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Prenatal genetics > Week 5: US findings and structural abnormalities > Flashcards

Week 5: US findings and structural abnormalities Flashcards

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1
Q

What is a malformation

A

-result from intrinsic abnormalities in one or more genetic programs operating in development
-Many have multifactorial inheritance
-Ex: cleft lip/palate, ONTDs, extra fingers in Greig cephalopopolysyndactyly

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2
Q

What is a deformation

A

-caused by extrinsic factors impinging physically on the fetus during development
-especially common in the second trimester when fetus is constrained within amniotic sac and uterus
-most are apparent at birth and either resolve spontaneously or can be treated by external fixation devices
-ex: clubfoot, contractions of joints of the joints of the extremities (arthrogryposes) due to twin/triplet gestations or prolonged leakage of amniotic fluid

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3
Q

What is a disruption

A

-result from destruction or irreplaceable normal fetal tissue
-more difficult to treat than deformations because they involve loss of normal tissue
-may be the result of vascular insufficiency, trauma, or teratogens
-ex: amniotic bands or disruption which results in partial amputation of of fetal limb associated with strands of amniotic tissue

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4
Q

Can malformations, disruptions and deformations be present in one individual?

A

-yes they sometimes overlap
-ex: vascular malformations may lead to disruption of distal structures
-ex: urogenital malformations that cause oligohydramnios can cause fetal deformations.
-constellation of birth defects in an individual may represent combinations of malformations, deformations, and disruptions

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5
Q

How does pleiotropy apply to term “syndromes”?

A

-when a causative agent causes multiple abnormalities in parallel the collection of abnormalities is referred to as a syndrome

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6
Q

How does pleiotropy apply to the term “sequence”?

A

-if a mutant gene or teratogen affects only a single organ system at one point in time, and it is the malfunction of that organ system that causes the rest of the constellation of the pleiotropic defects to occur as secondary effects, the malformation is referred to as a sequence

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7
Q

About what percentage of live births have a congenital anomaly?

A

~3%

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8
Q

What are amniotic bands?

A

-Occurs when amnion is damaged causing strands of tissue to form and attach to fetal parts
-If body part becomes tangled and constricted, it can lead to deformities/amputations
-Cause mostly unknown, not associated with genetic syndrome

-Most commonly affects limbs and digits
-Limb-body wall complex: lethal
-Craniofacial abnormalities

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9
Q

What is Pierre Robin sequence?

A

-Restriction of mandibular growth before the 9th week of gestation causes the tongue to lie more posteriorly than usual which interferes with normal closure of the palatal shelves= U-shaped palate
-Etiologies: unknown, extrinsic impingement on developing mandible by twin in utero, genetic syndrome (Stickler syndrome)

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10
Q

Most congenital anomalies have what etiology?

A

Multifactorial! 40%

Chromosome abnormality: 35%
Single gene variant: 20%
Teratogen: 5%

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11
Q

Genetic syndromes are more likely or less likely with the presence of multiple anomalies compared to isolated anomalies?

A

More likely!!

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12
Q

Congenital heart defects (CHDs) occur in what percent of live births?

A

1% of live births

-Genetic risk dependent on type of CHD and the presence of other anomalies
-Overall, 20-30% of CHD have known genetic etiology

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13
Q

CHD of AV canal defect should think of what syndrome?

A

T21

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14
Q

CHD coarctation of the aorta should think of what syndrome?

A

Monosomy X

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15
Q

CHDs
-Tetralogy of Fallot
-Truncus Arteriosus
-Interrupted aortic arch
-Double outlet right ventricle
-other conotruncal defects

Should think of what syndrome?

A

22q11.2 deletion

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16
Q

CHD pulmonary valve stenosis should think of what syndrome?

A

Noonan syndrome

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17
Q

CHD supravalvular aortic stenosis should think of what syndrome?

A

Williams syndrome

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18
Q

What are neural tube defects?

A

-Group of malformations arising from failure of closure of the neural tube (usually closes by 6 wks gestation)
-Prevalence: .5-2/1000 live births
-Conditions range from surgically reparable to lethal (location and size predict severity)

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19
Q

What two ultrasound “signs” are related to neural tube defects?

A

-Lemon sign
-Banana sign

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20
Q

First trimester US is able to detect what types of NTDs?

A

-Anencephaly
-Encephalocele

UNLIKELY to detect spina bifida

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21
Q

Second trimester US is able to detect what types of NTDs?

A

-Spina bifida and spina bifida brain anomalies (Chiari II malformation)
-anencephaly
-Encephalocele??

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22
Q

What can be measured to assess for open neural tube defects?

A

AFP level

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23
Q

Causes for NTDs?

A

-If isolated probably multifactorial
-2-5% due to genetic condition
-Maternal factors (diabetes, anticonvulsant medication)

Risk for NTDs decreased by 70% with folic acid supp

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24
Q

All about Meckel Gruber syndrome?

A

-AR due to PV in 8 genes
-Hallmark features: occipital encephalocele, bilateral enlarged cystic kidneys, postaxial polydactyly
-Lethal condition

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25
Q

What is ventriculomegaly?

A

-Ventricles of the brain are enlarged due to increased cerebrospinal fluid
-5% risk for chromosome abnormalities in isolated cases (usually Down syndrome), higher risk for severe

Classifications:
-Mild: usually normal outcome, marker for Down syndrome
-Moderate: outcome usually favorable but increased risk for neurodevelopmental disabilities
-Severe: high risk for neurodevelopmental disabilities

26
Q

Severe ventriculomegaly in male fetus should raise suspicion for what condition?

A

L1 syndrome: X-linked condition caused by mutations in L1CAM

27
Q

What is agenesis of the corpus callosum?

A

-Failure of axons to cross the midline between right and left brain hemispheres
-May be symptomatic or cause ID
-Often associated with other brain malformations
-Up to 17% have genetic etiology

28
Q

What is Dandy Walker malformation?

A
  1. Enlarged posterior fossa (posterior fossa cyst)
  2. Defect in cerebellar vermis
  3. Dilation of the 4th ventricle

-Mostly multifactorial
-Chromosome abnormalities in ~16% of cases

29
Q

What is holoprosencephaly?

A

-Forebrain failed to separate into two hemispheres
-Four subtypes with varying severity
- ~40% have chromosome abnormality
+T13!!!

30
Q

What is gastroschisis?

A

-Free floating loops of bowel without membrane
-Deformation or disruption of body wall in embryonic period
-Usually sporadic and not associated with other structural abnormalities

31
Q

What is the greatest risk factor for gastroschisis?

A

Young maternal age

32
Q

What is an omphalocele?

A

-Herniated sac containing abdominal contents with membrane
-Due to a) extraembryonic gut fails to rotate back into abdomen 9-11wks or b) embryonic disk fails to fold at umbilicus 4-5wks
-Frequently associated with other anomalies (cardiac defects common)

33
Q

A small omphalocele (bowel only) is high risk for what?

A

Aneuploidy- T18 and T13 most commonly

34
Q

A large omphalocele (containing the liver) has a high or low risk for aneuploidy?

A

Lower risk

35
Q

Presence of an omphalocele, especially an isolated one, increases risk for what condition?

A

Beckwith-Wiedemann syndrome

36
Q

What is duodenal atresia and what condition does it raise suspicion for?

A

-Congenital absence or complete closure of portion of lumen in the duodenum
-Results in complete or partial blockage of duodenum
-“Double bubble” on US

-Down syndrome!!
-Small percentage have Feingold syndrome (present with multiple anomalies)

37
Q

What is clubfoot?

A

-Malformation of fetal ankle producing abnormal posturing of foot
-Male to female ratio 2:1
-2/3 bilateral, 1/3 unilateral
-Typically multifactorial when isolated

38
Q

What is polydactyly?

A

-Presence of extra finger or toe
-May contain bone or be soft tissue only
-Isolated: likely benign and not part of syndrome
+can be ancestral- more
common in Black
-Not isolated: T13, Bardet-Biedl

39
Q

List ultrasound findings that are suggestive of a skeletal dysplasia

A

-Very short long bones
-Bowing of long bones
-Poor mineralization
-Bone fractures
-Small chest circumference
-Short ribs

40
Q

Is ultrasound reliable for differentiating between skeletal dysplasias?

A

No, but it can be reliable for predicting lethal/not lethal based on chest circumference

41
Q

What gene causes achondroplasia and is it lethal?

A

-FGFR3
-Not lethal
-Usually presents >24wks with short long bones, macrocephaly, frontal bossing

42
Q

What gene causes osteogenesis imperfecta and is it lethal?

A

-Many genes causative
-Many types of OI
-OI type II is lethal: severe shortening and bowing of long bones, multiple fractures, narrow chest

43
Q

What gene causes thanatophoric dysplasia and is it lethal?

A

-FGFR3
-Most common lethal skeletal dysplasia
-Severe shortening and bowing of long bones, multiple fractures, narrow chest

cloverleaf skull

44
Q

What is renal agenesis?

A

-Absence of uni/bilateral kidneys
-Kidney doesn’t form due to nonexistance of ureteral bud or failure of ureteral bud to form
-2.5X more common in males
-Bilateral=lethal

-If isolated: low risk for chromosome abnormalities
-Increased risk for genetic syndrome if additional findings (T21, T18, T13, T22, monosomy X, XXY, triploidy, 22q, etc)
-VACTERL association
-Maternal diabetes

45
Q

What is Potter sequence?

A

Possible cause:
-Bilateral renal agenesis or bilateral dysplastic kidneys
-Reduced fetal urine output
-Oligohydramnios cause fetal compression

46
Q

What is VACTERL association?

A

-Group of congenital anomalies seen together without known cause
-Not caused by genetic etiology but overlap with many genetic syndromes

Must have 3+ features:
V= Vertebral
A=anal atresia
C cardiac defects
T= tracheoesophageal fistula
E= esophagus thing above
R= renal anomalies
L= limb anomalies

47
Q

What is congenital diaphragmatic hernia?

A

-Incomplete formation of diaphragm allowing abdominal viscera to herniate into the chest
-Interferes with lung development
-2-3% with genetic etiology
+T21, T18, T13
+Single gene

48
Q

What are orofacial clefts?

A

-Include cleft lip alone, cleft lip with cleft palate, cleft palate alone
-Results from closure failure 5-6wks
-Prevalence depends on ethnicity and fetal sex
-Genetic etiologies: T13, 22q11, Treacher Collins, Stickler

-30% of clip lip and palate together are syndromic
-50% of cleft palate are syndromic

49
Q

What 2 anomalies are strongest evidence for T21?

A
  1. Cardiac defects (AV canal most common)
  2. Duodenal atresia
50
Q

What 2 anomalies are strongest evidence for T18?

A
  1. Fetal growth restriction
  2. Choroid plexus cysts
51
Q

What 2 anomalies are strongest evidence for T13?

A
  1. Midline defects
  2. Brain abnormalities (holoprosencephaly)
52
Q

What 2 anomalies are strongest evidence for monosomy X?

A
  1. Cystic hygroma/hydrops
  2. Cardiac defects (coarctation of aorta)
53
Q

What is the testing strategy for abnormal ultrasound typically?

A

FISH, if abnormal then karyotype, if normal then microarray

If FISH/karyotype/microarray normal then molecular testing can be considered

54
Q

What are some challenges with prenatal testing?

A

-Incomplete phenotype: US does not provide full picture
-Limited phenotypic information on prenatal findings of genetic syndromes
-Small portion of labs accept prenatal samples
-Insurance coverage/cost
-Time constraints (termination)

For these reasons, it is often difficult to narrow down a differential diagnosis to a few specific syndromes–important to determine class of conditions!!

55
Q

What are ciliopathies?

A

-Group of disorders caused by disruption of formation/function of cilia
-Often AR
-Common features: renal cystic disease, organs on wrong side of body, retinal degeneration, cerebellar anomalies, polydactyly
-Ex: Meckel Gruber, Bardet-Biedl, primary ciliary dyskinesia

56
Q

Tetralogy of Fallot (TOF) is most strongly associated with what syndrome?

A

22q deletion syndrome

Combination of 4 specific heart defects

57
Q

Is the recurrence risk for isolated CHDs higher if the mother or father is affected?

A

Mother

58
Q

Is the recurrence risk for isolated CHDs higher for 1 sibling affected or 2 siblings affected?

A

2 siblings

59
Q

What is the general population risk for a child to have autism?

A

~2-3%

60
Q

Younger male siblings of child with autism are more or less likely to be affected than female siblings?

A

More likely

Risk of autism recurrence greatest for younger brothers of females with ASD

61
Q

If you see severe ventricomegaly in male fetus, what disorder should you think of?

A

L1 syndrome

Prenatal genetics (9 decks)

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