1. Organ Specific Anomalies
Agenesis: complete absence of an organ
Atresia: absence of an opening
Hypoplasia: incomplete development or under- development of an organ with decreased numbers of cells
Hyperplasia: overdevelopment of an organ associated with increased numbers of cells
Hypertrophy: increase in size with no change in number of cells
Dysplasia:) describes an abnormal organization of cells
NOTE the pediatric definition and examples of dysplasia are DIFFERENT from the pre-neoplastic definitions we learned about many time previously.

2. Embryonic Development
Embryonic period
weeks 1- 8 of pregnancy
organogenesis occurs in this period
Fetal period
weeks 9 to 38
marked by further growth and maturation
You can’t call a fertilized ovum an embryo until about ONE WEEK post-fertilization.
And after 8 weeks, you have to call it a FETUS.

3. Perinatal Infection Transcervical (ascending)
inhalation of infected amniotic fluid
pneumonia, sepsis, meningitis
commonly occurs with PROM—premature rupture memb.
passage through infected birth canal
herpes virus– caesarian section for active herpes
Transplacental (hematogenous)
mostly viral and parasitic
HIV—at delivery with maternal to fetal transfusion
bacterial
Listeria monocytogenes
During childbirth, the infant is exposed to maternal blood and body fluids without the placental barrier intervening and to the maternal genital tract. Because of this, microorganism transmitted by blood (Hepatitis B, HIV), organisms associated with sexually transmitted disease (Neisseria gonorrhoeae and Chlamydia trachomatis), and normal flora of the genito-urinary tract are among those commonly seen in infection of the newborn.

4. Inborn Errors of Metabolism (Genetic)
PhenylKetonUria (PKU)
Galactosemia
Cystic Fibrosis (CF) (Mucoviscidosis)
As we learned in genetics chapter, almost ALL IEM diseases are autosomal recessive. Recall the differences between AR and AD diseases, from a pedigree and clinical point of view.

5. PHENYLKETONURIA (PKU)
Ethnic distribution
common in persons of Scandinavian descent
uncommon in persons of African-American and Jewish descent
Autosomal recessive
Phenylalanine hydroxylase deficiency leads to hyperphenylalaninemia, brain damage, and mental retardation
Phenylalanine metabolites are excreted in the urine
Treatment is phenylalanine restriction
Variant forms exist

6. Cystic Fibrosis (Mucoviscidosis)
Autosomal recessive
Most common lethal genetic disease affecting Caucasians
2-4% of population are carriers
Uncommon in Asians and African-Americans
Widespread disorder in (epithelial chloride transport) affecting fluid secretion in exocrine glands
epithelial lining of the respiratory, gastrointestinal, and reproductive tracts
Abnormally viscid mucus secretions

7. Etiology & pathogenesis:
The primary defect is in the regulation of epithelial chloride transport by a--- chloride channel protein--- encoded by the cystic fibrosis gene.
The impact of this defect in chloride transport differs in various tissue example:
In sweat gland ducts it leads to decreased reabsorption of sodium chloride from the lumen, thus resulting in increase concentrations of sweat chloride, the basis of clinical diagnosis of CF.

8. Cellular Metabolism Of The Cystic Fibrosis Transmembrane Regulator (CFTR)
Cellular metabolism of the cystic fibrosis transmembrane regulator (CFTR) protein conductance (red). In a normal cell (left), CFTR is synthesized in the rough endoplasmic reticulum (RER), is glycosylated in the Golgi apparatus, and functions as a Cl– channel and regulator of other ion channels when located in the plasma membrane. Two possible outcomes of mutations in the CF gene are shown (right). (1) If a mutation disturbs protein folding, e.g., the F508 mutation, CFTR is degraded intracellularly so that no protein is transported to the plasma membrane. (2) With other mutations, the abnormal protein is processed and trafficks to the plasma membrane but functions abnormally at that site.
Harrison’s Internal Med, 16th Ed

9. In the airway epithelium: there is reduction of chloride secretion into airways. Active sodium absorption is also increase, both of these ions increase water reabsorption from the lumen causing lowering the water content of the mucus material leading to viscid secretions
The cystic fibrosis gene is located on chromosome 7 which encodes chloride channel protein.

10. Pancreatic abnormalities are present in approximately 85 to 90% of patients.
Thick viscid plugs of mucus may also be found in the small intestine of infants. Sometimes these cause small bowel obstruction, known as meconium ileus.
The salivary glands are frequently involved, with histologic changes include progressive dilation of ducts, squamous metaplasia of the lining epithelium, and glandular atrophy followed by fibrosis.

11. In most cases, the diagnosis of cystic fibrosis is based on persistently elevated sweat electrolyte concentrations (often the mother makes the diagnosis because her infant tastes salty) and characteristic clinical findings (gastrointestinal or pulmonary) or a family history
There are new reports suggesting an increased risk of digestive tract cancer in patients with cystic fibrosis. These cancers affect the entire gastrointestinal system, the biliary tract, liver, and pancreas. The pathenogenesis of such cancers is unclear.

12. The pulmonary changes are seen in almost every case and are the most serious complications of this disease. These stem from the viscous mucus secretions of the submucosal glands of the respiratory tree with secondary obstruction and infection of the air passages.
obstruction of the epididymis and vas deferens, which is responsible for azoospermia and infertility in 95% of the males who survive to adulthood.

13. Organ Pathology
Plugging of ducts with viscous mucus and loss of ciliary function of respiratory mucosa
Pancreas
atrophy of exocrine pancreas with fibrosis
islets are not affected
Liver
plugging of bile canaliculi with portal inflamation
biliary cirrhosis may develop
Genitalia
Absence of vas deferens and azoospermia
Sweat glands
normal histology

14. Pancreas in Cystic Fibrosis
Pancreas in Cystic Fibrosis. Note that the ducts contain inspisated material and the acini are atrophic and the stroma exhibits fibrosis and chronic inflamation. The islets are preserved.

15. Neonatal Respiratory Distress Syndrome (RDS)
Incidence is inversely proportional to gestational age
The cause is lung immaturity with decreased alveolar surfactant
surfactant decreases surface tension
first breath is the hardest since lungs must be expanded
without surfactant, lungs collapse with each breath
RDS also previously referred to as HMB (Hyaline Membrane Disease)

16. RDS Risk Factors 1) Prematurity 2) Maternal diabetes mellitus
by far the greatest risk factor
affected infants are nearly always premature
2) Maternal diabetes mellitus
insulin suppresses surfactant secretion
3) Cesarean delivery
normal delivery process stimulates surfactant secretion

17. RDS Pathology Gross Microscopic solid and airless (no crepitance)
sink in water
appearance is similar to liver tissue*
Microscopic
atelectasis and dilation of alveoli
hyaline membranes composed of fibrin and cell debris line alveoli .
minimal inflammation
Also remember that the term “hepatization” is a term used to describe the “consolidation” or loos of crepitance in the adult lungs during pneumonia also.

19. “Hyaline “ membranes are proteins, e.g., fibrin, and dead calls

20. Necrotizing Enterocolitis
Incidence is inversely proportional to gestational age
approaches 10% with severe prematurity
Pathogenesis
not fully understood
intestinal ischemia
inflammatory mediators
breakdown of mucosal barrier

21. Necrotizing Enterocolitis
Figure Necrotizing enterocolitis. A, Postmortem examination in a severe case of NEC shows the entire small bowel is markedly distended with a perilously thin wall (usually this implies impending perforation). B, The congested portion of the ileum corresponds to areas of hemorrhagic infarction and transmural necrosis microscopically. Submucosal gas bubbles (pneumatosis intestinalis) can be seen in several areas (arrows), caused by gas forming bacteria.

22. Sudden Infant Death Syndrome
Definition
sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history
Also called crib death
If a disease is defined as ABSENCE of etiologies, then it is understandable that it would be ridiculous to ask, “What is the etiology of SIDS?”

23. TUMORS
Benign
Malignant

24. BENIGN Hemangiomas Lymphatic Tumors Fibrous Tumors
Teratomas (also can be malignant)

25. Congenital Capillary Hemangioma
Figure Congenital capillary hemangioma at birth (A) and at age 2 years (B) after spontaneous regression. (Courtesy of Dr. Eduardo Yunis, Children's Hospital of Pittsburgh, Pittsburgh, PA.)
At 2 years
After spontaneous regression
At birth

26. Teratomas
Composed of cells derived from more than one germ layer, usually all three
Sacrococcygeal teratomas
most common childhood teratoma
frequency 1:20,000 to 1:40,000 live births
4 times more common in boys than girls
Approximately 12% are malignant
often composed of immature tissue
occur in older children

27. Sacrococcygeal Teratoma
Figure Sacrococcygeal teratoma. Note the size of the lesion compared with that of the infant.

28. Malignant Tumors The main differences are:
Cancers of infancy and childhood differ biologically and histologically from their counterparts occurring later in life.
The main differences are:
Incidence and type of tumor
Prevalence of underlying familial or genetic aberrations
Tendency of fetal and neonatal malignancies to regress spontaneously or cytodifferentiate
Improved survival or cure of many childhood tumors,

29. INCIDENCE AND TYPES
The most frequent childhood cancers arise in the hematopoietic system (leukemia & lymphoma), nervous tissue (including the central and sympathetic nervous system, adrenal medulla, and retina), soft tissues, bone, and kidney.
Histologically, many of the malignant pediatric neoplasms are unique. In general, they tend to have a more primitive (embryonal)
These tumors are frequently designated by the suffix -blastoma, for example, nephroblastoma (Wilms' tumor), hepatoblastoma, and neuroblastoma.

30. Neuroblastomas Second most common malignancy of childhood
Neural crest origin
adrenal gland – 40 %
sympathetic ganglia – 60%
In contrast to retinoblastoma, most are sporadic but familiar forms do occur
Median age at diagnosis is 22 months

31. Neuorblastoma Morphology
Small round blue cell tumor
neuorpil formation
rosette formation
immunochemistry – neuron specific enolase
EM – secretory granules (catecholamine)
Usual features of anaplasia
high mitotic rate is unfavorable
evidence of Schwann cell or ganglion differentiation favorable
Other prognostic predictors are used by pathologists and oncologists

32. Neuorblastoma ** * *Neuropil **Homer-Wright Rosettes
You MUST remember:
What a ROSETTE looks like
The fact that they are CLASSICALLY the hallmarks of neuroblastomas
*Neuropil **Homer-Wright Rosettes

33. Clinical Course and Prognosis
Hematogenous and lymphatic metastases to liver, lungs and bone
90% produce catecholamines, but hypertension is uncommon
Age and stage are most important prognostically
< 1 year age: good prognosis regardless of stage
Amplification of N-myc oncogene
present in 25-30% of cases and is unfavorable
up to 300 copies on N-myc has been observed
Risk Stratification
low risk: 90% cure rate
high risk 20% cure rate
A wide variety of expensive genetic and other tests can be done to help put neuroblastoma patients into risk rates.