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Diseases of Infancy & Childhood. Diseases of Infancy and Childhood Congenital Anomalies Congenital Anomalies Birth Weight and Gestational Age Birth Weight.

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Presentation on theme: "Diseases of Infancy & Childhood. Diseases of Infancy and Childhood Congenital Anomalies Congenital Anomalies Birth Weight and Gestational Age Birth Weight."— Presentation transcript:

1 Diseases of Infancy & Childhood

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

3 INFANT MORTALITY USA 1970: 20 USA 1970: 20 USA 2000: 7 USA 2000: 7 USA WHITE: X USA WHITE: X USA BLACK: 2X USA BLACK: 2X SWEDEN 3 SWEDEN 3 INDIA 82 INDIA 82

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

5 MORTALITY by TIME SPAN NEONATE (0-4 WEEKS): CONGENITAL, PREMATURITY NEONATE (0-4 WEEKS): CONGENITAL, PREMATURITY UNDER ONE YEAR: CONGENITAL, PREMATURITY/WEIGHT, SIDS UNDER ONE YEAR: CONGENITAL, PREMATURITY/WEIGHT, SIDS 1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS 1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS 5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES 5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES ACCIDENTS, HOMICIDE, SUICIDE (NONE ARE “NATURAL” CAUSES) YEARS: ACCIDENTS, HOMICIDE, SUICIDE (NONE ARE “NATURAL” CAUSES)

6 1 Rates are expressed per 100,000 population 2 Excludes congenital heart disease

7 Congenital Anomalies Definitions Definitions Causes Causes Pathogenesis Pathogenesis

8 Malformations –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

9 Malformations Polydactyly & syndactyly Cleft LipSevere Lethal Malformation

10 Disruption by an amniotic band

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

12 The Oligohydramnios “Sequence”

13 Infant with oligohydramnios sequence

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

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

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17 #1 #2#3

18 CAUSES OF ANOMALIES Genetic karyotypic aberrations single gene mutations Environmental infection maternal disease drugs and chemicals irradiation Multifactorial Unknown

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20 Embryonic Development Embryonic period Embryonic period weeks 1- 8 of pregnancy weeks 1- 8 of pregnancy organogenesis occurs in this period organogenesis occurs in this period Fetal period Fetal period weeks 9 to 38 weeks 9 to 38 marked by further growth and maturation marked by further growth and maturation

21 Critical Periods Of Development

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

24 Drugs and Chemicals Drugs Drugs 13 cis-retinoic acid (acne agent) 13 cis-retinoic acid (acne agent) warfarin warfarin angiotensin converting enzyme inhibitors (ACEI) angiotensin converting enzyme inhibitors (ACEI) anticonvulsants anticonvulsants oral diabetic agents oral diabetic agents thalidomide thalidomide Alcohol Alcohol Tobacco Tobacco

25 Teratogen Actions Proper cell migration to predetermined locations that influence the development of other structures Proper cell migration to predetermined locations that influence the development of other structures Cell proliferation, which determines the size and form of embryonic organs 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 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 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 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 Hormonal influences and mechanical forces, which affect morphogenesis at many levels

26 Diabetes Mellitus Fetal Macrosomy (>10 pounds) Fetal Macrosomy (>10 pounds) maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with growth hormone effects maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with growth hormone effects Diabetic Embryopathy Diabetic Embryopathy most crucial period is immediately post fertilization most crucial period is immediately post fertilization malformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNS malformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNS Oral agents not approved in pregnancy Oral agents not approved in pregnancy Diabetics attempting to conceive should be placed on insulin Diabetics attempting to conceive should be placed on insulin

27 Birth Weight and Gestational Age Appropriate for gestational age (AGA) Appropriate for gestational age (AGA) between 10 and 90 th percentile for gestational age between 10 and 90 th percentile for gestational age Small for gestational age (SGA), <10% Small for gestational age (SGA), <10% Large for gestational age (LGA), >90% Large for gestational age (LGA), >90% Preterm Preterm born before 37 weeks (<2500 grams) born before 37 weeks (<2500 grams) Post-Term Post-Term delivered after 42 weeks delivered after 42 weeks

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

29 Fetal Growth Restriction At least 1/3 of infants born at term are < 2.5kg At least 1/3 of infants born at term are < 2.5kg Undergrown rather than immature Undergrown rather than immature Commonly underlies SGA (small for gestational age) Commonly underlies SGA (small for gestational age) Prenatal diagnosis: ultrasound measurements Prenatal diagnosis: ultrasound measurements Classification Classification Fetal Fetal Placental Placental Maternal Maternal

30 Fetal FGR Chromosomal abnormalities Chromosomal abnormalities 17% of FGR overall 17% of FGR overall up to 66% of fetuses with ultrasound malformations up to 66% of fetuses with ultrasound malformations Fetal Infection Fetal Infection Infection: TORCH ( T oxoplasmosis, O ther, R ubella, C ytomegalovirus, H erpes) Infection: TORCH ( T oxoplasmosis, O ther, R ubella, C ytomegalovirus, H erpes) Characterized by symmetric growth restriction – head and trunk proportionally involved Characterized by symmetric growth restriction – head and trunk proportionally involved

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

32 Maternal FGR Most common cause of FGR by far Most common cause of FGR by far Vascular diseases Vascular diseases preeclampsia (toxemia of pregnancy) preeclampsia (toxemia of pregnancy) hypertension hypertension Toxins Toxins ethanol ethanol narcotics and cocaine narcotics and cocaine heavy smoking heavy smoking

33 Organ Immaturity Lungs Lungs alveoli differentiate in 7 th month alveoli differentiate in 7 th month surfactant deficiency surfactant deficiency Kidneys Kidneys glomerular differentiation is incomplete glomerular differentiation is incomplete Brain Brain impaired homeostasis of temperature impaired homeostasis of temperature vasomotor control unstable vasomotor control unstable Liver Liver inability to conjugate and excrete bilirubin inability to conjugate and excrete bilirubin

34 APGAR ( A ppearance, P ulse, Grimace, A ctivity, R espiration)

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

37 Fetal Lung Maturation

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

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

40 RDS Pathology Gross Gross solid and airless (no crepitance) solid and airless (no crepitance) sink in water sink in water appearance is similar to liver tissue* appearance is similar to liver tissue* Microscopic Microscopic atelectasis and dilation of alveoli atelectasis and dilation of alveoli hyaline membranes composed of fibrin and cell debris line alveoli (HMD former name) hyaline membranes composed of fibrin and cell debris line alveoli (HMD former name) minimal inflammation minimal inflammation

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43 V/Q Mismatch

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

45 Treatment Complications Oxygen toxicity Oxygen toxicity oxygen derived free radicals damage tissue oxygen derived free radicals damage tissue Retrolental fibroplasia Retrolental fibroplasia hypoxia causes ↑ V ascular E ndothelial G rowth F actor (VEGF) and angiogenesis hypoxia causes ↑ V ascular E ndothelial G rowth F actor (VEGF) and angiogenesis Oxygen Rx suppresses VEGF and causes endothelial apoptosis Oxygen Rx suppresses VEGF and causes endothelial apoptosis Bronchopulmonary “dysplasia” Bronchopulmonary “dysplasia” oxygen suppresses lung septation at the saccular stage oxygen suppresses lung septation at the saccular stage mechanical ventilation 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 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 lung septation is still impaired

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

47 Necrotizing Enterocolitis

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

49 Hydrops Fetalis

50 Immune Hydrops Fetus inherits red cell antigens from the father that are foreign to the mother 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 Mother forms IgG antibodies which cross the placenta and destroy fetal RBCs Fetus develops severe anemia with CHF and compensatory ↑ hematopoiesis (frequently extramedullary) Fetus develops severe anemia with CHF and compensatory ↑ hematopoiesis (frequently extramedullary) Most cases involve Rh D antigen Most cases involve Rh D antigen mother is Rh Neg and fetus is Rh Pos mother is Rh Neg and fetus is Rh Pos ABO and other antigens involved less often ABO and other antigens involved less often

51 Pathogenesis of Sensitization Fetal RBCs gain access to maternal circulation largely at delivery or upon abortion 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 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) 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 In utero identification of at risk infants via blood typing by amniocentesis, (Chorionic Villi Sampling) CVS, or fetal blood sampling identification of at risk infants via blood typing by amniocentesis, (Chorionic Villi Sampling) CVS, or fetal blood sampling fetal transfusions via umbilical cord fetal transfusions via umbilical cord early delivery early delivery Live born infant Live born infant monitoring of hemoglobin and bilirubin monitoring of hemoglobin and bilirubin exchange transfusions exchange transfusions

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54 Kernicterus

55 Pathogenesis of Immune Hydrops

56 Inborn Errors of Metabolism (Genetic) P henyl K eton U ria (PKU) P henyl K eton U ria (PKU) Galactosemia Galactosemia C ystic F ibrosis (CF) (Mucoviscidosis) C ystic F ibrosis (CF) (Mucoviscidosis)

57 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 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

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

60 Cystic Fibrosis (Mucoviscidosis) Autosomal recessive Autosomal recessive Most common lethal genetic disease affecting Caucasians (1 in 3,200 live births in the USA) Most common lethal genetic disease affecting Caucasians (1 in 3,200 live births in the USA) 2-4% of population are carriers 2-4% of population are carriers Uncommon in Asians and African-Americans Uncommon in Asians and African-Americans Widespread disorder in epithelial chloride transport affecting fluid secretion in Widespread disorder in epithelial chloride transport affecting fluid secretion in exocrine glands exocrine glands epithelial lining of the respiratory, gastrointestinal, and reproductive tracts epithelial lining of the respiratory, gastrointestinal, and reproductive tracts Abnormally viscid mucus secretions Abnormally viscid mucus secretions

61 Cellular Metabolism Of The Cystic Fibrosis Transmembrane Regulator (CFTR) Harrison’s Internal Med, 16 th Ed

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

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

64 Chloride Channel Defect and Effects

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

66 Clinical Manifestations Of Mutations In The Cystic Fibrosis Gene

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

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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

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72 Cystic Fibrosis Clinical Manifestations

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

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

75 S udden I nfant D eath S yndrome (SIDS) Epidemiology Epidemiology Morphology Morphology Pathogenesis Pathogenesis

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

77 Epidemology of SIDS Leading cause of death in USA of infants between 1 month and 1 year of age 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 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) In USA 2,600 deaths in 1999 (down from 5,000 in 1990)

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

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

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

82 Diagnosis of SIDS SIDS is a diagnosis of exclusion SIDS is a diagnosis of exclusion Complete autopsy Complete autopsy Examination of the death scene Examination of the death scene Review of the clinical history Review of the clinical history Differential diagnosis Differential diagnosis child abuse child abuse intentional suffocation intentional suffocation

83 TUMORS Benign Benign Malignant Malignant

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

85 Hemangioma Benign tumor of blood vessels Benign tumor of blood vessels Are the most common tumor of infancy Are the most common tumor of infancy Usually on skin, especially face and scalp Usually on skin, especially face and scalp Regress spontaneously in many cases Regress spontaneously in many cases

86 Congenital Capillary Hemangioma At birth At 2 years After spontaneous regression

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

88 Sacrococcygeal Teratoma

89 MALIGNANT Neuroblastic Tumors Neuroblastic Tumors Wilms Tumor Wilms Tumor Incidence and Types Incidence and Types

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91 Small Round Blue Cell Tumors Frequent in pediatric tumors Frequent in pediatric tumors Differential diagnosis Differential diagnosis Lymphoma Lymphoma Neuroblastoma Neuroblastoma Wilms tumor Wilms tumor Rhabdomyosarcoma Rhabdomyosarcoma Ewings tumor Ewings tumor Diagnostic procedures Diagnostic procedures immunoperoxidase stains immunoperoxidase stains electron microscopy electron microscopy chromosomal analysis and molecular markers chromosomal analysis and molecular markers

92 Neuroblastomas Second most common malignancy of childhood (650 cases / year in USA) Second most common malignancy of childhood (650 cases / year in USA) Neural crest origin Neural crest origin adrenal gland – 40 % adrenal gland – 40 % sympathetic ganglia – 60% sympathetic ganglia – 60% In contrast to retinoblastoma, most are sporadic but familiar forms do occur In contrast to retinoblastoma, most are sporadic but familiar forms do occur Median age at diagnosis is 22 months Median age at diagnosis is 22 months

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

94 Neuorblastoma *Neuropil**Homer-Wright Rosettes * **

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97 Clinical Course and Prognosis Hematogenous and lymphatic metastases to liver, lungs and bone Hematogenous and lymphatic metastases to liver, lungs and bone 90% produce catecholamines, but hypertension is uncommon 90% produce catecholamines, but hypertension is uncommon Age and stage are most important prognostically Age and stage are most important prognostically < 1 year age: good prognosis regardless of stage < 1 year age: good prognosis regardless of stage Amplification of N-myc oncogene Amplification of N-myc oncogene present in 25-30% of cases and is unfavorable present in 25-30% of cases and is unfavorable up to 300 copies on N-myc has been observed up to 300 copies on N-myc has been observed Risk Stratification Risk Stratification low risk: 90% cure rate low risk: 90% cure rate high risk 20% cure rate high risk 20% cure rate

98 Wilms Tumor Most common primary renal tumor of childhood Most common primary renal tumor of childhood Incidence 10 per million children < 15 years Incidence 10 per million children < 15 years Usually diagnosed between age 2-5 Usually diagnosed between age – 10 % are multi-focal, i.e., bilateral 5 – 10 % are multi-focal, i.e., bilateral synchronous synchronous metachronous metachronous

99 Clinical Features Most children present with a large abdominal mass Most children present with a large abdominal mass Treatment Treatment nephrectomy and combination chemotherapy nephrectomy and combination chemotherapy two year survival up to 90% even with spread beyond the kidney 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 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 Familial disposition for Wilms is rare, and most of these patients have de novo mutations Nephrogenic rests of adjacent parenchyma Nephrogenic rests of adjacent parenchyma present in 40% of unilateral tumors, 100% of bilateral tumors 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 if found in one kidney, these rests predict an increased risk for tumor in the contralateral kidney

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

102 Wilms Tumor

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