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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