Pediatric PathologyDan Lodge-Rigal, MD

Outline

Pathology of Intrauterine Growth and Development

Intrauterine Growth RestrictionProblems of ImmaturityCongenital Malformations and Teratogenesis

Pathology of the Neonate

Respiratory Distress SyndromeHydrops and Hemolytic Disease of the Newborn

Metabolic and Genetic Disorders

Cystic FibrosisPhenylketonuriaGalactosemia

Sudden Infant Death Syndrome

Pediatric Neoplasia

Reading: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.504

Online case: Young girl with a cough, case 20 on both the website and disc.

Disorders of Intrauterine Development

Disorders of Growth and Maturation

Assessing intrauterine growth and development:

Correlation of Birth Weight with Gestational Age

Intrauterine Growth Restriction (IUGR)

Etiology :

Fetal

Placental

Maternal factors

symmetric versus asymmetric IUGR

Complications of Immaturity Specific Organ Systems:

Lungs:

Brain:

Liver:

Abnormalities of Form: “Birth Defects”

Incidence

Clarification of concepts: Congenital Malformations (anomalies)

Malformations

Deformations

Disruptions

Malformation Sequences and Syndromes

Potter’s Sequence

Etiologic Factors and Teratogenesis

Causes of Congenital Malformations:

Genetic

Environmental

Multifactorial

Unknown

Importance of Timing and Targets

Molecular Events:

Birth Injuries

Risk factors:

Common injuries:

Perinatal Infections

Ascending infection:

Hematogenous (trans-placental) infection:

Respiratory Distress of the Newborn

Lung Development and Maturation

Surfactant: Lecithin and Sphingomyelin

Factors effecting surfactant maturation weeks gestation

Respiratory Distress SyndromeClinical Featuresrespiratory distress: tachypnea, grunting respirations

hypoxemia, cyanosis

diffuse granular infiltrates on CXR

risk factors: prematurity, maternal diabetes, cesaerean section

Pathogenesis

surfactant deficiency

hypoxemia

Pathologic Features

Gross:

heavy lungs (don’t float)

Microscopic:

hyaline membranes in distal airspaceslater: organization and fibrosis

Sequelae of RDS

1)

2)

3)

Consequences of therapy:

1)

2)

Fetal Hydrops

Definition:

Causes

Immune 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 integrity

Pathology:

Generalized edema: Hepatomegaly

Pathology of underlying disorder. i.e. TORCH infection, parvovirus

Hemolytic Disease of the Newborn

Etiology: maternal/fetal blood antigen incompatibility (Rh, ABO, other)

Pathogenesis: sensitization and antibody production

Immune hemolysis

Anemia and hyperbilirubinemia of fetus and newborn

sequelae:Cardiac failure and hydropsKernicterus

Interventions

Prevention:

Rh-immunoglobulin (RhoGam) to PREVENT SENSITIZATION

Monitoring hemolysis: amniocentesis and cord blood sampling bilirubin in the amniotic fluid: change in optical density (OD)

Selected Metabolic Diseases

Phenylketonuria

Definition and Incidence

Pathogenesis

Diagnosis and Screening

Treatment

Galactosemia

Definition and Incidence

Pathogenesis

Diagnosis and Screening

Treatment

Cystic Fibrosis

Definition:

Incidence:

Pathogenesis:

Defect in membrane chloride channel protein Cystic Fibrosis Transmembrane Regulator Protein or CFTR

Effects of abnormal CFTR

Damage to gland parenchyma (pancreas, salivary epithelium, bile ducts)and airway obstruction and inflammation

Chronic respiratory infection: pseudomonas auruginosa (mucoid) Burkholderia cepacia

Sequelae of chronic lung disease: 1)

2)

Genetics of Cystic Fibrosis

CFTR gene located on long arm of Chromosome 7

most common mutation involves phenylalanine codon at position 508 (delta 508)other mutations documented, can have variable phenotypic expression

Pathologic Features:

Lungs:

Pancreas:

Liver:

GI:

Other

Diagnosis and Clinical Course:

Median survival: 36 years, death from infection, respiratory failure

Treatment:

Sudden Infant Death Syndrome

Definition

The 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 HISTORY

Incidence and Epidemiology

8000 deaths/year in US attributed to SIDS; most common cause of postnatal mortality

Most cases occur in infants 2-4 months of age

Prematurity is strongly correlated

Most cases occur during sleep, but some cases are witnessed

Variety of “risk factors” described involving features of the mother, home environment, prior family history of SIDS

per 1000 live births

Pathologic Features

The crucial finding is an ABSENCE of a potentially LETHAL abnormality

Common findings in SIDS include:

pleural/pericardial petechiaeastrogliosis of brainstempersistent hepatic hematopoiesis

Theories of Pathogenesis

cardiovascular abnormality (conduction system)

neuroendocrine immaturity

metabolic abnormality

sleeping position: prone vs supine “smothering”

Pediatric Neoplasia

Pediatric versus Adult Tumors

most common pediatric neoplasms involve the hematopoietic system

some pediatric tumors associated with abnormal development

spontaneous regression

familial tendency, genetic basis

Benign Tumors

Hemangioma

Lymphangioma

Teratomas

Malignant Neoplasms

Neuroblastoma

Cell of origin:

Common sites: adrenal medulla (25-30%)sympathetic chainbrain

Gross: variably sized, hemorrhagic tumors

Microscopic: primitive small cells with high N/C ratio, mitosespseudorosettes+/- neuronal differentiationmay show differentiation into benign neoplasm, or regression

Cytogenetics: deletion of short arm of chromosome 1 (del 1)associated with poor prognosis

Oncogene: 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

Retinoblastoma

Cell of origin: Age of onset: Site: orbit, solitary vs bilateral/multifocalInherited form: 6-10% are familial (most bilateral)

Gross: nodular retinal massoccasional extraocular spread, metastasis

Micro: small primitive cell, high N/C ratiohemorrhage and necrosis commonrosette formation

Genetic abnormality:

Retinoblastoma gene (Rb) on long arm of 13

Other clinical features:1)2)3)

Wilms Tumor

Cell 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-1

Beckwith- Wiedemann Syndrome: organomegalyhemihypertrophyrenal cystadrenal cytomegalygenetic abnormality involving 11p15.5 (WT-2)

Gross:Large fleshy mass in kidney

___ % bilateral

Micro:3 elements:

1)2)3)

Clinical presentation:

1)2)

Treatment

Other Solid Tumors

Concept of “Small Round Blue Cell Tumors of Childhood”

PEDIATRIC PATHOLOGY

For 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?