Pediatric pathology Flashcards
Ages of Embryo, Fetus, Neonatal, Parinatal, Infancy, Childhood
Embryo – implantation until completion of first 8 weeks
Fetus – 9 weeks to birth (legal definitions vary by state in the U.S.)
Neonatal – first 4 weeks after birth (Most hazardous)
Perinatal – 5 months before to one month after birth
Infancy – first year after birth
Childhood – between birth and puberty or legal adult age
Infant mortality rates US, Japan, Afghanistan
6.17/ 1,000 US
Japan- 2.13
Afghanistan: 117.23
In the US, infant mortality rates per 1,000 live births – black ethnicity
12.40
Most common causes of death for less than 1 year
Congenital malformations, deformations, and chromosomal anomalies
Disorders related to short gestation and low birth weight
Sudden infant death syndrome (SIDS): MOST COMMOM CAUSE >1-
most common reasons for death 1-4 years old
Accidents (unintentional injuries)
Congenital malformations, deformations, and chromosomal abnormalities
Malignant neoplasms
most common causes of death for 5-9 years
accidents
malignant neoplasms
most common causes of death for 10-15 years
accidents
Notes on congenital anomalies
present at birth
disease may not be expressed until later in life
Up to 3% of newborns have a major anomaly
The most severe anomalies cause intrauterine death (blighted ovum or abortion)
Most common birth defect
bicuspid aortic valve - 46.0/ 10,000 live births
holoprosencephaly
the cyclops one
amniotic band
- a disruption
wraps around some part of the fetus and can cut off supply to that limb/ finger/ etc.
deformations
Extrinsic disturbance of development from abnormal biomechanical forces leading to structural abnormalities
Disruptions
Secondary destruction of previously normal structure (extrinsic disturbance of normal morphogenesis)
e.g. amniotic bands, environmental causes
Not heritable!
Sequence
a pattern of cascade anomalies set off by one initiating aberration
May be called a “complex”
Malformation Syndrome
cannot be explained by a single initiating event
May be called a “complex”
Oligohydramnios (Potter) Sequence
baby not making enough urine (some osbtruction or something– Potter described it as renal agenesis)
- -> oligohydramnios
- -> pulmonary hypoplasia, altered facies, positioning defects of feet, hands, breech presentation
Potter facies: Ocular hypertelorism Low-set ears Receding chin Flattening of the nose
cleft lip/ palate
With malformation syndrome: severe cardiac defects
Can also be isolated and not part of a syndrome
Infectious Torch Syndrome
Toxoplasma Other (T. pallidum) Rubella Cytomegalovirus Herpes simplex
–> choriortinitis, cataract, conjunctivitis, microcephaly, focal cerebral calcification, microphthalmia, pneumonitis, heart disease, hepatomegaly and jaundice, splenomegaly, petechiae and purpura
atresia
absence of an opening usually in hollow organ, e.g. trachea, intestines
aplasia
Complete absence of an organ due to primordium development failure (but primordium is/was present, e.g. streak gonads)
Dysplasia of Abdominal Wall
oomphalocele- abdominal musculature fails to form (perittoneal sac is intact)
gastroschisis- part of the abdominal wall fails to form
most common congenital anomalies in huans
multifactorial and unknown
Pathogenesis of
Congenital Anomalies
Timing: Major impact on occurrence and type (4-5 weeks big impact on lots of systems including heart, CNS, eyes, etc.)
Teratogens may act in similar manner as genetic mutations
Genes affected: certain genes now known to be major players in organogenesis
Environmental Teratogens That Cause Malformations (Disruptions)*
Timing of exposure critical
Less than 3 weeks, injury lethal or induces spontaneous abortion
Between 3 & 9 weeks, very susceptible to teratogenesis with peak at 4 - 5 weeks (most organs forming)
eg. Ventricular septal defect of heart exposure
Viral infections and pregnancy
Most known: rubella and CMV
Rubella: Conception 16 weeks (50% 1st month, 20% 2nd,7% 3rd)
CMV (most common): 2nd trimester.
Rubella=rubella embryopathy: tetrad of cataracts, deafness, (numerous) heart defects, and mental retardation
CMV: CNS involvement major feature
Present with microcephaly, mental retardation, deafness, and hepatosplenomegaly
Organogenesis almost complete in second semester so frequency of anomalies lower than rubella, but damage can cause severe defects
teratogenic Drugs and Chemicals in pregnancy
13-cis-retinoic acid (=Accutane=isotretinoin) Thalidomide valproic acid (antiepileptic) disrupts HOX genes Fetal alcohol syndrome
Fetal Alcohol Syndrome
most common cause of mental retardation
growth retardation, microcephaly, atrial septal defect (ASD), short palpebral fissures, maxillary hypoplasia (affects retinoic acid and Hedgehog signaling pathways)
KEY: indistinct philthrum and wide-set eyes
Phthalates
Plasticizers added to polyvinyl chloride (PVC) and used in flexible plastics
“Exposure to in laboratory animals causes endocrine disruption and a testicular dysgenesis syndrome
Different from Bisphenol A (BPA) used in polycarbonate plastics
Maternal Diabetes
–> diabetic embryopathy
–> fetal macrosomia
caput succadaneum
(scalp edema) extremely common
cephalhematoma
common, does not cross suture lines. Check for intracranial hemorrhages
intracranial hemorrhages
major concern
Genetic Causes of Malformations
Genes producing transcription factors for embryonic/fetal development
Karyotypic (chromosomal) aberrations
Single gene mutations-e.g. holoprosencephaly/sonic hedgehog gene
Multifactorial-2 or more genes; gene(s) + environmental factor(s)
major genes controlling organ development
HOX genes, tell stuff where to go. Head: 1-4, distal 9-14
HOXD13
gain mutations induce syndactyly/ polydactyly
HOXA13
mutations cause hand-foot-genital syndrome (distal limb .and distal urinary tract malformations)
Teratogens acting on HOX genes
Sodium valproate
retinoic acid and isoretinoin act as teratogens disruption HOX gene expression
PAX genes: PAX 2,3,6
PAX2- Renal-coloboma syndrome (developmental defects of the kidneys, eyes, ears, and brain)
PAX3 - Waardenburg syndrome (congenital pigment abnormalities and deafness)
PAX6- Aniridia (congenital absence of the iris)
Karyotypic Aberrations
Virtually all chromosomal syndromes have congenital anomalies
Down > Kleinfelter (47XXY) > Turner (45X) > Trisomy 13 (Patau)
Multifactorial inheritance
Cleft lip and palate (ethanol, rubella, thalidomide)
Neural tube defects-folic acid (B9) lowers incidence
Congenital dislocation of the hip
- Genetic- shallow acetabulum and ligament laxity
- Environment- breech presentation (flexed hips and extended knees)
Apgar
assesment: probability of survival
NOT normal life thereafter
Perfect score is 10
5 fxns evaluated from 0-2
Premature
before 37 weeks
postmature: after42 weeks
Gestational Age
AGA- appropriate
SGA- small for gestational age = fetal growth restriction *** under 2500 g
LGA- large for gestational age
PPROM and PROM
Preterm Premature Rupture of Membranes (PPROM)
and Premature Rupture of the Membranes (PROM)
PROM is any time the membrane ruptures before active labor
prematurity: intrauterine infection- 2 types
chorioamnionitis (membranes) and funisitis (cord)
prematurity: maternal and placental structural anomalies
Fibroids (leiomyomata)
Incompetent cervix
Placenta previa: implantation in lower uterus (hypovascularized)
Placenta accreta (no decidua): implantation into uterine wall, cannot be separated from the uterine musculature –> hysterectomy
Fetal causes of FGR
Fetal causes usually have symmetric FGR (growth restriction) (proportionate FGR)
Chromosomal disorders (triploidy, trisomies, etc.)
Congenital anomalies
Infection by a TORCH organism (Toxoplasma, Rubella, CMV, Herpes), syphilis & other viruses
Placental Causes of FGR
(Placenta is both fetal and maternal in origin)
Uteroplacental insufficiency is an important cause during 3rd trimester-vigorous growth
Usually results in asymmetric FGR with brain spared (disproportionate FGR)
Post fertilization mutation: early-fetus and placenta involved late-can involve just cells of placenta=Confined placental mosaicism (seen in 15% of cases of FGR) -trisomy 7 frequent
Maternal causes of FGR
Most frequent causes of SGA
Hypertension, hypercoagulable states, Alcohol, narcotics, heavy smoking, drugs (dilantin)
General malnutrition
Immaturity of organs in pre-term
Lungs
Kidneys: many glomeruli immature but usually deep glomeruli mature enough for survival
Liver: generally OK but bilirubin handled poorly so many jaundiced (more later)
Brain: not developed but if tragedy avoided can develop. Temperature regulation & respiration control affected.
Respiratory distress in the newborn
Excessive maternal sedation Fetal head injury Blood or amniotic fluid aspiration Intrauterine hypoxia from nuchal cord Hyaline membrane disease
Hyaline Membrane Disease
a.k.a. Neonatal respiratory distress syndrome
deficiency of pulmonary surfactant (secreted by Type II pneumocytes)
20 weeks: lungs are glandular
30 weeks: saccular
term: alveolar
important ratio: lecithin to sphingomyelin. Want it to be high.
thin layer chromatography is the gold standard for measuring substitutes: Flourescence polarization Foam stability index Lamellar body count
RDS- surfactant
The first breath of life requires a large inspiratory effort but once inflated the lungs remain ~ 40% inflated with normal surfactant levels
If inadequate surfactant, lungs collapse and every breath is as hard as the first
Stiff lungs and soft chest wall work together to make breathing difficult
Glucocorticoids (stress) and thyroxine induce surfactant secretion
High levels of insulin inhibit secretion
Labor induces synthesis
Prematurity, maternal diabetes, and caesarean delivery predisposing factors to RDS
RDS – Classic Clinical Picture
Preterm and AGA
Male sex, maternal DM, C-section
Low 1 minute Apgar score, may need resuscitation
Then may do well for short time (less than 1 hour)
Becomes cyanotic
Fine pulmonary rales (crackles)
Reticulonodular/ground glass chest x-ray
Oxygen therapy needed
Death or recovery in 3 – 4 days
Clinical Course RDS
Outlook much more favorable today
Administration of surfactant (less than 26-28 weeks)
Antenatal treatment with steroids (24-34 weeks)
Monitoring amniotic fluid for surfactant for lung maturity
Death now unusual
Recovery begins at about 4 days
Therapy with O2 carries risks of
Retinopathy and
Bronchopulmonary dysplasia
Retrolental Fibroplasia
a.k.a. Retinopathy of Prematurity
Phase I: O2 therapy and hyperoxia → ↓VEGF → endothelial cell apoptosis
Phase II: Then relative hypoxia (room air) → ↑VEGF → angiogenesis (neovascularization)
Even with very careful O2 monitoring retinopathy can result suggesting other causes
Bronchopulmonary Dysplasia
Alveolar hypoplasia & thickened walls
O2 thought to decrease lung maturation
Dysmorphic capillaries and decreased VEGF
Necrotizing Enterocolitis (NEC)
Etiology uncertain but intestinal ischemia prerequisite
occurs after first feeding
Platelet activating factor elevated in stool
Germinal Matrix Hemorrhage
Subependymal (periventricular) hemorrhage with extension into ventricles occurs in preterm infants
The microcirculation in area extremely sensitive to hypoxia and changes in perfusion pressure
Common cause for admissions to neonatal intensive care units in under 1500 g.
Perinatal Infections Transplacental (hematologic) infections:
parasites, viruses, bacteria
TORCH
Parvovirus B19 - 5th disease
Perinatal Infections: Transcervical (Ascending) infections
Most bacterial, some viral (HSV II)
Inhalation of infected amniotic fluid (in utero) or infected passing through infected birth canal
PROM frequent with preterm delivery
Chorioamnionitis/funisitis common
Pneumonia, sepsis and meningitis common if infected via inhalation
Gonococcal infections
Chlamydial conjuntivitis
perinatal infections: post-natal via maternal milk
Cytomegalovirus
- Usually blocked by maternal antibodies
Human immunodeficiency virus
- More likely with continued late breast feeding
Hepatitis B
- Rx –give hepatitis immune globulin and vaccine to infant
HTLV I
- More likely with continued late breast feeding
- May lead to adult T-cell leukemia/lymphoma
Heat-labile E. coli enterotoxin
- Reported to cause pediatric diarrhea
perinatal sepsis in the week
Group B strep #1
Fetal hydrops
(Hydrops fetalis)
Accumulation of edema in fetus during intrauterine growth
Immune hydrops (mother antibodies to fetal RBC)
Nonimmune hydrops more common in U.S.A.
If accompanied by anemia can lead to erythroblastosis fetalis
some causes of fetal hydrops
cardiovascular chromosomal- turner syndrome, trisomy 21, trisomy 18 thoracic causes - diaphragmatic hernia fetal anemia- thalassemia, parvovirus B19, iRh/ ABO incompatibility twin gestation infection- CMV, syphilis, toxoplasmosis Genitourinary tract malformations tumors genetic / metabolic disorders
Immune hydrops
Concurrent ABO incompatibility helps prevent sensitization to Rh
Maternal response dose dependent, needs more that 1 ml of fetal cells
When there is a high IgG response, antibodies cross placenta and attack fetal RBCs
This induces anemia and jaundice - hydrops and kernicterus (after birth)
Fetal cord blood ** Coombs ** positive
Administration of Rhesus anti-D immune globulin to mothers at 28 weeks and within 72 hours after birth greatly reduced rate of immune hydrops
Amniocentesis or chorionic villus biopsy or cloning RHD gene in maternal blood to identify children at risk
If hemolysis occurs in utero, treated by in utero transfusion and early delivery
Kernicterus
Related to level of unconjugated hyperbilirubinemia
Prevention via unconjugated bilirubin + UV lights → dipyrroles
Bilirubin deposited in brain after birth
Infants who survive develop long-term neurologic sequelae
Abnormalities Suggesting
Inborn Errors of Metabolism
abnormal body or urine odor cataracts cherry red macula dislocated lens GI trouble
Cystic Fibrosis (Mucoviscidosis)
Widespread disorder in epithelial transport affecting fluid secretion in exocrine glands and the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts
Leads to abnormally viscid mucous secretions, which obstruct organ passages
Have pancreatic insufficiency, steatorrhea, malnutrition, hepatic cirrhosis, intestinal obstruction, male infertility and recurrent pulmonary infections that lead to chronic lung disease
CFTR gene
Protein-Energy Malnutrition (PEM)
Marasmus: Caloric deprivation
Kwashiorkor : Protein deprivation (relatively greater than the reduction in total calories)
Marasmus
Weight less than 60% of normal for sex, height, and age
Somatic compartment affected more
Serum albumin levels are either normal or only slightly reduced
Anemia usually also present
Kwashiorkor
Visceral compartment is depleted more severely in kwashiorkor with relative sparing of fat and muscle
Low levels of serum proteins albumin, transferrin, and others
Hypoalbuminemia gives rise to generalized or dependent edema
Hair has loss of color or alternating bands
Weight typically 60%-80% of normal
Liver is enlarged and fatty
Small bowel atrophy
Anemia
Pediatric tumors
Heterotopia or choristoma: normal cells from a tissue type in the wrong place (e.g. pancreas in the stomach wall)
Hamartoma: Overdevelopment of tissue normally present (e.g. mass of cartilage in lung)
Hemangioma
usually in skin
most common tumor of infancy
often spontaneous regression
Lymphangiomas
skin or deeper
most common malignant neoplasms of infancy and childhood
Leukemia (ALL) #1 cause of deaths
Neuroblastoma- #2 solid tumor
CNS tumors- #1 solid tumor
Neuroblastoma
17q gain, 1 p deletion
N-myc amplification
DNA hyperdiploidy, near triploidy.
elevation in f urinary catecholamines
Most common extracranial solid tumor of childhood (700 new cases per year in U.S.)
Small blue cell tumor that may have Homer-Wright pseudorossettes
Very treatable
Ewing Sarcoma
translocation t(11;22)
Rhabdomyosarcoma
PAX3-FKHR and PAX-FKHR
Lymphoblastic lymphoma/ acute lymphoblastic leukemia
TdT+ Terminal deoxynucleotidl transferase
Wilms tumor
11p13 (WT1) deletion
Retinoblastoma
13q14 (RB) deletion/ mutation
Medulloblastoma
17p deletion
Isochromosome 17q
Neuroblastoma cutaneous metastases
can look like blueberry muffin baby
Staging of neuroblastomas
1- localized tumor with complete gross excision (nodes adherent to the primary tumor may be positive for tumor)
2A- incomplete gross resection, nodes negative
2B- Localized tumor with or without complete gross excision, ipsilateral nonadherent lymph nodes positive for tumor; enlarged contralateral lymph nodes, which are negative for tumor microscopically.
3- Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement.
4- dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs
4S- (“S” = special): Localized primary tumor (as defined for stages 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow; stage 4S is limited to infants younger than 1 year.
Retinoblastoma
Most common malignant eye tumor of childhood
Familial (60-70% ) have germline RB1gene mutation
Sporadic (30-40%) have somatic RB1 gene mutation
More information in eye lecture
Flexner-Wintersteiner rosettes
Nephroblastoma
Wilms Tumor
Triphasic histology-stromal, epithelial tubules and blastemal elements
WT1 mutations – 11 p13
