Developmental, Genetic, & Pediatric Disease

Developmental Abnormalities
Congenital means present at birth
may not reveal itself for years

Congenital malformation
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 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 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

 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 malformations
chemical infectious agent drugs ionizing radation

hypospadias

Patent ductus arteriosus

VSD

ASD

Cleft lip

Spina bifida

anencephaly

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 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 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
cant transmit genetic defects

Chromosomes
autosomes sex chromosomes

Genotype
genetic makeup

Phenotype
physical expression of traits

Karyotype

Disease
Genetic
mutations of germ cells hereditary disease

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
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

Sex-Linked Recessive
Present on X chromosome Genes on Y chromosome related to sperm production 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 not expressed

Autosomal Dominant Diseases

Physically expressed if only one copy of gene is present An affected parent has a 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 only if both chromosomes carry a copy of the gene

Enzyme Defects
Accumulation of a substrate or deficiency of an end product Gaucher disease
accumulation of glucocerebrosides in macrophages

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

Cytogenetic Diseases
Abnormalities involving large parts or whole chromosomes usually occurring during the production of ova & sperm One or more extra chromosomes Missing chromosomes

 Monosomy
Loss of an autosome Results in spontaneous abortion as this is not compatible with life

Trisomy
Extra copy of a chromosome Most result in spontaneous abortion
Exceptions are chromosomes 13, 18, 21

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 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

 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

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 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

Birth Injury
About 1 in 5000 live births LGA infants injured more often Most common injuries
fractured clavicle facial nerve injury brachial plexus injury skull fracture or intracranial injury humeral fracture

CP
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

Infections of Children
Viral most common Respiratory syncytial virus (RSV) Measles
rubeola

Rubella Mumps Infectious mononucleosis

Caused by EBV Heterophile antibodies Varicella-zoster virus Usually S. pneumoniae & H. influenzae Usually caused by RSV Bordatella pertussis Influenzae A or B Corynebacterium diphtheriae H. influenzae

Chickenpox

Acute otitis media

Bronchiolitis Whooping cough Croup Diphtheria Acute bacterial epiglottitis

Sudden Infant Death Syndrome (SIDS)

crib death Cause unknown Characterized by its epidemiology
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

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 common
choristoma
hamartoma

Acute leukemia