Congenital Anomaly/Toxicology

Question 1

What is an anomaly? Distinguish between major and minor anomalies. List the three main classifications of anomalies.

Answer 1

Anomaly - basic unit of syndromes + sequences
Major: severe cosmetic or impairs function
Minor: less severe cosmetic or little clinical significance
Malformation, Deformation, Disruption

Question 2

What is a malformation? What causes malformation?

Answer 2

Due to poor formation of tissue
60% unknown
20% multifactorial
7.5% Monogenic Disorder
6.5% Maternal influence during development
6.0% Chromosomal Abnormality

Question 3

Give Examples of the different kinds of malformation.

Answer 3

Incomplete Morphogenesis: Syndactyly, Renal Agenesis, ASD (Common)
Redundant Morphogenesis: Ear tag, Polydactyly (Uncommon)
Aberrant Morphogenesis: Mediastinal Thyroid, Paratesticular Spleen (Rare)
Monogenic Malformation Syndromes:
Apert Syndrome - AD - syndactyly + craniosyntosis
Ectrodactyly - AD - “Lobster Claw”
Treacher-Collins - AD - Cleft P, Coloboma, deafness
Ellis van Creveld Syndrome - AR - dwarfism, Polydactyly, Ectodermal dysplasia
Chondrodysplasia Punctata - XLR - Dwarfism, tiny nose, brachytelangitic CDP
SPINA BIFIDA - meningomyelocele

Question 4

What is a deformation? What can cause them?

Answer 4

Unusual Forces on Normally Developed Tissue
Extrinsic - forces external to fetus - Mechanical (Amniotic Tear/Oligohydramnios, Unusual Implantation site, Uterine Leiomyoma, Twins, Maternal Uterine Malformation)
Intrinsic - fetus creates forces - Malformational (Spina bifida, bilateral renal agenesis, urethral atresia/OHA) or Functional (Neuro/Muscular Disturbances)

Question 5

Give examples of Deformations.

Answer 5

1. Plagiocephaly (abnormal skull shape)
2. Potter’s sequence (bilateral renal agenesis - OHA - compressed head, upturned feet)
3. Micrognathia
4. Mandibular Asymmetry
5. Torticollis
6. Club Foot

Question 6

What is a disruption? Give causes.

Answer 6

Breakdown of normal dissue

1. constricted amniotic bands - amputations
2. necrosis of tissues - skull defects

Question 7

When do different types of anomalies occur?

Answer 7

1. Malformations - EMBRYO - disturbs ORGAN - risk for mortality - no correction except surgery
2. Deformations - FETUS - disturbs anatomic REGION - low mortality risk - spontaneous correction or with posture
3. Disruptions - UNKNOWN - some REGION - may be mortal, no spontaneous correction

Question 8

What is a sequence? Give example.

Answer 8

Describes a genesis of syndromes, nature of developing a pattern of multiple anomalies
ROBIN SEQUENCE
1a. Malformation (Mandibular Hypoplasia)
1b. Deformation (Mandibular Constraint)
2. Failure of Tongue Descent (tongue interferes with arch formation)
3. Cleft Palate
Treacher-Collins Syndrome: Pierre-Robin Sequence: U-shape CP, deafness

Question 9

Significance of minor abnormalities

Answer 9

1. Presence of 3 suggests underlying major 1
2. Present in multiple congenital anomaly syndromes
3. Suggest potential developmental intellectual disability

Question 10

What is a teratogen? List the TORCH agents.

Answer 10

Teratogen - agents that affect viability or development of specific organ systems of an embryo; SPECIFIC + CONSISTENT
T - toxoplasmosis
O - syphilis 
R - rubella
C - cytomegalovirus
H - herpes

Question 11

How does the Dose of Teratogen affect the pregnancy? What factors affect teratogen dosage?

Answer 11

1. Low - no effect; intermediate - specific malformation; high - loss of pregnancy [Some have all-or-none effect]
2. Maternal Dose, Route of Administration, Factors affecting mom’s biodistribution (genotype, use of other drugs, comorbid diseases), efficiency drug can cross plasma, fetal genotype, exposure duration

Question 12

How does the developmental stage of the embryo/fetus affect the teratogen’s effects?

Answer 12

Specific Defect needs to develop at specific time during organogenesis (can’t occur once developed)
Weeks 1-2: “all or none” effect
Weeks 2-8: specific deformations, major anomalies, embryo developing organs
Weeks 8+: unlikely to cause malformation, minor anomalies, fetus already developed

Question 13

How does the fetal genotype affect teratogen’s effects? What maternal factors affect the teratogen?

Answer 13

FG: determine susceptibility through how efficient fetal drug metabolism is
MF: 1. DM - can’t control glucose levels - 3x risk of developing malformations, caudal regression syndrome, spine/leg malformations, congenital heart disease, renal + CNS malformations
2. PKU - uncontrolled PHE - 90% malformations, microencephaly, intellectual disability, congenital heart defects

Question 14

List the types of teratogenic agents.

Answer 14

1. Infectious Agents (TORCH)
2. Maternal Factors (DM, PKU)
3. Physical Agents (Ionizing Radiation, Drugs)

Question 15

How do ionizing radiation and drugs cause malformations?

Answer 15

1. IR - very high doses during weeks 2-5: neural tube abnormalities, ocular defects, growth retardation
2. Thalidomide: treats morning sickness, phocomelia - limb defects
3. Warfarin: brachytelephalangic CDP: punctate calcification of cartilagenous bone precursors, small nose, XLR
   Mechanism: 1. Coumarin Drug - 2. Inhibition of Arylsulfatase E - 3. Arylsufatase E deficiency - Phenotype
   XLR Mechanism: 1. XL CDP - 2. Mutation in Arylsulfatase E - 3. Permanent Arylsulfatase E deficiency - Phenotype + Intellectual disability
   Hard to predict drug effects because different species react differently/not at all to different agents