From Iusmicm

Contents 1 Basic Embryology and Teratology 1.1 Objectives 1.2 Vignette 1.3 Definitions: Malformation, Disruption, Deformation, Dysplasia 1.3.1 Malformation 1.3.2 Disruption 1.3.3 Deformation 1.3.4 Dysplasia 1.4 Vignette 1.5 Vignette 1.6 Causes of Anomalies 1.6.1 Incidence of Anomalies 1.6.2 Genetic causes of congenital anomalies 1.6.2.1 Trisomy 21 1.6.2.2 Fragile X Syndrome 1.6.3 Environmental causes of congenital anomalies 1.6.3.1 Congenital Rubella Syndrome 1.6.3.2 Thalidomide 1.6.4 Multifactorial inheritance 1.6.4.1 Neural Tube Defects 1.6.4.2 Cleft Lip and Palate 1.6.5 Basic principles of Teratology 1.6.5.1 Teratogen Vignette 1.6.5.2 Period of “all or none” 1.6.5.3 Dosage Effects 1.6.5.4 Genotype of the Embryo 1.7 Examples of Major Anomalies 1.7.1 Anencephaly 1.7.2 Omphalocele 1.7.2.1 U/S Findings with Omphalocele 1.8 Summary

Basic Embryology and Teratology

Objectives

• That there are 4 clinically significant types of anomalies: malformation, disruption, deformation and dysplasia.
• The causes of congenital anomalies are divided into genetic, environmental and multifactorial.
• The incidence of major and minor congenital anomalies.
• Some of the basic principles of teratology.
  • You will use this info to counsel patients.
• About some examples of teratogenic agents
• And some examples of major anomalies we frequently see in prenatal diagnosis.

Vignette

• A 23 yo gravida 1, para 0 delivers a baby with rocker bottom feet, spina bifida, and a cardiac defect.
• Karyotype analysis shows trisomy 18 (47, XY +18).
• You explain to the mother that her son’s anomalies are an example of which basic type:

1. Malformation 2. Disruption 3. Deformation 4. Dysplasia

Definitions: Malformation, Disruption, Deformation, Dysplasia

Malformation

• A malformation is defined as a morphological defect of an organ, part of an organ, or larger region of the body that results from an intrinsically abnormal developmental process.
• Intrinsic implies from the beginning such as a chromosomal anomaly present at fertilization.
• Most malformations are considered to be a defect of a morphogenetic or developmental field which responds as a coordinated unit to embryonic interaction and results in complex or multiple malformation.

Disruption

• A disruption is a morphological defect of an organ, part of an organ, or body region that results from the extrinsic breakdown of or interference with an originally normal developmental process.
• Disruption, for an example, might be caused by a teratogen that causes derailment of a normal development pattern.
  • Teratogens can include drugs or viruses.

Deformation

• A deformation is an abnormal form, shape, or position of a body part that results from mechanical forces.
• Examples of mechanical forces that can cause deformations include intrauterine compression by oligohydramnios or large myomas of the uterus.
  • Recall that oligohydraminos is a deficiency of amniotic fluid.
  • Oligohydramnios can cause clubfoot or Potter's sequence (renal agenesis).
  • Large myomas can cause skull defects.
• In deformations, the normal development is mechanically changed to an abnormal state.

Dysplasia

• Dysplasia is an abnormal organization of cells into tissue that results in morphological anomalies.
• "Dyshistiogenesis" is defined as abnormal tissue formation.
• Therefore dysplasia is the process and consequence of dyshistiogenesis.
• Examples of dysplasia include renal dysplasia secondary to bladder outlet obstruction.
  • When the bladder is obstructed, hydronephrosis occurs which causes dyshistiogenesis (and is thus called a dysplasia).

Vignette

• A 34 yo G3P2 presents for a screening ultrasound evaluation.
• The following ultrasound anomalies are seen:
  • clubbed foot
  • banana sign (abnormal cerebellum)
  • lemon sign (head shape)
  • normal longitudinal spine
  • normal longitudinal view of spine
  • open spine visible from sagital section
  • ventriculomegaly

• You inform this patient that her fetus has:

1. Anencephaly 2. Open neural tube defect 3. A lethal condition 4. Spina bifida occulta 5. None of the above are correct

The clubbed feet in this clinical scenario are an example of which type of fetal anomaly: 1. Malformation 2. Disruption

3. Deformation

4. Dysplasia 5. None of the above

�==Vignette==

• 27 yo gravida 1 para 0 at 20 weeks gestation was found to have a fetus with amniotic band syndrome which has caused complete amputation of the lower fetal arms and legs.
• This type of anomaly would be classified as:

1. Malformation

2. Disruption

3. Deformation 4. Dysplasia 5. None of the above

Vignette

• 33 year old patient in her first pregnancy at 10 weeks gestation (10 weeks from her last normal menstrual period) contracts a case of primary rubella (German measles) infection.
• Her baby is examined after birth and found to have a cardiac defect, cataracts, tooth defects and deafness.

• The anomalies in this case of congenital rubella syndrome are an example of:

1. Malformation 2. Disruption 3. Deformation 4. Dysplasia 5. Association

Causes of Anomalies

• Genetic: chromosomal anomaly such as trisomy 18
• Environmental: such as drugs, chemicals or infections
• Multifactorial: many common congenital anomalies are caused by genetic and environmental factors acting together in a multifactorial inheritance pattern

• Estimated Incidence of Causes of Major Congenital Anomalies Causes:
  • Chromosome abnormalities (6-7%)
  • Mutant Genes (7-8%)
  • Environmental factors (7-10%)
  • Multifactorial inheritance (20-25%)
  • Unknown etiology (50-60%)

• Which of the following statements are true concerning the incidence of congenital anomalies:

1. Single minor anomalies are seen in up to 4-5% of newborn infants and likely have no clinical significance. 2. Multifactorial inheritance is rarely a cause of major congenital anomalies. 3. Three percent of all live born infants will have an obvious major anomaly. 4. The incidence of major anomalies is higher in term infants than in spontaneous abortions. 5. None of the above are true.

Incidence of Anomalies

• Anomalies may be single or multiple, major or minor.
• Single minor anomalies are quite common and occur in approximately 14% of deliveries (ear tags, single umbilical anomaly, hemangiomas).
• Minor anomalies are of no serious medical significance but may alert clinician to the presence of a major anomalies.
• 90% of infants with 3 or more minor anomalies will have 1 or more major defects.
• 3% of infants born will have a major anomaly.
• Major developmental defects are much more common in early embryos (10-15%) than newborn infants (3%) but most of them abort spontaneously.
• Chromosomal anomalies are present in 50-56% of spontaneously aborted fetuses.

Genetic causes of congenital anomalies

• Examples of genetic causes:
  • Trisomy 21 (Down syndrome)
  • Triploidy (69, XXX)
  • Fragile X syndrome
  • Chromosome translocations, deletions

Trisomy 21

• Trisomy 21 is characterized by:
  • flattened nose and face
  • upward slanting eyes (laterally)
  • widely separated first and second toes
  • increased skin creases on the sole
  • single palmar crease
  • short fifth finger that curves inward

Fragile X Syndrome

• Most common inherited cause of mental retardation
• Frequency of 1/1000-1500 male births
• Fragile X is due to an unstable repeat of CGG at Xq27.
• All full mutations are dereived from premutation carriers.
  • Full mutations are >200 repeats.
  • Premutations are 56-200 repeats.
  • Female carriers facilitate migration from premutation to full mutation.
• The number of repeats correlates with the severity of the disease.

• Diagnosis confirmed by chromosome analysis
  • Demonstration of excessive, small area on long arm of X chromosome.
  • This area may look like it could break off.
    • Has a pinched segment.
    • Hence the name “fragile X” syndrome.

Environmental causes of congenital anomalies

• Fetal (maternal) infections such as CMV, Parvovirus, toxoplasmosis, varicella, rubella viruses.
• Drugs such as alcohol, methotrexate, cocaine, DES, tetracycline, phenytoin (Dilantin), thalidomide, warfarin (Coumadin), valproic acid (Valproate).
• Chemicals such as PCBs, mercury, lead.
• Radiation exposure.

• Environmental factors account for 7-10% of congenital anomalies.
• Teratogens cause developmental disruptions following maternal exposure.
• Teratogens are not effective until cellular differentiation has begun.
• Exact mechanisms by teratogens they induce abnormalities are usually unknown and may be affected by hereditary influences.

Congenital Rubella Syndrome

• Rubella peaked in 1964 and 1965.
  • 12.5 million cases were reported (USA)
  • 20,000 babies were born with birth defects.
  • 6,200 babies were stillborn.
  • 5,000 births were aborted both naturally and assisted.
• Vaccination only became available in 1969.
• The disease was dangerous because in children it was almost unnoticeable and pregnant women often did not know that they had been exposed.

• Children infected with rubella before birth (a condition known as congenital rubella) are at risk for the following:
  • growth retardation
  • malformations of the heart, eyes, and brain,
  • deafness,
  • liver, spleen, and bone marrow problems.

Thalidomide

Multifactorial inheritance

• Multifactorial traits are usually single major anomalies
• Many anomalies have familial distributions:
  • cleft lip and palate,
  • NTD,
  • pyloric stenosis,
  • congenital dislocation of the hip
• Some multifactorial inheritance may occur as part of a phenotype in syndromes determined by single-gene inheritance, chromosomal anomaly or an environmental teratogen.

Neural Tube Defects

Cleft Lip and Palate

• Facial cleft involving the upper lip and / or palate.
  • Usually occurring to the left or right of midline.
• Cleft lip and / or cleft palate may occur as an isolated malformation or as part of a multiple malformation syndrome.
• Midline facial cleft may be associated with underlying brain malformations, especially holoprosencephaly.
• 1:1,000 births for cleft lip and / or cleft palate.
  • M > F
• 1:200 births for isolated cleft palate
  • M1:F2
• Marked ethnic and racial variation in incidence
• Medial facial clefts account for less than 1% of all facial clefts

• Most isolated cleft lips or cleft palates show multifactorial inheritance.
• Dominant, recessive and X-linked syndromes have been described.
• The pattern of inheritance depends on an accurate diagnosis.

• Cleft lip / palate teratogens: alcohol, maternal PKU, hyperthermia, hydantoin, trimethadione, aminopterin and methotrexate.

Basic principles of Teratology

• The stage of development of an embryo when teratogen is present determines its susceptibility to a teratogen.
• The most critical period is when cell division, cell differentiation and morphogenesis at are their peak.

Teratogen Vignette

• A 37 year old patient who is in her fourth pregnancy learns she is pregnant and currently at 12 weeks gestation (12 weeks from her last normal menstrual period).
• She comes to your office extremely concerned because she had 3 CT scans for severe abdominal pain 10 weeks ago.
• She is very concerned with the radiation exposure that she incurred.
• She is extremely worried about the risk of miscarriage.
• You counsel her:

1. She has received an exceptionally high dose of radiation at a critical period in organ development and the pregnancy will be affected. 2. She did not receive the radiation during the period of organogenesis but rather in the “all or none” period and the pregnancy will not be affected. 3. The pregnancy may be affected depending on the dose of radiation to the fetus and you will need to have the radiation safety officer calculate the dosage. 4. None of the above are true.

Period of “all or none”

• First 2 weeks after fertilization may interfere with cleavage of zygote or implantation causing early death and spontaneous abortion.
• Teratogens during this time don’t cause fetal congenital anomalies because the fetus experience early loss or death.
• Most of the development during this time is concerned with the formation of the extra embryonic structures (amnion, chorion, yolk sac, etc).

Dosage Effects

• Animal research has shown a dose-response relationship for teratogens.
• But animal dose-related data may not be extrapolated to humans.
  • Many times the dose levels to produce anomalies in animals is much higher than doses that cause anomalies in humans.

Genotype of the Embryo

• There are genetic differences in response to a teratogen.
• Phenytoin (Dilantin) is well known human teratogen but only 5-10% of exposed embryos will develop fetal hydantoin syndrome.
• Warfarin (Coumadin) exposure during weeks 6-8 causes:
  • 15%: nasal hypoplasia, stipples epiphyses, hypoplastic phalanges, eye anomalies, mental retardation.
  • 20%: fetal loss

Examples of Major Anomalies

• Anencephaly and Omphalocele

Anencephaly

Omphalocele

• Omphalocele is a transparent sac of amnion attached to umbilical ring that contains abdominal viscera.
• Failure of lateral body-fold migration and closure or embryonic persistence of body stalk
• 1 per 2,500 births
  • M1:F5

• 50% have assoc anomalies including congenital heart defects, bladder extrophy, imperforate anus, NTD, cleft lip / palate, or diaphragmatic hernia.
• 25% have chromosome abnormalities
• 14% have Beckwith-Wiedemann syndrome
• Maternal serum screening detects 40%
• Prognosis dependent on assoc anomalies

U/S Findings with Omphalocele

• Upon ultrasound, omphalocele is often found to have liver or gut bulging into the circumscribed cord insertion site.
• 80% have liver intrusion through the site.
  • Omphaloceles with liver intrustion may show ascites, too.
  • These without the intrusion are less likely to be caused by chromosomal defects.
• 20% do not have liver intrustion.
  • These (that do not have liver intrusion) are more likely to be chromosomal defects.
• Ultrasound findings can vary and hint at the cause (chromosomal defect or not).

• Ruptured omphalocele a rare complication.
• Suspect an omphalocele if you can see cord running through the center of the U/S mass.
• Hydraminos is often concurrent with omphalocele.
  • Recall that hydraminos is excess amniotic fluid.
• The abdominal circumference cannot be measured.
• Diagnose after 12 weeks due to physiological gut herniation.
  • That is, the diagnosis is often after week 12 because there has to be internal gut development before the guts can spill outward.

Summary

• The 4 clinically significant types of anomalies: malformation, disruption, deformation and dysplasia.
• The causes of congenital anomalies are divided into genetic, environmental and multifactorial.
• The incidence of major and minor congenital anomalies.
• Some of the basic principles of teratology.