Hummel - Congenital Malformation Flashcards
What is the most common cause of premature death besides prematurity of newborns?
Congenital malformations
When do most anomalies occur in a fetus?
Bonus: When do teratogenic effects tend to be more prevalent?
First trimester
Bonus: In embryonic period
What is the study of abnormal form (congenital anomalies)?
–> study of birth defects
–> one who shows a problem with generalized growth and/or in the growth and formation of one or more structures of the body.
Dysmorphology
What are the three areas that overlap within Dysmorphology?
Genetics
Clinical Medicine
Embryology
What is the difference between congenital anomalies and birth defects?
Congenital malformations:
- Physical or neurological defects that are present at the time of delivery.
- Some problems will not become apparent until later in life.
- Divided into major and minor malformations.
A congenital anomaly refers to an abnormality present at birth from any cause.
- _____ of all newborns have a recognizable major congenital anomaly
- Up to ______ of all births will be diagnosed with a congenital defect prior to age 6 year.
- 3%
- 7%
Fact: Syndromes/Multiple Malformations
- Mendelian: single genes
- Teratogenic: not as prevalent as thought, small %!
- Chromosomal: with advent of chromosomal arrays, can find multiple genes lost
**Largely unknown!
What morphological alteration occurs in 3‑5% of newborns?
Definition: defects that require medical or surgical intervention.
- Will have a significant impact on the health of the infant
Bonus: give an example
Major Anomaly
Bonus: VSD
Examples of what kind of morphologic alteration?
- Neural tube defects
- Cleft lip, cleft palate
Major congenital malformations
What morphological anomalies are variants that are of no serious medical or cosmetic significance and occur in less than 4% of the population
- 3 or more minor anomalies increase suspicion for a possible major anomaly.
Minor anomalies
If you see a child with:
- palmar crease
- Epicanthal folds
- Upsliding palpebral fissures
What else might you think they have?
Heart defects
Hirsphrung’s disease
Duodenal atresia
–> Down syndrome!
Normal variants are features that fall to the far end of the spectrum of normal minor anomalies or normal variants and can serve as indicators of _____________ and clues to patterns of malformation
- e.g. flat nasal bridge, hydrocele, syndactyly of 2nd and 3rd toes
Altered morphogenesis
Another way to look at congenital anomalies
What are the 3 types of problems in morphogenesis?
A. _______: early, genetic; programmed early change in migration of protein
- Intrinsically abnormal developmental process, eg. cleft lip, polydactyly
B _______: later in embryonic development; molds it out of place
- Mechanical compression, eg. clubfoot, plagiocephaly (lop-sided head)
C _______: Later in embryonic development; acute change in blood flow to structure
- Breakdown of otherwise normal developmental process, eg. amniotic band amputation, porencephaly
A. Malformation
B. Deformation
C. Disruption
What type of congenital anomaly?
- an abnormality of morphogenesis due to an intrinsic problem within the developing structure.
- MECHANISMS: altered tissue formation, growth or differentiation due to genetic, environmental or a combination of factors
Malformation
i.e. Fetal Alcohol Syndrome affects brain development
Neural Tube Defects
Example: Malformation
What nutrient is critical to normal neural tube formation in the fetus?
- Leads to THF formation
- Runs many systems - e.g. nucleotide biosynthesis, and methylated DNA, protein, lipid
Folic Acid
What enzyme converts 5,10-methylene-THF to 5-methyl-THF
- a gene that is integral in recycling folate
- when have a defect here, homocysteine stays around longer, platelets are stickier, and don’t perform processes well
Methyl THF Reductase
(MTHFR)
What type of abnormality includes the following:
- Lack of development - renal agenesis
- Hypoplasia - microcephaly, micrognathia
- Incomplete closure - cleft palate, iris coloboma
- Incomplete separation - syndactyly
- Incomplete migration - extrophy of the bladder
- Incomplete rotation - malrotation of the gut
- Incomplete resolution of early form - Meckel diverticulum, cloana atresia
- Persistence of early location - low set ear
Incomplete morphogenesis
What type of abnormality includes the following?
A. e.g. polydactyly, ear tag
B. e.g. mediastinal thyroid
A. Redundant morphogenesis
B. Aberrant morphogenesis
What type of congenital anomaly?
- an abnormality of morphogenesis due to extrinsic force on a normally developing or developed structure; pushes away
- MECHANISM: fetal constraint, if take away molding process - it will spring back
Deformation
What etiology?
Deformation
What deformation?
- Asymmetric head
- Occurs pre or post natal
- Corrected by helmets or positioning
- Compensatory growth, sutures are still open - head only grows while the brain is pushing it out
Plagiocephaly
What deformation?
- Can cast and will repair
- If bones of the ankle are malformed, will need surgery
Club foot
What congenital anomaly?
- an abnormality of morphogenesis due to a destructive force acting upon the developing structure.
- Tends to be asymetric
- MECHANISMS: cell death or tissue destruction due to vascular, infectious, or mechanical force
Disruption
What congenital anomaly?
Disruption
What is one disruption that occurs often in West Virginia?
- Twisted gut - may lose due to gangrene
- Occlusion of the omphalomesenteric artery may cause this
- Body wall defect with herination
- Can be placed back into cavity, once it starts moving again, the babies do fine
(due to mother’s smoking)
Gastroschisis
What congenital anomaly?
- Different genetic etiology than gastroschisis
- More of a malformation, under genetic control
- May not have a lot of problems with gut, but have other anomalies and may not survive with them
Omphalocele
Fact - Other vascular causes of birth defects:
- Aberrant vessels
- Vascular occlusion
- Vasculitis
- Thrombosis
- Embolism
- Hypoperfusion
- Vasoactive drugs
- Cocaine
- Amphetamines
What congenital anomaly?
Vascular accident - Occlusion of a cerebral artery may cause
- Cyst in the brain,
- Can be due to blood clot in carotid arteries
- Not as devastating as you would expect, due to plasticity of brain of baby
When brain infarcts, it tends to liquefy.
Porencephaly
What anomaly?
- More of a sequence
- Due to a vascular disruption
- Subclavian artery disruption
- Absent pectoral muscle defect
- Ipsilateral limb defects
Poland Sequence
Considerations for what?
- Can all the child’s abnormalities be explained on the basis of a single problem that leads to a cascade of subsequent structural defects?
- Did one defective gene or group of genes cause the observed defects?
Multiple anomalies
What is a cascade of effects stemming from a single localized abnormality in early morphogenesis. ‑‑ the single localized abnormality (1st defect) may be of the malformation, deformation or disruption type?
Sequence
What congenital anomaly?
- Closely spaced eyes (hypotelorism)
- Midline cleft
- Primary malformation leads to incomplete closure of the prosencephalon, and faulty bifacial development
- can be As bad as cyclopia with proboscis, to just a central inscisor
Holoprosencephaly
What gene is activated by cholesterol (good for embryo!!!) that leads to activation of a trascription factor -> preventing holoprosencephaly?
**HER FAVORITE!!!
Sonic hedge hog (Shh)
What sequence?
- Small chin is the initiating sequence - Micrognathia
- Abnormal tongue position due to small chin
- U-shaped cleft palate, because incapable of closing
- Possible airway obstruction because tongue falls back
- Can be intrinsic or extrinsic problem
- Intrinsic - chin tends not to catch up, do surgical correction
- Most common cause of intrinsic case of this disease?
Robin Sequence
collagen defect leading to Stickler syndrome.
Bonus: Stickler syndrome (looks like Marfan syndrome - high myopia, hearing loss, prone to retinal detachments)
What sequence?
- Not adequate amniotic fluid
- Lungs do not form properly
- “Smooshed” facies
- Micrognathia, large ears
- Limb abnormalities
- Renal agenesis
- Pulmonary hypoplasia
- Children usually die due to respiratory insufficiency*
Potter sequence
Fact:
- Due to amniotic leak or lack of kidneys
What syndrome?
- Male fetus cannot pee
- Posterior urethral valves
- Massive hydrocephalus
- Kidneys enlarge - stretches abdominal wall, breaking down muscular development
Massive renal failure if you do not place stents.
Prune Belly Syndrome
What is a combination of anomalies which occur together more frequently than by chance alone?
- The underlying etiology is unknown
- Most cases sporadic
- sort of like Syndromes
Association
What association?
- Coloboma of eye
- Heart defects
- Atresia of the choanne (respiratory distress) - can’t breathe through their nose
- Retardation of growth and development
- Genital anomalies
- Ear anomalies
CHARGE Association –> has become CHARGE syndrome (CHD7 mutation)
What associations?
A. –vertebral defects, imperforate anus, tracheo-esophageal fistula, renal or radial ray defects
B. – mullerian duct, renal and cervical vertebral defects
A. VATER
B. MURCS
Anomalies of several different structures, all of which lie in the same body region during embryogenesis?
- e.g. OEIS (omphalocele, exstrophy, imperforate anus, spinal defects - lower pole of embyro is disrupted)
Complex
Dealt with most often?
- Multiple structural defects in one or more tissues thought to be due to a particular chromosomal, genetic, teratogenic or unknown insult that impairs multiple tissues
- From Greek – “running together”
Syndrome
What syndrome?
- Short stature
- Mental retardation
- Limb defects
- Characteristic facies (bushy eyebrows/unibrow)
- caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B
Cornelia de Lange Syndrome
What is an essential cofactor Vitamin for embryonic development?
- Disrupted by the drug, Accutane –> teratogenic!
Vitamin A
What drug leads to?
- Midline hemangioma, flat nasal bridge, phocomelia (limb defects - from hypoplasia to complete absence of radius, ulna, and humerus; fibula and tibia less commonly involved)
- Offered in the 60s
- Good for wasting syndromes, HIV, leprosy
Thalidomide
