2.3 congenital anomalies Flashcards
highest frequencies of death under 1 year
congenital mlaformation, deformation, and chromosomal abnormalities, disorders related to short gestation and low birth weight, sudden infant death syndrome (SIDS)
congenital anomalies
morphological defects present at birth, may not be expressed until later in life, can or cannot be genetic defect, 3% of newborns have a major anomaly (cosmetic or functional significance), most common cause of death in first year of life, significant cause of mortality and morbidity in all early years of life, in reality, observed anomalies in live births represent the leaset serious that occur
malformations
primary error of morphogenesis with intrinsic abnormal development (anencephaly, congenital heart defects). Multifactorial. Single/multiple
disruptions
secondary destruction of organ/body region that was previously normal in development. Extrinsic distrubance (amniotic bands that compress portions of fetus)
Anencephaly
neural tube defect with absence of cerebral hemisphere, skull, and skin
cleft lip/palate
if isolated - compatible with life, with malformation syndrome - severe cardiac defects
deformations
like disruptions these are due to extrinsic disturbance as a localized/generalized fetal compression by biomechanical forces –> structural anomalies (uterine constraint, oligohydramnios) –>(club feet)
Sequence
cascade of anomalies triggered by one initiating event
Potter sequence of oligohydramnios
renal agenesis, amniotic leak, maternal HTN, toxemia (U/O insff) —-> all lead to oligo hydramnios —–>can lead to amnion nodosom (plaques of squamous cells and fibrin), pulmonary hypoplasia, and fetal compression —-> fetal compression can lead to pulmonary hypoplasia, altered facies, positioning defects of feet and hands, breech presentation
syndrome
a constellation of congenital anomalies that are thought to be pathologically related but unlike a sequence can not be explained by a single initiating event. Can have a single etiology, eg a viral disease or chromosomal alteration that affects different tissues
Causes of anomalies
genetic, environmental and multifactorial (50 - 75% unknown)
genetic causes of congenital anomalies
chromosomal (karyotypic) abberations, single gene mutsionts
karyotypic abberations
10-15% of CA
when do most karyotypic abberations occur
during gametogenesis (not familial)
ex of karyotypic abberation
Down’s a la Robertsonian translocation of 21 with another chromosome (4%)
karyotypic abberations and death
80-90% of chromosomal number abberations die in the uterus
single gene mutations inheritance
90% AD or AR and 10% X-linked
examples of loss of fn genes involved in normal organogenesis
sonic hedgehog - holoprosencephally, HOXGL13 - digit anomalies (polydactyly, syndactyly)
holoprosencephaly
incomplete separation of cerebral hemispheres across the midline
syndactyly
fused fingers
Environmental causes of CA
viral infections, drugs and chemicals, radiation, maternal diabetes
most common viral infections in CA
rubella, CMV (MOST COMMON - most asymptomatic)
risky period to contract rubella
conception to 16 weeks
incidence of rubella
50% 1st month, 20% 2nd, 7% 3rd
fetal defects that rubella causes
tetrad of cataracts, heart defects (numerous), deafness, and mental retardation (rubella embryopathy)
risky period to contract CMV
2nd tirmester –organogenesis is almost complete by this time so frequency of anomalies is less than rubella, but damage can cause sever defects in formed organs
fetal defects that CMV causes
microcephaly, mental retardation, deafness, hepatosplenomegaly
drugs and chemicals
<1% of CA
Examples of drugs/chemicals on CA
retinoic acid (vit A def), Thalidomide, folate antagonists, anticonvulsants, warfarin, androgenic hormones, smoking
Thalidomide
50-80% incidence of limb developmental defect (phocomelia),
smoking
inconclusive data on nicotine spontaneous abortions, premature labor, placental abnormalities, dec birth weight, SIDS
Fetal alcohol syndrome
even 1 drink/day associated with inc risk of: growth retardation, microcephaly, ASD, short palpebral fissures, maxillary hypoplasia, facial dysmorphism, MR
what is the most common preventable form of mental retardation in the USA
fetal alcohol syndrome
fetal alcohol syndrome facies
epicanthal folds, flat nasal bridge, smalll palpegral fissures, railroad track ears, upturned nose, smooth philtrum, thin upper lip, hockystick crease
radiation
mutagenic, carcinogenic, teratogenic, when radiation is used to treat cervical cancer of pregnant women microcephaly, blindness, skull defects, spinabifida, and numerous others occurred
incicence of CA due to maternal diabetes
60-10%
maternal diabetes induced CA
hyperglycemia (mother)–>hyperinsulinemia (infant) –> inc body fat, muslce mass, organomegaly (fetal macrosomia) - also cardiac anomalies and neural tube defects, higher incidence of RDS
with a 12lb baby suspect
maternal diabetes
incidence of CA due to multifactorial causes
50%
multifactorial CA result from
inheritance of multiple genetic pleomorphism that lead to succeptibility phenotype, and that plus the environment leads to manifestation
factors affecting pathogenesis of congenital anomalies
timing - major impact on occurrence and type, teratogens - may act in similar manner as genetic mutations, genes affected - certain genes no known to be major players in organogenesis - hedgehog, homeobox
timing - critical periods in development
within the first 9 months organs are formed –this is the most critical time, after this you might see minor abnormalities, 4-5 monts??
what is the period that leads to lethal injury or induces abortion
3 weeks
what period is very succeptible to teratogenisis
3 and 9 weeks, with peak at 4 to 5 weeks, organs forming
fetal period
relatively resistant but formed organs can be affected as to sized or function
functions affected during development
cell migration, cell proliferation, cellular interactions, cell-matirx interactions, apoptosis, hormonal influences, mechanical forces
major genes controling onrgan development
sonic hedghog, homeobox genes (HOS), pared box genes (PAX)
sonic hedgehog genes are involve in
cell migration patterns during development
cyclopamine
disrupts expression of hedgehog genes. Derived form california lily plant. Pregnat sheep that eat california lilies give birth to offspring with severe craniofacial abnormalities including ——>cyclopia and holoprosencephaly.
pts with holoprocencephaly commonly have mutations in
sonic hedgehog genes
hox genes
discovered in drosophilia mutant antennapedia where mutations caused legs to appear where antennae should be
hox genes in vertebrates are involved in
development of limb, vertebrae, and craniofacial structures
what mutations induce synopolydactyly and hand-foot-genital syndrome (distal limb and distal urinary tract malformations)
HOXD13
PAX gene code for
DNA binding proteins
PAX2 mutated in
renal-coloboma, defects in kidney, eyes, ears, and brain
PAX3 mutated in
Waardenberg Syndrom (pigment anomalies and deafness)
PAX6 mutated in
congenital absence of the iris (aniridia)
traslocation associated with alveolar rhabdomyosarcoma
PAX 3 and 7
translocation associated with lymphomas
PAX 5
translocation associated with thyroid tumors
PAX 8
