chromosomal abnormalities

numerical or structural
occur in 10% of spermatozoa & 25% of mature oocytes
1. CA common cause of early spontaneous miscarriage
estimated incidence in live born infants= 1 in 150
Down syn (trisomy 21)
1. commonest autosomal trisomy
2. commonest genetic cause of severe LD
3. incidence (w/o screening) in live born infants = 1 in 650
4. clinical features
  1. usually suspected at birth
    1. due to baby's facial appearance
    2. diag needs confirming by paediatrician
  2. clinical manifestations
    1. typical craniofacial appearance
      1. round face & flat nasal bridge
      2. upslanted palpebral fissures
      3. epicanthic folds
        a fold of skin running across inner edge of palpebral fissure
      4. Brushfield spots in iris (pigmented spots)
      5. small mouth
      6. protruding tongue
      7. small ears
      8. flat occiput & 3rd fontanelle
    2. other anomalies
      1. short neck
      2. hands
        single palmar creases
        incurved 5th finger
      3. wide 'sandal' gap btw toes
      4. duodenal atresia
      5. hypotonia
      6. Hirschsprung disease
    3. later medical probs
      1. delayed motor milestones
      2. moderate to severe LD
      3. small stature
      4. increased susceptibility to infections
      5. hearing impairment for secretory otitis media
      6. visual impairment from cataracts, squints, myopia
      7. increased risk of leukaemia & solid tumours
      8. risk of atlanto-axial instability
      9. increased risk of hypothyroidism & coeliac disease
      10. epilepsy
      11. Alzheimer's disease
  3. fluorescent in situ hybridisation techniques to test blood for Down syn
5. Cytogenetics
  1. extra chromosome 21 may result from
    1. meiotic non-disjunction (94%)
      1. most cases result from error @ meiosis
        the pair of chromosome 21 fails to separate
        so 1 gamete has 2 chromosome 21s & 1 has none
        fertilisation of gamete w/ 2 chromosome 21s-> zygote w/ trisomy 21
      2. no need to examine parental chromosomes
      3. incidence related to maternal age
        but proportion of older mums small
        so most affected babies born to young mums
      4. can occur in spermatogenesis
        extra chromosome 21 is of paternal origin
      5. all pregnant women now offered screening tests measuring biological markers in blood samples
      6. ultrasound
        nuchal thickening
      7. when increased risk IDed, amniocentesis offered to check fetal karyotype
      8. after having one child w/ trisomy 21 due to non-disjuncn
        risk of recurrence of Down syn
        1 in 200 for mums over 3 years
    2. translocation (5%)
      1. Robertsonian translocation
        when extra chromosome 21 is joined onto another chromosome
        usually chromosome 14
        sometimes chromosome 15, 21 or 22)
        can be present in phenotypically normal carrier
        w/ 45 chromosomes (2 joined together)
        can present in someone w/ Down syn
        set of 46 copies but 3 copies of choromsome 21 material
      2. parental chromosomal analysis
        one of parents may carry translocation in balanced form
        in 25% of cases
      3. risk
        risk of recurrence = 10-1155 if mum is translocation carrier & 2.5% if dad is TC
        if parent carries the rare 21:21 translocation
        all offspring will all have Down syn
        in neither parent carries a traslocation, risk of recurrence <1%
    3. mosaicism
      1. some cells normal, some cells have trisomy 21
      2. usually arises after formation of charcteristically normal zygote by non-disjunction @ mitosis
        can arise by later mitotic non-disjunction in a trisomy 21 conception
      3. phenotype sometimes milder in Down syn mosaicism
Edwards syn (trisomy 18)
1. rarer than Down syn
2. 1 in 8000 liver births
3. clinical features
  1. low birthweight
  2. prominent occiput
  3. small mouth & chin
  4. flexed overlapping fingers
  5. rocker-bottom feet
  6. cardiac & renal malformations
4. most affected babies dies in infancy
5. affected fetuses detected by US scan during 2nd trimester
  1. diag confirmed antenatally
    1. amniocentesis
    2. chromosome analysis
6. recurrence risk
  1. except when trisomy due to balanced chromosome rearrangement in 1 of the parents
Patau syn (trisomy 13)
1. clinical features
  1. structural defect of brain
  2. scalp defects
  3. small eyes (microphthalmia)
  4. cleft lip & palate
  5. cardiac malformations
Turner syn (45, X)
1. > 95% Turner syn-> early miscarriage
2. increasingly detected by antenatal ultrasound
  1. fetal oedema of neck, hands or feet
  2. cystic hygroma
3. clinical features
  1. lymphoedema of hands & feet in neonate
    1. may persist
  2. spoon-shaped nails
  3. short stature
    1. cardinal feature
  4. neck webbing or thick neck
  5. wide carrying angle (cubitus valgus)
  6. widely spaced nipples
  7. congenital heart defects (esp coarctation of aorta)
  8. delayed puberty
  9. ovarian dysgenesis-> infertility
    1. but pregnancy possible w/ IVF (using donated ova)
  10. hypothyroidism
  11. renal anomalies
  12. pigmented moles
  13. recurrent otitis media
  14. normal intellectual function in most
4. incidence 1 in 2500 live born females
5. Rx
  1. growth hormone therapy
  2. oestrogen replacement
    1. for development of 2ndary sexual characteristics @ time of puberty
      1. but infertility remains
6. cytogenetics
  1. 50% of cases
    1. 45 chromosomes, w/ only 1 X
  2. deletion of short arm of one X chromosome
  3. isochromosome w/ 2 long arms but no short arms
  4. presence of Y chromosome seq may increase risk of gonadoblastoma
7. incidence doesn't rise w/ maternal age
8. low risk of recurrence
Klinefelter syn
1. 1.2 per 1000 live born infants
2. very low recurrence risk
3. clinical features
  1. infertility
    1. the commonest presentation
  2. hypogonadism w/ small testes
  3. pubertal development may appear normal
    1. some males benefit from testosterone therapy
  4. gynaecomastia inadolescence
  5. tall stature
  6. normal intelligence
    1. some have educational & psychological probs
reciprocal translocation
1. =exchange of material btw 2 different chromosomes
2. if no loss or gain of material
  1. reciprocal translocation is balanced
    1. no phenotypic effect
    2. relatively common
      1. 1 in 500 of general popn
    3. some appear balanced on conventional chromosome analysis but may still involve loss of genes or disruption of single gene @ a chromosomal breakpoint
      1. -> abnormal phenotype
    4. finding balanced translocation in 1 parent
      1. =recurrence risk for future pregnancies
        antenatal diag
        chorionic villus sampling
        amniocentesis
        test relatives who might be carriers
3. unbalanced
  1. contain incorrect amount of chromosomal material
    1. impair physical & cognitive development->
      1. dysmorphic features
      2. congenital malformations
      3. developmental delay
      4. LD
  2. prognosis har to predict in newborn
    1. effect usually severe
    2. need to check parents' chromosomes
      1. did abnormality arise de novo?
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chromosomal abnormalities

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	Created by v.djabatey almost 11 years ago