Robbins Ch 10: Diseases of Infancy and Childhood

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3 leading causes of death in the first 12 months of lie

1. congenital anomalies
2. d/o related to prematurity and low birth weight
3. SIDS

Definition of a malformation

primary error of morphogenesis in which there is an intrinsically abnormal developmental process
Multiple genetic loci

Definition of a disruption

secondary destruction of an organ or body region that was previously normal in development-->extrinsic disturbance in morphogenesis

Classic example of a disruption

amniotic bands--rupture of amnion with resultant formation of "bands" that encircle, compress, or attach to parts of the developing fetus

Definition of a deformation

extrinsic disturbance of development due to localized or generalized compression of fetus by abnormal biomechanical forces

Most common underlying factor for deformation

uterine constraint: rapid increase in size of size outpaces growth of uterus, which relative amount of amniotic fluid decreasing as well. Usually occurs between 35 and 38 weeks

Maternal factors increasing likelihood of deformation

first pregnancy, small or malformed uterus, and leiomyomas

Fetal or placental factors increasing likelihood of deformation

oligohydramnios, multiple fetuses, and abnormal fetal presentation.

Example of deformation

clubfeet, often a component of Potter sequence

Definition of a sequence

cascade of anomalies triggered by one initiating aberration in organogenesis

Example of a sequence

oligohydramnios or Potter sequence--decreased amniotic fluid leading to fetal compression-->flattened facies, positional abnormalities of hands and feet, dislocated hips, nodules in amnion (amnion nodosum), and compromised growth of chest well and hypoplastic lungs-->fetal demise

Causes of oligohydramnios

1.chronic leakage of amniotic fluid due to amnion rupture
2. uteroplacental insufficiency due to maternal HTN or severe toxemia
3. renal agenesis in the fetus

Definition of a syndrome

constellation of congenital anomalies pathologically related that cannot be explained on the basis of a single, localized, initiating defect

Definition of aplasia

absence of an organ due to failure of development of the primordium. Agnesis is complete absence of an organ and its associated primordium

Definition of atresia

failure of an opening, usually in a hollow visceral organ such as the trachea or intestine

Examples of chromosomal defects

1. down syndrome (trisomy 21)
2. trisomy 13
3. trisomy 18

Examples of orofacial defects

1. cleft palate
2. cleft lip with and without cleft palate

Examples of CV defects

1. AV septal defect (endocardial cushion defect)
2. transposition of great arteries
3. tetrology of Fallot

Examples of CNS defects

1. spina bifida without anencephalus
2. anencephalus

Examples of GI defects

1. rectal and large intestinal atresia/stenosis
2. esophageal atresis/trachoesophageal fistula

Examples of M/S defects

1. gastroschisis
2. diaphragmatic hernia
3. omphalocele

Cytogenic aberrations tend to arise as defects in...

gametogenesis, so they are not familial

What percent of fetuses with aneuploidy/chromosome number abnormalities die in utero?

80-90%, majority in the earliest stages of gestation

Holoprosencephaly is defect in what?

forebrain and midface due to Hedgehog signaling pathway loss-of-function mutations

Achondroplasia is defect in what?

most common form of short-limb dwarfism
gain-of-function mutations in FGFR3-->negative regulator of bone growth

8 viruses implicated in causing malformations

1. rubella
2. cytomegalic inclusion dz (CMV)
3. herpes simplex
4. varicella-zoster
5. influenza
6. mumps
7. HIV
8. enterovirus

At-risk period for rubella infection

extends from shortly before conception to the sixteenth week (greater in first 8 weeks)

Consequences of rubella syndrome

1. cataracts
2. heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia/stenosis, ventricular septal defect, tetralogy of Fallot)
3. deafness
4. MR

At-risk period for intrauterine CMV infection

second trimester

Consequences of CMV infection on fetus

CNS changes: MR, microcephaly, deafness, and hepatosplenomegaly

7 examples of teratogenic drugs and chemicals

1. thalidomide
2. folate antagonists
3. androgenic hormones
4. EtOH
5. anticonvulsants
6. warfarin
7. 13-cis-retinoic acid

Mechanism of thalidomide teratogenicity

downregulating WNT signaling pathway through upregulation of WNT repressors
high frequency of limb abnormalities

Consequences of FASDs

growth retardation, microcephaly, atrial septal defect, palpebral fissures, and maxillary hypoplasia.

What two seminal development signaling pathway does EtOH disrupt?

retinoic acid and Hedgehod

Malformations caused by radiation

microcephaly, blindness, skull defects, spina bifida

Malformations caused by maternal hyperglycemica-induced fetal hyperinsulinemia

increased body fat, muscle mass, and organomegaly (fetal macrosomia); cardiac anomalies, neural tube defects, and other CNS malformations
aka diabetic embryopathy

Genetic factors in congenital dislocation of the hip

shallow acetabular socket and laxity of supporting ligaments

Environmental factors in congenital dislocation of the hip

frank breech position in utero with hips flexed and knees extended

When in the early embryonic period is the fetus extremely susceptible to teratogenesis?

between third and nine weeks (peak between 4 and 5 weeks), during which organs are developing out of the germ cell layers

During the fetal period, to what type of injury is the fetus susceptible?

growth retardation or injury to already formed organs.
reduced susceptibility to teratogenic agents

Cyclopamine causes what anomalies in lambs?

severe craniofacial abnormalities, including holoprosencephaly and cyclopia. Inhibits Hedgehog signaling.

Valproic acid causes what anomalies in vertebrates?

abnormal patterning of limbs, vertebrae, and craniofacial structures-->valproic acid embryopathy
disrupts homeobox (HOX) proteins

Deficiency in all-trans retinoic acid causes:

malformations affecting eyes, GU system, CV system, diaphragm, and lungs

Excess exposure to retinoic acid causes:

retinoic acid embryopathy: CNS, cardiac, and craniofacial defects (cleft lip and cleft palate)
deregulation of TGF-beta?

3 classifications for birth weight and gestational age

1. AGA: appropriate for gestational age
2. SGA: small for gestational age
3. LGA: large for gestational age

Infants born before --- week are considered pre-term

37 weeks

Infants born after --- week are considered post-term

42 weeks

4 risk factors for prematurity

1. preterm premature rupture of placental membranes
2. intrauterine infection
3. uterine, cervical, and placental structural abnormalities
4. multiple gestation

Difference between PPROM and PROM

PPROM: spontaneous ROM before 37 weeks
PROM: spontaneous ROM after 37 weeks

Risk factors for PPROM

1. prior hx of preterm delivery
2. preterm labor and/or vag bleeding during preg
3. maternal smoking
4. poor
5. poor maternal nutrition
6. polymorphism in immune regulation (e.g. TNF) or collagen breakdown (e.g. MMP 1,8,9)

Pathophysiology of PPROM

inflammation of placental membranes and enhanced collagen degradation by MMP

Two histologic correlates of intrauterine infection

1. inflammation of the placental membranes (chorioamnionitis)
2. inflammation of the fetal umbilical cord (funisitis)

6 most common microorganisms involved in intrauterine infections leading to preterm labor

1. Ureaplasma urealyticum
2. Mycoplasma hominis
3. Gardnerella vaginalis
4. trichomonas
5. gonorrhea
6. chlamydia

Key players in the molecular mechanisms of inflammation-induced preterm labor

endogeneous TLRs, specifically TLR-4 activation by bacterial lipopolysaccharide deregulating prostaglandin expression-->induces smooth muscle contraction

4 examples of structural abnormalities causing preterm labor

1. uterine distortion (uterine fibroids)
2. compromised structural support of cervix (cervical incompetence)
3. placenta previa
4. abruptio placentae

5 hazards of prematurity for the newborn

1. hyaline membrane dz (aka neonatal respiratory distress syndrome)
2. necrotizing enterocolitis
3. sepsis
4. intraventricular hemorrhage
5. long-term complications, like developmental delay

Infants who as SGA often have underlying

fetal growth restriction (FGR)

How can FGR be detected before delivery?

U/S measuring biparietal diameter, head or abd circumference, femur length, total intrauterine volume

Fetal influences resulting in FGR

chromosomal disorders--triploidy, trisomy 18, 21, 13
congenital anomalies
fetal infection: toxoplasmosis, rubella, CMV, herpesvirus, syphilis)

Infants who are SGA due to fetal factors are usually characterized by:

symmetric growth restriction (proportionate FGR), meaning that all organ systems are similarly affected

Placental influences resulting in FGR

uteroplacental insufficiency--due to umbilical-placental vascular anomalies (single umbilical artery, abnormal cord insertion, placental hemangioma), placental abruption, placenta previa, placental thrombosis/infarction, placental infection, or multiple gestations

Placental causes of FGR tend to produce what type of growth retardation?

asymmetric, with relative sparing of the brain
down-regulation of growth in the latter half of gestation due to limited availability of nutrients or oxygen

What is meant by genetic mosaicism confined to the placenta?

up to 15% of preg with FGR-->viable genetic mutations occurring after zygota formation, causes different forms of chromosomal mosaicism. Dependent on timing and cell of origin of mutation.
Trisomy 7 most frequently documented

Maternal influences resulting in FGR

maternal conditions resulting in decreased placental blood flow.
Vascular dz: preeclampsia (toxemia of preg) and chronic HTN
Inherited thrombophilias: factor V leiden mutation
narcotic abuse, EtOH, heavy cigarette smoking
Dilantin
prolonged hypoglycemia

5 causes of respiratory distress in the newborn

1. excessive sedation of mother
2. fetal head injury during delivery
3. aspiration of blood or amniotic fluid
4. intrauterine hypoxia due to umbilical cord coiling about the neck
5. hyaline membrane dz, aka RDS-->deposition of a layer of hyaline proteinacecous material in peripheral airspaces of infants with this condition. Most common cause

Common clinical presentation of RDS

preterm and AGA-->male, maternal DM, C-section
resuscitation may be needed, but within a few minutes rhythmic breathing and normal color re-established
30 minutes--dyspnea
few hours--cyanosis
Bilateral rales
CXR: ground-glass picture: uniform minute reticulogranular densities

If therapy staves off death for --- days, infant has excellent chance of recovery

3-4 days

Fundamental defect in RDS

deficiency of pulmonary surfactant causing immaturity of lungs

Components of pulmonary surfactant

dipalmitoyl phosphatidylcholine (lecithin)
phosphatidylglycerol
hydrophilic glycoproteins SP-A and SP-D
hydrophobic surfactant proteins SP-B and SP-C to reduce surface tension

When is surfactant production by type 2 alveolar cells accelerated?

After 35th week of gestation

Deficiency of surfactant: what happens to lungs at birth

Increased surface tension-->lungs collapse with each successive breath, so infants must work as hard with each successive breath as they did with the first.

Normal surfactant--lungs retain their residual air volume after first breath so successive breaths require far lower inspiratory pressures

What compounds problem of stiff atelectatic lungs?

soft thoracic wall pulled in as the diaphragm descends

Consequence of atelectasis in RDS

uneven perfusion and hypoventilation-->hypoxemia and CO2 retention-->acidosis-->pulmonary vasoconstriction-->endothelial/epithelial damage-->plasma leak into alveoli-->fibrin and necrotic cells (hyaline membrane)
protein-rich, fibrin-rich exudation in to the alveolar spaces with the formation of hyaline membranes-->vicious cycle

What hormone class is especially important in surfactant synthesis?

glucocorticoids. Therefore, synthesis suppressed by high insulin levels (DM mothers), C-section (labor increases surfactant synthesis)

Morphology of RDS

lungs: normal size, but solid, airless, and reddish purple
alveoli: poorly developed, collapsed
terminal bronchioles and alveolar ducts: necrotic cellular debris incorporated within eosinophilic hyaline membranes made up of fibrin with cell debris from type 2 pneumocytes

Clinical course of RDS

1.delay labor until lungs reach maturity or induce maturation of lungs
2. analyze pulmonary secretions discharged in the amniotic fluid-->phospholipid analysis
3. prophylactic administration of exogenous surfactant at birth
4. antenatal corticosteroids to mom with threatened premature delivery

Hazards with oxygen therapy of RDS

oxygen toxicity
1. retrolental fibroplasia in the eyes--changes in VEGF expression
2. bronchopulmonary dysplasia--airway epithelial hyperplasia and squamous metaplasia, alveolar wall thickening, and peribronchial and interstitial fibrosis; decrease alveolar septation and dysmorphic capillary configuration

Infants who recover from RDS are at risk for what complications?

patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis

What is necrotizing enterocolitis?

associated with prematurity, enteral feeding, infectious agents, inflammatory mediators (especially PAF increasing mucosal permeability)
Ultimately, breakdown of mucosal barrier-->migration of gut bacteria-->inflammation, mucosal necrosis, sepsis, shock

Clinical course of NEC

bloody stools, abd distention, circulatory collapse
abd XR: gas within interstinal wall (pneumatosis intestinalis)
involves terminal ileum, cecum, and right colon-->distended, friable, congested or gangrenous

What condition is a complication of NEC?

intestinal perforation with accompanying peritonitis

Microscopic findings in NEC

mucosal or transmural coagulative necrosis, ulceration, bacterial colonization, and submucosal gas bubbles

Tx NEC

managed conservatively
resection of necrotic bowel

Consequences of surviving NEC

post-NEC strictures from fibrosis caused by granulation tissue and fibrosis after an acute episode

What type of infections are acquired by cervicovaginal (transcervical or ascending) route?

most bacterial and a few viral (e.g. herpes simplex II) infections

acquired by inhaling infected amniotic fluid shortly before brith or through an infected birth canal during delivery

Most common sequelae due to infection by inhalation of amniotic fluid

pneumonia, sepsis, and meningitis

Types of infections acquired by transplacental (hematologic) infections

parasitic (toxoplasma, malaria) and viral infections, plus a few bacterial infections (listeria, treponema)

via chorionic villi; occurring at any time during gestation or at time of delivery via maternal-to-fetal transfusion (e.g. hep B and HIV)

Consequences of parvovirus B19 in a minority of intrauterine infections

spont AB (esp second trimester), stillbirth, hydrops fetalis, and congenital anemia.

Infects erythroid cells; diagnostic viral inclusions seen in early erythroid progenitor cells

TORCH group of infections: clinical and pathological manifestations

fever, encephalitis, chorioretinitis, hepatosplenomegaly, pneumonitis, myocarditis, hemolytic anemia, and vesicular or hemorrhagic skin lesions

Chronic sequelae: growth and mental retardation, cataracts, congenital cardiac anomalies, and bone defects

Early onset sepsis: timeline, symptoms, and responsible pathogens

within first 7 days of life; acquired at or shortly before birth, resulting in pneumonia, sepsis, and meningitis symptoms within 4-5 dyas of life

Group B streptococcus

Late-onset sepsis: timeline and pathogens responsible

from 7 days to 3 months; Listeria and Candida

Fetal hydrops refers to:

accumulation of edema fluid in the fetus during intrauterine growth; can be immune or nonimmune hydrops

3 categories of consequences of hydrops

1. progressive, generalized edema of fetus (hydrops fetalis), usually lethal
2. localized degrees of edema (isolated pleural and peritoneal effusions)
3. postnuchal fluid accumulation (cystic hygroma) compatible with life

When may fetal RBC's reach the maternal circulation?

1. during last trimester when the cytotrophoblast is no longer present as a barrier
2. during childbirth

Which Rh antigen is the major cause of Rh incompatibility?

D antigen

3 factors influencing the immune response to Rh-positive RBC's that reach the maternal circulation

1. ABO incompatibility protects mother against Rh immunization, since fetal RBC's are promptly coated and removed by anti-A or anti-B IgM antibodies that do not cross the placenta
2. dose-dependent; requires mother experience a significant transplacental bleed
3. Rh dz uncommon in first preg (IgM only); during next preg, IgG ab response

Administering ---- to Rh-negative mother decreases risk of hemolytic dz in future pregs

Rhesus immune globulin containing anti-D antibodies

In what cases does ABO hemolytic dz occur?

infants of group A or B born to group O mothers

3 reasons why ABO incompatibility causing hemolytic dz is rare

1. anti-A and anti-B abs are IgM so don't cross placenta
2. fetal RBCs express antigens poorly
3. cells other than RBCs express antigens so they absorb some of the transferred ab.

How does the developing infant respond to mild hemolysis?

extramedullary hematopoeisis in spleen and liver

Consequences of severe hemolytic in infant

progressive anemia-->hypoxia to heart and liver.
plasma protein synthesis drops
cardiac decompensation and failure
reduced plasma oncotic pressure and hydrostatic failure-->generalized edema and anasarca-->hydrops fetalis
Elevated bilirubin in blood-->lipid soluble-->travels to brain-->kernicterus (CNS damage)

3 major causes of nonimmune hydrops

1. CV defects--congenital cardiac defects and arrhythmias-->intrauterine cardiac failure and hydrops
2. chromosomal anomalies--Turner syndrome and trisomies 21 and 18
3. fetal anemia (not caused by Rh or ABO)--due to thalassemias or Parvovirus B19

Why does Turner syndrome cause hydrops?

Abnl lymph drainage from neck-->postnunchal fluid accumulation (cystic hygromas)

Why do trisomies 21 and 18 cause hydrops?

due to underlying structural cardiac anomalies associated with the chromosomal aberrations

Why does parvovirus B19 cause fetal anemia?

enters into erythroid precursors-->apoptosis of red cell precursors-->red cell aplasia

What is kernicterus?

brain is enlarged, edematous, and when sectioned has a bright yellow color especially in the basal ganglia, thalamus, cerebellum, gray matter, and spinal cord

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