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Chromosome Abnormalities in Humans – Down Syndrome, Turner Syndrome, and Klinefelter Syndrome
In diploid condition, a body cell contains 46 chromosomes and each chromosome remains in pair. Therefore, all the chromosomes may be divided into 2 sets, each set containing 23 chromosomes. Out of these 23 chromosomes, 22 are called autosomes and one is the sex chromosome. Therefore, among the 46 chromosomes of a somatic cell, 44 chromosomes or 22 pairs represent autosomes and one pair represents sex chromosomes. In human males, the pair of sex chromosomes varies by morphology and structural organization. These male-specific sex chromosomes are called X and Y. On the other hand, the females contain two identical sex chromosomes i.e., the X chromosome. The human male and female differ only by their sex chromosome combination.
Chromosomes are the bearer of hereditary material. Hence, the genes for different characters are present on the chromosomes. Any change in the structural organization of the chromosome or in their number in any organism affects the phenotype and physiology, thereby causing the abnormality. Several examples of structural aberration of chromosomes and numerical aberration in animals/plants resulting in the development of variation or defects may be indicated in the following table.
Chromosome Aberration of Various Forms:
|Type of Aberration||Form||Effects||Example|
|Structural Aberration||1. Deletion||Part of a chromosome is lost.||Cri-du-chat syndrome in man (A part of the small arm of the 5th chromosome deleted).|
|2. Duplication||A part of the chromosome increases by number.||Bar eye mutation Drosophila (Due to duplication of a segment of X).|
|3. Inversion||A part of the chromosome is broken and inverted at 180° at the same position as the chromosome.||–|
|4. Translocation||Exchange of parts between two non-homologous chromosomes and shifting of a part of the chromosome from one position to the other.||Burkitt’s Lymphoma due to translocation between chromosomes 8 and 11.|
|Numerical Aberration||1. Euploidy||Haploidy||Only one set of chromosomes forms the body.||In animal rare, only in males of honey bees haploid chromosomes are present.|
|Polyploidy||The number of sets of chromosomes becomes more than two.||Triploid condition.|
|2. Aneuploidy||Monosomy||Only one chromosome of the pair is present.||Turner’s syndrome due to monosomy of X.|
|Trisomy||Increase of one chromosome with the diploid set.||Klinefelter’s syndrome, Down Syndrome.|
|Nullisomy||Both the homologs are a lot from the set.||No example.|
Down syndrome is a very well-known congenital abnormality in humans. The syndrome is developed due to trisomy of chromosome 21, but in certain cases, a translocation between chromosome 14 and chromosome 21 may also result in a similar abnormality in men. It is known as familial Down syndrome. British physician John Langdon Down described the syndrome in 1866 and the syndrome was named after Langdon Down. The Down syndrome that may be developed due to chromosome 21 trisomy was identified by Dr. Jerome Lejeurne, in 1959. Down syndrome may be identified by direct observation or in foetus by prenatal screening.
Sign and Symptoms of Down Syndrome:
The affected individual with Down syndrome may show all or many of the features such as:
- Microglia: abnormally small chin.
- Oblique eye fissures on the inner eye corner.
- Hypotonia of muscles: Poor muscle tone.
- Flat nasal bridge.
- Single palmar fold.
- Protruding tongue due to small oral cavity and enlarged tongue.
- Face flat and broad.
- Short neck.
- Brushfield spot: white spots on the iris.
- Excessive joint laxity including atlantoaxial instability.
- Excessive space between the large toe and second toe.
- Short fingers.
- Higher no. of the ulnar loop.
Height, weight, and head circumference are smaller in children with Down’s syndrome in comparison to those of normal children of the same age. Adults with DS (Down Syndrome) appear to be small in height and bowed legs. The average height for men is 5’1” (154 cm) and 4’9” (144 cm) for women. They have a high risk of obesity as they age. Individuals of DS show some features with an increased frequency whereas some other features with decreased frequency as indicated in the following table.
Common Symptoms of Down’s Syndrome:
|1. Stunted growth||100%|
|2. Mental retardation||99.8%|
|3. Flexible ligament||80%|
|6. Smaller genitalia||75%|
|7. Eyelid crease||75%|
|8. Shortened extremities||70%|
|9. Oval palate||69%|
|10. Low set and rounded ear||60%|
|11. Flattened nose||60%|
|12. Small teeth||60%|
|14. Umbilical hernia||51%|
|15. Short neck||50%|
|16. Shortened hands||50%|
|17. Congenital heart disease||45%|
|18. Macroglosia (larger tongue)||43%|
|19. Epicanthic fold||43%|
|20. Brushfield Spots (iris)||35%|
Cause of Occurrence:
Down syndrome is a genetic disorder and it has been found that in 95% of cases, the syndrome appears due to trisomy 21. Therefore, the affected person contains an extra chromosome 21 and the affected person usually contains 47 chromosomes in their body cells. However, in 3-4% of cases, a translocation of a part of chromosome 21 to chromosome 14 could be noticed. This type of Down syndrome is called familial Down syndrome.
The incidence of Down syndrome has a relation with maternal age. With the increase in maternal age, the risk of birth of a baby with Down syndrome increases. When at the age of 29 of the mother, the risk of the birth of a DS baby has been estimated to be 1 in 1000; whereas at the age 35, this risk comes to about 1 in 385. At the age of 40, this risk comes to about 1 in 106.
Down syndrome has been presumed to be a nondisjunction event when a mother produces a female gamete with two 21 chromosomes.
Management of Down Syndrome:
The incidence of Down syndrome is about 1 in 800. The Down babies are physically handicapped. They are usually severely mentally retarded having learning disabilities. Besides, they are also prone to several fatal diseases. Hence, they become a social burden. Therefore, management of the babies with Down syndrome is a serious concern. Education and proper care may improve their quality of life.
Turner syndrome represents a genetic defect in humans when the affected person appears phenotypically female with a number of unusual features. The syndrome is developed due to an aneuploid condition in which the affected individual contains 45, X chromosome condition, i.e., instead of containing 46 chromosomes, the female contains 45 chromosomes containing one X chromosome. In this situation, though the individual becomes a phenotypic female she develops many abnormal features. It is also known as gonadal dysgenesis. This abnormal female phenotype associated with chromosomal anomaly was first described by H. H. Turner in 1938. Turner syndrome occurs in about 1 in 2500 live female birth.
Signs and Symptoms of Turner Syndrome:
The affected individual with Turner syndrome shows usually the following symptoms:
- Short stature.
- Swelling of hands and feet (Lymphedema).
- Low hairline.
- Low-set ears.
- Rudimentary ovaries as a gonadal streak.
- Absence of menstrual period (Amenorrhoea).
- Reproductive sterility.
- Obesity and increased weight.
- Broad chest (Shield’s chest) with widely spaced nipples.
- Small fingernails.
- Webbed neck from cystic hygroma in infancy.
- Horseshoe kidney.
- Constriction of the aorta.
- Visual impairment.
- High waist-to-hip ratio: hips are not much bigger than the waist.
It is to be pointed out that the affected person may have a combination of many features as indicated above. A Turner individual may include some other features such as micrognathia (small lower jaw), cubitus valgus, drooping eyelids, palmar crease, and soft upturned nails. This female lacks a Barr body in her somatic cells.
Genetics of Turner Syndrome:
The normal female contains two X chromosomes along with normal autosomal sets. The Turner female contains one X chromosome having 45, X condition. This lack of one X chromosome in the female body results in the development of Turner syndrome. The missing X chromosome with loss of genetic material in one X-chromosome in the female may be stated as the cause of Turner syndrome. Sometimes a Turner female may exhibit partial loss from one of the X-chromosomes. Scientists could be able to identify a gene called SHOX that is important for bone development and growth. Loss of one copy of SHOX is presumed to be associated with abnormalities in women with Turner syndrome. The individual with Turner syndrome usually lacks a Barr body in the somatic cell nucleus.
Sometimes a woman with Turner syndrome shows some of her body cells with a normal complement of X chromosome (2X). Such Turner female is known as Mosaic Turner. Mosaicism in Turner females is estimated to be relatively common (-67-90%). In case of partial deletion associated with Turner syndrome, the p arm (short arm) of the X chromosome is deleted and such a case may be denoted as 46, Xdel Xp.
In Turner syndrome, the monosomic X chromosome comes from the mother, and non-disjunction in the father during gametogenesis may contribute to this condition. The normal female gamete being fertilized by a male gamete may develop a Turner female. Karyotype analysis from the Turner patient may reveal the genetic constitution of the affected person.
Klinefelter’s syndrome is a type of abnormality in men that is developed due to chromosomal trisomy. In this case, the affected person contains two or more X chromosomes along with a Y chromosome. The affected person appears phenotypically male but contains some features like a female. In population, iMdtong 500 maybe with Klinefelter syndrome. H.F. Klinefelter in 1942 first described the chromosomal basis of the syndrome.
Symptoms of Klinefelter Syndrome:
The symptoms of this syndrome in general may be enumerated as:
- Phenotypically male with sparse hair in the beard and mustache.
- Tall stature.
- High-pitch voice.
- Presence of gynecomastia.
- Maybe with undescended testis.
- Sub-fertile to sterile in nature.
- Presence of Barr body in the somatic cells.
However, the sign and symptoms of the affected individual may be detected from the very childhood.
Signs and Symptoms of Klinefelter Syndrome at Different Life Periods:
|Life Period||Sign and Symptoms|
|1. Childhood||Delay in starting to talk or walk, learning difficulty.
Trouble in listening or concentrating in class.
Poor motor development or coordination (sometimes leading to shyness).
Reduced muscle strength or tone.
|2. Puberty||Small testicles (hypogonadism)
Lack of facial, pubic, and underarm hair.
Gynaecomastia (Breast tissue development)
Weight gain, especially on the stomach or trunk
Tiredness and fatigue
Disproportionately long arms and legs compared to the length of the body.
Taller than average height.
Difficulties in sexual functioning.
High pitch voice.
|3. Birth||Small penis
Hypospadias (the urethra is located on the underside of the penis).
The person affected with Klinefelter syndrome may develop some complications as indicated below:
- Diabetes mellitus
- Breast cancer
- Testicular cancer
- Sleep apnoea
- High cholesterol
- Tooth decay
- Varicose vein
Genetics of Klinefelter Syndrome:
Klinefelter syndrome is developed in an aneuploid condition when the affected person contains two X chromosomes along with a Y chromosome. In the karyotype of the affected person 47, XXY condition may be observed. Sometimes the number of X-chromosomes may be more than two also. But always the chromosomes remain associated with the Y chromosome. The presence of the Y chromosome makes the affected person a male. Extra X chromosome probably develops abnormality in the Klinefelter individual. Due to the presence of more than one X chromosome, the Klinefelter individual shows the presence of Barr’s body in his somatic cell nucleus. The number of Barr bodies in a cell depends on the number of X chromosomes present in the affected individual.
A baby with Klinefelter syndrome may be developed if a female gamete containing 2 X chromosomes is fertilized by a Y-bearing male gamete to produce a zygote with an XXY chromosome combination. A female gamete may abnormally contain 2 X chromosomes if non-disjunction occurs during meiotic cell division involving X chromosomes of the ovum mother cell. This may again occur post-zygotically from one normal XY chromosome-bearing zygote. In this case, also non-disjunction of splitted X-chromosome occurs during mitotic cell division of the zygote.
XXY chromosome combination in the germ mother cells of the affected individual promotes impaired gametogenesis in Klinefelter males. Hence, spermatogenesis fails to develop an adequate number of normal spermatozoa. For this reason, the Klinefelter male is either subfertile or infertile in nature. Klinefelter syndrome and its variants are not inherited; this chromosomal abnormality usually occurs as random events during the formation of reproductive cells in a parent. An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. The adverse effect of Klinefelter syndrome in testicular growth, resulting the formation of smaller testicles than normal testicles which can lead to the lower production of testosterone hormone. Most men with Klinefelter syndrome produce little amount or no sperm. But assisted reproductive procedures may make it possible for some men with Klinefelter syndrome to father children.