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Pediatric PathologyDan Lodge-Rigal, MD OutlinePathology of Intrauterine Growth and DevelopmentIntrauterine Growth RestrictionProblems of ImmaturityCongenital Malformations and TeratogenesisPathology of the NeonateRespiratory Distress SyndromeHydrops and Hemolytic Disease of the NewbornMetabolic and Genetic DisordersCystic FibrosisPhenylketonuriaGalactosemiaSudden Infant Death SyndromePediatric NeoplasiaReading:Robbins Basic Pathology Chapter 6 , pp 223-228 (metabolic diseases); 245-263 (pediatric diseases)Clinical Lab Source: L/S ratio and PG: pg.346 Phenylalanine: pg.417 Sweat Chloride: pg.504Online case: Young girl with a cough, case 20 on both the website and disc. Disorders of Intrauterine DevelopmentDisorders of Growth and MaturationAssessing intrauterine growth and development: Correlation of Birth Weight with Gestational Age358902015240000Intrauterine Growth Restriction (IUGR)Etiology :FetalPlacentalMaternal factorssymmetric versus asymmetric IUGR3474720762000Complications of Immaturity Specific Organ Systems:Lungs: Brain:Liver:Abnormalities of Form: “Birth Defects”IncidenceClarification of concepts: Congenital Malformations (anomalies)MalformationsDeformationsDisruptions290322012255500Malformation Sequences and SyndromesPotter’s SequenceEtiologic Factors and TeratogenesisCauses of Congenital Malformations:GeneticEnvironmentalMultifactorialUnknownImportance of Timing and Targets197929514986000Molecular Events: Birth InjuriesRisk factors:Common injuries:Perinatal InfectionsAscending infection:Hematogenous (trans-placental) infection:Respiratory Distress of the NewbornLung Development and MaturationSurfactant: Lecithin and Sphingomyelin-685806096000 30175204572000 Factors effecting surfactant maturation weeks gestationRespiratory Distress SyndromeClinical Featuresrespiratory distress: tachypnea, grunting respirationshypoxemia, cyanosisdiffuse granular infiltrates on CXRrisk factors: prematurity, maternal diabetes, cesaerean section381762069342000Pathogenesissurfactant deficiencyhypoxemia Pathologic FeaturesGross: heavy lungs (don’t float)Microscopic: hyaline membranes in distal airspaceslater: organization and fibrosisSequelae of RDS1)2)3)Consequences of therapy: 1)2) Fetal HydropsDefinition:CausesImmune 1)2)3)Non-Immune1)2)3)4)Pathogenesis: EFFLUX of fluid out of vasculature due to some combination of:increased hydrostatic pressuredecreased oncotic pressuredamage to vascular integrityPathology:Generalized edema: HepatomegalyPathology of underlying disorder. i.e. TORCH infection, parvovirusHemolytic Disease of the NewbornEtiology: maternal/fetal blood antigen incompatibility (Rh, ABO, other)Pathogenesis: sensitization and antibody production416052041148000Immune hemolysisAnemia and hyperbilirubinemia of fetus and newbornsequelae:Cardiac failure and hydropsKernicterusInterventionsPrevention:Rh-immunoglobulin (RhoGam) to PREVENT SENSITIZATIONMonitoring hemolysis: amniocentesis and cord blood sampling bilirubin in the amniotic fluid: change in optical density (OD) Selected Metabolic DiseasesPhenylketonuriaDefinition and IncidencePathogenesis146304023749000Diagnosis and ScreeningTreatmentGalactosemiaDefinition and IncidencePathogenesis2743201397000Diagnosis and ScreeningTreatmentCystic FibrosisDefinition:37033205334000Incidence: Pathogenesis:Defect in membrane chloride channel protein Cystic Fibrosis Transmembrane Regulator Protein or CFTR201739511239500Effects of abnormal CFTR18745202349500Damage to gland parenchyma (pancreas, salivary epithelium, bile ducts)and airway obstruction and inflammationChronic respiratory infection: pseudomonas auruginosa (mucoid) Burkholderia cepaciaSequelae of chronic lung disease: 1)2)Genetics of Cystic FibrosisCFTR gene located on long arm of Chromosome 7most common mutation involves phenylalanine codon at position 508 (delta 508)other mutations documented, can have variable phenotypic expressionPathologic Features: Lungs: Pancreas: Liver:GI: OtherDiagnosis and Clinical Course:2743205334000 Median survival: 36 years, death from infection, respiratory failureTreatment: Sudden Infant Death SyndromeDefinitionThe sudden death of an infant under one year of age which remains unexplained after a thorough case investigation including a COMPLETE AUTOPSY, DEATH SCENE INVESTIGATION, and REVIEW OF CLINICAL HISTORYIncidence and Epidemiology8000 deaths/year in US attributed to SIDS; most common cause of postnatal mortalityMost cases occur in infants 2-4 months of agePrematurity is strongly correlatedMost cases occur during sleep, but some cases are witnessedVariety of “risk factors” described involving features of the mother, home environment, prior family history of SIDS 118745000 per 1000 live births2788920-10668000Pathologic FeaturesThe crucial finding is an ABSENCE of a potentially LETHAL abnormalityCommon findings in SIDS include:pleural/pericardial petechiaeastrogliosis of brainstempersistent hepatic hematopoiesisTheories of Pathogenesiscardiovascular abnormality (conduction system)neuroendocrine immaturitymetabolic abnormalitysleeping position: prone vs supine “smothering”Pediatric NeoplasiaPediatric versus Adult Tumorsmost common pediatric neoplasms involve the hematopoietic systemsome pediatric tumors associated with abnormal developmentspontaneous regressionfamilial tendency, genetic basisBenign TumorsHemangioma358902010985500LymphangiomaTeratomasMalignant NeoplasmsNeuroblastomaCell of origin: Common sites: adrenal medulla (25-30%)sympathetic chainbrainGross: variably sized, hemorrhagic tumorsMicroscopic: primitive small cells with high N/C ratio, mitosespseudorosettes+/- neuronal differentiationmay show differentiation into benign neoplasm, or regressionCytogenetics: deletion of short arm of chromosome 1 (del 1)associated with poor prognosisOncogene: n-myc oncogene amplification (double minutes or homogeneously staining regions)Biogenic amine production: urinary HVA, VMAPrognosis:Favorable features:1)2)3)4)5)Unfavorable features:1)2)3)4)5)Treatment RetinoblastomaCell of origin: Age of onset: Site: orbit, solitary vs bilateral/multifocalInherited form: 6-10% are familial (most bilateral)Gross: nodular retinal massoccasional extraocular spread, metastasisMicro: small primitive cell, high N/C ratio29698952222500hemorrhage and necrosis commonrosette formationGenetic abnormality: Retinoblastoma gene (Rb) on long arm of 13Other clinical features:1)2)3)Wilms TumorCell of origin: primitive nephrogenic cellAge of onset: Site: Inherited forms:WAGR syndrome: Wilms tumor, aniridia, genital anomalies, retardationautosomal dominant or sporadic deletion of 11p13 (WT-1)Denys-Drash Syndrome: gonadal dysgenesis, nephropathymajority develop Wilms tumor associated with WT-1Beckwith- Wiedemann Syndrome: organomegalyhemihypertrophyrenal cystadrenal cytomegalygenetic abnormality involving 11p15.5 (WT-2)Gross:Large fleshy mass in kidney___ % bilateral36080701079500Micro:3 elements:1)2)3)Clinical presentation:1)2)TreatmentOther Solid TumorsConcept of “Small Round Blue Cell Tumors of Childhood”PEDIATRIC PATHOLOGYFor All Budding Pediatric PathologistsStudy Questions Fetal Growth and Maturation /Congenital Anomalies1. What are the crucial time periods of development for teratogenesis2. Distinguish Malformation, Deformation, Disruption3. What is the difference between symmetric vs asymmetric growth retardation4. What are the 3 major areas to consider in the causality of intrauterine growth restriction? Give a couple of examples of factors from each area.5. What is a sequence? What are sequelae of the oligohydramnios (Potter) sequence6. How does retinol impact the expression of homeobox genes such as the HOX genes.7. What are the major predisposing factors for Respiratory Distress Syndrome (RDS)8. Describe the pathophysiologic sequence of events in development of hyaline membrane disease9. What are hyaline membranes made of? Why do they form?10. What are 2 complications of RDS? What is 1 potential complication from therapy of RDS?11. Give one example of a clinical symptom/sign in a neonate which would be reflective of underlying organ immaturity (other than RDS)12. What is a Caput Succedaneum?13. Why does Hemolytic Disease of the Newborn typically NOT affect the firstborn child?14. When is RhoGam given? Why?15. What are 3 causes of NON-IMMUNE HYDROPS?16. What is the enzymatic defect in Phenylketonuria (PKU). What are the typical clinical findings?17. What is benign hyperphenylalaninemia (say that 3 times real fast!)? Maternal PKU?18. What is the most common enzymatic defect in galactosemia? What urine test is might be an initial indicator of the disease?19. What organs are involved in galactosemia? 20. Describe the CFTR protein, its function, and the consequences of abnormal CFTR function in sweat glands and in the lungs.21. What organisms are commonly implicated in lung infections in patients with cystic fibrosis (CF)?22. Describe examples of different types of CFTR mutations. What is the most common detected mutation?23. What are the major organs affected by CF other than the lungs? What is congenital absence of the vas deferens?24. In an infant presenting with intestinal obstruction, CF might be in your differential diagnosis. Why?25. What is our current understanding of the etiology of SIDS?26. Why is an autopsy appropriate for every unexpected infant death?27. What are 2 disorders recently found to underly a small number of deaths previously attributed to SIDS?28. Give an example of a pediatric neoplasm, where there appears to be a close link with developmental abnormalities.29. What are some favorable prognostic features in neuroblastoma? Unfavorable?30. What is the most common site for neuroblastoma?31 What is unusual about Stage IVs neuroblastoma?32 What percentage of Wilm’s Tumors are bilateral.?33 Name 2 genetic syndromes associated with Wilm’s tumor.34 True or False: The vast majority of cases of sporadic Wilm’s tumor have mutation in either the WT-1 or WT-2 gene or both.35 What is the most common pediatric malignancy? ................
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