WEEK 4: Birth Defects

Question 1

What is dysmorphology?

Answer 1

Study of abnormal features.

This term is used to encompass the variability of normal physical traits, as well as pathologic features resulting from abnormal development.

Question 2

Define the following specific terms used to describe congenital abnormalities.
Malformations
Deformations
Disruptions
Dysplasia

Answer 2

1. Malformations:
   Intrinsic errors in embryonic development leading to structural abnormalities.
   These are typically intrinsic errors in the formation of organs or body parts, resulting from genetic mutations, chromosomal abnormalities, or other factors affecting embryonic development. Malformations are present at birth and are often irreversible.
2. Deformations:
   Changes in shape or form due to external mechanical forces acting on a normally developing structure.
3. Disruptions:
   Abnormalities arising from destructive events affecting previously normal structures.
4. Dysplasia:
   Abnormal development of tissues or organs, often involving cellular-level alterations.

Question 3

Are defects of organs or body parts due to an intrinsically abnormal developmental process.

A structure is not formed, is partially formed, or is formed in an abnormal fashion.

Often result from a defect in embryonic development.

Can result from genetic or environmental forces.

Deficiency of folic acid—Neural tube defect
Single or multiple gene defects

Name the described phenomenon.

Answer 3

Malformation

Question 4

Malformations can be classified as major and minor.

Discuss major malformations with examples.

Answer 4

Major malformations are those that have medical and/or social implications.

These often require surgical repair.

As an example, the neural tube defects, such as meningomyelocele or orofacial cleft (cleft lip and palate), are common major malformations.

Question 5

Discuss minor malformations with examples.

Answer 5

Minor malformations have mostly cosmetic significance.

They rarely are medically significant or require surgical intervention.

They represent part of the normal variation in the general population.

Examples of minor anomalies include ear tags, clinodactyly (incurving of the fifth finger), and single transverse palmar creases.

Question 6

Are abnormalities of the position of body parts due to extrinsic intrauterine mechanical forces that modify a normally formed structure.

Intrauterine forces, such as decreased amniotic fluid, uterine tumors, and uterine malformations (e.g., bicornuate or septated uterus) can lead to foetal compression.

Can also occur with foetal crowding due to multiple gestations.

Name the phenomenon described above.

Answer 6

Deformation

Question 7

State examples of deformation.

How can they be corrected?

Answer 7

Examples of common deformations include.
*Clubfoot: Pointed down and in.
*Congenital dysplasia of the hip
*Plagiocephaly (lopsided or flattened skull due to compression)

These often can be corrected by physical therapy, casting, or the use of a special helmet to remodel the skull while the fontanels are still open.

Question 8

Are defects of organs or body parts that result from destruction of or interference with normal development.

Destruction can result from vascular or mechanical processes that lead to tissue compromise,
Such as compression, strangulation, haemorrhage, or thrombosis.

Most cases of are single events that are sporadic rather than inherited.

Their recurrence risk is very low.

Name the phenomenon described above.

Answer 8

Disruption

Question 9

Define amniotic band syndrome (ABS).

Answer 9

The amniotic band syndrome (ABS) is a group of structural abnormalities that involve mostly the limbs, but also may affect the craniofacial region and trunk.

ABS occurs in association with amniotic bands, but the mechanism of amniotic band formation and the pathogenesis of ABS are not firmly established.

ABS is perhaps the most common example of intrauterine disruption.

Question 10

Refers to anomalies that result from the abnormal organization of cells into tissues.

An example is abnormal growth of bone resulting in skeletal dysplasia, such as achondroplasia.

This disorder is caused by mutations in the fibroblast growth factor receptor 3 gene, leading to abnormalities in endochondral ossification.

Name the phenomenon described above.

Answer 10

Dysplasia

Question 11

State 4 PATTERNS OF DEFECTS

Answer 11

Multiple malformations are often grouped in a recognizable pattern.

*Syndrome
*Sequence
*Field defect
*Associations

Question 12

Define a syndrome.

Answer 12

A syndrome is a pattern of anomalies that occur together and are pathogenically related.

Some syndromes have known cause and others the cause may be unknown.

Question 13

Examples for Known syndromes.

-Turner syndrome

-Down syndrome

Unknown
-Aicardi syndrome:
This is an X-linked dominant disorder characterized by a classical triad that includes agenesis of the corpus callosum, chorioretinal lacunae, and seizures.
It is seen in females and lethal in males.

State the causes of the above-mentioned syndromes of known causes.

Answer 13

-Turner syndrome (monosomy of X chromosome),

-Down syndrome (trisomy of chromosome 21)

-Klinefelter: Male with extra X chromosome

-Marfan syndrome: mutation in the FBN1 gene, which encodes the protein fibrillin-1.

Question 14

Some syndromes are inherited, such as Marfan syndrome or achondroplasia.

Other congenital malformation syndromes may appear to be non-genetic and have a very low recurrence risk.

An example is Cornelia de Lange syndrome (also called Brachman de Lange syndrome)

Question 15

What is a sequence?

Answer 15

A sequence is a pattern of anomalies in which a single known defect in development causes a cascade of subsequent abnormalities.

Question 16

Potter sequence is an example of this group of disorders.

Describe this disorder.

Answer 16

This disorder is caused by oligohydramnios secondary to renal agenesis or other renal anomalies that reduce foetal urine output production.

The decreased volume of amniotic fluid restricts foetal movements, resulting in characteristic anomalies. These include:

*Flat facies, depression of the nasal tip, abnormal ear folding,
*Wrinkled skin, and malposition of the feet, including clubfoot deformities.
*Pulmonary hypoplasia is often associated with the external deformities.

Question 17

Define Developmental field defect.

Answer 17

It is a pattern of anomalies caused by disturbance of a region of the embryo that develops in a contiguous physical space.

This region is known as a developmental field.

Holoprosencephaly is a classic example of a developmental field defect.

Holoprosencephaly is a rare congenital disorder characterized by abnormal development of the brain and facial structures. This condition occurs during early embryonic development when the forebrain, which normally divides into the right and left hemispheres, fails to separate properly. As a result, there is incomplete formation of the cerebral hemispheres, and the brain may appear fused.

Question 18

Holoprosencephaly is a classic example of a developmental field defect.

Describe.

Answer 18

The clinical manifestations are variable.

They range from very severe cases with almost absent forebrain to milder manifestations, such as a single central incisor.

The primary defect is the lack of normal induction by the prechordal mesoderm on the forebrain, resulting in abnormal cleavage of the embryonic forebrain.

Question 19

Give other examples of developmental field defects.

Answer 19

Bladder exstrophy and cloacal exstrophy represent another developmental field defect.

These conditions include:
*Urinary, genital, gastrointestinal,
*Orthopedic abnormalities

Question 20

What is an association?

Answer 20

Is defined as two or more anomalies that are not pathogenically related and occur together more frequently than expected by chance.

In general, the etiology of associations is not defined.

It is possible that some represent developmental field defects.

Question 21

Examples of this pattern include the VATER or VACTERL association.

What does it stand for?

Answer 21

VACTERL association includes:
*Vertebral anomalies,
*Anal atresia,
*Cardiac defects,
*TE fistula (tracheoesophageal fistula),
*Renal defects, and
*Limb defects

Question 22

The causes of congenital anomalies are genetic and non-genetic.
Genetic abnormalities include.

Answer 22

*Chromosomal disorders (e.g., Down syndrome);

*Single gene (monogenic) disorders, including those that are autosomal recessive (e.g., cystic fibrosis), autosomal dominant (e.g., Marfan syndrome), or X-linked (e.g., haemophilia).

*Multifactorial disorders that result from the interaction of multiple genes and environmental factors.

These latter include cleft lip/palate, congenital heart disease, and neural tube defects.

Question 23

Non genetic aetiologies include:
State 4.

Answer 23

*Environmental factors
*Maternal phenylketonuria (PKU) or diabetes,
*Teratogens (e.g., alcohol, oral isotretinoin),
*Infections (cytomegalovirus [CMV], rubella), and twinning

Question 24

Frequency

State the % proportions of the following anomalies.

Not known
Multifactorial
Familial
Chromosomal
Single gene
Teratogen
Uterine factors
Twinning

Answer 24

The rate of various aetiologies was identified in a report of surveillance for congenital malformations performed in 69,277 infants of gestational age ≥20 weeks.

The proportions of anomalies were
Not known – 43.1 percent
Multifactorial – 22.8 percent
Familial – 14.4 percent
Chromosomal – 10.1 percent
Single gene – 4.1 percent
Teratogen – 4.1 percent
Uterine factors – 2.5 percent
Twinning – 0.4 percent

Question 25

What is teratology?

Define teratogens.

Answer 25

Teratology refers to the study of congenital malformations caused by environmental or drug exposure.

The term is derived from the Greek word “teratos,” which means monster.

Teratogens—A teratogen is an agent that can cause abnormalities in the form or function of a developing fetus.

It acts by producing cell death, altering normal growth of tissues, or interfering with normal cellular differentiation or other morphologic processes.

The consequences of these actions can be fetal loss, fetal growth restriction, birth defects, or impaired neurologic performance.

Question 26

Approximately 4 to 6 percent of birth defects are caused by exposure to teratogens in the environment.

Response to the teratogenic agent is highly individual and is influenced by multiple factors.

Give examples of teratogens.

Answer 26

These include.
*Maternal illnesses (eg, diabetes mellitus or phenylketonuria [PKU])

*Infectious agents (e.g., TORCH - Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus, and Herpes - infections)

*Physical agents (e.g., radiation or heat exposure), and

*Drugs (e.g., thalidomide, antiepileptic drugs) and chemical agents (e.g., mercury)

Question 27

Timing

The pattern and type of malformation depends in part upon the time of exposure and/or the site of gene action.

Describe.

Answer 27

A significant exposure that occurs during the first 10 to 14 days post conception may result in cell death.

If enough cells die, spontaneous abortion may occur.

If only a few cells are damaged, then their roles may be compensated by other cells.

This is known as the all-or-none theory.

An example is an early significant exposure to radiation, which usually results in either pregnancy loss or no abnormalities.