106 terms

Robbins Ch 10: Diseases of Infancy and Childhood

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
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
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)
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
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