Ch10-infancy and Childhood diseases.ppt

Diseases of Infancy And Childhood Diseases of Infancy and Childhood Congenital Anomalies Disorders of Prematurity Perinatal Infections Prematurity & Fetal growth restriction Fetal hydrops Inborn errors of metabolism & other genetic disorders Sudden Infant Death Syndr...

Diseases of Infancy And Childhood Diseases of Infancy and Childhood Congenital Anomalies Disorders of Prematurity Perinatal Infections Prematurity & Fetal growth restriction Fetal hydrops Inborn errors of metabolism & other genetic disorders Sudden Infant Death Syndrome (SIDS) Tumors & tumorlike lesions of infancy & childhood  INFANT MORTALITY RATE (ZUIGELINGEN STERFTE) number of infant deaths (one year of age or younger) per 1000 live births SUR 1980: 40/1000 SUR 2006: 29/1000 2010: 27/1000 NED 2006: 4/1000 AFRICA : 180/1000  Perinatal mortality (Perinatale sterfte) WHO definitie: Overlijden v/e foetus (≥ 22 wkn), of baby in de eerste 7 dagen na de geboorte. Sterftemaat per 1.000 levend- en doodgeborenen.  Major Time Spans Neonatal period first four weeks of life Infancy the first year of life Age 1 – 4 years Age 5 – 14 years  MORTALITY by TIME SPAN NEONATE (0-4 WEEKS): CONGENITAL, PREMATURITY UNDER ONE YEAR: CONGENITAL, PREMATURITY/LOW BIRTH WEIGHT, SIDS 1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS 5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES 15-24 YEARS: ACCIDENTS, HOMICIDE, SUICIDE  Congenital Anomalies Definitions Causes Pathogenesis  Congenital Anomalies Malformations Disruptions Deformations Sequence Syndrome  Malformations primary errors of morphogenesis Intrinsic abnormal developmental process usually multifactorial, not single gene or chromosomal defect e.g. congenital heart defect  Malformations Polydactyly & Cleft Lip Severe Lethal Malformation syndactyly  Disruptions Secondary destruction of organ or body region that was previously normal in development Extrinsic disturbance in morphogenesis, not heritable e.g. amniotic bands Disruption by an amniotic band  Deformations extrinsic disturbance of development by biomechanical forces e.g. uterine constraint  Sequence cascade of anomalies triggered by one initiating aberrations e.g.. Oligohydramnios (Or Potter) Sequence  Syndrome a constellation of developmental abnormalities believed to be pathologically related Contrast to sequence can’t be explained by a single, localized,initiating event e.g Turner syndrome  Case study A 28-year-old woman, 39 weeks pregnant , presents to the emergency room in active labor. She has been followed by the high-risk obstetric service for the last two months, since a fetal ultrasound examination had shown oligohydramnios (diminished amniotic fluid) and very small fetal kidneys. Her pregnancy had been otherwise unremarkable, and she denied drug, alcohol, or tobacco use. She has two healthy children at home. A 2800-gram female infant is born by vaginal delivery. Her size is appropriate for the gestational age, Apgar scores of 8 at 1 minute and 8 at 5 minutes. It is noted that she has an unusual appearance with low-set ears, a flattened nasal profile, inner canthal folds beneath her eyes and a talipes equinovarus (clubfoot) deformity of the left foot. Several minutes after birth, she develops grunting(knorrend) and chest retractions. She remains dusky (grauw) even with administration of oxygen. She is intubated and transferred to the neonatal intensive care unit. A chest radiograph shows bilateral pneumothoraces, and chest tubes are placed. Despite aggressive ventilatory management, she expires two hours after birth. Autopsy reveals severe pulmonary hypoplasia and bilateral multicystic dysplasia of the kidneys. This infant shows the typical facial abnormalities due to compression secondary to oligohydramnios. These changes are known as Potter facies and include the flattened nasal profile, low-set ears, and a crease at the inner corner and under the eye known as an inner canthal fold. Also notice her large, flattened hand. Questions: Are abnormal facial features in this case an example of a malformation, a deformation, or a disruption? The abnormal facial features are examples of deformations. What are some common causes of oligohydramnios? Amniotic fluid leak, bilateral renal agenesis, and cystic renal dysplasia are common causes of oligohydramnios. This infant has talipes equinovarus (a club foot deformity) of her left leg. This deformation results from fetal compression due to insufficient amniotic fluid. Other limb defects may be seen, including bowed legs and large, flattened hands. Question: Why is a breech presentation seen more commonly with oligohydramnios? The lack of amniotic fluid inhibits the baby's movements, restricting its ability to rotate to a vertex position prior to delivery. This thoracic organ block from the autopsy examination shows severe lung hypoplasia. The lungs are only about 30% of the size they should be for a baby of this size. Respiratory insufficiency due to pulmonary hypoplasia is the most common cause of death associated with the oligohydramnios sequence. Question: Why does pulmonary hypoplasia occur with oligohydramnios? Lung development is stimulated by the lung expansion that occurs from in-utero respiratory movements. A lack of amniotic fluid limits the amount of fluid available to expand the lungs and also limits expansion of the thoracic cage. Placenta, amnion nodosum The fetal surface of the placenta is studded with numerous tan nodules of fetal squames (sloughed skin squamous epithelial cells). Question: In which amniotic fluid disorder is this a typical finding? Oligohydramnios. Small multicystic dysplastic kidneys The kidneys are very small and malformed in this case. Cysts are visible on the surface of one side. Notice how much larger the adrenal glands appear relative to the kidneys Question: Why do renal abnormalities lead to oligohydramnios? Fetal urine is the main source of amniotic fluid in the latter part of pregnancy. Renal diseases that impair urine production lead to oligohydramnios. The Oligohydramnios (Potter)“Sequence” Flattened facies Club foot Talipes equinovarus  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) Organ Specific Anomalies Agenesis: complete absence of an organ and associated primordium Aplasia: complete absence of an organ due to development failure of primordium Atresia: absence of an opening of hollow visceral organ Organ Specific Anomalies 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  Causes of anomalies Genetic causes Environmental Viruses Drugs & other chemicals Maternal diabetes Multifactorial causes single gene mutations  Genetic Causes Chromosomal abnormalities 80-90% of fetuses with aneuploidy die in utero trisomy 21 (Down syndrome) most common karyotypic abnormality trisomies 13 & 18 second most common autosomal chromosomal deletion usually lethal karyotyping frequently done with aborted fetuses with repeated abortions  Environmental causes Maternal Viral Infection Rubella (German measles) at risk period first 16 weeks gestation congenital rubella syndrome defects in lens (cataracts) heartdefects (PDA, pulm art hypoplasia or stenosis, VSD, tetralogy of Fallot) deafness mental retardation  Environmental causes Maternal Viral Infection Cytomegalovirus most common fetal infection highest at risk period is second trimester central nervous sytem defects: mental retardation,microcephaly, deafness & hepatosplenomegalie  Environmental causes Drugs & other Chemicals Thalidomide (tranquilizer/anti-neoplastic agents)-> limb abnormalities Thalidomide baby  Environmental causes Drugs & other Chemicals Alcohol-> fetal alcohol syndrome: growth retardation Microcephaly ASD short palpebral fissures maxillary hypoplasia mechanism: disruption retinoic acid & hedgehog signaling pathways.  Environmental causes Drugs & other Chemicals Sigarette smoke-> spontaneous abortions, premature labor, placental abnormalities, low birth weight, prone to SIDS  Environmental causes Diabetes-> maternal hyperglycemia induced fetal hyperinsulinemia -> increase body fat increase muscle mass organomegaly, cardiac anomaly neural tube effects ( PATAU syndrome ) ( EDWARDS syndrome ) Disorders of Prematurity Perinatal Infections Fetal Hydrops Intra-uterine 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 Critical Periods Of Development  Classification of infants Birth Weight and Gestational Age Appropriate for gestational age (AGA) between 10 and 90th percentile for gestational age Small for gestational age (SGA) Large for gestational age (LGA) Preterm born before 37 weeks ( ↑ Vascular Endothelial Growth Factor (VEGF) -> neovascularization Bronchopulmonary dysplasia oxygen suppresses alveolar septation at the saccular stage (large alveolar structures) Histology : airway epithelial hyperplasia squamous metaplasia alveolar wall thickening peribronchial and interstitial fibrosis Necrotizing Enterocolitis Incidence is inversely proportional to gestational age 10% of severe prematurity 2500 cases yearly in USA Pathogenesis not fully understood intestinal ischemia inflammatory mediators breakdown of mucosal barrier Associated with enteral feeding Necrotizing Enterocolitis Clinical course Onset of bloody stools Abdominal distention Circulatory collaps X-abdomen: gas in intestinal wall (pneumatosis intestinalis) Typically effects term.ileum, cecum & right colon Morphology NEC Morphology NEC  Hydrops Fetalis Accumulation of edema in fetus during intrauterine growth, 2 types progressive-> hydrops fetalis-> usually lethal isolated -> pleural, peritoneal effusions & postnuchal accum -> compatible with live Classification: Immune hydrops: hemolytic disease caused by blood group incompatibility between mother & fetus Non-immune: cardiovasc effect, chromosomal abn, & fetal anemia Pathogenesis immune hydrops fetalis Causes non-immune fetal hydrops (45X ) (transplacental infection) (10 %) Red = major causes  Morphology Hydrops Fetalis Figure 10-13 Hydrops fetalis. Generalized accumulation of fluid in the fetus. In B, fluid accumulation particularly prominent in soft tissues of the neck (cystic hygroma.), leading cause, constitutional chromosomal anomalies such as 45,X0 karyotypes.  Morphology Hydrops Fetalis Hydrops fetalis = most severe & generalized Lesser degree=isolated pleural, peritoneal or post nuchal fluid collections Dysmorphic features (chromos. abn) Cardiac anomaly CNS damage -> kernicterus (bilirubin accum) Hydrops with fetal anemia Fetus & placenta pale Hepatosplenomegaly (due to heart failure & congestion) Bone marrow hyperplasia erythroid precursor Extramedull hematopoesis , Kernicterus  Sudden Infant Death Syndrome Definition sudden death of an infant < 1 year unexplained after thorough case investigation, (complete autopsy, examination of the death scene, and review of the clinical history Crib death (wiegendood) most cases die in their sleep  Epidemology of SIDS Leading cause of death in USA of infants between 1 month and 1 year of age 90% of deaths ≤ 6 months age, mostly between 2 and 4 months USA: 1992 120/ 100.000 2002 57/ 100.000  Morphology of SIDS diagnosis of exclusion Non-specific autopsy findings Multiple petechiae (thymus, visceral & parietal pleura & epicardium) Pulmonary congestion ± pulmonary edema CNS: astrogliosis of brainstem & cerebellum Hepatic extramedull hematopoiesis & periadrenal brown fat (non- specific) Autopsy :no clear cause of death  Pathogenesis of SIDS Multifactorial Triple risk model Vulnerable infant (before term, low birth weight) Critical development period in homeostatic control Exogenous stressors (see T 10-7 environment)  Pathogenesis of SIDS Brain stem abnormalities, associated defective arousal & cardio-respiratory control Maternal risk factors: Smoking Young maternal age Frequent childbirths Inadequate prenetal care Prevent ion of SIDS  Diagnosis of SIDS diagnosis of exclusion Complete autopsy Examination death scene Review of clinical history Differential diagnosis child abuse intentional suffocation (smoren) TUMOR BenignS Malignant BENIGN Hemangiomas Lymphatic Tumors Fibrous Tumors Teratomas (also can be malignant)  Hemangioma Benign tumor of blood vessels most common tumor of infancy Usually on skin, especially face and scalp (port- wine stain) Regress spontaneously in many cases Congenital Capillary Hemangioma At birth At 2 years After spontaneous regression  Lymphatic tumors Lymfangiomas: cystic & cavernous spaces Lymphangiectasis: abnormal dilatations of preexist lymph channels  Fibrous tumors Fibromatosis: sparsely proliferation of spindle cells Congenital infantile fibrosarcomas: richly cellular lesions, T(12;15)(p13;q25)  Teratomas Composed of cells derived from more than one germ layer, usually all three Occurrence: Well diff cystic lesions( mature teratomas) Indetermediate potential ( immature form) Malignant form Incidence: 2yr & early adulthood  Teratomas 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 Sacrococcygeal Teratoma  Malignant tumors Differences with adults Incidence & tumor type Frequent demonstration of relationship between abn development & tumor induction Prevelance of underlying familial or genetic aberrations Regress spontaneously Improved survival or cure Small Round Blue Cell Tumors Frequent in pediatric tumors Differential diagnosis Lymphoma Neuroblastoma Wilms tumor Rhabdomyosarcoma Ewings tumor Medulloblastoma & retinoblastoma Diagnostic procedures immunoperoxidase stains electron microscopy chromosomal analysis and molecular markers  Neuroblastomas Spontaneous or therapy induced diff of primitive neuroblasts into mature elements spontaneous tumor regression wide range clinical behaviour & prognosis most common malignancy of childhood (1: 7000 live births) 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  Neuroblastomas pathogenesis Germline mutation in anaplastic lymphoma kinase  Neuorblastoma Morphology Small round blue cell tumor neurophil formation* rosette formation(Homer-Wright pseudorosettes**) 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  Neuorblastoma ** * *Neuropil **Homer-Wright Rosettes  Clinical Course and Prognosis Hematogenous & lymphatic metastases to liver, lungs and bone 90% produce catecholamines, but hypertension is uncommon Age & stage are most prognostically < 1 year age: good prognosis regardless of stage Amplification of N-myc oncogene present in 25-30% of cases and is unfavorable Risk Stratification low risk: >90% cure rate high risk 20% cure rate  Prognostic Factors in Neuroblastomas Most profound impact on prognosis  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  Pathogenesis of Wilms Tumor Increased risk in 3 groups: W(ilms tumor) A(niridia) G(enital anomalies) R(edartion mental) syndrome (del 11p13) Wilms tumor -> WT1 gene. Tumor devel. explained by 2 Hit theory First hit -> WT1 germline deletion Second hit -> nonsense or frameshift mutation in second WT1 allele Aniridia -> PAX6 gene Denys-Drash syndrome (male pseudohermaphroditism & early onset nephropathy leading to renal failure) Wilms tumor -> dominant negative missense mutation in WT1gene  Pathogenesis Wilms tumor Beckwitch – Wiedemann syndrome Organomegaly Macroglossia Hemihypertrophy Omphalocele Adrenal cytomegaly Abnormality in WT2 gene (chrom 11p 15.5)  Morphology Wilms Gross Tumor 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 Epithelial Blastema  Clinical Features large abdominal mass Treatment nephrectomy and combination chemotherapy two year survival up to 90% even with spread beyond the kidney SUCCES