Presentation on theme: "Diseases of Infancy & Childhood"— Presentation transcript:
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 AnomaliesBirth Weight and Gestational AgeBirth InjuriesPerinatal InfectionsRespiratory Distress Syndrome (RDS)Necrotizing EnterocolitisIntraventricular HemorrhageHydropsInborn Metabolic/Genetic ErrorsSudden Infant Death Syndrome (SIDS)Tumors
3 INFANT MORTALITY USA 1970: 20 USA 2000: 7 USA WHITE: X USA BLACK: 2X SWEDEN 3INDIA 82Good 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 lifeInfancythe first year of lifeAge 1 – 4 years (preschool)Age 5 – 14 years (school age)Definitions to know well.
5 MORTALITY by TIME SPAN NEONATE (0-4 WEEKS): CONGENITAL, PREMATURITY UNDER ONE YEAR: CONGENITAL, PREMATURITY/WEIGHT, SIDS1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES15-24 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 population2Excludes 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 multifactoriale.g. congenital heart defectDisruptionssecondary disruptions of previously normal organ or body regione.g. amniotic bandsDeformationsextrinsic disturbance of development by biomechanical forcese.g. uterine constraintSequencea pattern of cascade anomalies explained by a single localized initiating event with secondary defects in other organse.g. Oligohydramnios (Or Potter) SequenceSyndromea constellation of developmental abnormalities believed to be pathologically relatede.g Turner syndromeKnow a classic example of each!
9 Polydactyly & syndactyly MalformationsFigure 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 & syndactylyCleft LipSevere 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 agenesisAmniotic leakFetal Compressionflattened faciesclub foot (talipes equinovarus)Pulmonary hypoplasiafetal respiratory motions important for lung developmentBreech PresentationNote 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 organAtresia: absence of an openingHypoplasia: incomplete development or under- development of an organ with decreased numbers of cellsHyperplasia: overdevelopment of an organ associated with increased numbers of cellsHypertrophy: increase in size with no change in number of cellsDysplasia: in the context of malformations (versus neoplasia) describes an abnormal organization of cellsNOTE 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 weeksImplantation occurs at day 6-775% of loses are implantation failures and are not recognizedPregnancy loss after implantation is 25-40%Do most losses occur around fertilization/implantation time? YESNEJM 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#3What 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 aberrationssingle gene mutationsEnvironmentalinfectionmaternal diseasedrugs and chemicalsirradiationMultifactorialUnknownWhy 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.
20 Embryonic Development Embryonic periodweeks 1- 8 of pregnancyorganogenesis occurs in this periodFetal periodweeks 9 to 38marked by further growth and maturationYou 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 uterotrisomy 21 (Down syndrome) most common karyotypic abnormality (21,18,13)sex chromosome abnormalities next most common (Turner and Klinefelter)autosomal chromosomal deletion usually lethalkaryotyping frequently done with aborted fetuses with repeated abortionsSingle gene mutationscovered in separate chapters
23 Maternal Viral Infection Rubella (German measles)at risk period first 16 weeks gestationdefects in lens (cataracts), heart, and CNS (deafness and mental retardation)rubella immune status important part of prenatal workupCytomegalovirusmost common fetal infectionhighest at risk period is second trimestercentral nervous system infection predominates1st trimester:Rubella2nd trimester CMV
24 Drugs and Chemicals Drugs Alcohol Tobacco 13 cis-retinoic acid (acne agent)warfarinangiotensin converting enzyme inhibitors (ACEI)anticonvulsantsoral diabetic agentsthalidomideAlcoholTobaccoBy 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 levelsAs 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 effectsDiabetic Embryopathymost crucial period is immediately post fertilizationmalformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNSOral agents not approved in pregnancyDiabetics attempting to conceive should be placed on insulinIf 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 ageSmall for gestational age (SGA) , <10%Large for gestational age (LGA) , >90%Pretermborn before 37 weeks (<2500 grams)Post-Termdelivered after 42 weeksNotice 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 prematurityPreterm Premature Rupture Of fetal Membranes (PPROM)Intrauterine infectionUterine, cervical, and placental abnormalitiesMultiple gestation
29 Fetal Growth Restriction At least 1/3 of infants born at term are < 2.5kgUndergrown rather than immatureCommonly underlies SGA (small for gestational age)Prenatal diagnosis: ultrasound measurementsClassificationFetalPlacentalMaternalWhy 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 overallup to 66% of fetuses with ultrasound malformationsFetal InfectionInfection: TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes)Characterized by symmetric growth restriction – head and trunk proportionally involvedAs 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 infarctionmultiple gestationConfined placental mosaicismmutation in trophoblasttrisomy is commonPlacental FGR tends to cause asymmetric growth with relative sparing of the headPlacental weight correlates with fetal weight ~500g/3000g
32 Maternal FGR Most common cause of FGR by far Vascular diseases Toxins preeclampsia (toxemia of pregnancy)hypertensionToxinsethanolnarcotics and cocaineheavy smokingWhat 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 injuryimmune rejection of the placentacompromised placental perfusionaltered vascular reactivityimbalance between prostacyclin and thromboxanedecreased glomerular filtration rate with retention of salt and waterdecreased intravascular volumeincreased central nervous system irritabilitydisseminated intravascular coagulationuterine muscle stretch (ischemia)dietary factors, including vitamin deficiencygenetic factorsair pollutionWhat does all this baloney mean? It means they still don’t know!
33 Organ Immaturity Lungs Kidneys Brain Liver alveoli differentiate in 7th monthsurfactant deficiencyKidneysglomerular differentiation is incompleteBrainimpaired homeostasis of temperaturevasomotor control unstableLiverinability to conjugate and excrete bilirubinYou can also think of these as being the CHIEF CONCERNS in treating premies.
35 Apgar Score and 28 Day Mortality Score may be evaluated at 1 and 5 minutes5 minute scores0-1, 50% mortality4, 20% mortality≥ 7, nearly 0% mortality
36 Perinatal Infection Transcervical (ascending) inhalation of infected amniotic fluidpneumonia, sepsis, meningitiscommonly occurs with PROMpassage through infected birth canalherpes virus– caesarian section for active herpesTransplacental (hematogenous)mostly viral and parasiticHIV—at delivery with maternal to fetal transfusionTORCHparvovirus B19 (Fifth), erythema infectiosumbacterialListeria monocytogenesDuring 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 MaturationName the three histologic changes in lung maturation. Ans:capillaries approaching pneumocytes,cuboidalsquamous,higher air/non-air ratio
38 Neonatal Respiratory Distress Syndrome (RDS) (HMD) 60,000 cases / year in USA with 5000 deathsIncidence is inversely proportional to gestational ageThe cause is lung immaturity with decreased alveolar surfactantsurfactant decreases surface tensionfirst breath is the hardest since lungs must be expandedwithout surfactant, lungs collapse with each breathRDS also previously referred to as HMB (Hyaline Membrane Disease)
39 1) Prematurity RDS Risk Factors 2) Maternal diabetes mellitus by far the greatest risk factoraffected infants are nearly always premature2) Maternal diabetes mellitusinsulin suppresses surfactant secretion3) Cesarean deliverynormal delivery process stimulates surfactant secretion
40 RDS Pathology Gross Microscopic solid and airless (no crepitance) sink in waterappearance is similar to liver tissue*Microscopicatelectasis and dilation of alveolihyaline membranes composed of fibrin and cell debris line alveoli (HMD former name)minimal inflammationAlso 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/QMismatchUneven 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 matureamniotic fluid phospholipid levels are useful in assessing fetal lung maturityInduce fetal lung maturation with antenatal corticosteriodsPostnatal surfactant replacement therapy with oxygen and ventilator support
45 Treatment Complications Oxygen toxicityoxygen derived free radicals damage tissueRetrolental fibroplasiahypoxia causes ↑ Vascular Endothelial Growth Factor (VEGF) and angiogenesisOxygen Rx suppresses VEGF and causes endothelial apoptosisBronchopulmonary “dysplasia”oxygen suppresses lung septation at the saccular stagemechanical ventilationepithelial hyperplasia, squamous metaplasia, and peribronchial and interstitial fibrosis were seen with old regimens of ventilator usage and no surfactant use, but are now uncommonlung septation is still impaired
46 Necrotizing Enterocolitis Incidence is directly proportional to prematurity, like RDSapproaches 10% with severe prematurity2000 cases yearly in USAPathogenesisnot fully understoodintestinal ischemiainflammatory mediatorsbreakdown 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 hygromasotherCardiovascular with heart failureanemia with high output failureimmune hemolytic anemiahereditary hemolytic anemia (α-thalassemia)parvovirus B19 infectiontwin to twin in utero transfusioncongenital heart defectsHydrops = Water = Heart failure
49 Hydrops FetalisFigure 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 HydropsFetus inherits red cell antigens from the father that are foreign to the motherMother forms IgG antibodies which cross the placenta and destroy fetal RBCsFetus develops severe anemia with CHF and compensatory ↑ hematopoiesis (frequently extramedullary)Most cases involve Rh D antigenmother is Rh Neg and fetus is Rh PosABO and other antigens involved less oftenHemolytic 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 abortionSince IgM antibodies are involved in primary response and prior sensitization is necessary, the first pregnancy is not usually affectedMaternal 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 uteroidentification of at risk infants via blood typing by amniocentesis, (Chorionic Villi Sampling) CVS, or fetal blood samplingfetal transfusions via umbilical cordearly deliveryLive born infantmonitoring of hemoglobin and bilirubinexchange 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 KernicterusUnconjugated 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.
56 Inborn Errors of Metabolism (Genetic) PhenylKetonUria (PKU)GalactosemiaCystic 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.
57 PHENYLKETONURIA (PKU) Ethnic distributioncommon in persons of Scandinavian descentuncommon in persons of African-American and Jewish descentAutosomal recessivePhenylalanine hydroxylase deficiency leads to hyperphenylalaninemia, brain damage, and mental retardationPhenylananine metabolites are excreted in the urineTreatment is phenylalanine restrictionVariant 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 glucoseabsence of GALT activity → galactosemiaSymptoms appear with milk ingestionliver (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 tissueTreatment is removal of galactose from diet for at least the two first years of lifeInfants 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 ModifiersMorphologyClinical Course
60 Cystic Fibrosis (Mucoviscidosis) Autosomal recessiveMost common lethal genetic disease affecting Caucasians (1 in 3,200 live births in the USA)2-4% of population are carriersUncommon in Asians and African-AmericansWidespread disorder in epithelial chloride transport affecting fluid secretion inexocrine glandsepithelial lining of the respiratory, gastrointestinal, and reproductive tractsAbnormally 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: NormalCystic Fibrosis Transmembrane Conductance Regulator (CFTR)CTFR → epithelial chloride channel proteinagonist induced regulation of the chloride channelinteracts with epithelial sodium channels (ENaC)Sweat glandCTFR activation increases luminal Cl− resorptionENaC increases Na+ resorptionsweat is hypotonicRespiratory and Intestinal epitheliumCTFR activation increases active luminal secretion of chlorideENaC is inhibited
63 CFTR Gene: Cystic Fibrosis Sweat glandCTFR absence decreases luminal Cl− resorptionENaC decreases Na+ resorptionsweat is hypertonicRespiratory and Intestinal epitheliumCTFR absence decreases active luminal secretion of chloridelack of inhibition of ENaC is opens sodium channel with active resorption of luminal sodiumsecretions are decreased but isotonicCF 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 knownThese are grouped into six classesmild to severePhenotype is correlated with the combination of these allelescorrelation is best for pancreatic diseasegenotype-phenotype correlations are less consistent with pulmonary diseaseOther 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 PathologyPlugging of ducts with viscous mucus and loss of ciliary function of respiratory mucosaPancreasatrophy of exocrine pancreas with fibrosisislets are not affectedLiverplugging of bile canaliculi with portal inflamationbiliary cirrhosis may developGenitaliaAbsence of vas deferens and azoospermiaSweat glandsnormal 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.
70 Lung Pathology in CFMore than 95% of CF patients die of complications resulting from lung infectionViscous bronchial mucus with obstruction and secondary infectionS. aureusPseudomonasHemophilusBronchiectasisdilatation of bronchial luminascarring 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.)
74 Clinical Course and Treatment Highly variable – median life expectance is 30 years7% of patients in the United States are diagnosed as adultsClearing of pulmonary secretions and treatment of pulmonary infectionTransplantationlungliver-pancreas
75 Sudden Infant Death Syndrome (SIDS) EpidemiologyMorphologyPathogenesisSIDS remains a basic mystery, still, even after all these years, mostly because it is a diagnosis of exclusion.
76 Sudden Infant Death Syndrome NIH Definitionsudden 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 historyCrib deathanother name based on the fact that most die in their sleepIf 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 SIDSLeading cause of death in USA of infants between 1 month and 1 year of age90% of deaths occur ≤ 6 months age, mostly between 2 and 4 monthsIn 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 pregnancyDrug abuse in either parent, specifically paternal marijuana and maternal opiate, cocaine useShort intergestational intervalsLate or no prenatal careLow socioeconomic groupAfrican American and American Indian ethnicity (? socioeconomic factors)InfantBrain stem abnormalities, associated defective arousal, and cardiorespiratory controlPrematurity and/or low birth weightMale sexProduct of a multiple birthSIDS in a prior siblingAntecedent respiratory infectionsEnvironmentProne sleep positionSleeping on a soft surfaceHyperthermiaPostnatal passive smoking
79 Morphology of SIDS SIDS is a diagnosis of exclusion Non-specific autopsy findingsMultiple petechiaePulmonary congestion ± pulmonary edemaThese may simply be agonal changes as they are found in non-SIDS deaths alsoSubtle changes in brain stem neuronsAutopsy typically reveals no clear cause of death
80 Pathogenesis of SIDS Generally accepted to be multifactorial Triple risk modelVulnerable infantCritical development period in homeostatic controlExogenous stressorsBrain stem abnormalities, associated defective arousal, and cardio-respiratory control
81 Prevention of SIDS Maternal factors Environmental attention to risk factors previously mentionedredress problems in medical care for underprivilegedEnvironmentalavoid prone sleepingback to sleep program: infant should sleep in supine positionAvoid sleeping on soft surfacesno pillows, comforters, quilts, sheepskins, and stuffed toysSleeping clothing (such as a sleep sack) may be used in place of blankets.Avoid hyperthermiano excessive blanketsset thermostat to appropriate temperatureavoid space heaters
82 Diagnosis of SIDS SIDS is a diagnosis of exclusion Complete autopsy Examination of the death sceneReview of the clinical historyDifferential diagnosischild abuseintentional suffocationIf a cause for SIDS was found, would it still be called SIDS?
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 infancyUsually on skin, especially face and scalpRegress spontaneously in many casesWhat 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 yearsAfter spontaneous regressionAt birth
87 TeratomasComposed of cells derived from more than one germ layer, usually all threeSacrococcygeal teratomasmost common childhood teratomafrequency 1:20,000 to 1:40,000 live births4 times more common in boys than girlsAproximately 12% are malignantoften composed of immature tissueoccur 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 tumorsDifferential diagnosisLymphomaNeuroblastomaWilms tumorRhabdomyosarcomaEwings tumorDiagnostic proceduresimmunoperoxidase stainselectron microscopychromosomal analysis and molecular markersGood 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 NeuroblastomasSecond most common malignancy of childhood (650 cases / year in USA)Neural crest originadrenal gland – 40 %sympathetic ganglia – 60%In contrast to retinoblastoma, most are sporadic but familiar forms do occurMedian age at diagnosis is 22 months
93 Neuorblastoma Morphology Small round blue cell tumorneuorpil formationrosette formationimmunochemistry – neuron specific enolaseEM – secretory granules (catecholamine)Usual features of anaplasiahigh mitotic rate is unfavorableevidence of Schwann cell or ganglion differentiation favorableOther prognostic predictors are used by pathologists and oncologists
94 Neuorblastoma ** * *Neuropil **Homer-Wright Rosettes You MUST remember:What a ROSETTE looks likeThe fact that they are CLASSICALLY the hallmarks of neuroblastomas*Neuropil **Homer-Wright Rosettes
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 bone90% produce catecholamines, but hypertension is uncommonAge and stage are most important prognostically< 1 year age: good prognosis regardless of stageAmplification of N-myc oncogenepresent in 25-30% of cases and is unfavorableup to 300 copies on N-myc has been observedRisk Stratificationlow risk: 90% cure ratehigh risk 20% cure rateA 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 yearsUsually diagnosed between age 2-55 – 10 % are multi-focal, i.e., bilateralsynchronousmetachronousWhat 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 FeaturesMost children present with a large abdominal massTreatmentnephrectomy and combination chemotherapytwo 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 lociFamilial disposition for Wilms is rare, and most of these patients have de novo mutationsNephrogenic rests of adjacent parenchymapresent in 40% of unilateral tumors, 100% of bilateral tumorsif found in one kidney, these rests predict an increased risk for tumor in the contralateral kidney
101 Pathology of Wilms Tumor Grosswell circumscribed fleshy tan tumorareas of hemorrhage and necrosisMicroscopic: triphasic appearanceBlastema: small blue cellsEpithelial elements: tubules & glomeruliStromal elementsAnaplasiacorrelates with p53 mutation and poor prognosis and resistance to chemotherapy