CHROMOSOMAL ANOMALIES

• DNA is the basic template that provides the blueprint for the formation and maintenance of an organism

• DNA is packaged into chromosomes

• Cytogenetics: The study of chromosomes and cell division

• The nucleus of human somatic cells consists of 46 chromosomes, arranged in 23 pairs

• Autosomes: 22 pairs

• Sex chromosomes: 2 X chromosomes in females

X and Y chromosome in males.

• 20,000 chromosomal abnormalities have been registered

• Approximately 1 in 200 newborn infants has some form of chromosomal abnormality.

• In 50% of first-trimester spontaneous abortions, the fetus has a chromosomal abnormality

• Abnormalities of chromosomes - a) Numeric abnormalities

b) Structural abnormalities

• May involve one or more autosomes, sex chromosomes or both simultaneously.

NUMERIC ABNORMALITIES• The normal chromosome count is 46 ( 2n =46).

• Euploid- Any exact multiple of the haploid number (n)

• Polyploid-Chromosome numbers such as 3n and 4n

Polyploidy generally results in a spontaneous abortion.

• Aneuploid- Any number that is not an exact multiple of n

a) Monosomy

b) Trisomy

• Mosaicism - presence of two or more populations of cells with different complements of chromosomes in the same individual

STRUCTURAL ABNORMALITIES• Chromosomal breakage followed by loss or rearrangement of

material

• Deletion - loss of a portion of a chromosome.

• Translocation - transfer of a part of one chromosome to another chromosome.

• Inversions - two interstitial breaks in a chromosome, and the segment reunites after a complete turnaround.

• Isochromosomes - the centromere divides horizontally rather than vertically

• Insertions - a segment removed from one chromosome is inserted into a different chromosome, either in its usual orientation or inverted

• Ring chromosome - After loss of segments from each end of the chromosome, the arms unite to form a ring

• Duplications - A portion of the chromosome is duplicated, resulting in extra genetic material

DOWN SYNDROME

• Incidence at birth – USA 1: 800• Chromosomal findings – Trisomy 21 ( 95% ) – Robertsonian translocation ( 4% ) – Mosaicism• Maternal age has a strong influence on the incidence of Down syndrome.• Down syndrome is a leading cause of severe mental retardation• Approximately 80% of those afflicted have an IQ of 25 to 50.

• Clinical features

Flat facial profileProtruding tongue(furrowed)BrachycephalySmall ears

Epicanthic foldUpward sloping palpebral fissureBrushfield spot

HypotoniaSleepyExcess nuchal skinFlat occiput

Sandal gap deformity

Simian creaseSmall middle phalanx of 5th finger

• Congenital cardiac defects - 40% ( ASD,VSD, AV valve malformations )

• Malformations such as duodenal atresia and tracheoesophageal fistula are more common

• 10 to 20 fold increased risk of developing acute leukemia.

• Alzheimer disease, a degenerative disorder of the brain

• Abnormal immune responses

PRENATAL SCREENING

Triple test

• Combined biochemical test - Maternal Serum AFP, hCG and unconjugated estriol.

• The level of Maternal Serum AFP and Unconjugated estriol tend to be low while that of hCG is high.

• It is performed at 15–18 weeks. It gives a risk ratio and

For confirmation amniocentesis has to be done.

PATAU SYNDROME

• Incidence - 1 in 15,000 to 25,000 births.

• Associated with increased maternal age

• 20% of the cases are caused by an unbalanced translocation

• The empirical risk that a subsequent live born child will have the syndrome is less than 2%.

• Clinically severe - about 50% individuals die within the first month.

• Growth retardation and severe mental retardation

Clinical features

Postaxial polydactyly Hands clench with overlapping of digitsSimian crease may be present

Microcephaly Cleft lip and palateMalformed ears

Rocker-bottom feet

MicrophthalmiaMalformed, low set ears

Severe CNS malformationslike holoprosencephaly.

• Congenital cardiac defects – VSD, PDA

• Urogenital defects - Cryptorchidism

Bicornuate uterus and hypoplastic ovaries

Polycystic kidneys

EDWARDS SYNDROME

• Incidence in liveborn infants - 1 in 7500 births

• About 95% are aborted spontaneously.

• Postnatal survival is poor

• Increased maternal age is a factor,

• In 20% of cases, there is a translocation involving chromosome 18

• The trisomy may also be present in mosaic form

• Mental retardation and failure to thrive present

• Hypertonia is a typical finding

Prominent occiput Jaw recedesThe ears are low-set and malformed.

The fists clench in a characteristic way, the second and fifth digits overlapping the third and fourthHypoplastic nails

The feet have a “rocker-bottom” appearance, with prominent calcanei.

• Congenital heart defects• Urogenital defects• Limited hip abduction

KLINEFELTER SYNDROME

• Male hypogonadism that develops when there are at least 2 X chromosomes and one or more Y chromosomes.

• Incidence - 1 in 1000 male live births

• Most affected patients have a 47 XXY karyotype

• Variants – 48 XXYY, 48 XXXY, and 49 XXXXY.

• As a rule, the additional X chromosomes cause a correspondingly more severe phenotype

• Advanced maternal age and a history of irradiation in either parent

• Klinefelter syndrome is the most common cause of hypogonadism in males

HypogonadismEunuchoid body habitusTall and thin,long legsReduced facial body and pubic hairTesticular atrophy – infertilityMild mental retardation

Gynaecomastia

• Persistent androgen deficiency results in decreased muscle tone, loss of libido and decreased bone mineral density.

• The risk of breast cancer is 20 to 50 times higher

• Increased risk of extragonadal germ cell tumors and autoimmune diseases such as systemic lupus erythematosus

TURNER SYNDROME

• Primary hypogonadism in phenotypic females due to partial or complete

monosomy of the short arm of the X chromosome

• Incidence : 1 in 5000 to 1 in 10000 live births

• 99% abort spontaneously.

• 50% patients have 45 X karyotype

• Mosaicism i.e 45X/46XX in 20%

• Intelligence is usually considered to be normal

• The chromosome error leading to loss of a sex chromosome is usually paternal

Swelling of the nape of the neck due to distendedlymphatic channels

Lymphedema of the hands and feet

Webbed neckLow posterior hairline Broad chest with widely spaced nipples

Short statureCubitus valgusInfantile genitaliaMinimal breast development is minimal

Gonadal dysgenesis (usually streak gonads)Primary amenorrhoea and infertility

• Congenital malformations - horseshoe kidney,

- bicuspid aortic valve

- coarctation of the aorta (15%)

• Cardiovascular abnormalities are the most common cause of death in childhood.

• Oestrogen replacement therapy should be initiated at adolescence

TRIPLE X SYNDROME

• Incidence - 1 in 1000 female births.

• Mild reduction of IQ present

• Adults are fertile

• Severity of mental retardation proportional to number of extra X chromosomes

XYY SYNDROME

• Incidence - 1 in 1000

• Increased risk of educational or behavioural problems in comparison with chromosomally normal males.

• They have normal intelligence and are not dysmorphic.

• Fertility is usually normal

• IQ scores are about 10 to 15 points below average.

• Attention deficits, hyperactivity and impulsiveness

CRI DU CHAT SYNDROME• Terminal or interstitial deletion of part of the short arm of

chromosome 5(5p15)

• Crying infants with this disorder sound like a mewing cat.

• Accounts for about 1% of all institutionalized mentally retarded patients.

• Moderate to severe mental retardation and heart defects

MicrocephalyMicrognathia

HypertelorismEpicanthal foldsLow-set ears

SYNDROME CHROMOSOME

Smith-Magenis syndrome 17p deletion

DiGeorge syndrome/ Velocardiofacial syndrome

22q deletion

Williams syndrome 7q deletion

Angelman syndrome 15q deletion

Prader willi Syndrome 15q deletion

WAGR syndrome 11p deletion