Developmental Abnormalities Congenital means present at birth may - - PDF document

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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 embryologic intrinsically 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 g development, 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
• rgan to differentiate
• r 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
• Cytomegalovirus

Cytomegalovirus

• 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 35-38 weeks 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

– Recessive Recessive

• 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

production X & 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 & therefore genes, most being recessive & therefore not expressed

Autosomal Dominant Diseases

• Physically expressed if
• nly one copy of gene is

present

• An affected parent has a

50% chance of passing 50% 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
• nly 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 macrophages

Gl 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 life compatible with life

Trisomy

• Extra copy of a

chromosome

• Most result in

spontaneous p abortion

– 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 of genetic 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 virus Varicella 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 months 90% 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
• bstructs 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 common

choristoma hamartoma Acute leukemia