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Chromosomal disorders


Chromosomal disorders (cytogenetic disorders)

  • Chromosomal mutation may cause -
  1. Abnormal number of chromosomes
  2. Alteration in the structure of chromosomes.
  1. Abnormal number of chromosomes
  • There are 23 pairs of chromosomes (46, XX in females and 46, XY in males)
  • An exact multiple of the 23 (haploid number) is called euploidy.
  • When the numbers of chromosomes are not an exact multiple of 23, it is referred as aneuploidy. eg - Trisomy or monosomy.

Pathogenesis of aneuploidy

In aneuploidy error occurs either in meiosis or in mitosis.

  1. Error in meiosis
  • It is the most common cause of aneuploidy.
  • The usual causes are nondisjunction or anaphase lag.
  • In nondisjunction, chromosomal pair fails to separate in first meiotic division during gametogenesis, so one gamete has an extra chromosome (n+ 1) and the other has one less chromosome (n-1). Fertilization of such gametes with normal gamete results in two types of zygotes - trisomy (2n+1) or monosomy (2n-1).
  1. Error in Mitosis
  • Error in mitosis in early development give rise to two or more different types of populations in the same individuals a condition referred as mosaicism.
  • Mosaicism affecting the sex chromosome is common.
  • In the division of an fertilized ovum, an error may lead to one of the daughter cell receiving three sex chromosomes, where as the other receives only one, yielding 45 , X/47, XXX mosaic. That means the same individual will have both types of cells cells having 45, X and cells having 47, XXX.

What is the difference between Monosomy / trisomy and masochism?

  • Trisomy/monosomy are due to defect in meiosis and before fertilization, so that after fertilization all cells have same number of chromosome either monosomy or trisomy.
  • In mosaicism, defect is in mitosis and after fertilization so that same individual has cells of two different population e.g. 45, X and 47, XXX.

Important chromosomal abnormalities

  1. Involving autosomes
  • Down syndrome (Trisomy 21)
  • Edward syndrome (Trisomy 18)
  • Patau syndrome (Trisomy 13)
  1. Involving sex chromosomes
  • Klinefelter syndrome (47, XXY)
  • Turner syndrome (45, X)  

Important facts

  • Autosomal monosomies (loss of one autosome) are incompatible with fetal development and are not found in live births. Only monosomy compatible with live birth is due to involvement of sex chromosome, i.e. Turner syndrome (45 X).
  • Most of the meiotic non-dysjunctions occur during l st meiotic division. In trisomy 18, it is more commonly seen in 2nd meiotic division.

Inherited autosomal recessive syndromes of defective DNA repair

  • Ataxia Telangiectasia       
  • Fanconia anemia
  • Hereditary Nonpolyposis cancer (Only autosomal dominant)
  • Bloom syndrome
  • Xeroderma pigrnentosum  

These disorders are associated with such a high level of chromosomal instability that they are known as chromosome – breakage syndrome.



  • It is the study of chromosomes.
  • It is used in cytogenetics to study the chromosomal abnormalities.
  • A karyotype is a standard arrangement of a photographed or imaged stained metaphase spread in which chromosome pairs are arranged in order of decreasing length.
  • To produce a karyotype, one must obtain cells capable of growth and division as karyotyping is done by arresting mitosis in dividing cells in metaphase.
  • Samples used are
    • Amniotic fluids (cells from amnion, skin, urogenital system, respiratory system and GI system)
    • Chorionic villi   
    • Bone marrow
    • Skin fibroblasts        
    • Peripheral blood lymphocytes
    • Fetal umbilical blood
    • Lymph node tissue
    • Solid tumor sample

Method of karyotyping

  • Dividing cells are arrested in metaphase by addition of colchicine or Colcemid (deacetylmethyl colchicine).
  • Subsequently, cells are exposed to a hypotonic solution to induce swelling of the cell for enhancing spreading of the chromosomes.
  • The metaphase cells are then fixed with methanol/glacial acetic acid mixture and stained by one of the several banding techniques.
  • After staining chromosomes are analyzed under a microscope and photographed.
  • Finally, a karyotype is constructed by manual or automated pattern.
  • Chromosomes are arranged in pairs and decreasing order of length.


  • Staining allows identification of each individual chromosome on the basis of distinctive and reliable pattern of alternating light and dark bands. One of the following banding techniques may be used.

G-Banding (Giemsa banding)

Q-Banding (Quinacrine banding)

C-Banding (Constitutive banding)

'R Banding' (Reverse staining Geimsa banding)

Most commonly used

Demonstrates bands along Chromosome

Demonstrates constitutive heterochromatin

Gives pattern opposite to G-Banding



Gene therapy

  • Gene transfer is a novel area of therapeutics in which the normal gene (DNA sequence) is delivered to target somatic cells.
  • Because delivery of naked DNA or RNA to a cell is inefficient process, most gene transfer is carried out using a vector (gene delivery Vehile).  

Visualization of a specific DNA or RNA fragment among the many thousand of contaminating molecules requires the convergence of number of techniques collectively termed the blot transfer.

Southern blot  Detects DNA

Northern blot  Detects RNA

Western blot Detects proteins (proteins are separated by electrophoresis, renatured and analyzed for and interaction by hybridization with a specific labeled DNA Probe)


Down’s Syndrome

  • Down's syndrome is a condition in which extra genetic material causes delay in the way a child develops, and often leads to mental retardation.
  • In Down's syndrome the child gets an extra chromosome, a total of 47 chromosome instead of 46 chromosome
  • This extra genetic material causes the physical and cognitive delays associated with Down's syndrome.
  • There is a well-recognized association with advancing maternal age; the risk considerably increases in women> 35 years of age.
  • Advanced paternal age has very little effect.

Clinical features

  • Most striking feature in the neonate is hypotonia and although the diagnosis is usually evident at this time, it may sometimes be missed if the baby is very premature or his facial features are concealed by ventilatory apparatus.
  • Other clinical features include:-
  1. General :- Mental retardation, short stature
  2. Cranio-facial: - Brachycephaly, epicanthic fold, protruding tongue, small ears, upward sloping palpebral fissures, strabismus, nystagmus, Brushfied spots in iris.
  3. Limbs: - Fifth finger clinodactyly, single palmar crease (simian crease), and wide gap between first and second toes.
  4. Congenital heart disease: - Common AV canal, ASD, VSD, PDA, Fallot tetralogy.
  5. GIT:- Anal atresia, Duodenal atresia.
  6. Increased incidence of leukemia (1%)

Some characteristic features of Down's syndrome

  • Virtually all patients with trisomy 21 older than age 40 develop neuropathologic changes characteristic of Alzheimer’s disease.
  • Children with trisomy 21 have a 10 fold to 20 fold increased risk of developing acute leukemia. Both acute lymphoblastic leukemia and acute myeloid leukemia occur.
  • Patients with Down's syndrome have abnormal immune response that predisposes them to serious infections.
  • The most common cause of trisomy 21 (Down's syndrome) is maternal nondisjunction in meiosis 1. In most cases the meiotic nondisjunction of chromosome 21 occurs in the ovum and ill 95% of the cases the extra chromosome is of maternal origin.

Turner's Syndrome

  • Turner's syndrome is the most common sex chromosomal disorder in phenotypic females.
  • Turner's syndrome results from complete or partial loss of one X chromosome (45, X) and is characterised by hypogonadism in phenotypic females

Features of Turner syndrome in children

  • The most severely affected patients generally present during infancy with edema (owing to lymph stasis) of the dorsum of the hand and foot and sometimes swelling of the nape of the neck.
  • Swelling of the neck is related to markedly distended lymphatic channels, producing so called cystic hygroma.
  • As these infants develop, the swelling subsides but often leave bilateral neck webbing and persistent looseness of skin on the back of the neck.
  • Congenital heart disease is also common particularly pre-ductal coarctation of Aorta and bicuspid Aortic valve.

Features of Turner's syndrome in Adolescents and Adult

  • At puberty there is failure to develop normal secondary sex characteristics.
  • The genitalia remain infantile, breast development is inadequate and there is little pubic hair. Nipples are widely spaced
  • Turner syndrome is the single most important cause of primary amenorrhea
  • Short stature
  • The mental status of these patients is usually normal but subtle defects in nonverbal, visual spatial information processing have been noted (mental retardation is associated with the presence of extra chromosome not with loss of X chromosome).
  • About 50% of the patients develop autoantibodies directed to the thyroid gland and up to one half of these patients develop hypothyroidism.
  • Other features include low posterior hairline, webbing of neck, cubitus valgus, streak ovaries.
  • Glucose intolerance, obesity and insulin resistance are also seen.

Klinefelter’s Syndrome

  • Klinefelter syndrome is the most common chromosomal disorder associated with male hypogonadism and Infertility
  • It is defined classically by a 47, XXY karyotype with variants demonstrating additional X and Y chromosomes. (Other variants can have 48 XXXY, rarely 49 XXXXY or mosaics can be there with some cells containing normal 46, XY and others 47, XXY).
  • Classically, it results from meiotic non-dysjunction of sex chromosomes


  • The addition of more than 1 extra X or Y chromosome to a male karyotype results in variable physical and cognitive abnormalities.
  • In general, the extent of phenotypic abnormalities, including mental retardation, is related directly to the number of X chromosomes.


  • Because of an additional X chromosome on an XY background, this condition is seen in males only.




  • Height velocity is increased by age 5 years, and adult height usually is taller than average. Affected individuals also have disproportionately long arms and legs.

Central nervous system

  • Most 47, XXY males have normal intelligence. Subnormal intelligence or mental retardation may be associated with the presence of a higher number of X chromosomes.

Sexual characteristics

  • Patients may lack secondary sexual characteristics because of a decrease in androgen production. This results in sparse facial/body/sexual hair, a high-pitched voice. They have eunuchoid body habitus.
  • By late puberty, Reticent manifest gynecomastia. The risk of developing breast carcinoma is at least 20 times higher than normal.
  • Testicular dysgenesis may be present in postpubertal patients.
  • Infertility is seen in practically all individuals with a 47, XXY karyotype.
  • Patients may have an increased frequency of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.

Cardiac and circulatory problems

  • Mitral valve prolapse
  • Varicose veins
  • The prevalence of venous ulcers is 10-20 times higher than normal and the risk of deep vein thrombosis and pulmonary embolism is increased.


  • Plasma FSH and LH levels are elevated

Barr body (Sex - chromatin)

  • It is a densely staining inactivated condensed 'X' chromosome that is present in each somatic cells of female.
  • It is found in the nucleus.
  • It is used as a test of genetic femaleness; it is possible to determine the genetic sex of an individual according as to whether there is a chromatin mass present on the inner surface of the nuclear membrane of cells with resting or intermittent nuclei.
  • Chromatid body (Barr body or sex chromatin) is derived from one of the two X-chromosomes which becomes inactivated.
  • The number of Barr bodies is thus one less than the number of X-chromosomes.


  • Kleinefelter's syndrome (XXY) ~ Two 'X' chromosomes ~ 1 Barr body (2-1).
  • Turner syndrome (XO) ~ one 'X' chromosome ~ No Barr body (1-1 = 0).
  • Superfemale (XXX) ~ Three 'X' chromosome ~ 2 Barr bodies (2-1).


  • Barr body is found in female but-
    • Klinefelter syndrome is male with Barr body.
    • Turner syndrome is female without Barr body



Type I

Type IIa

Type IIb

Type III

Type IV

Type V


Decreased lipoprotein lipase or Apo C-II

LDL receptor deficiency

LDL receptor, increased Apo B-100

Defect in Apo-E

Increased VLDL production and decreased elimination (Due to Apo V deficiency)

Same as in type IV, but more severe


Elevated chylomicrons (also VLDL some times)




Increased chylomicron remnants and IDL


VLDL and chylomicron

















Tendon, Tuberous


Palmer, Tuberoeruptive










Coronary atherosclerosis







Peripheral atherosclerosis








Familial lipoprotein lipase deficiency

Familial hyper cholesterolemia

Familial combined hyperlipopreinemia

Familial dysbeta lipopreinemia

Familial hyper triglyceridemia

Endogenous hyper-triglyceridemia



Location of important Genes on chromosomes









Folate transporter
































Cystic fibrosis








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