Birth Defects

Question 1

Birth defects - Statistics

Answer 1

Birth defects are the leading cause of death outside of prematurity in the first year of life

5-7% overall prevalence

2% of infants are born with potentially life-threatening defects

Question 2

Developmental fields

Answer 2

Tissues sharing gene expression - i.e. hedgehog signaling pathways

Tissues related to each other through location - i.e. branchial arches

Tissues sharing developmental timing - i.e. embryonic inner cell mass

Tissues affected by interacting processes

Question 3

VACTERL

Answer 3

Birth defects associating with each other more frequently than be accounted for by chance alone

Vertebral anomalies 
Anal atresia 
Cardiac anomalies (primarily septal defects) 
Tracheo-esophageal fistula / atresia 
Renal anomalies 
Limb anomalies

Question 4

Phenocopy

Answer 4

Similar abnormal phenotypes resulting from predominantly genetic or predominantly environmental factors

Ex: Tetrology of Fallot

Question 5

Tetrology of Fallot - Clinical syndrome

Answer 5

Pulmonary artery stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

Question 6

Causes of Tetrology of Fallot

Answer 6

Genetic - deletions on chromosome 22

Environmental - Accutane exposure

Question 7

Common teratogens (5)

Answer 7

Thalidomide
Vitamin A analogues (Accutane) 
Statins 
Anticonvulsants 
Ethyl alcohol

Question 8

Fetal Alcohol Syndrome - Presentation

Answer 8

Growth retardation
Dysmorphic features
Cognitive deficiencies

Question 9

Where are particularly high rates of NTDs seen?

Answer 9

Western England and Northern Ireland

Question 10

Population-based screening exists for which 2 common birth defects?

Answer 10

Down Syndrome

NTDs

Question 11

Targeted screening exists for which 2 clustered disorders?

Answer 11

Tay Sachs

Cystic Fibrosis

Question 12

Down Syndrome - Maternal Serum Analytes

Answer 12

Low AFP, uE3, and PAPP-A

high hCG and Inhibin

Question 13

Cell-free fetal DNA testing

Answer 13

Fetal DNA fragments enter maternal circulation with increasing gestational age; levels are sufficiently high to be used for chromosomal trisomy screening > 9 weeks

Question 14

At what point can a developing embryo be visualized by US?

Answer 14

6 weeks

Question 15

Indications for ultrasound

Answer 15

Advanced maternal age (> 35)
Positive aneuploidy screening test
Abnormal ultrasound findings (anatomic, IUGR, amniotic fluid volume)
Known parental chromosomal rearrangements
Previously affected child

Question 16

Amniocentesis

Answer 16

Performed under ultrasound guidance between 14-20 weeks

0.5% increased risk of fetal loss

Allows access to fetal cells for DNA analysis (FISH, karyotype, etc.) and amniotic fluid (biochemical analysis)

Question 17

Chorionic villous sampling

Answer 17

Performed under US guidance between 9.5 - 12.5 weeks gestation

Risk of fetal loss is 0.5-1% higher than amniocentesis (1-1.5% absolute risk increase)

Question 18

Percutaneous umbilical cord blood sampling (PUBS)

Answer 18

Highly invasive - complication rate is 1-2%

Usually reserved for diagnosis of fetal infections / anemia in severely compromised pregnancies

Question 19

Tay Sachs

Answer 19

AR deficiency of Hexosaminidase A causing accumulation of gangliosides in the CNS; presents with blindness, severe neurologic disease, and death by age 6

Diagnosed in at-risk pregnancies by fetal DNA extraction from amniocentesis or CVS; molecular DNA testing detects 94% of heterozygotes

Question 20

Thalassemia - Diagnosis

Answer 20

Fetal MCV < 80% with exclusion of iron deficiency anemia

Hb electrophoresis showing elevated HbA2 and HbF confirms B-talassemia

DNA-based testing necessary to detect a-globin deletions in alpha-thalassemia

Question 21

Sickle Cell Disease - Diagnosis

Answer 21

Fetal MCV < 80% with exclusion of iron deficiency anemia

Confirmed by Hb electrophoresis

Question 22

Cystic Fibrosis - Approach to diagnosis

Answer 22

Screening is offered to all pregnant women; if woman tests positive, screening is offered to partner; if both test positive, amniocentesis or CVS is done to test for CF gene

Question 23

Cystic Fibrosis - Diagnostic assay

Answer 23

Pan-ethnic mutation panel using 23 mutant CF alleles with a frequency of > 0.1% in the general population

Question 24

Cystic Fibrosis - Most common mutation

Answer 24

DF508 - results in loss of phenylalanine

Responsible for 75% of CF disease in non-Ashkenazi whites of European descent; screening solely for this mutation identifies 50% of couples at-risk for CF offspring

Question 25

Estimation of gestational age and fetal weight

Answer 25

First trimester - Crown-rump length (CRL) estimates gestational age

> 12 weeks:

Bi-parietal diameter
Abdominal circumference
Femur length

Question 26

Down Syndrome - Genetics

Answer 26

95% due to trisomy 21 due to non-dysfunction in the oocyte during meiosis 1; these cases are related to maternal age

5% due to genetic mosaicism and translocations (14;21)

Question 27

Down Syndrome - Epidemiology

Answer 27

Most common genetic cause of intellectual disability

US prevalence is 1/800 live births

Only 25% of fetuses survive to term

Question 28

Fetal nuchal thickness

Answer 28

Measured between 10-14 weeks gestation by US; interpreted as multiples of the median based on crown-rump length

65-85% of Down Syndrome fetuses have increased nuchal thickness

Question 29

Maternal serum analytes - NTD

Answer 29

Elevated AFP with elevated AChE by amniocentesis

Question 30

Unconjugated estriol (uE3)

Answer 30

The substrate of estriol production is DHEA-S from the fetal adrenal gland, which is converted by the placenta to estriol, which enters maternal circulation

uE3 is low in Trisomy 21