Intro to Birth Defects
Learning Objectives
Define and distinguish major categories of congenital anomalies
Explain why timing, dose, susceptibility, and mechanism influence teratogenic outcomes
Use embryologic reasoning to connect a disrupted developmental process to an anatomic defect
If a structure is abnormal at birth, what do we need to know to explain it embryologically?
One can trace back a birth abnormality by first comparing it to what anatomy normally forms.Then we can determine what tissue or cell population was involved in producing this structure, followed by what and when the processes they underwent in occurred. Once this context is established, a conclusion can be drawn for what processes may have failed and what would have been the consequence of those failed processes.
Fetal interruption syndrome
Zika virus - south and central america
German measles
What percent of zygotes do not implant by week 2?
30-50%
What percent of recognized pregnancies end in miscarriage during the first 12 weeks?
15%; most likely higher due to many unrecognized pregnancies
60% of miscarried conceptuses have what?
chromosomal abnormalities
How does the high rate of chromosomal abnormalities (60%) in early miscarriages contrast or non-implantation (30-50%) of zygotes by week two contrast with the causes of birth defects often seen in live births?
Severe genetic errors largely contribute to miscarriage and non-implantation, and function as a built in biological filter for non viable conceptuses. Live births with birth defects are more often driven by gene-environment interactions, environmental teratogens, or less severe genetic defects, like Trisomy 21 which allows for survival to term.
What percent of neonatal deaths are attributed to congenital malformations?
20%
What percent of live birth have at least one birth defect?
1.5-3.5% of live births
What additional percent of birth defects are discovered by end of 1st year of life? Why might this be?
3-7%. Defects could be less severe or not apparent without more time such with developmental delay both physically and cognitively. Internal structural abnormalities may be asymptomatic at birth as well.
Birth defects are attributed to what?
Environmental exposures (5-10%)
Discernible genetic cause (15-20%)
Gene-environment interaction (70-80%) — Majority
Are development and growth interchangeable?
NO, development refers to a progression of stages, starting with an undifferentiated, primordial state to a highly organized, specialized and mature state, capable of carrying out a function. Growth, refers an increase in size either through the formation or enlargement of like tissues.
What are the two main types of normal morphogenesis? Example?
Plasia refers to cell proliferation, or an increase in the relative number of cells through mitosis. Trophy is an increase in the relative size of cells. Both processes can be seen in the development of long bones. The growth plate contains a zone of proliferation, which continuously supplies cells to the zone of cell maturation and hypertrophy, where cells enlarge. Both work together to lengthen the long bone.
What are the two main types of dysmorphogensis?
Dysmorphogensis can be caused by dysplasia, or an abnormal number of cells and dystrophy, abnormal cell size. Abnormally high and low cell division is referred to as hyperplasia and hypoplasia respectively. Similarly, abnormally large or small cell size is referred to as hypertrophy and hypotrophy.
What might contribute to some major birth defects having higher or lower report prevalence?
Many major identified birth defects affect vital organs, particularly cardiovascular defects. Oral facial defects, such as cleft palates, are especially easy to identify as they are externally presented. Clubfoot is also highly reported. Many chromosomal abnormalities are also more likely to be identified as they are often characterized by widely recognized physical features, such as trisomy 21 and due to routine prenatal screening. Birth defects that require more extensive genetic screening or internal scans may be less likely to be immediately reported if symptoms are not apparent.
What is a congenital anomaly?
An abnormality presented at birth in either structure, function, metabolism or behavior. It is not acquired later in life, from injury or disease.
What is Teratology?
The study of the causes, development and mechanism of congenital malformation or birth defects
What is dysmorphology?
The study of abnormal form, especially patterns of congenital anomalies
What are the mechanism by which birth defects occur?
malformation
disruption
deformation
What is malformation? Examples?
A primary error in formation of a structure. It occurs early in development (embryonic period) because the error arises as the structures begin to form.
Trisomy 21, orofacial cleft, anacephaly
What is disruption? Example?
The destruction or interference with a structure that had begun to form normally. Inherently requires an initial stage of normal development, so typically occurs later in development. Can occur in both embryonic or fetal stage.
Hemifacial microsomia, facial tissues were destroyed during development because the artery of the second arch failed to develop so structures didn’t receive proper blood supply
What is deformation? Example
An abnormal shape or position caused by mechanical forces. It requires the structure to be first formed, so it also occurs later in development. It is the only mechanism capable of self correction. It can be reversed or go away.
Hydrocephalus (water on the brain), deforms the skull bones because of increased intracranial pressure
What is dysplasia?
The production of an abnormal number of cells (high or low). This can occur during any stage of development exhibiting mitosis.
What are the patterns of multiple anomalies?
They can either be a sequence, syndrome or association
What is a sequence? Example?
Refers to when a single developmental defect results in a chain of variably expressed secondary defects that all trace back to the initiating developmental event. (domino effect). The entire cascade of events is typically well understood in a sequence.
The primary defect in the Pierre Robin sequence is mandibular hypolasia —> causes posterior displacement of tongue —> impaired airway —> precludes closure of palatal arches
What is a syndrome?
A recognizable pattern of anatomically unrelated anomalies with a shared underlying (often genetic) cause. They can contain multiple variably expressed malformations and/or sequences. This means that a given anomaly can be only partially expressed or absent between different individuals of a syndrome. It is rare for a single malformation to be unique to and always be expressed in a syndrome. The relationships of the group of anomalies is frequently not understood.
A sequence may have ____ know causes, whereas a syndrome can often be traced to ___
multiple; a single genetic malformation
One or more ___ may be associated with various ____
sequences; syndromes
ex. Pierre Robin sequence is often seen in stickler syndrome
What is an association?
A nonrandom pattern of anomalies that occurs together more often than expected, without a single established cause.
What pattern of multiple anomalies does Trisomy 21 follow?
Trisomy 21 is a syndrome that occurs when there is an additional third 21st chromosome. It is characterized by a recognizable pattern of anomalies such as atrioventricular septal defect, duodenal atresia, hypotonia, loose joints, flatted nose brides, upslanting palpebral, small mouth, or protruding tongue. This is a syndrome because there is one underlying cause, being a genetic defect that results in a collection of unrelated anomalies. There is no cascade of effects, rather they occur independent of one another. Different individuals with down syndrome can exhibit different anomalies and of varying degree.
Describe the Potter sequence
Bilateral renal agenesis, a defect in kidney development, is the underlying primary anomaly that produces a sequence of anomalies, starting with a cessation in fetal urine production. This leads to oligohydramnios, or severely low amniotic fluid, which acts as the single intermediate cause that triggers the cascade. Secondary consequential anomalies include pulmonary hypoplasia, Potter facies, and limb deformities (club foot and joint contracture), all due to the compression from the lack of space in the amniotic sac.
List the common etiology for birth defects
genetic factors
environmental factors/teratogens
multi factorial causes
mechanical factors
unknown causes (only 20% of cases have definite cause, 80% unknown)
How does genetics cause of birth defects?
chromosomal abnormalities
single gene disorders (gain of function, loss of function)
copy number or dosage effects
altered gene regulation (epigenetic)
How does the environment cause birth defects
infectious agents (fetal interruption brain syndrome —> Zika virus, rubella, German measles)
drugs/medications (prescription)
alcohol and other substances (fetal alcohols syndrome)
maternal diseases
nutrional factors (poor nutrition)
physical factors, radiation or mechanical constraints
What does it mean for the cause of birth defects to be multi factorial?
Many defects reflect both genetic susceptibility and environmental exposure. Gene-environment interactions refers to when an environmental exposure triggers an anomaly in an individual with a genetic susceptibility.
The same exposure may not affect every embryo in the same way
For example, a whole family can have a genetic mutation, but only some can present with an anomaly or birth defect. This is due to a difference in the time period where they were developing, such as an environmental effect that increase penetrance
What is penetrance?
An observable defect from a gene. For example, if there are two siblings, and only one has cleft palate = 50% penetrance
Having the cause and showing the effect
type of statistics
What example did we talk about in class about why timing matters?
Alcohol exposure during pregnancy can result in fetal alcohol syndrome. Symptom include short height, low body weight, ataxia, cognitive delays, behavioral problems, and typical facies (low nasal bridge, short nose, thin upper lip, small midface, flat philtrum ,small head, small eye openings, skin folds at corner of eye). The incidence rates are 0.2-9 in 1000 and have not significantly changed since first identified in the 1960s. Although the risks of drinking during pregnancy are well understood, the rates are still so high because recognition of pregnancy does not always immediately occur. The beginning of the third week of gestation is when a missed menstrual period may be recognized, however implantation bleeding could be mistaken for a cycle and many individuals have irregular cycles. Thus before the chance to recognize the second missed period, another four more weeks of development could have occurred. Major embryonic development occurs between weeks 3-8 and this stage has the highest sensitivity to teratogens, including alcohol. Unless an individual is actively family planning, a pregnancy could be easily missed, putting the embryo at risk of various exposures at its highest state of vulnerability.
What developmental vulnerabilities may occur in weeks 1-2, 3-8, or 8-birth of human development?
In the first two weeks of development, there is low sensitivity to teratogens due to the lack of an established blood supply with the mother. Rather this is an “all-or-none” stage, that may result in failure to implant or death, commonly due to severe genetic abnormalities.
What developmental vulnerabilities may occur in weeks 3-8 of human development?
Weeks 3-8 are the most susceptible to abnormal development and has a high sensitivity to teratogens as it is characterized organogensies, where the basic body plan and vital organs are being established. This period is when major structural malformations of the embryo is most common. It is so vulnerable due to the simultaneous rapid cell behaviors occurring including proliferation, differentiation, migration, folding, fusion, septation, and remodeling.
What developmental vulnerabilities may occur in weeks 8-birth of human development?
Weeks 8 and on mainly involves the growth, maturation and further functional refinement of vital organs and the fetus. Structural abnormalities are less common but functional disturbances may still occur, especially in the brain. No stage of development is safe from developmental disturbances.
____ ____ reflect disrupted developmental processes. examples?
structural defects
failed fusion → clefting/neural tube defects
abnormal septation → cardiovascular defects
altered migration/patterning → craniofacial or neural crest-related defects
A teratogenic exposure usually causes a defect only if the affected structure is ____
forming during that critical window
What are the principles of teratology?
Genotype matters
Embryonic and maternal genetic background can influence genetic susceptibility.
Is there a gene that causes this?
Developmental stage matters
The effect depends on what is forming at the time
During what window does this structure form?
Dose and duration matter
Greater dose or longer exposure often increases risk
What were you exposed to during this time? When did exposure stop?
Mechanism matters
Teratogens act by altering specific cellular or molecular processes
If we can identify the teratogen, which specific mechanism did it affect?
Outcome depends on the affected developmental process
proliferation, migration, fusion, septation, apoptosis, and patterning can all be disrupted
List the common teratogens
alcohol
retinoids
antiseziure drugs
classic drug teratogen
infections
maternal disease
tobacco/nicotine
radiation
nutrition
other medication
Alcohol
ethanol
FASD; growth, CNS, craniofacial and behavioral effects
Retinoids
isotretinoin, retinoic acid (vitamin A), acutane (sexually active pimply teens)
patterning defects, craniofacial anomalies
Antiseizure drugs
valproic acid
neural tube defect risk
Classic drug teratogen
thalidomide
limb malformations
Infections
rubella, CMV, toxoplasmosis, Zika
tissue disruption; CNS and systemic anomalies
Maternal disease
poorly controlled diabetes
increased risk of congenital anomalies
Tobacco/nicotine
smoking, nicotine exposure
growth restriction, pregnancy complications
Radiation
ionizing radiation
DNA damage, effects on rapidly dividing tissues
Nutrition
folate deficiency (very effective modern intervention, supplement food with folate)
neural tube defect risk
Other medications
warfarin, methotrexate
drug specific developmental toxicity
What are processes that can be disrupted?
proliferation
migration
fusion
septation
patterning
apoptosis/remodeling
differentiation
folding
How can proliferation be disrupted?
too few cells or too many cells; hypoplasia, overgrowth, agenesis
How can migration be disrupted?
cells fail to reach destination; neural crest or neuronal migration problems
How can fusion be disrupted?
persistent separation; clefts, neural tube closure defects
How can septation be disrupted?
persistent communication between spaces; cardiac/outflow/cloacal examples
How can patterning be disrupted?
wrong position or identity; axis or limb pattern abnormalities
How can apoptosis/remodeling be disrupted?
persistent tissue, abnormal sculpting, failure to remove temporary structures
How can differentiation be disrupted?
Cells fail to specialize appropriately; abnormal tissue identity of function
How can folding be disrupted?
Body wall, gut tube, neural tube, or organ shaped defects
How can prenatal defects be diagnosed?
imaging → can inform surgical planning, psychological preparation and future treatments
genetic screenings
may require analysis of fetal or placental genetic material (fluid or fetal tissue)
How does family planning help with defect prevention?
parents can undergo genetic screening
discuss risk behaviors (smoking, drinking, prescription medication)
maternal health optimization
avoid known teratogens and harmful exposures
prenatal vitamins, folic acid
vaccination
Does prenatal diagnosis replace embryological reasoning?
No, it identifies the defect but still requires tracing back to cause
Especially important to determine if subsequent pregnancies will also be at risk
Understanding birth defects requires connecting ___…
developmental timing → disrupted mechanism → anatomical outcome → clinical care
What is involved in care planning?
Anticipate related anatomy, function, delivery needs, surgical care, and long term follow up
Clinical application
prevention
prenatal detection
diagnosis and counseling
care planning
T/F birth defects are rare
F, birth defects affect 1/33 babies each year in the US
every 4.5 minutes a defect baby is born
Recessed mandible condition: name, clinical presentation, pathogenesis, incidence, diagnosis, where else is it seen?
Migrognathia
Underdeveloped mandible (small jaw). May cause feeding difficulties (especially in neonates). Airway compromise: risk of obstructive sleep apnea. Can sometimes “self correct” in non-syndrome cases
Pathogenesis varies including genetics, reduce condyle growth or altered rotations
Common in neonates
Diagnosed through comorbidities (feeding, airway, growth) and jaw index
Found in other craniofacial sequence and syndromes → Pierre robin, FAS, VCFS, Goldenhar
Pierre Robin Sequence: clinical definition, incidence, sequence of events, associated anomalies
micrognathia, glossoptosis, airway obstruction → needs all three to diagnose
~1/8500 - 14,000 live births. Comprised of syndromic and non syndromic cases
Small or slow growing jaw → posterior displacement of tongue → airway obstruction
failure to thrive, feeding problems, clef palate (u-shaped)
Glossoptosis: what is it, what can it lead to, clinical criteria, causes
defined as displacement of the tongue into the oropharynx
Leads to upper airway obstruction which can cause
feeding problems
apnea
cyanosis
can be life threatening
tends to be worse when sleeping (episodic)
Clinical criteria in diagnosis
Laberge 1: airway ok even supine but gets partially obstructed during feeding - mild/manageable
Laberge 2: obstructed when supine but ok with prone position - positional management
Laberge 3: can’t keep airway open even in prone position - these babies need intervention for sure (intubation/surgery)
Causes → PRS, hypotonia (poor muscle formation)
Describe cleft palate in PRS
PRS patients often present with cleft palate
pathogenesis often related to the sequence (tongue displacement posteriorly)
defect is often U shaped (as opposed to v)
not diagnostic of PRS
Causes of PRS - developmental
Meckel’s Cartilage and Mandibular Outgrowth (SOX9-related pathways)
Hypotonia reduces mandibular movement and tongue position
Causes of PRS - Deformation/Disruption
Twinning/intrauterine crowding
Causes of PRS - Teratogens
Alcohol (FAS)
Antiepileptics (hydantoin, trimethadione)
Causes of PRS - Genetics
Deletions (Chromosomal locations on 2,4,11 and 16)
Duplications (Chromosomal locations on 1)
Translocations (Unbalanced and Balanced)
Mutations
Causes of PRS - Syndromic
Stickler (Collagens)
VCFS (TBX1)
Steps of developmental reasoning in birth defects
what is abnormal → identify the structure or pattern
what normally should have happened → describe normal development first
when does that process occur → link timing to vulnerability
what developmental process was disrupted → fusion, migration, septation, proliferation, remodeling etc.
what caused or contributed to the disruption → genetic, environmental, multi factorial, mechanical or unknown
what additional anatomy might be affected → think by tissue origin, field, sequence, or syndrome