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1

Methods for acquisition of fetal and perinatal infections

-transplacental (hematogenous):most parasitic (toxo), viruses and some bacteria (listeria)
-transcervical (ascending): most bacterial and some viral (e.g. HSV); usually from inhaling infected amniotic fluid before birth or during birth through infected canal; results most often pneumonia, sepsis, meningitis

2

Parvovirus B19 effects during gestation

-spontaneous abortion (particularly in 2nd trimester), stillbirth, hydrops fetalis, and fetal anemia
-virus has tropism for fetal red cells and inclusions can be seen in these cells

3

Outcomes of TORCH infections

-fever, encephalitis, chorioamnionitis, hepatosplenomegaly, hemolytic anemia, hemorrhagic skin lesions
-chronic sequelae may include cataracts, mental retardation, cardiac anomalies, etc

4

Features at autopsy in cases of hydrops

-pale fetus and placenta
-hepatosplenomegaly
-compensatory hyperplasia of erythroid precursors in bone marrow
-extramedullary hematopoeisis (liver, spleen)
-kernicterus: edematous and yellow, especially basal ganglia, thalamus, cerebellum, cord
-may see dysmorphic features if chromosomal abnormality
-may see cardiac malformations

5

Phenylketonuria

-autosomal recessive
-most caused by biallelic mutation of the gene encoding phenylalanine hydroxylase but many mutations with variable effect
-biochemically, unable to convert phenylalanine into tyrosine
-develop progressive mental retardation due to toxic effects of phenylalanine
-effects can be avoided by limiting phenylalanine intake early in life
-women who fail to adhere to the diet have children with profound retardation and microcephaly due to teratogenic effects of phenylalanine

6

Galactosemia

-most cases with severe effects have a lack in galactose-1-phosphate uridyl transferase resulting in galactose-1-phosphate accumulation
-hepatosplenomegaly leading to cirrhosis, cataracts and nonspecific CNS effects but mental retardation not as severe as in PKU
-can be prevented by removed galactose from the diet for the first 2 years of life

7

Pathologic effects of CF

-decreased chloride and increased water and sodium reabsorption in the lung and intestine resulting in a low volume surface fluid layer
-dehydration reduces the function of the mucociliary transport system and causes accumulation of hyperconcentrated secretions
-pancreatic insufficiency results from abnormal bicarbonate transport with decreased luminal pH

8

Different classes of mutations in CF

1. Defective protein synthesis
2. Abnormal protein folding (includes most common deltaF508 mutation)
3. Defective regulation
4. Decreased conductance
5. Decreased abundance
6. Altered regulation of separate ion channels by CFTR

9

Some clinical scenarios with CFTR mutations without cystic fibrosis

-idiopathic chronic pancreatitis
-late onset chronic pulmonary disease
-idiopathic bronchiectasis
-obstructive azoospermia

10

List some special features of tumors in infancy and childhood

-may spontaneously regress or differentiate
-frequent association between abnormal development (teratogenesis) and tumor development
-presence of familial or genetic aberrations
-improved survival with new emphasis on late effects of childhood cancers and/or their treatment
-primitive appearance of many childhood tumors

11

What are neuroblastic tumors derived from?

-primordial neural crest cells at sites such as sympathetic ganglia and adrenal medulla

12

Special features of neuroblastic tumors

-most common extracranial solid tumor of childhood
-spontaneous or therapy-induced regression or differentiation into more mature counterpart

13

Name a gene implicated in familial neuroblastoma?

ALK

14

Distribution of neuroblastomas

Adrenal medulla (40%)
Paravertebral abdomen (25%)
Posterior mediastinum (15%)

15

Histologic features of neuroblastoma

-small round blue cells
-eosinophilic fibrillary material (neuropil)
-Homer-Wright pseudorosettes: cells surround neuropil
-++ mitoses and karryorhexis
-variable numbers of ganglion cells (ganglioneuroblastoma, ganglioneuroma; both of these require Schwannian stroma)
-EM: membrane bound catecholamine secreting granules
-IHC: NSE

16

What are favourable prognostic factors in neuroblastoma?

-low stage
-age <200/5000 cells
-hyperdiploid or near triploid (near diploid is poor prognosis)
-n-myc non amplified
-absence of 11q loss, 17q gain and 1p loss
-incorporated into Shimada classification

17

What are the most important determinants of outcome in neuroblastoma?

Age and stage are most important
NMYC amplifications bump otherwise good prognosis tumors into the high risk category
Ploidy and histology (differentiation) also important

18

Chromosomal aberrations involved in Wilms tumor

1.) WAGR (WT1 and PAX6 on chr 11p13
-Wilms tumor, aniridia (by PAX6), genitourinary anomalies, mental retardation
-mutation is the 1st hit, requires a 2nd hit in WT1 to develop Wilms tumor

2.)Denys-Drash syndrome: dominant negative missense mutation in the zinc finger of WT1 that affects its DNA binding properties
-90% risk of Wilms tumor
-gonadal dysgenesis including gonadoblastomas and early onset renal failure

3.) Beckwith-Wiedemann
-imprinting in chr 11q15 (WT2)
-organomegaly, macroglossia, omphalocele, adrenal cytomegaly

4.) Gain of function mutations in beta-catenin in 10% of sporadic Wilms tumors

19

What are nephrogenic rests?

-putative precursors to wilms tumor, found in many of unilateral and almost all bilateral cases
-document their presence because they may indicate a risk for development of a contralateral tumor

20

Histology of Wilms tumor

-triphasic: blastemal, epithelial and stromal
-5% have anaplasia: large pleomorphic nuclei and atypical mitoses; correlates with p53 mutations and resistance to chemotherapy

21

Prognosis of Wilms tumor

-excellent in most cases with cure expected
-anaplasia correlates with poor prognosis
-certain chromosomal abnormalities may correlate with worse prognosis
-increased risk of a second tumor as a result of therapy in survivors