what are the four time spans in the development of the infant
neonatal period–> first 4 weeks of life
infancy–> first year of life
age 1-4 years
age 5-14 years
what is the most common cause of mortality in the first year of life
birth defects
what are malformations
primary errors of morphogenesis
intrinsically abnormal development process
multiple genetic loci
what is a disruption
secondary destruction of an organ or body region that was previously normal in development
extrinsic disturbance
amniotic bands - classic example
can be caused by environmental agents
not heritable
what is a deformation
extrinsic disturbance of development
fundamental to this is localized or generalized compression of the growing fetus by abnormal biomechanical forces
commonly caused by uterine constraint
factors leading to this include: first pregnancy small uterus malformed uterus leiomyomas
oligohydramnios
multiple fetuses
abnormal fetal presentation
example is clubfeet
what is a sequence
cascade of anomalies triggered by one initiating aberration
Potter sequence:
oligohydramnios caused by leakage of amniotic fluid, uteroplacental insufficiency (caused by maternal HTN or toxemia) and renal agenesis in the fetus (b/c fetal urine is a major constituent of amniotic fluid)
oligohydramniosis causes compression of the newborn infant which causes:
- flattened facies
- positional abnormalities of the hands and feet
- dislocated hips
- poor growth of chest wall and lungs
- nodules in the amnion (amnion nodosum)
what is a syndrome
constellation of congenital anomalies that are pathologically related and cannot be explained on the basis of a single, localized, initiating defect
most often caused by a single etiologic agent, such as a viral infection or chromosomal abnormality
which then affects Several tissues
agenesis
complete lack of an organ
and its primmordium
aplasia
absence of an organ but one due to failure of development of the primordium
atresia
absence of an opening
usually of a hollow visceral organ such as the trachea and intestine
hypoplasia
incomplete development of decreased size of an organ with decreased number of cells
hyperplasia
enlargement of an organ due to increased numbers of cells
what are the three major categories of causes of congenital abnormalities
genetic
environmental
multifactorial
unknown
what is holoprosencephaly
the most common developmental defect of the forebrain and midface in humans
the hedgehog signaling pathway plays a critical role in the morphogenesis of these structures and there is loss of function of these components in patients with a family history of holoprosencephaly
single gene mutation
what is achondroplasia
what is the cause
mechanism
the mot common form of short limb dwarfism
caused by gain of function mutations in fibroblast growth factor (FGFR3)
FGFR3 protein is a negative regulator of bone growth and the activating FGFR3 mutations in achondroplasia are thought to exaggerate this physiologic inhibition, resulting in dwarfism
single - gene mutation
what viruses are associated with anomalies
rubella cytomegalic inclusion disease herpes simplex varicella-zoster influenza mumps HIV enterovirus
***age at which the infection occurs in the mother is critically important
what is the at risk age for rubella infection?
what are the fetal defects associated with this infection
extends from shortly before conception to the sixteenth week of gestation
defects:
cataracts
heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia or stenosis
ventricular septal defect, tetralogy of fallot)
deafness
metal retardation
***congenital rubella syndrome
intrauterine infection with cytomegalovirus ….
when is the fetus most at risk for this….
what are the outcomes
most common fetal viral infection
the highest at-risk period is the second trimester of pregnancy
b/c organogenesis is completlet by the end of the first trimester, congenital malformations occur less frequently than in rubella
involvement of the CNS is a major feature
mental retardation
microcephaly
deafness
hepatosplenomegaly
what are some drugs/chemicals that are teratogenic
thalidomide folate antagonists androgenic hormones alcohol anticonvulsants warfarin 13-cis retinoic acid (acne)
thalidomide causes what to occur
what is the mechanism
limb abnormalities
downregulation of the developmentally important wingless (WNT) signaling pathway through upregulation of endogenous WNT repressors
these drugs are used to treat neoplasms
what are the effects alcohol has on development
fetal alcohol spectrum disorders
growth retardation microcephaly atrial septal defect short palpebral fissures maxillary hypoplasia
mechanism:
affects the developmental signaling pathways –> retinoic acid and hedghog
what are the effects of radiation exposure during organogenesis
microcephaly
blindness
skull defects
spina bifida
what are the effects of maternal diabetes
results in:
increased body fat, muscle mass, and organomegaly (fetal macrosomia)
cardiac anomalies
neural tube defects and other CNS malformations
this is called diabetic embryopathy
multifactorial causes of abnoramlities
arise as a result of inheritance of multiple genetic polymorphisms that confer a susceptibility phenotype
the interaction of this phenotype and the environment is then required before the disorder manifests
what is the embryonic period
first 9 weeks of pregnancy
what is the fetal period
after 9 weeks and terminating at birth
in the early embryonic period (first 3 weeks after fertilization) what can occur
an injurious agent damages either enough cells to cause death and abortion or only a few cells –> allowing the embryo to recover without developing defects
what is significant about the time b/w the third and 9th weeks in the embryo’s development
when is the peak sensitivity during this period
the embryo is EXTREMELY susceptible to teratogenesis
peak sensitivity–> b/w the 4th and 5th weeks during which time the organs are being crafted out of the germ cell layers
what occurs during the fetal period
further growth and maturation of the organs
reduced susceptibbility to teratogenic agents
fetus is susceptible to growth retardation or injury to already formed organs
what does cyclopamine cause
what is the mechanism
derived from “California lily”
craniofacial abnormalities including holoprosencephaly and cyclopia (single fused eye)
inhibitor of hedgehog signaling in the embryo
what is valproic acid normally used for
what is the mechanism for its teratogenic actions
anti-epileptic
disrupts expression of HOX (transcription factors) (homeobox)
the genes encoding HOX proteins have a 190 nucleotide motif, dubbed the homeobox, which binds DNA in a sequence-specific fashion
HOX proteins in humans have been implicated in the patterning of limbs, vertebrae, and craniofacial structures
what is all-trans-retinoic acid essential for
what happens in its absence during embryogenesis (vitamin A deficiency)
what occurs with excessive retinoic acid
vitamin A (retinol) is essential for normal development and differentiation
its absence during embryogenesis resultis in multiple organ systems affected –> eyes, GU, CV, diaphragm, lungs… etc.
in excess–> CNS, cardiac and craniofacial defects (cleft lip, cleft palate)
Cleft palate is caused by retinoic-acid mediated deregulation of components of the TGF-beta signaling pathway (involved in palatogenesis)
critical period of development for CNS
heart
eyes
ears
CNS- 3-5 weeks
heart 3.5-6.5
eyes- 4.5-8.5
ears- 4.5- 9.5
critical period of development for arms legs teeth/palate external genitalia
arms/legs –> 4.5-8 weeks
teeth/palate–> 6.75-9
external genitalia–> 7.5-9.75
above or below what percentile for a given gestational age are children considered SGA or LGA
below 10th percentile or above 90th percentile
what is premature
less than 37 weeks
second most common cause of neonatal mortality
rate of premature babies is actually increasing and is around 12 percent
what are the major risk factors for prematurity
preterm premature rupture of placental membranes (before 37 weeks)
intrauterine infection
- seen with inflammation of placental membranes and fetal umbilical cord
- common organisms include ureaplasma urealyticum, mycoplasma hominis, gardnerella vaginalis, treichomonas, gonorrhea, chlamydia
- HIV and malaria
- TLR-4 activation by bacterial lipopolysaccharide is one of the initiating events in inflammation-induced preterm labor (TLR-4 deregulates prostaglandin expression which in turn induces uterine smooth muscle contractions)
uterine, cervical and placental structural abnormalities
multiple gestations (twins)
what are the hazards of prematurity
hyaline membrane disease (neonatal resp distress syndrome)
necrotizing enterocolitis
sepsis
intraventricular hemorrhage
developmental delay
what are the fetal influences resulting in FGR (fetal growth restriction)
despite an adequate supply of nutrients
chromosomal disorders -triploidy -trisomy 18 -trisomy 21 trisomy 13 -deletions and translocations
congenital anomalies
congenital infections TORCH group of infections -toxolasmosis -rubella -cytomegalovirus -herpesvirus -syphyilis
typically these infants are SGA and symmetric - all organ systems are similarly affected
what are the placental influences that occur with FGR
uteroplacental insufficiency
causes: umbilical-placental vascular anomalies (single umbilical artery) placental abruption placenta previa placental thrombosis and infarction placental infection multiple gestations
tend to be ASYMMETRIC growth retardation of the fetus and viewed as a downregulation of growth in the latter half of gestation b/c of limited availability of nutrients or oxygen
what is genetic mosicism confined to the placenta…
cause of FGR
usually mosaicism is caused by genetic mutations after the zygote has formed
occurs later and within the dividing trophoblast or extraembryonic progenitor cells of the inner cell mass
common to see trisomy 7
what are the maternal influences in FGR
decreased placental blood flow is the most common
- preclampsia
- chronic HTN
what are some causes of neonatal respiratory distress syndrome ?
excessive sedation of the mother fetal head injury during delivery aspiration of blood or amniotic fluid intrauterine hypoxia brought about by coiling of the umbilical cord about the neck hyaline membrane disease
hyaline membrane disease
deposition of a layer of hyaline proteinaceious material in the peripheral airspaces of infants who succumb to this condition
presentation: preterm and AGA male gender maternal diabetes c- section
usually a steady breathing rhythm occurs, but then within 30 minutes breathing becomes difficult and cyanosis may occur
fine rales
ground-glass picture on chest X-ray
etiology and pathogenesis of RDS (neonatal respiratory distress syndrome)
immaturity of the lungs
deficiency in pulmonary surfactant
SP-A and SP-D in surfactant
role in pulmonary host defense and innate immunity
SP-B and SP-C
reduction of surface tension –> less pressure is then required to keep the lungs patent and hence aerated
what produces surfactant
type II alveolar cells
what hormones modulate surfactant synthesis
growth factors–> cortisol, insulin, prolactin, thyroxine and TGF-Beta
intrauterine stress and FGR increase corticosteroid release… what is the signficance of this
this lowers the risk of developing RDS
surfactant synthesis is supressed by the compensatory high blood levels of insulin in infants of diabetic mothers, which counteracts the effects of steroids. this may be why infants with diabetic mothers have higher risk of developing RDS
why does C-section cause increased risk for RDS
b/c labor is known to increase surfactant synthesis
what is the path that leads to formation of hyaline membranes i nthe lungs in RDS
prematurity–> reduced surfactant synthesis, storage and release–> decreased alveolar surfactant
increased alveolar surface tesnion–> atelectasis –> uneven perfusion and hypoventilation
hypoxemia and CO2 retention–> acidosis –> pulmonary vasoconstriction–> pulmonary hypoperfusion –> endothelial and epithelial damage —>
plasma leak into alveoli–> fibrin and necrotic cells (hyaline membrane)
this leads to a increased diffusion gradient
oxygen toxicity causes what two common things
high concentrations of oxygen administered for prolonged periods cause 3 complications
retrolental fibroplasia: eyes
-due to changes in VEGF expression which is induced by hypoxia
bronchopulmonary dysplasia:
associated with disregulation of cytokines causing arrested pulmonary development
-infants with BPD have dysmorphic capillaries and reduced levels of VEGF
necrotizing enterocolitis
PAF- platelet activating factor : causes increasing mucosal permeability by promoting enterocyte apoptosis and compromising intercellular tight junctions
there is a breakdown of mucosal barrier functions and transluminal migration of bacteria occurs
clinical course: bloody stools abdominal distention circulatory collapse gas in the intestinal wall on radiographs
transcervical infections
most bacterial, some viral infection acquired this way
caught by either inhaling infected amniotic fluid in to the lungs shortly before birth or by passing through an infected birth canal
pneumonia, sepsis, and meningitis are the most common sequelae in a fetus infected via this route
transplacental infection (hematologic)
most parasitic, and viral infections and some bacterial gain access to the fetal bloodstream transplacentally via the chorionic villi
parovirus B19- high affinity for erarly erythroid progenitor cells
TORCH group of infections causing: fever, encephalitis choriorteinitis hepatosplenomegaly pneumonitis myocarditis hemolytic anemia vesicular or hemorrhagic skin lesions
early onset sepsis
within the first 7 days of life
result in clincial signs and symtpoms of pneumonia, sepsis, meningitis
Group B streptococcus is the most common organism isolated in early-onset sepsis and is the most common cause of bacterial meningitis
late-onset sepsis
from 7 days to 3 months
listeria and candida
what is fetal hydrops
accumulation of edema fluid in the fetus during intrauterine growth
commonly caused by rh fetal incompatibility
immune hydrops
hemolytic disease caused by blood group incompatibilty b/w mother and fetus
caused when the mother is exposed to fetal red cells and the mother thus becomes sensitized to the foreign antigen
the D antigen is a major cause of Rh incompatibility
the initial exposure to Rh antigen evokes the formation of IgM antibodies, so Rh disease is uncommon with the first pregnancy
exposure during a second pregnancy generally leads to braisk IgG antibody response and the risk of immune hydrops
what are the consequences of excessive destruction of red cells in the neonate ?
anemia:
can result in hypoxic injury to the heart and liver
if there is liver damage–> there is decreased plasma protein synthesis
cardiac hypoxia may lead to cardiac decompensation and failure
*** the combination of reduced plasma oncotic pressure and increased hydrostatic pressure in the circulation secondary to cardiac failure results in edema and anasarca–> hydrops fetalis
jaundice:
hemolysis produces unconjugated bilirubin
can result in kernicterus b/c bilirubin can cross the BBB and bind to lipids in the brain
what are the 3 main causes of nonimmune hydrops
cardiovascular defects
chromosomal anomalies
- -45,X (turner) –> abnormalities of lymphatic drainage from the neck may lead to postnuchal fluid accumulation (**Cystic hygroma)
- -trisomy 21 and 18
fetal anemia:
-alpha-thalassemia
how does the parvovirus B19 cause nonimmune hydrops
it enters into erythroid precursors
leads to apoptosis of red cells progenitors and isolated red cells aplasia
what is the clinical presentation of hydrops fetalis
treatment?
minor cases:
pallor
hepatosplenomegaly
grave cases:
intense jaundice
generalized edema
neurological involvement
treatment:
phototherapy (toxic unconjugated bilirubin converted to readily excreted water soluble dipyrroles)
exchange transfusion
PKU (phenyketonuria)
abnormalities in pheylalanine metabolism
autosomal recessive
mutation in the gene encoding the enzyme phenylalanine hydroxylase (PAH)
inability to convert phenylalanine into tyrosine
without PAH there is excess metabolites (pheylpyruvic acid) these are excreted in the urine and have a “mousy” odor
what is the clinical presentation of PKU
at birth they are normal but after a few weeks they develop a rising plasma phenylalanine level . this can affect brain development
by 6 months severe mental retardation can become apparent
seizures
decreased pigment of hair and skin
eczema
Galactosemia mechanism
autosomal recessive
normally lactose is split into glucose and galactose in the intestine by lactase
galactose is then converted to glucose in 3 steps
Mechanism:
1) total lack of galactose 1 phosphate uridy trasnferase (GALT) involved in rxn 2
2) the other variant (less common) arises from deficiency of galactokinase, involved in reaction 1
Galactose1phosphate accumulates in the liver, spleen, lens of the eye, kidneys, heart, cerebral cortex, erythrocytes
what is the clinical presentation of galactosemia
Hepatomegaly–> due to fatty chagne, cirrhosis may develop later
Opacification of the lens (cataracts)
Nonspecific alterations appear in the CNS- loss of nerve cells, gliosis, edema
Failure to thrive
Vomiting and diarrhea appear within a few days of milk ingestion
jaundice and hepatomegaly
aminoaciduria
increased e.coli b/c of depressed neutrophil bactericidal activity
Hemolysis and coagulopathy occur too
how can you diagnose galactosemia
presence of a reducing sugar other than glucose in the urine
Assay of GALT activity in cultured amniotic cells
Mutations in GALT:
glutamine to arginine substitution at codon 188 in non-hispanic whites
serine-to-leucine substitution at codon 135 is most common in African americans
how can galactosemia be treated
removal of galactose from the diet in the first 2 years of life especially
cystic fibrosis
what is it
disorder of ion transport in epithelial cells that affects fluid secretion in exocrine glands and the epithelial lining of the respiratory, gastrointestinal and reproductive tracts
abnormal function of an epithelial chloride channel protein encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q
viscous secretions
autosomal recessive
what are the clincal features of cystic fibrosis
chronic lung disease secondary to recurrent infections pancreatic insufficiency steatorrhea malnutrition hepatic cirrhosis intestinal obstruction male infertility
what is the relationship of CFTR and the ENaC
CFTR regulates this epithelial sodium channel
the ENaC is on the apical surface of exocrine epithelial cells and is respsonsible for sodium uptake from luminal fluid, rendering the luminal fluid hypotonic
the ENaC is normally inhibited by CFTR, thus is cystic fibrosis ENaC activity increases and sodium uptake increases across the apical membrane
EXCEPTION–> in sweat ducts ENaC activity is decreased by CFTR mutation and therefor a hypertonic luminal fluid containing both high sweat chloride and high sodium cotnent is formed “Salty sweat” in infants
what is the major function of CFTR in the sweat glands
reabsorb luminal chloride ions and augment sodium reabsorption via the ENaC
loss of CFTR leads to decreased reabsorption of sodium chloride and production of hypertonic sweat
what happens with CFTR defect in the respiraotyr and intestinal epithelium
CFTR is normally important for the active luminal secretion of chloride
at these sites, a loss of CFTR results in reduction of chloride secretion in the lumen
this causes increased passive water reabsorption from the lumen, lowering the water content of the surface fluid layer coating mucosal cells
-create an isotonic but low-volume surface fluid layer
leads to defective ciliary action and the accumulation of hyperconcentrated viscid secretions that obstruct the air passages
CFTR and bicarbonate ions?
SLC26 are anion exchangers co-expressed on the apical surface with CFTR
mutants of CFTR have decreased bicarb secretion –> leading to acidic secretions
increased acidity –> increased mucine precipitation and plugging of the ducts and increased binding of bacteria to plugged mucins
class I CFTR gene defect
defective protein synthesis
lack of CFTR on the surface
Class II CFTR mutant
abnormal protein folding, procesing and trafficking
lack of CFTR on surface
class III CFTR mutant
defective regulation
present on the surface but nonfunctional
Class IV CFTR
decreased conductance
normal CFTR amount but reduced in function
mild
class V CFTR
reduced abundance
mild
class VI CFTR mutations
altered regulation of separate ion channels
alginate?
a mucoid polysachardie capsule
this is produced when there is static mucus that creates a hypoxic environment in the airway surface fluid
this permits the formation of a biofilm that protects bacteria from antibodies and antibiotics -> chronic obstructive lung disease
classic fibrosis morphology
atrophy of the exocrine glands and fibrosis of pancreas
meconium ileus- small bowel obstruction
steatosis of liver
focal biliary cirrhosis
bronchioles show hyperplasia and hypertrophy of mucus secreting cells
staphylococcus aureus, hemophilus influenza and pseudomonas aeruginosa are the three most common organisms
azoospermia and infertility
congenital bilateral absence of the vas deferens
what are the clinical features of cystic fibrosis
exocrine pancreatic insufficiency
- protein and fat malabsorption
- avitaminosis
- hypoproteinemia may cause edema
Cardiorespiratory complications:
- harbor P.aeruginosa
- nasal polyps
- clubbing
- chronic cough and sputum production
GI and nutritional abnormalities:
Intestine–> meconium ileus,obstruction
hepatic–> chronic hepatic disease with cirrhosis, prolonged neonatal juandice
nutritional- failure to thrive
Salt-loss syndromes:
-chronic metabolic alkalosis
Mal urogenital abnormalities:
congenital bilateral absence of vas deferens
what are the criteria for diagnosis of cystic fibrosis
one or more characteristic phenotype features
OR a history of cystic fibrosis in a sibling
OR a positive newborn screening test result
AND
An increased sweat chloride concentration on two or more occasions
OR identification of two cystic fibrosis mutations
OR demonstration of abnormal epithelial nasal ion transport
how is cystic fibrosis managed
antimicrobial therapies
pancreatic enzyme replacement
bilateral lung tranpslantation
gene therapy
what is sudden infant death syndrome
it is sudden death due to something unknown! even after autopsy
see the other flashcard set (CIS) for the rest of SIDS info)
what are the environmental risk factors associated with SIDS
prone or side sleep position
sleeping on a soft surface
hyperthermia
co-sleeping in first 3 months of life
what are postmortem abnormalities detected in cased of sudden unexpected infant death?
infections
- viral myocarditis
- bronchopneumonia
unsuspected congenital anomaly
- congenital aortic stenosis
- anomalous origin of the left coronary artery from the pulmonary artery
traumatic child abuse
-intentional suffocation
genetic and metabolic defects -long QT syndrome fatty acid oxidation disorders histiocytoid cardiomyopathy abnormal inflammatory responsiveness
what is an ALTE
apparent life threatening event
characterized by some combination of apnea, marked change of color or muscle tone, choking or gagging
it has differnet risk factors and age of onset compared to infants with SIDS
often premature
what is the morphology of SIDS
multiple petechiae are the most common findings
-on the thymus, visceral and parietal pleura, epicardium
Lungs are congested and vascular engorgement with or without pulmonary edema is demonstratable
CNS:
astrogliosis of the brainstem and cerebellum
-hypoplasia of the arcuate nucleus
hepatic extramedullary hematopoiesis and periadrenal brown fat
what is the delayed development of arousal and cardiorespiratory control
the infant who dies of SIDS may have problems with arousal response to environmental stressors
in what position should a baby sleep
supine
heterotopia (or choristoma)
microscopically normal cells or tissues that are present in abnormal locations 1
hamartoma
excessive, focal overgrowth of cells and tissues native to the organ in which it occurs
the cellular elements are mature and identical to those found in the reaminder of the organ, they do not reproduced the normal architecture of the surroundingtissue
what are the most common neoplasms of childhood
soft-tissue tumors of mesenchymal derivation
in adults the most common tumors are of epithelial origin
hemangioma
most common tumor of infancy **
both cavernous and capillary hemangiomas may be encountered
most are located on the skin (face and scalp) where they produce flat to elevated, irregular, red-blue masses
port-wine stains–> large lesions
usually they spontaneously regress
can represent one facet of the Von Hippel Lindau disease
lymphatic tumors
lymphangiomas-> cystic and cavernous space
may occur in the skin but are more often encountered in the deeper regions of the neck, axilla, mediastinum, retroperitoneal tissue and elsewhere.
increase in size after birth
lymphangiectasis–> diffuse swelling of part or all of an extremity; considerable distortion and deformation may occur as a consequence of the spongy, dilated subcutaneous and deeper lymphatics l
lesion is not progressive
fibromatosis
sparsely cellular proliferations of spindle-shaped cells
congenital-infantile fibrosarcomas
richly cellular lesions indistinguishable from fibrosarcomas occurring in adults
chromosomal translocation: t(12;15) –> results in generation of ETV6-NTRK3 fusion transcript (NTRK3 is also known as TRKC) and is a tyrosine kinase which is constitutively active in this disease –> stimulates signaling through RAS and PI-3K/AKT pathways
what is the ETV6-NTRK3 fusion transcript a marker for?
the soft-tissue tumor unique to fibrosarcomas and is useful as a diagnostic marker
mature teratoma
benign well differentiated
immature teratoma
indeterminate potential
teratomas
peaks of incidence (2)
first peak of incidence–> 2 year of age
-typically congenital neoplasms
2nd –> late adolescence or early adulthood
-prenantal origin
what are the most common teratomas of childhood?
sacrococcygeal teratoma
four times more common in girls
associated with congenital anomalies
most of these are mature
NOTE: most benign teratomas are encountered in younger infants (<4 months) whereas children with malignant lesions tend to be somewhat older
what are the 8 common malignant neoplasms of infancy and childhood from 0-4 years
leukemia retinoblastoma neuroblastoma Wilms tumor hepatoblastoma soft-tissue sarcoma (especially rhabdomyosarcoma) teratomas CNS tumors
what are the common malignant neoplasms from 5-9 yeras
leukemia retinoblastoma neuroblastoma hepatocellular carcinoma soft-tissue sarcoma central nervous system tumors ewing sarcoma lymphoma
what are the common malignant neoplasms from 10-14 years of age …
hepatocellular carcinoma soft-tissue sarcoma osteogenic sarcoma thyroid carcinoma hodgkin disease
compare the most common sites of tumor development in infants and adults
children:
hematopoietic system
nervous tissue
what are neuroblastic tumors
tumors of sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells
characteristics:
spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements, spontaneous tumor regression, and a wide range of clinical behavior and prognosis
neuroblastoma
most common extracranial solid tumor and the most frequently diagnosed tumor of infancy
median age at diagnosis is 18 months
germline mutations in ALK gene are a cause of familial predisposition to neuroblastoma
children under 18 months of age tend to have a signifiacntly better prognosis than older individuals
what is the morphology of neuroblastoma?
Childhood:
40 % arise in the adrenal medulla
Paravertebral region of the abdomen (25%)
Posterior mediastinum (15%)
stage 1 of neuroblastoma
localized tumor with complete gross excision with or without microscopic residual disease
representative ipsilateral nonadherent lymph nodes negative for tumor
stage 2A
localized tumor with incomplete gross resection
representative ipsilateral nonadherent lymph nodes negative for tumor microscopically
stage 2B
localized tumor with or without complete gross excision
ipsilateral nonadherenet lymph nodes positive for tumor
enlarged contralateral lymph nodes which are negative for tumor
stage 3
unresectable unilteral tumor infiltrating across the midline with or without regional lymph node involvment or localized unilateral tumor with contralateral regional lymph node involvement
stage 4
any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs
stage 4S
S = special
localized primary tumor with dissemination limited to skin, liver, bone marrow
LIMITED TO infants younger than 1 year of age!!
what stages of neuroblastoma are favorable/unfavorable
favor–> 1, 2A, 2B, 4S
unfavor–> 3, 4
NOTE most children present with stage 3 or 4 (60-80%)
age favorable in neuroblastoma
less than 18 months is FAVORABLE
age > 18 months is not favorable
N-myc status in prognosis of neuroblastomas
favorable –> not amplified
not favorable–> amplified
if there is N-Myc amplification, it bumps the tumor into a high risk category irrespective of age, stage or histology
is TRKA expression favorable or not?
FAVORABLE if it is present
TRKB expression in neuroblastoma?
not favorable
chromosome 17q gain
chromosome 1 p loss
chromosome 11q loss
all absent in favorable prognosis of neuroblastoma
telomerase expression in neuroblastoma prognosis?
low or absent is FAVORABLE
highly expressed is NOT favorable
is evidence of schwannian stroma and gangliocytic differenation favorable or not in neuroblastomas?
favorable !
what is the presentation of neuroblastoma ?
in young children under 2 presents with large abdominal masses, fever, weight loss
older children- may not present until they have metastasized –> bone pain, respiratory symptoms, GI complaints
Proptosis
blueberry muffin baby - deep blue discoloration of the skin with cutaneous metastases
90% of neuroblastomas produce catecholamines –> can have elevated levels of VMA and HVA
age and stage are the most important determinants of outcome ….
stages 1,2A or 2B are excellent prognosis
ploidy in neuroblastoma diagnosis/prognosis?
correlates with outcome in children less than 2 years of age but loses its independent prognostic significance in older children
near-diploid–>
hyper-diploid–> better prognosis
have defect in the underlying mitotic machinery leading to chromosomal nondisjunction and near-triploidy
Wilms tumor
most common primary renal tumor of childhood
the risk of wilms tumor is increased in association with at least four recognizable groups of congenital malformations associated with distinct chromosomal loci.
WAGR syndrome
aniridia
genital anomalies
mental retardation
and 33% chance of developing wilms tumor
carry deletions of 11p13
These patients have:
WT1 - wilms tumor associated gene
PAX6- deleted autosomal dominant gene for aniridia
typically the first hit is a deletion of 1 WT1 allele
the second hit is the deletion of the 2nd WT1 allele and the subsequent development of Wilms tumor
what is the phenotype of a patient with a deletion restricted to PAX6 with normal WT1 function?
develop sporadic aniridia but they are NOT at increased risk for Wilms tumors
Denys-Drash syndrome
gonadal dysgenesis (male pseudohermaphorditism) and early onset nephropathy leading to renal failure
the characteristic glomerular lesion in these patients is a diffuse mesangial sclerosis
These patients have abnormalities in WT1
HOWEVER, it is different than WAGR in that it is a dominant-NEGATIVE- missense mutation in the zinc-finger region of WT1 that affects its DNA-binding properties
the mutation interferes with the function of the remaining wild-type allele, and is sufficient in only causing genitourinary abnormalities but NOT tumorigenesis
wilms tumors in denys drash syndrome demonstrate bi-allelic inactivation of WT1
also at increased risk for developing gonadoblastomas
What does WT1 encode for
a DNA binding transcription factor that is expressed in several tissues including the kidney and gonads
the WT1 protein is critical for normal renal and gonadal development
Beckwith-Wiedemann Syndrome (BWS)
role of IGF2?
role of CDKN1C
these children have increased risk of developing WIlm’s tumor
this disease is characterized by enlargement of body organs
macroglossia
hemihypertrophy
omphalocele
abnormal large cells in the adrenal cortex
Patients with BWS are also at increased risk for hepatoblastoma, pancreatoblastoma, adrenocrotical tumors, rhabdomyosarcomas
BWS is a case of genomic imprinting
the chromosomal region implicated in this disease is WT2- this region contains multiple genes that are normally expressed from only one of the two parental alleles, with transcriptional silencing (imprinting) of the other
IGF2 (insuline like growth factor 2) is expressed in this region, solely from the PATERNAL allele –> in some Wilm’s tumors loss of imprinting (expression of the maternal IGF2) leads to overexpression of IGF2 protein
Sometimes there is selective deletion of the maternal allele, combined with duplication of the transcriptionally activie paternal allele (uniparental paternal disomy) –> overexpression of IGF2
IGF2 overexpression can lead to overgrowth and imprinting abnoramlities in IGF2 have the strongest releationship to tumor predisoposition in BWS
Mutations of the CDKN1C (cell cycle regulator) in BWS (aka p57 or KIP2)–> lower risk for developing Wilms tumor
what is the role of B-catenin in WIlms tumors
B-catenin belongs to the developmentally important WNT signaling pathway
Gain-of-function mutations of the gene encoding Bcatenin are elucidated in 10% of sporadic Wilms tumors
what are nephrogenic rests
putative precrusor lesions of WIlms tumors and are seen in the renal parenchyma adjacent to approximately 25% to 40% of unilateral tumors and neearly 100% in bilateral WIlms tumors
appearance:
varies from an expansile mass that resembles Wilms tumors to sclerotic rests consisting of predominantly fibrous tissue and occasional admixed immature tubules or glomeruli
if a person has a resected kidney with nephrogenic rests then they are at increased risk of devloping wilms tumors in the contralteral kidney
what is the morphology of Wilms tumor
large, solitary, well circumscribed mass
soft, homogenous, tan to gray with occassional foci of hemorhage, cyst formation, and necrosis
blastemal component:
sheets of small blue cells with few distinctive features
5% of tumors reveal anaplasia –> correlates with p53 mutations (loss of p53 means there is loss of a pro-apoptotic signal)
what are the clinical feature of wilms tumor?
large abdominal mass unilateral or very large and extending across midline or down into the pelvis
hematuria, pain in the abdomen, intestinal obstruction and appearance of HTN
pulmonary metastases
Although there is increased survival of individuals with Wilms tumor, there is increased risk of developing secondary tumors–> breast, leukemia, lymphoma.
