Chromosomal Disorders Flashcards
aneuploidy
any chromosome number that is not an exact multiple of the haploid number (23)
leading genetic cause of intellectual disability
- aneuploidy
* common forms: trisomy and monosomy
trisomy statistics
- autosomal trisomies make up about 30% of aneuploidy
* trisomy 16 is the most common (~15%), but never seen in liveborns
monsomy x statistics
- make up about 10% of aneuploidy
* 99% abort
monsomies of autosomes
complete monosomies = lethal
most common parental origin of 45,X
mainly paternal NDJ
parental contributions to XXY
maternal and paternal NDJ roughly equal
parental origins of trisomies 21, 18, 13 and XXX
primarily maternal, and primarily MI NDJ
dysmorphology of down syndrome (trisomy 21)
- upslanting palpebral fissure
- overfolded helices
- single palmar transverse crease
- short, bent 5th fingers
other problems associated with down syndrome
- congenital heart disease (40-50%)
- hearing loss due to otisis media
- strabismus and refractive errors
- hypothyroidism
- moderate intellectual disability
statistics of causes of down syndrome
- 95% due to NDJ
- 75% meiosis I
- 25% meiosis II
- 4% robertsonian translocation 21;14 or 21;22
- ~1% mosaic trisomy 21
Presentation of Trisomy 18 (edwards syndrome)
- low frontal hairline
- short palpebral fissures
- bluntanasal tip with small nostrils
- small chin
- “fawn-like” ears
- high nasal bridge
- short sternum
- overlapping fingers w/ clenched fists
- genital anomaly
- possible missing digits
- rockerbottom feet
other problems associated with trisomy 18
- cardiac defect
- renal anomaly
- severe intellectual disability
Presentation of Trisomy 13 (patau syndrome)
- holoprosencephaly with premaxillary agenesis (atypical median cleft lip/palate)
- micropthalmia
- short, prominent sternum
- flexed fingers
- polydactyly
- “rocker-bottom feet”
- abnormal scrotum/micropenis
- normal birthweight
other problems associated with trisomy 13
- cryptorchidism
- cardiac defects (VSD common)
- cystic dysplastic kidneys
- omphalocele
5p- syndrome presentation
- aka cri du chat syndrome
- cat like cry due to hypotonia and laryngeal abnormality
- growth restriction
- microcephaly
- round face, widely spaced eyes
- single palmar crease
- moderate to severe intellectual disability
microdeletion syndromes
- sometimes called contiguous gene deletion syndromes
* may not be detected on karyotype; FISH and microarray allow more detail
22q11.2 deletion syndrome presentation
- previously DiGeorge or Velocardiofacial syndrome
- Autosomal dominant!
- mild facial dysmorphology
- cleft palate
- slow growth
- others associated with 4th pharyngeal arch, and 3rd/4th pouches
other problems associated with 22q11.2 deletion syndrom
- thymus and parathyroid
- cardiac defects (interrupted aortic arch, tetralogy of fallot)
- also VSD
Mechanisms of 22q11.2 deletion
- non-allelic homologous recombination (NAHR)
* LCRs thought to be involved in crossover and may be implicated with the deletion
a good test for 22q11.2 deletion syndrome
FISH
Autosomal dominant
WAGR syndrome
- microdeletion on 11p13
- W=wilms tumor of kidney -> WT1 gene at 11p13
- A=Aniridia (no iris) -> del of PAX6 gene at 11p13
- G=genital anomalies -> del of WT1 at 11p13
- R=retardation of growth and dev
Williams syndrome presentation
- a contiguous gene deletion; microdeletion of 7q (elastin gene)
- depressed nasal bridge
- blue eyes, stellate pattern
- long philtrum, wide mouth
- delayed development, cocktail personality
Klinefelter syndrome presentation
- 47, XXY (one or more extra X)
- small firm testes
- hyalinization of seminiferous tubules with azospermia
- long limbs
- gynecomastia: breast cancer risk = with that of women
- variant: 48, XXXY mental retardation and dysmorphology
- may need testosterone therapy
key points of XXX, XXY, and XYY
- ~10 IQ deficit compared with family
- most employed and married
- reported over-representation in psych hospitals
- generally good outcome if low stress home
47, XYY and 47, XXX
- not syndromes -> no abnormal phenotype, generally normal fertility
- offspring usually chromosomally normal
turner syndrome
- absence of a normal second sex chromosome in females
- phenotypically female
- absence of all or part of an X chromosome
- 50% 45, X
- 25% mosaic (may include Y)
- various X deletions, rings, isochromosomes
diagnosis of turner syndrome
- newborns: edema of hands and feet, web neck
- adolescents: lack of puberty and short stature
- suspect in any girl with short stature
- can have coarctation of aorta
- 80% due to absence of father’s X or Y
46, XY female
- SRY gene on Y chromosome has been deleted -> no development of male sex organs
- 2nd X is needed in females for ovarian maintenance -> streak gonads in 46, XY female
What is deletion of WT1 gene at 11p13 associated with
wilms tumor of kidney
AND genital anomalies
WAGR syndrome
what is deletion of PAX6 gene at 11p13 associated with
aniridia (no iris)
WAGR syndrome
Other problems associated with Williams syndrome
- supravalvular aortic stenosis (75%) (ELN gene may be involved)
- hyperalcemia (33%)
deletion involved in williams syndrome
7q (elastin or ELN gene)
Key presentation of turner syndrome in newborns
edema of hands and feet, web neck
key presentation of turner syndrome in adolescents
lack of puberty and short stature
other problems associated with turner syndrome
can have coarctation of aorta
what should be suspected in any female with short stature?
turner syndrome
most of turner syndrome is caused by
80% due to absence of father’s X or Y
common presentations of turner syndrome
uworld
- narrow, high-arched palate
- low posterior hairline
- broad chest, widely spaced nipples (shield chest)
- cubitus valbus (forearm angled away from body to a greater degree than normal)
- short stature
common associated problems with turner syndrome
uworld
- coarctation of aorta
- bicuspid aortic valve (most common cardiac abnormality in TS)
- horseshoe kidney
- streak ovaries, amenorrhea, infertility
Abnormalities of lymphatic outflow in turner syndrome can cause:
- cystic hygroma (posterior neck mass)
* lympedema (can be described as bilateral extremity swelling)
diminished femoral pulses could be suggestive of
coarctation of the aorta
most common gastrointestinal complication in down syndrome babies
duodenal atresia
