LECTURE Klinefelter,Turner & Down

SyndromeMuhammad Faiyaz-Ul-Haque, PhD, FRCPath

Lecture Objectives:Lecture Objectives:

By the end of this lecture, the students should be able to:

• Define non-disjunction and describe its consequences for meiosis and mitosis.

• Classify chromosomal abnormalities • Understand the common numerical chromosomal disorders:

mono and trisomy• Understand the common numerical sex chromosome disorders:

Turner`s & Klinefelter`s syndromes

Stages of Mitosis & MeiosisMitosisMitosis MeiosisMeiosis

Non-disjunction in MeiosisNon-disjunction in Meiosis

Nondisjunction ("not coming apart") is the failure of chromosome pairs to separate properly during meiosis stage 1 or stage 2.

As a result, one daughter cell has two chromosomes or two chromatids, and the other has none.

The result of this error is a cell with an imbalance of chromosomes (Aneuploidy)

can affect each pair of chromosomes is not a rare event non disjunction in first meiotic

division produces 4 unbalanced gametes.

non disjunction in second division produces 2 normal gametes & 2 unbalanced gametes

can affect each pair of chromosomes is not a rare event non disjunction in first meiotic

division produces 4 unbalanced gametes.

non disjunction in second division produces 2 normal gametes & 2 unbalanced gametes

Meiotic non-disjunction

MEIOSIS MITOSIS

Down SyndromeDown Syndrome

Three copies of chromosome 21

Down’s SyndromeDown’s Syndrome

3 copies = trisomy

1 copy = monosomy

Down syndrome, trisomy 21Down syndrome, trisomy 21Karyotype: 47, XY, +21Karyotype: 47, XY, +21

• The incidence of trisomy 21 rises sharply with increasing maternal age

• Most cases arise from non disjunction in the first meiotic division

• The father contributing the extra chromosome in 15% of cases (i.e. Down syndrome can also be the result of nondisjunction of the father's chromosome 21)

• A small proportion of cases are mosaic and these probably arise from a non disjunction event in an early zygotic division

Short, broad hands Stubby fingersRough skinImpotency in malesMentally retardedSmall round faceProtruding tongueShort lifespan

Down SyndromeDown Syndrome

• Low muscle tone• Head and facial malformations• Abnormalities of the extremities• Developmental delays• Heart malformations• Increased risk of infectious disease• Early death

Features of Down SyndromeFeatures of Down Syndrome

Down SyndromeDown Syndrome

Turner’s SyndromeTurner’s Syndrome

• Monosomy of sex chromosome

(only one X chromosome present)

• Occurrence – 1 in 2500 live female births

Turner SyndromeTurner Syndrome

Monosomy of sex chromosome (only one X chromosome present)

Occurring in 1 in 2500 phenotypic females

The only viable monosomy in humans

Characteristics: Webbed neck, Individuals are genetically female, not mature sexually, Sterile, Short stature, Broad chest, Low hairline, Streak ovaries, Normal intelligence, Normal life span

Monosomy of sex chromosome (only one X chromosome present)

Occurring in 1 in 2500 phenotypic females

The only viable monosomy in humans

Characteristics: Webbed neck, Individuals are genetically female, not mature sexually, Sterile, Short stature, Broad chest, Low hairline, Streak ovaries, Normal intelligence, Normal life span

Turner’s syndrome (Monosomy X: 45, XO)

Turner’s syndrome (Monosomy X: 45, XO)

• Short stature• Lack of ovarian development• Neck abnormalities• Skeletal disorders• Increased risk of osteoporosis,

cardiovascular constriction, diabetes, and kidney and thyroid problems

Features of Turner SyndromeFeatures of Turner Syndrome

Turner Syndrome (XO), Incidence: 1 in 2500 female births

XO – Turner SyndromeXO – Turner Syndrome

96-98% do not survive to birth

Cardiovascular Bicuspid aortic valve Coarctation of the aorta Thoracic aortic aneurysm (aortic root dilatation) Skeletal Short stature Short fourth metacarpal/matatarsal bone may be unusually short (+/- short 3rd and 5th). Osteoporosis (due to lack of estrogen) Scoliosis Reproductive Women with Turner syndrome are almost universally infertile.

Cardiovascular Bicuspid aortic valve Coarctation of the aorta Thoracic aortic aneurysm (aortic root dilatation) Skeletal Short stature Short fourth metacarpal/matatarsal bone may be unusually short (+/- short 3rd and 5th). Osteoporosis (due to lack of estrogen) Scoliosis Reproductive Women with Turner syndrome are almost universally infertile.

Turner’s SyndromeTurner’s Syndrome

Klinefelter’s SyndromeKlinefelter’s Syndrome

1 in 1,100 births

47 chromosomesXXY only

47, XXY

#23 Trisomy Nondisjunction

Klinefelter’s SyndromeKlinefelter’s Syndrome

• Male sex organs; unusually small testes which fail to produce normal levels of testosterone breast enlargement (gynaecomastia) and other feminine body characteristic

• Patients are taller and thinner than average and may have a slight reduction in IQ but generally they have normal intelligence

• No spermatogenesis sterile• Very rarely more extreme forms of Klinefelter

syndrome occur where the patient has 48, XXXY or even 49, XXXXY karyotype. These individuals are generally severely retarded.

• Klinefelter Syndrome (XXY), Incidence: 1:1000 male births

Klinefelter Syndrome: 47,XXY malesKlinefelter Syndrome: 47,XXY malesKlinefelter Syndrome: 47,XXY malesKlinefelter Syndrome: 47,XXY males

Scarce beardLonger fingers and armsSterileDelicate skinLow mental abilityNormal lifespan

Klinefelter’s SyndromeKlinefelter’s Syndrome

Brown spots (nevi)

• Tall • Sexually underdeveloped • Infertility • Sparse facial and body hair• Developmental delays• Increased risk of autoimmune disorders,

breast cancer, osteoporosis, leg ulcers, depression, and dental problems

Features of Klinefelter SyndromeFeatures of Klinefelter SyndromeFeatures of Klinefelter SyndromeFeatures of Klinefelter Syndrome

47, XYY May be without any symptoms. Males are tall but normally proportioned. 10 - 15 points reduction in IQ compared to sibs.

XXX femalesIt seems to do little harm, individuals are fertile and do not transmit the extra chromosome. They do have a reduction in IQ comparable to that of Kleinfelter's males

Sex chromosome unbalance Sex chromosome unbalance is much less deleteriousis much less deleterious

Sex chromosome unbalance Sex chromosome unbalance is much less deleteriousis much less deleterious

• Prenatal: maternal age>37yrs; USS changes; Family history

Triple test = increased risk

• Postnatal:Learning & developmental disability; growth retardation

• Infertility:Recurrent miscarriage, primary infertility

When to do a chromosomal testWhen to do a chromosomal test

• Autosomal: – Trisomy 21 (Down syndrome)

• Sex chromosome:– 47XXY (Klinefelter syndrome)– 45X (Turner syndrome)

AneuploidyAneuploidy

• Available on amniocentesis sample• Uncultured amniocytes• FISH probes for X,Y, 21• Result in 24-48 hours• Proceed onto full karyotype (11-14 days)

Rapid Aneuploidy Screening by FISHRapid Aneuploidy Screening by FISH

• qf (quantitative) PCR – able to measure number of copies of a chromosome – used for trisomy screening

• Fetal DNA – at 6-8 weeks to determine sex – look for presence of Y chromosome material

New techniquesNew techniques

• Polyploidy (extra sets of chromosomes) can produce stronger and larger plants.

• Important crop plants are produced this way, including bananas!

Not all chromosomal mutations are harmful.

Not all chromosomal mutations are harmful.

• Chromosome abnormalities can be numerical or structural.

• Numerical abnormalities include aneuploidy and polyploidy.

• In mono or trisomy, a single extra chromosome is absent or present, usually as a result of non-disjunction in the 1st or 2nd meiotic division.

• Structural abnormalities include translocations, inversions, deletions, isochromosome & rings.

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