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6/29/2011
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Developmental, Genetic, & Pediatric Disease
HIHIM 409
Developmental Abnormalities
• Congenital means “present at birth”– may not reveal itself for years
• Congenital malformation– intrinsically abnormal embryologicintrinsically abnormal embryologic
development– genetic defects
• Congenital deformation– maternal mechanical factors that distort the
fetus
Major Determinants of Disease
• Most congenital defects result from faulty development of the embryo
• The fetus is especially vulnerable to injury during weeks 3-9 of embryologic g y gdevelopment, when fetal organs are forming
• Some congenital disease results from an inherited genetic defect & may not be apparent at birth
• About 3% of newborns have a significant cosmetic or functional defect
• About 250,000 infants are born with a serious birth defect
• Congenital defects responsible for about• Congenital defects responsible for about 50% of the deaths of newborns & children in developed nations
Embryologic Development
• Loss of a cell before differentiation not a problem• Beginning week 3, organogenesis
Congenital Malformations
• Occur because of failure of a space to close properly
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• Failure of tissue to divide polydactyly
syndactyly
• Failure of an embryologic structure to disappear normally
• Failure of a tissue or organ to differentiate or grow
Congenital Malformations
• Flawed embryologic development• Cause unknown• Result from mutations & environmental factors• Teratogens are capable of inducing fetal• Teratogens are capable of inducing fetal
malformations– chemical– infectious agent– drugs– ionizing radation
hypospadias
Patent ductus arteriosus VSD
ASD
Cleft lip Spina bifida
anencephaly
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Fetal Alcohol Syndrome
• 1:1000• Mom consumes
alcohol– how much determines
the severity• Fetal growth
restriction, CNS abnormalities, distinctive facial features
TORCH• Common infectious
agents• Toxoplasmosis• Rubella• CytomegalovirusCytomegalovirus• Herpesvirus• In about 1-5% of live
births• Worse if during weeks
3-9
Congenital Deformations• Caused by maternal
mechanical factors that distort fetus
• Usually arise during weeks 35-38weeks 35 38
• Maternal factors include– malformed uterus due to
leiomyomas– crowding from multiple
fetuses– decreased amniotic fluid
clubfoot
hip dislocation
Genetic Disorders
• Major determinants of disease– Almost every disease is influenced to some
degree by genetic variations that confer vulnerabilities to environmental influences
• not always predictable– Strictly genetic disease is caused by
mutations of the DNA in a predictable manner
• 2 types of cells– germ– somatic
• can’t transmit genetic defects
• Chromosomes– autosomes– autosomes– sex chromosomes
• Genotype– genetic makeup
• Phenotype– physical expression of traits
Karyotype
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Disease
• Genetic– mutations of germ cells– hereditary disease
E i t• Environment– affects somatic cells
• Combination– both environment influences & strong familial
tendencies
Mutations
• Permanent change in DNA
• Mutagens– chemicals– radiation
• Can occur in utero
• Terminology– Allele
• one of a gene pair– Homozygous
• alleles are identical– Heterozygous
• alleles are not identical– Dominant
• expressed– RecessiveRecessive
• not expressed– Carrier
• has recessive gene but no disease– Expressivity
• qualitative characteristic• trait expressed in various ways
– Penetrance• quantitative characteristic• degree or severity of the abnormality
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Sex-Linked Recessive
• Present on X chromosome• Genes on Y chromosome related to sperm
productionX & Y h ll l di d ff t• X & Y share no alleles so disorders affect males more often
• > 5,000 monogenic disorders have been identified with more being discovered
• Most humans have about 6-8 defective genes most being recessive & thereforegenes, most being recessive & therefore not expressed
Autosomal Dominant Diseases• Physically expressed if
only one copy of gene is present
• An affected parent has a 50% chance of passing50% chance of passing the gene to a child
• Have the gene, have the defect
• No carriers• Some are due to new
mutations
Autosomal Recessive Diseases
• Physically expressed only if both chromosomes carry a copy of the gene
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Enzyme Defects• Accumulation of a substrate or deficiency of an
end product• Gaucher disease
– accumulation of glucocerebrosides in macrophagesGl di• Glycogen storage disease– defect in the enzyme that converts glycogen to
glucose so no glucose• Alpha-1-antitrypsin deficiency
– protein that protects tissue from excessive digestion by enzymes from neutrophils
Defects in Membrane Receptors or Transport Proteins Disease of Growth Control Proteins
• Neurofibromatosis– von Recklinghausen
Defects in Structural Proteins
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Cytogenetic Diseases
• Abnormalities involving large parts or whole chromosomes usually occurring during the production of ova & sperm
• One or more extra chromosomes• One or more extra chromosomes• Missing chromosomes
• Monosomy– Loss of an autosome– Results in spontaneous abortion as this is not
compatible with lifecompatible with life
Trisomy
• Extra copy of a chromosome
• Most result in spontaneous pabortion– Exceptions are
chromosomes 13, 18, 21
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Klinefelter syndrome
• XXY
Turner Syndrome
• XO
Genetic Diagnosis• If mother is 35yo or greater• If already have a child with a known genetic disorder• If have a family history of genetic problems
Pediatric Disease
• Major determinants of disease– pediatric diseases differ materially from adult
diseases– genetic defects are a common cause ofgenetic defects are a common cause of
pediatric disease– maternal factors are the cause of many fetal &
neonatal disorders
Terminology• Perinatal period
– from 28th week of pregnancy to 7th day after birth• Neonatal period
– 1st month after birth• Full-term pregnancy
– 38-40 weeks• Normal birth weight
– 3500gms• Post-term infant
– born after 42 weeks• Premature infant
– born before the end of the 37th week• Low birth weight
– < 2500gms• Gestational age
– length of time in the womb
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• Length of gestation, birth weight, & organ maturity all related Apgar Score
• 5 minute score of 0-1 have 50% mortality rate• 7 or better almost 0 mortality rate
Intrauterine Growth Restriction• About 1/3 of low birth weight infants• SGA• Maternal factors are most common causes
– HTN of pregnancy– malnutrition– drug or alcohol abuse
cigarette smoking– cigarette smoking• Placental factors
– insufficient placental blood flow– placenta previa– placenta abruptio
• Fetal factors– genetic disease– congenital anomalies– infections
Prematurity• Before the end of the 37th week• Low birth weight• 5-10% of pregnancies• Causes
preterm rupture of the amnion– preterm rupture of the amnion– intrauterine infection– multiple fetuses– structural abnormalities of the uterus, cervix, placenta– placental hemorrhage– abnormal placental implantation– relaxed cervix
Liver
• Not fully capable of processing bilirubin until about 2 weeks of age
• Treat with– phototherapy– exchange transfusion
kernicterus
Lungs• Do not reach full maturity until
6-8yo• Weeks 28-32 begin to secrete
surfactant• If not enough surfactant, have
RDS– hard to keep alveoli open– breathing becomes difficult
with grunting & retractions– hypoxic & cyanotic– damage to alveoli & vessels– fluid accumulation– protein in the exudate not
absorbed & forms a membrane coating
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Birth Injury• About 1 in 5000 live births• LGA infants injured more often• Most common injuries
– fractured clavicle– facial nerve injury– facial nerve injury– brachial plexus injury– skull fracture or intracranial injury– humeral fracture
• Cerebral Palsy– varying degrees of motor difficulty including paralysis,
uncontrolled movements, & inability to coordinate body movements
Fetal & Newborn Infections
• Some cross the placenta (TORCH) but most are from vaginal microbes– herpesvirus
necrotizing enterocolitis– necrotizing enterocolitis
Infections of Children• Viral most common• Respiratory syncytial virus (RSV)• Measles
– rubeola• Rubella• Mumps• Infectious mononucleosis
– Caused by EBV– Heterophile antibodies
• Chickenpox– Varicella-zoster virusVaricella zoster virus
• Acute otitis media– Usually S. pneumoniae & H. influenzae
• Bronchiolitis– Usually caused by RSV
• Whooping cough– Bordatella pertussis
• Croup– Influenzae A or B
• Diphtheria– Corynebacterium diphtheriae
• Acute bacterial epiglottitis– H. influenzae
Sudden Infant Death Syndrome (SIDS)
• “crib death”• Cause unknown• Characterized by its epidemiology
– 90% of victims < 6 months90% of victims < 6 months– most routinely sleep in the prone position– higher than normal history of prematurity or low birth
weight– males > females– mothers usually < 20yo, unmarried, smokers or drug
abusers
Hemolytic Disease of the Newborn (HDN)
• Erythroblastosis fetalis• Effects include
– anemia– high bilirubin– high output CHF– osmotic edema
Hydrops Fetalis
• Combination of osmotic edema & heart failure
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Cystic Fibrosis• Most common lethal genetic
disease of caucasians• Affects Cl- transporters
resulting in decreased Cl- in glandular secretions
• Causes thick mucus that obstructs airways & ducts– chronic pancreatitis– malabsorption– malnourishment– chromic inflammation of the
liver– low sperm count– impaired respiration
Tumors & Tumor-Like Conditions
• 2nd most common cause of death even though uncommon
• Benign tumors more commonchoristoma
hamartoma
Acute leukemia