Cram 5 Flashcards
Max resolution of a high res karyotype?
2-3Mb
w h a t s y nd r o me s i s p o l y d a c t y l y a f e a t u r e o f ?
- meckel -gruber
- trisomy 13
- Pallister-hall
- chondroectodermal dysplasia (ellis- van Creveld) -Greig cephalopolysyndactyly syn
Warburg syndrome
-di es at 10 days of age -agyri a -cerebel l ar hypopl asi a -dandy-wal ker cyst - mi crophthal mi a -reti nal detachment wi th reti nal dyspl asi a
Lang e r - Giedion s y nd r o me
del (8)(q24.11-24.13)
- only 1/4 are cytogenetically visible
- true contiguous gene syndrome
- TRPS1 gene and EXT1 gene
- MR, microcephaly, multiple exostoses, redundant skin, sparse hair
campomelic dysplasia SOX9
-skeletal dysplasia with ambiguous genitalia or female genitalia with XY
- distinctive facies, Pierre robin seq w cleft palate
-shortening and bowing of long bones
-club feet
-laryngotracheomalacia w respiratory compromise
-often neonatally lethal
-AD, most de novo -
seq’g (90%), deletion analysis (5%)
incontinentia pigmenti IKBKG (akaNEMO)@Xq28
XLD, lethal inmales, Xq28
- eosinophilia
- four stages of skin changes: erythema>blister>hyperpigmented streaks>atrophic skin patches
- hypo/anodontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting
- retinal neovascularization causing retinal detachment
- MR is rare
- tests: free melanin granules if hyperpigmented streak biopsied
- molecular: southern blot for common exon4-10 del (80%)
meckel-gruber17q22
AR 3 major features: -occipital encephalocele -cystic kidneys- postaxial polydactyly also: potter-like facies; short webbed neck; dandy-walker malformation; arnold-Chiari malformation; fibrotic liver -perinatal death -prenatal dx by ultrasound
chondrodysplasia punctata
non-specific finding of punctate calcifications throughout the skeleton, seen in fetuses and young children
- etiologically heterogeneous
- –genetic causes
- —- arylsulfatase onXp22-
- —Zellweger syndrome
- –non-genetic causes—– warfarin exposure
l owe syndrome (ocul o-cerebral -renal ) synrome OCLR @ Xq26
XL -defect ininositol metabolism-DD, hypotonia, DTRs absent -delayed motor
milestones -cataracts (all affected boys), infantile glaucoma (50%) -generalized aminoaciduria-renal tubulardysfunction(fanconi type)-dx:enzymeactivity<10% ( o n f i b r o b l a s t s ) - s e q u e nc i ng ( 9 5 % )
NTD risks
genpop in US: 1/1000 one sib: 2% wo sibs: 10% one parent: 4% SDR: 1% TDR: 0.5%
Fryns syndrome
diaphragmatic defect (hernia, eventration, hypoplasia oragenesis)-facies (coarse, ocularhypertelorism, broad and flat nasal bridge, thick nasal tip, long philtrum, low-set and poorlyformed ears, tented upperlip, macrostomia, mi crognathi a) -di stal di gi tal hypopl asi a (nai l s, phal anges) -pul monary hypopl asi a -ass'd anomalies(polyhydramnios,cloudycorneasand/ormicropthalmia,orofacial clefting, renal dysplasia/renal cortical cysts) -neonatal lethal, usually (MR if not) -nogenesortesting;clinical diagnosis
correct PCR primerorientation?
3’———————————————- |||||||||||3’ >
What proportion of oocytes is an aneuploid?
20-25%
triploidy
1-3% of all recognized pregnancy es -15-20% of all chromosomally abnl SAB -6% of all SAB -<1/20,000 liveborns -85% diandric - 2 sperm most common -diandric: **well-grown fetus, **large placenta with appearance of partial hydatidiform mole, **usual l y don't survive to term , 3/4 syndactyl y -dyginic: growth retarded fetus ** w macrocephaly **, small and fibrotic placenta* *, can survive to term* *, 3/4 syndactyly
greatest risk for choriocarcinoma?
complete mole
Aneuploidy risk ass'd with u/s anomalies? -cystic hygroma -holoprosencephaly - VSD -T-e fistula -hydrops - multiple anomalies -CHD
cystic hygroma - 60% holoprosencephaly - 47% VSD - 38% TE fistula - 40% hydrops - 32% multiple anomalies - 29% CHD - 17%
c h r o mo s o me a b no r ma l i t i e s a s s ‘ d w i t h i nc r e a s e d r i s k o f c a nc e r
trisomy 8 - myeloid neoplasia down syndrome - acute leukemia 47,xxy - breast cancer 4 5 , x / 4 6 , x y - gonadoblastoma 5 q 2 1 - 2 2 - c o l o n c a 1 1 p 1 3 , 1 1 p 1 5 - Wilms tumor 13q14.2- retinoblastoma
what proportion of birth defects are due to teratogens?
2-3% of birth defets are due to drug treatment (more defects are due to other exposures - infection, maternal disease state, etc.)
what happens if there is exposure to a teratogenbefore implantation?(up to 7 days post-fertilization)
all or none period
what happens if there is exposure to a teratogen during the embryonic period?
18- 6 0 d a y s a f t e r c o nc e p t i o n
3 - 8 w e e k s
this is the period of organogenesis -maximumsensitivity to teratogeneicity b/c ti ssues devel opi ng rapi dl y and b/c damage becomes i rreparabl e -greatest likelihood of structural anomaly
w h a t h a p p e ns i f t h e r e i s e x p o s u r e t o a t e r a t o g e n d u r i ng t h e. f e t a l p h a s e ?
a f t e r 8 weeks
growth and functional maturationof organs and systems -teratogen exposure affect fetal growth (eg. IUGR), size of organ, function organ-structural anomalies less likely -called ‘fetal toxicity’ -psychoactive agents (antidepressants,
a nt i e p i l e p t i c s ,
a l c o h o l ,
o t h e r d r u g s o f a b u s e ) c a n h a v e a n a f f e c t o n the C N S - - > behavioral teratology
Can the effect of teratogenic exposure manifest afterbirth?
yes ! for example, most adenocarcinomas as s ‘ d w i t 1 s t t r i me s t e r e x p o s u r e t o s y nt h e t i c e s t r o g e n ( d i e t h y l s t i l b e s t r o l ) , o c c u r ma ny y e a r s a f t e r e x p o s u r e
what evidence is suggestive of humanteratogenicity?
recognizablepatternof anomalies-statisticallyhigherprevalenceof particular anomaly inpatients exposed to anagent thaninappropriate controls -presence of agent intehstageororganogenesisof theaffected organsystem-decreased incidenceof theanomalyinthepopulationpriortotheintroductionof theagent -
productionof the anomaly inexperimental animals by administering the agent in the cri ti cal peri od of organogenesi s
F D A c a t e g o r i e s f o r t e r a t o g e ns A B C D X
-A - controlled studies show no risk. eg. thyroxine B - no evidence of risk inhumans. -eitheranimal studiesshowrisk,buthumanstudiesdon’t;ornohumandatabut ani mal data i s negati ve (eg predni sone) C - ri sk cannot be rul ed out. –human studiesarelacking,animal studiesareeitherlackingorpositive(eg.lorazepam) D - positive evidence of risk -humandata show risk to fetus. (eg. warfarin, valproic acid, lithium) B, C, D - benefits may still outweigh risks X - contraindicated in pregnancy -data shows fetal risk that clearly outweighs benefits (eg.
teratogenic counseling
get detai l s of exposure - l ength, dosage, ti mi ng -other exposures? -col l ect
r e l e v a nt c u r r e nt d a t a - a s s e s s r i s k - c o u ns e l : - - - b a c k g r o u nd r i s k - - - w h e t h e r r i s k i s
increased —any specific anoaly ass’d —methods of prenatal detectionand their limitations—limitationsinourknowledge—risksass’d withmaternal condition
i tsel f (ex. di abetes, epi l epsy) -i deal l y done preconeptual l y
teratogens- ACE inhibitors
use inlate pregnancy ass’d with fetal toxicity -neonatal hypotension, oliguria w renal failure, hyperkalemia -complications of oligohydramnios (limb contractures, lung hypoplasia, craniofacial anomalies) -prematurity -IUGR -fetal death
teratogens - DES (diethylstilbestrol)
used in1950s-1960sforrecurrent miscarriage-1st tri exposure-clearcell adenocarcinoma of the vagina inadulthood -benignadenosis of the vagina - i ncreased mi scarri age rate -mal es - geneti al l esi ons
teratogens - anti epi l epti cs
-carbamazepine/tegratol - 1% risk of NTD (RR=10) -hydantoins (phenytoin/dilantin, trimethadione/tridione) –“fetal hydantoinsyndrome” –
d y s mo p r h - w i d e a nt e r i o r f r o nt a ne l l e , o u l a r h y p e r t e l o r i s m, me t o p i c r i d g e , b r o a d depressed nasal bridge, short antevereted nose, bowed upperlip, cleft lip, cleft pal ate –hypopl asi a of di stal phal anges, nai l hypopl asi a, l ow arch dermal dri ge patterning -MR, growth retard’n, cardiac defects -valproate (depacon) –1st tri exposure – 1-2% risk of meningomyelocele -‘fetal valproate syndrome’ –narrow
teratogens - folic acid antagonists - aminopterinand methotrexate
evere embryopathy, leading to fetal death -many anomalies -aminopterinnow used forabortions
teratogens - isotretinoin(accutane, 13-cis-retinoic acid)
potent teratogen- behavioral and structural -‘retinoic acide embryopathy’ - craniofacial anomalies-microtiaoranotia,accessoryparietal sutures,narrow sloping forehead, micrognathia, flat nasal bridge, cleft lip and palate, ocular hypertelorism) -cardiac defects (primarily conotruncal) -abnormalities inthymic development -alterations inCNS development -40% risk of miscarriage
teratogens- thalidomide
malformations of tissues of mesodermal origin-primarily limbs, ears, cardiac, gut muscluature
FMRI prenatal testing
amniocytes are ideal specimen-CVS: —FMRI methylationstatus not yet established —folow-up CVS may be required if male fetus with 100-250 CGG repeats, not methylated -PGD —by detectionof normal parental alleles, therefore parents must have different numbers —POF issues inpremutation females
which neuro conditionresponds to l-DOPA?
d y s t o ni a d u e t o G T P c y c l y o h y d r o l a s e I mu t a t i o n i mp o r t a nt t o i d e nt i f y s i nc e i t ‘ s treatable
Featuresof DMD carriers
2 / 3 h a v e C K l e v e l s > 9 5 t h % l e - 1 5 - 2 0 % h a v e l e f t v e nt r i c u l a r d i l a t a t i o n, 7 % h a v e DCM -15% have muscle weakness -5% have cramps and myalgia -calf pseudohypertrophy is rare
hypertension, preeclampsia, which is assocaited with premature rupture of membranes, IUGR, abruptio placentae, perinatal death, ‘50% risk of
c o mp l i c a t i o ns ? a . M S A F P ‘ 2 . 5 M o M b . h C G ‘ 2 . 0 M o M c . M S A F P ‘ 2 . 5 M o M a nd hCG ‘ 2.0 MoM d. uE3 < 0.15 MoM
Elevated MSAFP AND hCG canbe associated with any of these findings. PROM and IUGR are not usually seenwith hCG elevationalone. Anelevationineither markercanbeassociated withhypertension,pre-eclampsia,orfetal and perinatal demise. What is noteworthy whenboth markers are elevated is the very high risk of a poor outcome
VWD vonwillebrand disase VWF
A D ( r a r e A R t y p e s ) - c o ng e ni t a l b l e e d i ng d i s o r d e r - ma y o nl y b e c o me a p p a r e nt o n hemostatic challenge
thrombophel i as and pregnancy compi cati ons ri sks
pre-eclampsia - highest risk with proteinC and S, but also antithrombinII, factor V , M T H F R h o mo z y g o s i t y - s t i l l b r i t h - h i g h e s t r i s k i w h t p r o t e i n S a nd f a c t o r V
L e i d e n - V T E - h i g h e s t r i s k w i t h f a c t o r V l e i d e n a nd p r o t h r o mb i n G 2 0 2 1 0 A , mu c h hi gher f or d oub l e het s f or t hese two
w h a t d i s e a s e c a n b e t e s t e d b y C V S b u t no t b y a mni o ?
osteogenesis imperfecta b/c collagenstudies canbe done onCVS but not on amnio
prenatal dx scenari os 30yo undergoe amni o b/c of abnl screeni ng w tri 21 ri sk of 1/125 resul t: 45,XX,rob(14)(q10;q10) i nterpretati on? next steps?
arental chromosome studi es to determi ne i f de novo or i nheri ted -i f i nheri ted and parent normal - no i ncreased ri sk -i f de novo, ri sk not i ncreased above background of 3%
prenatal dx scenari os 30yo undergoe amni o b/c of abnl screeni ng w tri 21 risk of 1/125result:45,XY,t6;8interpretation?nextsteps?
parental chromosome studi es -i f de novo, ri sk of abnl phenotype i s 6% -if inherited,risk for a bnl phenotype is low
prenatal dx scenari os 30yo undergoe amni o b/c of abnl screeni ng w tri 21 ri sk of 1/125 result: inversioninterpretation?next steps?
parental chromosome studi es -i f de novo, ri sk of abnl phenotype i s 9%
prenatal scenaorios36yohasamnioforAMA.results:markerchromosome
p a r e nt a l c h r o mo s o me s t u d i e s - i nh e r i t e d o r d e no v o ? - l a b c h a r a c t e r i z e t h e ma r k e r : —unabl e to characteri ze - 13% —i (18)p, i di c(22) or i (12)p - 100% ri sk —der (X) without XIST - 100% risk —no coding material (small, bisatellited) - no increasaed risk
p r e na t a l s c e na r i o t r i s o my 2 0 mo s a i c i s m o n a mni o c e nt e s i s - 4 7 , X Y + 2 0 / 4 6 , X Y
trisomy 20 is a fairly commonfinding onamnio -more likely to e found inbaldder, kdi neys, i ntesti ne -most cases are phenotypi cal l y normal , l ow ri sk of abnormal
o u t c o me
prenatal scenariosCVS-100%trisomy16
not trisomy 16 inthe fetus -trisomy 16 fetus wouldn’t make it to 10-13 weeks gestational age -BUT ass’d with IUGR and pre-eclampsia!!
v e r y g e ne r a l r u l e s o f t h u mb - e mp i r i c r e c u r r e nc e r i s k s f o r b i r t h d e f e c t s
1 FDR affected: 3-5% 2 sibs: 8-12% Both parents: 30-40% >3 FDR: 45-50%
what’s on the core AJ panel and the expanded?
core (ACOG 04) - CF, TS, canavan, familial dysautonomia expanded (ACOG 04) - MPSIV, nieman-pick A, fanconi anemia c, bloom, gaucher(ACMG08too)
A C O G 2 0 0 7 H B - o p a t h i e s g u i d e l i ne s
o f f e r c a r r i e r s c r e e ni ng t o i nd i v i d u a l s o f a f r i c a n, s o u t h e a s t a s i a n, me d i t e r a nne a nd e c e nt - b y C B C a nd H B e l e t r o p h o r e s i s - s o l u b i l i t y t e s t i na d e q u a t e - o f f e r c a r r i e r
c o u p l e s G C ‘ i ng , P N D x b y D N A analysis
CFTR and CBAVD?
inCBAVD pop’nmost commonCFTR mtnis delftaF508, oftentrans with 5T -85% are eithera het ordouble het forCFTR mutations
pancreati cancer risk w/ BRCA2 mutations?
10%
possible(and likely)explanationfornormal NF1 sequencinginfirst personinthe f a mi l y w i t h N F 1 ( o r N F 2 s e q u e nc i ng i n N F 2 ) ?
mo s a i c i s m! v e r y o f t e n t h e f i r s t p e r s o n i s mo s a i c . b e t t e r t o t e s t y o u ng e r g e ne r a t i o n.
which genetic conditions cancause azoospermia?
10-15% of menwith azoospermia have a karyotype abnormality -Yq deletions, DAZ ismostcommonmicrodeletioninazoospermia(10%)-CForCBAVD– isolated CBAVD causes obstructive azoospermia and cocurs in1-2% of infertile me n; 8 5 % o f me n w i t h C B A V D h a v e a t l e a s t o ne C F T R mu t a t i o n - 4 7 , x x y -
no no b s t r u c t i v e o l i g o o r a z o o
