corners of eye typical of the mongoloid race) brush field spots around the iris, short fingers, and a gap between the first and second toe.
Their striking feature is mental retardation with IQ ranging between 25 and 50 (normal average humans have an IQ of 80). Congenital heart disease and leukemia occur in many cases. Many have poor muscle tone during infancy. There is a higher incidence of Down’s syndrome among children of older mothers.
The patients live for a variable number of years. A Down’s male is usually sterile, females are fertile and rarely have produced offspring. The dermatoglyphic pattern (arrangement of lines on palm and fingers) shows in many cases a line called simian crease and distal axial triradius. Frequently all the ten fingers show ulnar loops.
As in most genetic diseases there is no cure for a Down’s patient. Affected individuals are usually institutionalised. However, after the birth of a Mongol child it is necessary for the parents to have proper genetic counselling to prevent the birth of another child with mongolism.
An accurate diagnosis through karyotype analysis of the affected child and both parents could provide an estimate of the recurrence risk. When mongolism is due to a translocation, the abnormality can be passed on to future generations through the gametes.
A child that inherits the translocation is affected and could in turn produce victims of Down’s syndrome. In contrast, Down’s syndrome due to non-disjunction, which is a rare event during gametogenesis, is not familial and the condition is not inherited.
ii. Edward’s Syndrome:
Edward and his colleagues in 1960 described a syndrome due to trisomy of an E group chromosome (16-18) and occurring more often in females than in males. The individual may also be a mosaic having a normal cell line and an 18 trisomic line. The incidence is about 1 in 3,500 live births.
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The physical and mental growth is much retarded and death usually occurs in early childhood. Patients have hyper-tonicity of skeletal muscles resulting in a peculiar characteristic by which the affected person keeps the fingers tightly clenched against the palm of the hand. The typical features also include micrognathia (small jaws), deformed ears, small sternum and pelvis, a characteristic dermatoglyphic pattern and severe retardation.
iii. Patau’s Syndrome:
In 1960 Patau and his associates described a clinical disorder originating from trisomy of D group chromosome (13-15). Most of the affected persons have a small head and abnormalities of the face, eyes and forebrain, cleft lip and palate, low set deformed ears, small chin, and the hands are often clenched in the manner described for Edward’s syndrome. In general the individual appears more severely malformed than in the previous two syndromes and the mean life span is only about 4 months.
iv. Cri Du Chat (Cat cry) Syndrome:
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An interesting abnormality in which the affected newborn cries in a manner resembling the mewing of a cat, was first described by Lejeune in 1963 in France, hence the name cri du chat (cat cry). A small head, widely spaced eyes, receding chin and congenital heart disease are some other typical features. The condition is due to a deletion in the short arm of the B group chromosome 5, and is very rare.
v. Wolf Syndrome:
Another very rare syndrome is caused by a deletion in the short arm of a B group chromosome (no. 4). It is distinct from the cat cry syndrome.
vi. The Philadelphia (Ph1) Chromosome:
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This is one of the best known cases of a specific association between a chromosomal anomaly and a human disorder. The bone marrow cells of most of the patients with chronic granulocytic leukemia show a deletion of the long arm of a G group chromosome (number 22) called Philadelphia or Phl chromosome.
The banding technique has further revealed that a portion of the long arm of chromosome 22 is actually translocated to a longer chromosome.
vii. Chromosome 13 and Retinoblastoma:
A deletion in the long arm of chromosome 13 is specifically associated with retinoblastoma, an autosomal dominant trait.
Type # 2. Sex Chromosome Anomalies:
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i. Klinefelter’s Syndrome:
In 1942 Klinefelter described a condition in phenotypic males which turned out to be due to an extra X chromosome (47, XXY). The affected individuals appear normal in childhood, the abnormalities becoming visible only in adult males. The syndrome is characterised by absence of spermatogenesis, gynaecomastia, and excessive secretion of gonadotropins in the urine.
Since buccal smears of Klinefelter’s males show Barr bodies, they are referred to as chromatin-positive males. Most of the patients are mentally retarded and develop a variety of psychiatric problems. Although many have the karyotype 47, XXY, some may have 48, XXXY, 49, XXXXY, or 48, XXYY, or they may be cytogenetic mosaics.
ii. Turner’s Syndrome:
This is shown by females characterised by a short stature, gonadal dysgenesis, sexual infantilism, webbed neck, prominent ears, cubitus valgus (increased carrying angle of the arms) dystrophy of the nails and hypoplastic nipples.
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Their sex chromosome constitution is XO and they have only 45 chromosomes. They are chromatin-negative females as they do not show Barr bodies. They are frequently mosaics with more than one cell line such as XO/XXX, XO/XX/XXX, and others. The incidence is one in about 5,000 births.
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iii. The XYY Male:
In 1965 Jacobs et al found that many of the men kept in institutions for the retarded due to aggressive and antisocial behaviour have 47 chromosomes with XYY sex chromosomes. They are usually tall but not always mentally retarded, frequently show hypogonadism and are sterile.
The presence of two Y chromosomes can be recognized as two brightly fluorescent bodies by proper staining. The discovery of this syndrome received publicity because of the possible association of a chromosome anomaly with human behaviour.
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iv. The Triple-X Syndrome:
These are individuals with 3X chromosomes designated super-females. They are mentally retarded, sexually normal and fertile. Although most triple-X females have 47, XXX karyotype, some may have 48, XXXX, 49, XXXX, and still others may be mosaics. They show 2, 3 or 4 Barr bodies in their buccal smears (always one Barr body less than the total number of X’s).
v. Intersex:
Individuals with both male and female gonadal tissues are called hermaphrodites (from Greek Hermaphrodites, the son of Hermes and Aphrodite). Their karyotype analysis shows that they are mosaics having both X and Y chromosomes in their cell lines. Their buccal smears may or may not show a Barr body. Their external genitalia are often ambiguous, and they are almost always sterile.
The condition of pseudo-hermaphroditism is also included among intersexes. Such individuals are cytogenetically normal with 46, XY (male pseudo-hermaphrodites) or 46, XX (female pseudo-hermaphrodites) chromosomes and normal buccal smears for one sex only. But phenotypically they show both male and female characters.
There are two classes. Male pseudo-hermaphrodites that have testes and either ambiguous or female-like external genitalia. The female pseudo-hermaphrodites have ovaries and either ambiguous or male like external genitalia. The pseudo-hermaphrodites have some defect in the biosynthesis of testosterone in the testes or in the adrenal glands or in both.
Type # 3. Chromosomes and Spontaneous Abortions:
About 15% of all human pregnancies terminate before the 22nd week by spontaneous abortion. A study of aborted foetuses by D.H. Carr (1967, 1971) has shown that 5-6% of abortions are due to chromosomal aberrations. Triploidy is frequently observed in aborted foetuses.
In fact the first cases of triploidy in humans were discovered from two aborted foetuses by Penrose and Delhanty in 1961. A characteristic clinical feature of triploid abortions is the hydatidiform mole of the placenta.
Trisomy is also very common in abortuses. Trisomy for all the 22 autosomal pairs has been observed in abortuses. The most frequent however is trisomy 16. The XO constitution is common in abortuses, and unbalanced translocations are also observed.
Type # 4. Chromosomes in Disorders with DNA Repair Defects:
There are four inherited disorders with DNA repair defects which show chromosomal anomalies. The affected persons are also predisposed to cancer. The most well studied is Xeroderma pigmentosum (XP described elsewhere). This is characterised by defects in repair of DNA lesions caused by UV rays and other mutagens. The patients often develop skin cancers.
In Bloom’s syndrome (BS) there is slow rate of DNA chain maturation dining replication. Patients are sensitive to sun’s rays and retarded in growth. Their cultured cells show an increased frequency of sister chromatid exchanges.
In ataxia-telangiectasia (AT) the cells are not able to repair damage caused to bases in DNA by gamma rays. Fanconi’s anemia (FA) affects bone marrow cells. There is faulty repair of cross links in DNA. In all the 4 disorders the cultured cells show one or the other chromosomal abnormality.
