Chromosomal Disorders

Question 1

aneuploidy

Answer 1

any chromosome number that is not an exact multiple of the haploid number (23)

Question 2

leading genetic cause of intellectual disability

Answer 2

• aneuploidy

* common forms: trisomy and monosomy

Question 3

trisomy statistics

Answer 3

• autosomal trisomies make up about 30% of aneuploidy

* trisomy 16 is the most common (~15%), but never seen in liveborns

Question 4

monsomy x statistics

Answer 4

• make up about 10% of aneuploidy

* 99% abort

Question 5

monsomies of autosomes

Answer 5

complete monosomies = lethal

Question 6

most common parental origin of 45,X

Answer 6

mainly paternal NDJ

Question 7

parental contributions to XXY

Answer 7

maternal and paternal NDJ roughly equal

Question 8

parental origins of trisomies 21, 18, 13 and XXX

Answer 8

primarily maternal, and primarily MI NDJ

Question 9

dysmorphology of down syndrome (trisomy 21)

Answer 9

• upslanting palpebral fissure
• overfolded helices
• single palmar transverse crease
• short, bent 5th fingers

Question 10

other problems associated with down syndrome

Answer 10

• congenital heart disease (40-50%)
• hearing loss due to otisis media
• strabismus and refractive errors
• hypothyroidism
• moderate intellectual disability

Question 11

statistics of causes of down syndrome

Answer 11

• 95% due to NDJ
  
  • 75% meiosis I
  • 25% meiosis II
• 4% robertsonian translocation 21;14 or 21;22
• ~1% mosaic trisomy 21

Question 12

Presentation of Trisomy 18 (edwards syndrome)

Answer 12

• 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

Question 13

other problems associated with trisomy 18

Answer 13

• cardiac defect
• renal anomaly
• severe intellectual disability

Question 14

Presentation of Trisomy 13 (patau syndrome)

Answer 14

• holoprosencephaly with premaxillary agenesis (atypical median cleft lip/palate)
• micropthalmia
• short, prominent sternum
• flexed fingers
• polydactyly
• “rocker-bottom feet”
• abnormal scrotum/micropenis
• normal birthweight

Question 15

other problems associated with trisomy 13

Answer 15

• cryptorchidism
• cardiac defects (VSD common)
• cystic dysplastic kidneys
• omphalocele

Question 16

5p- syndrome presentation

Answer 16

• 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

Question 17

microdeletion syndromes

Answer 17

• sometimes called contiguous gene deletion syndromes

* may not be detected on karyotype; FISH and microarray allow more detail

Question 18

22q11.2 deletion syndrome presentation

Answer 18

• previously DiGeorge or Velocardiofacial syndrome
• Autosomal dominant!
• mild facial dysmorphology
• cleft palate
• slow growth
• others associated with 4th pharyngeal arch, and 3rd/4th pouches

Question 19

other problems associated with 22q11.2 deletion syndrom

Answer 19

• thymus and parathyroid
• cardiac defects (interrupted aortic arch, tetralogy of fallot)
• also VSD

Question 20

Mechanisms of 22q11.2 deletion

Answer 20

• non-allelic homologous recombination (NAHR)

* LCRs thought to be involved in crossover and may be implicated with the deletion

Question 21

a good test for 22q11.2 deletion syndrome

Answer 21

FISH

Autosomal dominant

Question 22

WAGR syndrome

Answer 22

• 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

Question 23

Williams syndrome presentation

Answer 23

• a contiguous gene deletion; microdeletion of 7q (elastin gene)
• depressed nasal bridge
• blue eyes, stellate pattern
• long philtrum, wide mouth
• delayed development, cocktail personality

Question 24

Klinefelter syndrome presentation

Answer 24

• 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

Question 25

key points of XXX, XXY, and XYY

Answer 25

* ~10 IQ deficit compared with family * most employed and married * reported over-representation in psych hospitals * generally good outcome if low stress home

Question 26

47, XYY and 47, XXX

Answer 26

* not syndromes -> no abnormal phenotype, generally normal fertility * offspring usually chromosomally normal

Question 27

turner syndrome

Answer 27

* 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

Question 28

diagnosis of turner syndrome

Answer 28

* 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

Question 29

46, XY female

Answer 29

* 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

Question 30

What is deletion of WT1 gene at 11p13 associated with

Answer 30

wilms tumor of kidney AND genital anomalies WAGR syndrome

Question 31

what is deletion of PAX6 gene at 11p13 associated with

Answer 31

aniridia (no iris) | WAGR syndrome

Question 32

Other problems associated with Williams syndrome

Answer 32

* supravalvular aortic stenosis (75%) (ELN gene may be involved) * hyperalcemia (33%)

Question 33

deletion involved in williams syndrome

Answer 33

7q (elastin or ELN gene)

Question 34

Key presentation of turner syndrome in newborns

Answer 34

edema of hands and feet, web neck

Question 35

key presentation of turner syndrome in adolescents

Answer 35

lack of puberty and short stature

Question 36

other problems associated with turner syndrome

Answer 36

can have coarctation of aorta

Question 37

what should be suspected in any female with short stature?

Answer 37

turner syndrome

Question 38

most of turner syndrome is caused by

Answer 38

80% due to absence of father's X or Y

Question 39

common presentations of turner syndrome | uworld

Answer 39

* 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

Question 40

common associated problems with turner syndrome | uworld

Answer 40

* coarctation of aorta * bicuspid aortic valve (most common cardiac abnormality in TS) * horseshoe kidney * streak ovaries, amenorrhea, infertility

Question 41

Abnormalities of lymphatic outflow in turner syndrome can cause:

Answer 41

* cystic hygroma (posterior neck mass) | * lympedema (can be described as bilateral extremity swelling)

Question 42

diminished femoral pulses could be suggestive of

Answer 42

coarctation of the aorta

Question 43

most common gastrointestinal complication in down syndrome babies

Answer 43

duodenal atresia