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Diseases of Infancy & Childhood

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1 Diseases of Infancy & Childhood
Weenies! Not just the same diseases in smaller people, but DIFFERENT and UNIQUE DISEASES!

2 Diseases of Infancy and Childhood
Congenital Anomalies Birth Weight and Gestational Age Birth Injuries Perinatal Infections Respiratory Distress Syndrome (RDS) Necrotizing Enterocolitis Intraventricular Hemorrhage Hydrops Inborn Metabolic/Genetic Errors Sudden Infant Death Syndrome (SIDS) Tumors

SWEDEN 3 INDIA 82 Good relative numbers to remember. One of the greatest numbers to measure a country’s quality of medicine, is infant mortality.

4 Major Time Spans Neonatal period Infancy Age 1 – 4 years (preschool)
first four weeks of life Infancy the first year of life Age 1 – 4 years (preschool) Age 5 – 14 years (school age) Definitions to know well.

UNDER ONE YEAR: CONGENITAL, PREMATURITY/WEIGHT, SIDS 1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS 5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES 15-24 YEARS: ACCIDENTS, HOMICIDE, SUICIDE (NONE ARE “NATURAL” CAUSES) After infancy, ACCIDENTS are the number one cause of children’s mortality. What are the common childhood tumors? Leukemia and brain tumors.

6 The closer to birth, the riskier it is
The closer to birth, the riskier it is! (until teens, when homicides and suicides enter the picture) If you took the “unnatural causes” out of the last age group 15-24, it would be even smaller! 1Rates are expressed per 100,000 population 2Excludes congenital heart disease

7 Congenital Anomalies Definitions Causes Pathogenesis
Remember: In the classic anatomic classifications of diseases, degenerative, inflammatory, neoplastic, “CONGENITAL ANOMALIES” are the HARDEST to fit in. Embryologic errors is the best short definition.

8 Malformations Disruptions Deformations Sequence Syndrome
primary errors of morphogenesis, usually multifactorial e.g. congenital heart defect Disruptions secondary disruptions of previously normal organ or body region e.g. amniotic bands Deformations extrinsic disturbance of development by biomechanical forces e.g. uterine constraint Sequence a pattern of cascade anomalies explained by a single localized initiating event with secondary defects in other organs e.g. Oligohydramnios (Or Potter) Sequence Syndrome a constellation of developmental abnormalities believed to be pathologically related e.g Turner syndrome Know a classic example of each!

9 Polydactyly & syndactyly
Malformations Figure 10-1 Malformations. Human malformations can range in severity from the incidental to the lethal. Polydactyly (one or more extra digits) and syndactyly (fusion of digits), both of which are illustrated in A, have little functional consequence when they occur in isolation. Similarly, cleft lip (B), with or without associated cleft palate, is compatible with life when it occurs as an isolated anomaly; in the present case, however, this child had an underlying malformation syndrome (trisomy 13) and expired because of severe cardiac defects. The stillbirth illustrated in C represents a severe and essentially lethal malformation, where the midface structures are fused or ill-formed; in almost all cases, this degree of external dysmorphogenesis is associated with severe internal anomalies such as maldevelopment of the brain and cardiac defects. Polydactyly & syndactyly Cleft Lip Severe Lethal Malformation

10 Disruption by an amniotic band
Disruption. Disruptions occur in a normally developing organ because of an extrinsic abnormality that interferes with normal morphogenesis. Amniotic bands are a frequent cause of disruptions. In the illustrated example, note the placenta at the right of the diagram and the band of amnion extending from the top portion of the amniotic sac to encircle the leg of the fetus. (Lets click back to our original definition of “Disruption”) Did the hand and foot FORM normally before it was constricted? YES

11 Oligohydramnios (Or Potter) Sequence
Oligohydramnios (decreased amniotic fluid) Renal agenesis Amniotic leak Fetal Compression flattened facies club foot (talipes equinovarus) Pulmonary hypoplasia fetal respiratory motions important for lung development Breech Presentation Note that these differentiations are not always written is stone, e.g., Potter’s Sequence was formerly called Potter’s Syndrome. The term “sequence” implies, one thing leads to another. These events all follow the simple concept of oligohydramnios.

12 The Oligohydramnios “Sequence”
Schematic diagram of the pathogenesis of the oligohydramnios sequence, explaining the LOGIC of the findings. Amnion nodosum are nodules on the fetal surface of the amnion, and is frequently present in oligohydramnios

13 Infant with oligohydramnios sequence
Figure 10-4 Infant with oligohydramnios sequence. Note the flattened facial features and deformed right foot (talipes equinovarus), and nodules on the amnion (amnion nodosum)

14 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: in the context of malformations (versus neoplasia) 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.

15 Implantation and the Survival of Early Pregnancy
Only 50-60% of all conceptions advance beyond 20 weeks Implantation occurs at day 6-7 75% of loses are implantation failures and are not recognized Pregnancy loss after implantation is 25-40% Do most losses occur around fertilization/implantation time? YES NEJM 2001; 345:

16 Why would the term “WITHOUT CNS deformity” be used?
Which SYSTEM had the highest incidence of congenital anomalies, mostly, minor? Answer: GU

17 #1 #2 #3 What famous sports figure overcame her club foot to the maximum degree? Ans: Kristi Yamaguchi, gold medal 1992, figure skating

18 Unknown CAUSES OF ANOMALIES Genetic Environmental Multifactorial
karyotypic aberrations single gene mutations Environmental infection maternal disease drugs and chemicals irradiation Multifactorial Unknown Why is the last item on this list in the BIGGEST font? Ans: Because it is the majority of the cases. Most genetic studies on stillborns and severe anomalies yield negative results.

19 More precise figures.

20 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.

21 Critical Periods Of Development
Figure 10-5 Critical periods of development for various organ systems and the resultant malformations. As you might have guessed, most severe changes take place the earliest, and most changes take place a lot earlier that you think in general.

22 Genetic Causes Karyotypic abnormalities Single gene mutations
80-90% of fetuses with aneuploidy die in utero trisomy 21 (Down syndrome) most common karyotypic abnormality (21,18,13) sex chromosome abnormalities next most common (Turner and Klinefelter) autosomal chromosomal deletion usually lethal karyotyping frequently done with aborted fetuses with repeated abortions Single gene mutations covered in separate chapters

23 Maternal Viral Infection
Rubella (German measles) at risk period first 16 weeks gestation defects in lens (cataracts), heart, and CNS (deafness and mental retardation) rubella immune status important part of prenatal workup Cytomegalovirus most common fetal infection highest at risk period is second trimester central nervous system infection predominates 1st trimester:Rubella 2nd trimester CMV

24 Drugs and Chemicals Drugs Alcohol Tobacco
13 cis-retinoic acid (acne agent) warfarin angiotensin converting enzyme inhibitors (ACEI) anticonvulsants oral diabetic agents thalidomide Alcohol Tobacco By far the last two do ten times as much damage than the first one.

25 Teratogen Actions • Proper cell migration to predetermined locations that influence the development of other structures • Cell proliferation, which determines the size and form of embryonic organs • Cellular interactions among tissues derived from different structures (e.g., ectoderm, mesoderm), which affect the differentiation of one or both of these tissues • Cell-matrix associations, which affect growth and differentiation • Programmed cell death (apoptosis), which, as we have seen, allows orderly organization of tissues and organs during embryogenesis • Hormonal influences and mechanical forces, which affect morphogenesis at many levels As long as we opened the door to the term “teratogen” lets talk about how they are known to work. These are NOT just theories! If you suspect that the 3 usual suspects are also the major teratogens, you are correct.

26 Diabetes Mellitus Fetal Macrosomy (>10 pounds) Diabetic Embryopathy
maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with growth hormone effects Diabetic Embryopathy most crucial period is immediately post fertilization malformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNS Oral agents not approved in pregnancy Diabetics attempting to conceive should be placed on insulin If you ever asked any physician to give you the differential diagnosis of macrosomy, it is not likely he would ever recall anything beyond diabetes.

27 Birth Weight and Gestational Age
Appropriate for gestational age (AGA) between 10 and 90th percentile for gestational age Small for gestational age (SGA) , <10% Large for gestational age (LGA) , >90% Preterm born before 37 weeks (<2500 grams) Post-Term delivered after 42 weeks Notice these are all MATHEMATICAL definitions. Is PRETERM the same as PREMATURE? YES

28 Prematurity Defined as gestational age < 37 weeks
Second most common cause of neonatal mortality (after congenital anomalies) Risk factors for prematurity Preterm Premature Rupture Of fetal Membranes (PPROM) Intrauterine infection Uterine, cervical, and placental abnormalities Multiple gestation

29 Fetal Growth Restriction
At least 1/3 of infants born at term are < 2.5kg Undergrown rather than immature Commonly underlies SGA (small for gestational age) Prenatal diagnosis: ultrasound measurements Classification Fetal Placental Maternal Why is “Maternal” in the biggest font? Ans: MOST COMMON, by far. Is this the same as IMMATURITY? NO

30 Fetal FGR Chromosomal abnormalities Fetal Infection
17% of FGR overall up to 66% of fetuses with ultrasound malformations Fetal Infection Infection: TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes) Characterized by symmetric growth restriction – head and trunk proportionally involved As you can see, FGR is HIGHLY related to malformations (anomalies)

31 Placental FGR Vascular Confined placental mosaicism
umbilical cord anomalies (single artery, constrictions, etc) thrombosis and infarction multiple gestation Confined placental mosaicism mutation in trophoblast trisomy is common Placental FGR tends to cause asymmetric growth with relative sparing of the head Placental weight correlates with fetal weight ~500g/3000g

32 Maternal FGR Most common cause of FGR by far Vascular diseases Toxins
preeclampsia (toxemia of pregnancy) hypertension Toxins ethanol narcotics and cocaine heavy smoking What is “pre”-eclampsis (versus eclampsia)? What is the difference? What is the cause? Why is it also called “toxemia”? Many theories have attempted to explain why preeclampsia arises, and have linked the syndrome to the presence of the following: endothelial cell injury immune rejection of the placenta compromised placental perfusion altered vascular reactivity imbalance between prostacyclin and thromboxane decreased glomerular filtration rate with retention of salt and water decreased intravascular volume increased central nervous system irritability disseminated intravascular coagulation uterine muscle stretch (ischemia) dietary factors, including vitamin deficiency genetic factors air pollution What does all this baloney mean? It means they still don’t know!

33 Organ Immaturity Lungs Kidneys Brain Liver
alveoli differentiate in 7th month surfactant deficiency Kidneys glomerular differentiation is incomplete Brain impaired homeostasis of temperature vasomotor control unstable Liver inability to conjugate and excrete bilirubin You can also think of these as being the CHIEF CONCERNS in treating premies.

34 APGAR (Appearance, Pulse, Grimace, Activity, Respiration)

35 Apgar Score and 28 Day Mortality
Score may be evaluated at 1 and 5 minutes 5 minute scores 0-1, 50% mortality 4, 20% mortality ≥ 7, nearly 0% mortality

36 Perinatal Infection Transcervical (ascending)
inhalation of infected amniotic fluid pneumonia, sepsis, meningitis commonly occurs with PROM 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 TORCH parvovirus B19 (Fifth), erythema infectiosum 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.

37 Fetal Lung Maturation Name the three histologic changes in lung maturation. Ans: capillaries approaching pneumocytes, cuboidalsquamous, higher air/non-air ratio

38 Neonatal Respiratory Distress Syndrome (RDS) (HMD)
60,000 cases / year in USA with 5000 deaths 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)

39 1) Prematurity RDS Risk Factors 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

40 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 (HMD former name) 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.


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

43 V/Q Mismatch Uneven ventilation results is ventilation/perfusion mismatch. Lung that is perfused but not ventilated results in what amounts to right to left shunting of unoxygenated blood into the arterial circulation. Physiologically, perfusion is matched to ventilation by arterial constriction due to hypoxia, hypercarbia and acidosis so that nonventilated areas are not perfused. The same mechanism results in generalized pulmonary vasoconstriction in a pathological state with generalized hypoxia, etc. The endothelial and epithelial damage together with the hyaline membranes impair diffusion and result in a vicious cycle.

44 RDS Prevention and Treatment
Delay labor until fetal lung is mature amniotic fluid phospholipid levels are useful in assessing fetal lung maturity Induce fetal lung maturation with antenatal corticosteriods Postnatal surfactant replacement therapy with oxygen and ventilator support

45 Treatment Complications
Oxygen toxicity oxygen derived free radicals damage tissue Retrolental fibroplasia hypoxia causes ↑ Vascular Endothelial Growth Factor (VEGF) and angiogenesis Oxygen Rx suppresses VEGF and causes endothelial apoptosis Bronchopulmonary “dysplasia” oxygen suppresses lung septation at the saccular stage mechanical ventilation epithelial hyperplasia, squamous metaplasia, and peribronchial and interstitial fibrosis were seen with old regimens of ventilator usage and no surfactant use, but are now uncommon lung septation is still impaired

46 Necrotizing Enterocolitis
Incidence is directly proportional to prematurity, like RDS approaches 10% with severe prematurity 2000 cases yearly in USA Pathogenesis not fully understood intestinal ischemia inflammatory mediators breakdown of mucosal barrier

47 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.

48 Hydrops Fetalis Chromosomal abnormalities
Turner syndrome with cystic hygromas other Cardiovascular with heart failure anemia with high output failure immune hemolytic anemia hereditary hemolytic anemia (α-thalassemia) parvovirus B19 infection twin to twin in utero transfusion congenital heart defects Hydrops = Water = Heart failure

49 Hydrops Fetalis Figure Hydrops fetalis. There is generalized accumulation of fluid in the fetus. In B, fluid accumulation is particularly prominent in the soft tissues of the neck, and this condition has been termed cystic hygroma. Cystic hygromas are characteristically seen, but not limited to, constitutional chromosomal anomalies such as 45,X0 karyotypes. (Courtesy of Dr. Beverly Rogers, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

50 Immune Hydrops Fetus inherits red cell antigens from the father that are foreign to the mother Mother forms IgG antibodies which cross the placenta and destroy fetal RBCs Fetus develops severe anemia with CHF and compensatory ↑ hematopoiesis (frequently extramedullary) Most cases involve Rh D antigen mother is Rh Neg and fetus is Rh Pos ABO and other antigens involved less often Hemolytic disease of the newborn is another name for this entity and is most often used by non-pathologists. Name 3 ways that erythropoietic marrow can expand or hyperplase: Cellularity, into appendicular skeleton, extramedullary

51 Pathogenesis of Sensitization
Fetal RBCs gain access to maternal circulation largely at delivery or upon abortion Since IgM antibodies are involved in primary response and prior sensitization is necessary, the first pregnancy is not usually affected Maternal sensitization can be prevented in most cases with Rh immune globulin (Rhogam) given at time of delivery or abortion (spontaneous or induced)

52 Treatment of Immune Hydrops
In utero identification of at risk infants via blood typing by amniocentesis, (Chorionic Villi Sampling) CVS, or fetal blood sampling fetal transfusions via umbilical cord early delivery Live born infant monitoring of hemoglobin and bilirubin exchange transfusions

53 Extramedulary hematopoiesis consisting primarily of erythroid precursors in the liver sinusoids. Erythroblastosis fetalis is another term for immune hydrops. Remember that normally there may be some “extramedullary hematopoesis” in a fetal liver at birth, but this rather quickly (weeks?) resolves.

54 Kernicterus Unconjugated bilirubin is water insoluble and lipophilic. It can cross the blood brain barrier and lead to kernicterus. The basal ganglia and thalamus are particularly susceptible.

55 Pathogenesis of Immune Hydrops

56 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.

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 Phenylananine metabolites are excreted in the urine Treatment is phenylalanine restriction Variant forms exist

58 GALACTOSEMIA Autosomal recessive Lactose → glucose + galactose
Galactose-1-phosphate uridyl transferase (GALT) GALT is involved in the first step in the transformation of galactose to glucose absence of GALT activity → galactosemia Symptoms appear with milk ingestion liver (fatty change and fibrosis), lens of eye (cataracts), and brain damage involved (mechanism unknown) Diagnosis suggested by reducing sugar in urine and confirmed by GALT assay in tissue Treatment is removal of galactose from diet for at least the two first years of life Infants affected by galactosemia typically present with symptoms of lethargy, vomiting, diarrhea, failure to thrive, and jaundice. In the USA now, ALL newborns are screened for galactosemia.

59 Cystic Fibrosis Normal Gene Mutational Spectra
Genetic/Environmental Modifiers Morphology Clinical Course

60 Cystic Fibrosis (Mucoviscidosis)
Autosomal recessive Most common lethal genetic disease affecting Caucasians (1 in 3,200 live births in the USA) 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

61 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

62 CFTR Gene: Normal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) CTFR → epithelial chloride channel protein agonist induced regulation of the chloride channel interacts with epithelial sodium channels (ENaC) Sweat gland CTFR activation increases luminal Cl− resorption ENaC increases Na+ resorption sweat is hypotonic Respiratory and Intestinal epithelium CTFR activation increases active luminal secretion of chloride ENaC is inhibited

63 CFTR Gene: Cystic Fibrosis
Sweat gland CTFR absence decreases luminal Cl− resorption ENaC decreases Na+ resorption sweat is hypertonic Respiratory and Intestinal epithelium CTFR absence decreases active luminal secretion of chloride lack of inhibition of ENaC is opens sodium channel with active resorption of luminal sodium secretions are decreased but isotonic CF sweat is HYPERTONIC, and in general exocrine secretions are VISCOUS

64 Chloride Channel Defect and Effects
Chloride channel defect in the sweat duct (top) causes increased chloride and sodium concentration in sweat. In the airway (bottom), cystic fibrosis patients have decreased chloride secretion and increased sodium and water reabsorption leading to dehydration of the mucus layer coating epithelial cells, defective mucociliary action, and mucus plugging of airways. CFTR, Cystic fibrosis transmembrane conductance regulator; EnaC, Epithelial sodium channel.

65 CFTR Gene: Mutational Spectra
More than 800 mutations are known These are grouped into six classes mild to severe Phenotype is correlated with the combination of these alleles correlation is best for pancreatic disease genotype-phenotype correlations are less consistent with pulmonary disease Other genes and environment further modify expression of CFTR

66 Clinical Manifestations Of Mutations In The Cystic Fibrosis Gene
The many clinical manifestations of mutations in the cystic fibrosis gene, from most severe to asymptomatic. (Redrawn from Wallis C: Diagnosing cystic fibrosis: blood, sweat, and tears. Arch Dis Child 76:85, 1997.)

67 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

68 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.

69 Normal pancreas for comparison

70 Lung Pathology in CF More than 95% of CF patients die of complications resulting from lung infection Viscous bronchial mucus with obstruction and secondary infection S. aureus Pseudomonas Hemophilus Bronchiectasis dilatation of bronchial lumina scarring of bronchial wall

71 Figure 10-23 Lungs of a patient dying of cystic fibrosis
Figure Lungs of a patient dying of cystic fibrosis. There is extensive mucus plugging and dilation of the tracheobronchial tree. The pulmonary parenchyma is consolidated by a combination of both secretions and pneumonia—the green color associated with Pseudomonas infections. (Courtesy of Dr. Eduardo Yunis, Children's Hospital of Pittsburgh, Pittsburgh, PA.)

72 Clinical Manifestations
Cystic Fibrosis Clinical Manifestations

73 CF Diagnosis Clinical criteria Sweat chloride analysis
sinopulmonary gastrointestinal pancreatic intestinal salt loss male genital tract Sweat chloride analysis Nasal transepithelial potential difference DNA Analysis gene sequencing

74 Clinical Course and Treatment
Highly variable – median life expectance is 30 years 7% of patients in the United States are diagnosed as adults Clearing of pulmonary secretions and treatment of pulmonary infection Transplantation lung liver-pancreas

75 Sudden Infant Death Syndrome (SIDS)
Epidemiology Morphology Pathogenesis SIDS remains a basic mystery, still, even after all these years, mostly because it is a diagnosis of exclusion.

76 Sudden Infant Death Syndrome
NIH 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 Crib death another name based on the fact that most die in their sleep 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?”

77 Epidemology of SIDS Leading cause of death in USA of infants between 1 month and 1 year of age 90% of deaths occur ≤ 6 months age, mostly between 2 and 4 months In USA 2,600 deaths in 1999 (down from 5,000 in 1990) Even though the age range for SIDS is 0-1 year, most deaths are much closer to zero.

78 Risk Factors for SIDS Parental Young maternal age (age <20 years)
Maternal smoking during pregnancy Drug abuse in either parent, specifically paternal marijuana and maternal opiate, cocaine use Short intergestational intervals Late or no prenatal care Low socioeconomic group African American and American Indian ethnicity (? socioeconomic factors) Infant Brain stem abnormalities, associated defective arousal, and cardiorespiratory control Prematurity and/or low birth weight Male sex Product of a multiple birth SIDS in a prior sibling Antecedent respiratory infections Environment Prone sleep position Sleeping on a soft surface Hyperthermia Postnatal passive smoking

79 Morphology of SIDS SIDS is a diagnosis of exclusion
Non-specific autopsy findings Multiple petechiae Pulmonary congestion ± pulmonary edema These may simply be agonal changes as they are found in non-SIDS deaths also Subtle changes in brain stem neurons Autopsy typically reveals no clear cause of death

80 Pathogenesis of SIDS Generally accepted to be multifactorial
Triple risk model Vulnerable infant Critical development period in homeostatic control Exogenous stressors Brain stem abnormalities, associated defective arousal, and cardio-respiratory control

81 Prevention of SIDS Maternal factors Environmental
attention to risk factors previously mentioned redress problems in medical care for underprivileged Environmental avoid prone sleeping back to sleep program: infant should sleep in supine position Avoid sleeping on soft surfaces no pillows, comforters, quilts, sheepskins, and stuffed toys Sleeping clothing (such as a sleep sack) may be used in place of blankets. Avoid hyperthermia no excessive blankets set thermostat to appropriate temperature avoid space heaters

82 Diagnosis of SIDS SIDS is a diagnosis of exclusion Complete autopsy
Examination of the death scene Review of the clinical history Differential diagnosis child abuse intentional suffocation If a cause for SIDS was found, would it still be called SIDS?

83 TUMORS Benign Malignant

84 BENIGN Hemangiomas Lymphatic Tumors Fibrous Tumors
Teratomas (also can be malignant) Is it surprising that the top three benign tumors are all CONNECTIVE tissue (i.e., mesenchymal or stromal)?

85 Hemangioma Benign tumor of blood vessels
Are the most common tumor of infancy Usually on skin, especially face and scalp Regress spontaneously in many cases What is a “birth mark”?

86 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

87 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 Aproximately 12% are malignant often composed of immature tissue occur in older children

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

89 MALIGNANT Neuroblastic Tumors Wilms Tumor Incidence and Types
The TWO tumors comprise the vast majority of pediatric SOLID (non hematopoetic) malignant tumors.


91 Small Round Blue Cell Tumors
Frequent in pediatric tumors Differential diagnosis Lymphoma Neuroblastoma Wilms tumor Rhabdomyosarcoma Ewings tumor Diagnostic procedures immunoperoxidase stains electron microscopy chromosomal analysis and molecular markers Good general principle: almost all pediatric malignancies are composed of cells which have small round nuclei and minimal cytoplasm (blue), so that is why we make fun of the pediatric pathologists, and say, all the have to look at is SMALL ROUND BLUE cell tumors.

92 Neuroblastomas Second most common malignancy of childhood (650 cases / year in USA) 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

93 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

94 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

95 What are the RED streaks?

96 Ganglioneuroblastoma: note the typical neuroblastoma features in the lower portion of the picture. Towards the top there is evidence of maturation into ganglion cells, which is a favorable morphologic feature. This is a recurrent principle of the histopathology of tumors, i.e., if the tumor cells actually look like they are “differentiating” into something, this is a favorablr prognostic feature, than if they DO NOT!

97 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.

98 Wilms Tumor Most common primary renal tumor of childhood
Incidence 10 per million children < 15 years Usually diagnosed between age 2-5 5 – 10 % are multi-focal, i.e., bilateral synchronous metachronous What does “synchronous” and “metachronous” mean? Ans: synchronous means “occurring at the same time”, metachronous means NOT occurring at the same time, but one after another.

99 two year survival up to 90% even with spread beyond the kidney
Clinical Features Most children present with a large abdominal mass Treatment nephrectomy and combination chemotherapy two year survival up to 90% even with spread beyond the kidney

100 Pathogenesis of Wilms Tumor
10% of Wilms tumors arise in one of three congenital malformation syndromes with distinct chromosomal loci Familial disposition for Wilms is rare, and most of these patients have de novo mutations Nephrogenic rests of adjacent parenchyma present in 40% of unilateral tumors, 100% of bilateral tumors if found in one kidney, these rests predict an increased risk for tumor in the contralateral kidney

101 Pathology of Wilms Tumor
Gross well circumscribed fleshy tan tumor areas of hemorrhage and necrosis Microscopic: triphasic appearance Blastema: small blue cells Epithelial elements: tubules & glomeruli Stromal elements Anaplasia correlates with p53 mutation and poor prognosis and resistance to chemotherapy

102 Wilms Tumor

103 Find the blastema, epithelial elements, and stromal elements.

104 Find the blastema, epithelial elements, and stromal elements.
What do those things look like at the tip of the arrows? (Hint: this is a KIDNEY tumor)

105 Find the blastema, epithelial elements, and stromal elements.

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