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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