Aneuploidies (somatic and sex) Flashcards
What are the three aneuploidies common with postnatal survival?
Trisomy 21, 18, 13
What is the prevalence of Down syndrome?
1:660-1:700
What are some of the general features of T21?
hypotonia, hyperflexiblty of joints, small stature, learning disability
What hand/feet malformations are seen in T21?
clinodactlyly, single transverse palmar crease, gap btwn 1st and 2nd toe, crease btwn 1st and 2nd toe
What are common cardiac malformations in T21?
atrioventricular setpal defect
patent ductus ateriosis
ventricular septal defect
What are common GI tract features in T21?
duodenal atresia (double-bubble)
anal atresaia
agangliosis of colon
reflux
What are common MSK features of T21?
11 pairs of ribs vs. 12
predisposition to hip dislocation
What are the cytogenetic findings with T21?
95% result from nondisjunction
3-4% result from Robertsonian translocation (usually 21q w/ an acrocentric chromosome -> 14 or 22) - no relation w/ maternal age
1-2% mosaicism
Prenatal issues seen in T21?
at least 20% are SB
Infant features of T21?
hypotonia poor moro relfex increased flexiblty of joints excess nucahl skin flat facial profile upslanting eyes small ears clinodactylly transverse palmar crease congenital heart defect (roughly 50%)
Features seen in children with T21? Guidance?
hearing loss -> hearing screens, tubes may help prevent infection and improve hearing
delayed tooth eruption and growth
celiac disease (7-16%)
hypo- and maybe hyperthyroidism
Eye features in children w/ T21?
should see an ophthalmologist
cataracts (congenital or acquired)
thinning and stretching of cornea is common
Individuals with Down syndrome have an increased lifetime risk of this cancer:
Leukemia
Features seen in adults with Down syndrome?
early-onset Alzheimer’s disease (in their 40s)
incontinence
hearing loss
infertility in males
Trisomy 18 is also known as:
Edward syndrome
What is the incidence of trisomy 18?
1:6000-1:8000 birth
How do we note the karyotype of an individual with Edward syndrome?
47,XX,+18
47,XY,+18
Which sex seems to survive to term more in pregnancies affected by trisomy 18?
Females (3:1)
What are the features seen in T18?
prominent back of the skull unusual ears small mouth and jaw clenched hands flexed big toes w/ prominent heels
What general characteristics do we see in pregnancies with t18?
poor fetal movement 1/3 premature 1/3 past due date polyhydramnios single umbilical artery hypertonicity postnatally abdominal hernia males w/ undescended testes
What are the survival stats for infants born with trisomy 18?
50% mortality within the 1st wk
most don’t live past a year
What syndrome is also known as trisomy 13?
Patau syndrome
What is the incidence of trisomy 13?
1:12,000 live birth
What features are seen in more than 50% of trisomy 13?
Cleft lip and palate small for gestational age postaxial polydactyly clenched hands (outer finger overlapping middle) CNS issues Holoprosencephaly (severe -> cyclopia) microcephaly sloping forehead congenital heart defect renal issues undescended testes or hypoplastic ovaries rocker bottom feet cutis aplasia
What are some other features seen in trisomy 13?
hydrocephalus
spina bifida
omphalocele
kidney abnormalities
Inactivated Xs replicate _______ than active ones.
slower
What parts of the X chromosome lead to their inactivation?
CpG islands are highly methylated regions -> inactivation
What percentage of genes on the X chromosome escape inactivation? On which arm are most of them located?
10-15%
more on Xp than Xq
Xp is associated with what physical feature? Xp and Xq?
stature
ovarian function
Where is the X inactivatin center located?
What gene is associated with this?
Xq13
XIST
What is the product and function of XIST?
noncoding RNA
stays closely associated w/ inactive X (only expressed from inactive X)
X inactivation is random unless?
there is an abnormal X chromosome
there is an x;autosome translocation
Which X is inactivated if there is an abnormal X?
the abnormal X is preferentially inactivated
ex: Xi (isochromosome)
Which X is inactivated when there is an x; autosome translocation?
If translocation is unbalanced -> abnormal X is inactivated
if translocation is balanced -> normal X is inactivated
What syndrome is written as 45,X?
Turner syndrome
What is the incidence of Turner syndrome?
1:4000 live births
what are the major features of Turner syndrome?
low posterior hairline (looks like short neck) swelling of hands and feet broad chest and wideset nipples short stature ovaries not developed unusual shape and rotation of ears narrow maxilla or palate micrognathia
What cardiac abnormalities are seen in individuals with Turner syndrome? Which is emergent? What procedure should they have to assess?
bicuspid aortic valve coarctation of the aorta (urgent) aortic valve stenosis hypoplastic left heart mitral valve prolapse
echocardiogram
What are the cytogenetics seen with Turner syndrome?
50% 45,X 15% 46,X,i(Xq) 15% 45,X/46,XX mosaic 5% 45,X/46,X,i(Xq) mosaic 10% other abnormal karyotypes
ring X chromosome
Long arm deletion
short arm deletion
What gene is associated with short stature? Where is it located?
SHOX
Xp22.3
Yp11.3
located in pseudoautosomal region - errors in recombination can interfere
What cognitive features are seen in Turner syndrome?
intelligence at or above the average
deficient in spatial perception, perceptual-motor organization, and fine motor execution
nonverbal IQ is lower than verbal IQ
How is Turner syndrome treated?
growth hormone estrogen therapy (12-14yrs)
What adult issues are seen in individuals with Turner syndrome?
osteoporosis bone fractures insulin resistance (diabetes) hypertension obesity hyperlipidemia hearing loss
Turner syndrome prenatal outcomes? INdications?
seen in 1-2% of conceptus
99% result in spontaneous abortion
single X is usually of maternal origin
nuchal thickening (up to cystic hygroma) swelling/fluid growth delay
What karyotype do we see in Klinefelter syndrome?
47,XXY
What’s the incidence of Klinefelter syndrome?
1:1000 male births
What are the physical features of Klinefelter syndrome?
tall
small testes and penis
delayed puberty
breast development
What behavioral issues are common in Klinefelter syndrome?
learning problems below average verbal comprehension and ability shyness and unassertiveness apparent immaturity passivity
What are the cytogenetics seen in Klinefelter syndrome?
50% of errors in paternal meiosis (failure of normal Xp/Yp recombination)
maternal issues: most meiosis I, others in II, or postzygotic errors -> mosaicism (increase with age)
15% of individuals are mosaic
more Xs, more severe cognitive deficits
How can we treat Klinefelter syndrome?
hormone treatment
refer to endocrinolgoy
What are some other trisomies and their features?
47, XXX
1:1000
taller, usually fertile, 70% have learning problems, offspring have increased risk of chromosome abnormality
47,XYY
tall, increased educational and behavioral problems, normal IQ, fertility usually normal
What gene is associated with male differentiation? Where is it located?
SRY
near pseudoautosomal region
briefly expressed early in development to cause differentiation of testes
When do the gonads begin to differentiate? What happens if there’s no SRY or it’s ineffective?
around wk 6 of development
ovaries develop
What karyotypes are common in DSDs?
46,XX male
46,XY female
What often causes infertility in men? What gene(s) are associated? Should men be referred for genetic testing? If so, what?
Azoospermia
AZF gene clusters
yes, if it is idiopathic -> karyotype and Y chromosome-specific testing
What is uniparental disomy?
form of nondisjunction where both chromosomes are inherited from same parent
What is isodisomy?
same sister chromosomes
what is heterodisomy?
same homolgoues inherited frome same parent
What is the typical cause of UPD?
trisomy rescue -> cell’s attempt to return to disomic state in trisomic conceptus
results from 2nd nondisjunction event in early, postzygotic mitotic division
22q11.2 deletion is typically detected by
CMA (microarray)
What two conditions are common genomic imprinting disorders?
Prader-Willi
Angelman
What genes are associated with male development?
SRY
TDF
Infertility in men can be associated with what changes? Where are these found?
AZF gene cluster
AZFa, AZFb, AZFc
Yq
