Chromosomal abnormalities - A review

Shubhangi Khandekar, Alka Dive, Prashant Munde

Abstract
With the discovery in 1956 that the correct chromosome number in humans is 46, the new era of clinical cytogenetics began its rapid growth. During the next few years, several major chromosomal syndromes with altered numbers of chromosomes were reported, i.e. Downsyndrome (trisomy21), turner syndrome (45,x) and klinefelter syndrome (47,xxy). Since then it has been well established that chromosome abnormalities contribute significantly to genetic disease resulting in reproductive loss, infertility, stillbirths, congenital anomalies, abnormal sexual developmentmental retardation and pathogenesis of malignancy.specific chromosome abnormalities have been associated with over 60 identifiable syndromes. They are present in at least 50% of spontaneous abortions, 6% of stillbirths, about 5% of couples with two or more miscarriages and approximately 0.5% of newborns. In women aged 35 or over, chromosome abnormalities are detected in about 2% of all pregnancies. Some of the abnormalities and their clinical consequences will be Discussed in the following sections. Key Words: Chromosomal abnormalities, numerical, structural abnormalities, syndromes.

Introduction
A chromosomal disorder occurs when there is a change in the number or structure of the chromosomes. This change in the amount or arrangement of, the genetic information in the cells may result in problems in growth, development and/or functioning of the body systems1. The chromosomal abnormalities may occur either during the production of the egg or sperm or early after the baby's conception: a 2,3 spontaneous occurrence for unknown reasons .
Address for Correspondence

Chromosomal abnormalities may also be inherited from a parent. There are two main types of chromosomal disorders: changes in chromosome number and changes in chromosome structure

Chromosomal disorders
Major category of human disease, represent 1% of live births, 2% of pregnancies in women older than 35, 50% of all spontaneous first trimester abortions, responsible for more than 100 human syndromes and are more common than all Mendelian single-gene disorders5.

Dr. Shubhangi Khandekar

Professor, Department of Oral Pathology & Microbiology, VSPM Dental College & Research Centre, Nagpur 440019. Mob. : + 91 8149336195 E-mail : [email protected] 35

Chromosomal abnormalities
sometimes also called cytogenetic disorders are very common. Most fetuses with some chromosomal abnormality usually do not survive. About 50% of firsttrimester abortions

Central India Journal of Dental Sciences, Vol. 4 (1), Jan - Mar 2013

are connected with some cytogenetic mistake. The incidence of chromosomal abnormalities is 1 approximately 1 out of 200 of newborns . We are able to find the disorders due to karyotype testing. The cytogeneticists get the samples (blood, amnionic fluid), then stain the chromosomes and arrange them in the right order by their length. Then we can see some changes in pattern (banding). The most typical method is giemsa stain, so it is usually called "g banding". This is important for structural abnormalities. Numeral abnormalities we can 6, 7 identify even easier . Other classification of chromosomal abnormalities depends on fact which type of chromosome is affected autosomes (down syndrome, digeorge syndrome) or sex chromosomes (klinefelter syndrome, turner syndrome).

23 chromosomes from the mother and 23 chromosomes from the father. Cells of fetus are already diploid (2n). Mistake during meiosis leads to incorrect number of the chromosomes in the egg or in the sperm5. Child can get some extra chromosome (trisomy) or miss it (monosomy). The second type of cell division is the mitosis. It occurs in all non-reproductive cells. It is a form of duplication of the genetic information, followed by the halving of material. The parent cell has 92 chromosomes (4n), two subsidiary cells have 46 Chromosome each (2n).Mitosis starts immediately after fertilization and continues throughout whole life6,7. When mistake occurs, the chromosomes may not be equal. Problems in mitosis lead to the mosaicism more often.
Parent Cell (2N) Parent Cell (2N)

Etiology of chromosome abnormalities

Etiology of chromosome abnormalities is pretty variable. The most often reason is mistake which occurs during the cell division. It is connected with wrong development of the sperm or ovum 4 (female reproduction cell) . There are two types of cell division mitosis and meiosis. Other causes are the maternal age and the influence of the environmental. Chromosome abnormalities are usually fatal. Each second first-trimester abortion is caused by them. Children who survive and get born suffer from very serious mental and physical problems5. The screening for chromosome abnormalities is very important. The 6 cytogeneticists use the karyotype testing .

Daughter Cell (2N)

Daughter Cell (N)

Mitosis

Meiosis

Fig. 1 - Problems in the cell division

Age of parents
There is strong influence of the maternal age (especially in Down syndrome). The paternal age is less important, but still has its importance. The difference is in cell division of reproduction cells1. The number of eggs (females cells) is done by our birth. So eggs underway meiosis many times. The later age of delivery means the higher risk of some abnormalities. It takes just 72 hours to the development of sperm cells. It is less 3 probably to make a mistake during this period .

Problems in the cell division

There are two main types of the cell division. The first one is the meiosis. It is the process of division of reproduction cells. The result is a cell with 23 chromosomes (it is haploid). Fetus gets
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Central India Journal of Dental Sciences, Vol. 4 (1), Jan - Mar 2013

To the older women is recommended to visit some genetic counseling centre. "The older women" means more than 35 years. The prenatal diagnosis is the best way to find some affected children. The method of prenatal diagnosis as an amniocentesis5.

number of chromosomes (46 chromosomes) as well as no loss of genetic material stays the 2,3 same . Fortunately typical place of break is near the centromere, usually only small arms of the acrocentric chromosomes are lost. There are no crucially important genes coded by these chromosomal segments. So, a carrier of such robertsonian translocation can normally survive this cytogenetic change. Unfortunately problems occur during the fertilization with a gamete of a carrier of a balanced translocation. Carrier of the translocation may produce unbalanced zygotes, because the process of homologous chromosomes pairing during meiosis is interrupted. This is very important because unbalanced gametes lead to abnormalities in offspring. The reason is that the offspring receives altered chromosome from the carrier 6 which may lack several important genes . Therefore the only clinical symptom found in the carriers of balanced translocations may be the reproduction failure.

Fig. 2 - Relation between maternal age & development abnormalities

Influence of the environment

It is very hard to tell how important the environmental is. We cant find any significant differences between parents with child with a chromosome abnormality and parents with healthy child. They have usually very similar lifestyle or habits.5 But there are still some dangerous influences x-rays, medication or food. Most of them have a cumulative character. Because we are not sure about the origin of abnormalities, it is hard to recommend any prevention. Sometimes it is said that the folic acid has a positive role in prevention of congenital abnormalities. Pregnant women should also get vitamins to reduce risks7.

Karyotype 44,XY

Balanced trans location Chromosomal breaks

Types of structural abnormalities Translocation

During translocation, a part of one chromosome is transferred to another chromosome. It is very important whether the translocation is balanced or unbalanced. Balanced means that two chromosomes just exchange their parts but the
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Chromosome is too small

Karyotype 44,XY

Robertsonian trans location

Fig. 3 - Translocation

Central India Journal of Dental Sciences, Vol. 4 (1), Jan - Mar 2013

Types of translocation
Reciprocal translocation between two chromosomes ("a segment" goes to "b chromosome" and "b segment" goes to "a chromosome") Robertsonian translocation (or fusion) of two acrocentric chromosomes

Isochromosomes
Isochromosomes are created by the incorrect division of centromere. Normally centromere divides vertically. In this case it divides horizontally. The result is usually the loss of one arm. It means that newly created chromosome has just two long arms or two short arms which are normally connected by centromere. It occurs relatively frequently in X chromosome. It is a huge problem during the fertilization. Because fetus then becomes trisomic for one arm and monosomic for the second arm.
Two long arm Short arm Two short arm Centromore Horizontal Division

Segment Chromosome Aberration Chromosomal breaks

Fig. 4 - Robertsonian translocation

Deletion
Deletion is characterized by the loss of a part of chromosome. Two breaks have to occur for deletion of the interstitial segment. For deletion of terminal segment (telomere) one break is enough. Segments which were deleted from the chromosome are not able to "live" on their own and the genes present in those segments are lost. One special example of deletion exists. It is called "ring chromosome". It is a situation when chromosome lost both of its ends. The long and the small arms then connect together and chromosome became a ring shaped.
Chromosome Ring chromosome

Long arm Isochromosome

Fig. 6 - Isochromosome

Inversion
For inversion are typical two breakages in the different part of the chromosome. The newly created segments then replace each other. Inversion was discovered in 1921. Although we still dont know why inversion exists, we know that it is the most important mechanism of reorganizing of the genome. There are 2 types of inversion: Pericentric causing deletions, insertions or abnormal centromere; Paracentric more common type, it is less harmful for its carrier.

Segment Ends of chromosome

Inversion suppresses the recombination process.

Fig. 5 - Ring chromosome 38 Central India Journal of Dental Sciences, Vol. 4 (1), Jan - Mar 2013

Parts of a chromosome
When we want to describe the location of some structural abnormality we used special marks. We have to count the regions always from the centromere for both arms. Example: 1q13 The first number is a number of chromosome chromosome 1; (p) and (q) are used for marking of arm (p) for small arm and (q) for long arm the long arm; The third number is for the region of chromosome region 1; Chromosomal marking last number is for the band band 3. So the change is located on the long arm of chromosome 1

Aneuploidy in human sex chromosomes

X_ female (Turner Syndrome) Short stature; sterile (immature sex organs); often reduced mental abilities. About 1 in 2500 human female births

XXY male (Klinefelter syndrome)

Often not detected until puberty, when female body characteristics develop. Sterile; sometimes reduced mental abilities; testosterone shots can be used as a partial treatment; About 1 in 500 human male births.

XYY male (XYY syndrome)

Usually tall, with heavy acne; some correlation with mild mental retardation and with aggressiveness; usually still fertile. About 1 in 1000 human male births

Abnormalities in chromosomal number

Nondisjunction - Mistake in cell division where chromosomes do not separate properly in anaphase.Usually in meiosis, although in mitosis occasionally. In meiosis, can occur in anaphase I or II. Polyploidy complete extra sets (3n, etc.) fatal in humans, most animals.Aneuploidy missing one copy or have an extra copy of a single chromosome. Three copies of a chromosome in your somatic cells: TRISOMY. One copy of a chromosome in your somatic cells: Monosomy Most trisomies and monosomies are lethal well before birth in humans; exceptions covered below. Generally, autosomal aneuploids tend to be spontaneously aborted. Over 1/5 of human pregnancies are lost spontaneously after implantation.Chromosomal abnormalities are the leading known cause of pregnancy loss. Data indicate that minimum 10-15% of conceptions have a chromosomal abnormality. At least 95% of these conceptions spontaneously abort (often without being noticed)

XXX female (triple X syndrome)

Usually just like XX females, except for having 2 Barr bodies in somatic cells. HOWEVER, more likely to be sterile, and if fertile, more likely to have XXY and XXX children. About 1 in 1000 human female births. Aneuploidy in human autosomes

Autosomic monosomy
appears to be invariably fatal, usually very early in pregnancy. Most autosomic trisomy is fatal, but sometimes individuals trisomic for autosomes 13, 15, 18, 21, or 22 survive to birth and even beyond. Chromosome number reflects size; bigger number = smaller size, and usually fewer genes. Extra 13, 15, or 18 lead to multiple defects and usually death well before 1 year of age. Extra 22 is much like extra 21 (Down syndrome, covered below), but usually more severe, with shorter life expectancy.

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Central India Journal of Dental Sciences, Vol. 4 (1), Jan - Mar 2013

Trisomy 21 (Down syndrome)

The only autosomal trisomy condition in humans that allows an appreciable number of individuals to survive to adulthood Found in about 1 in 750 live births. A phenotypic ally identical condition occurs that is not due to a true trisomy (it involves a chromosomal translocation, covered later) Traits include abnormal facial appearance, high likelihood of mental retardation (degree varies considerably), and increased likelihood of developing leukemia and Alzheimer's disease Likelihood of a child being born with Down syndrome increases with the age of the mother rate is as high as 1 in 16 live births for mothers age 45 and over at conception. Not completely clear why the odds go up so dramatically, likely a combination of factors. It is clear that Nondisjunction is more common in eggs than sperm.Appears that spontaneous rejection of aneuploids pregnancies is more common in younger women.

References
1. Kumar, abbas, fausto, Mitchell, et al. Robbins basic pathology. 8th edition edition. 2007, 978-0-8089-2366-4. Emery's Elements of Medical Genetics 13 th Edition by Drs. Peter Turnpenny and Sian Ellard.2009 Nussbaum et al Genetics in Medicine (Edition 7.0), Saunders 2007 Rubin E., Farber J.L. [1999]. Pathology [3rd ed., p. 225]. Philadelphia: Lippincott-Raven Noviski, Edwards (1977) Human Genticsp1:16-NY. Strachan-Tomand read andrewp (1999)Human molecular Genetics second edition p 47-49 bios scientific publisher, oxford, uk. Mange,elaine johansen and mange (1990)Basic human genetics p-210-229.

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Source of Support : Nil, Conflict of Interest : None declared

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Central India Journal of Dental Sciences, Vol. 4 (1), Jan - Mar 2013