Pathology (Disorders of childhood1)
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What is the definition of SIDS?
the 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
.........is the leading cause of death between age 1 month and 1 year in US
What is the epidemiology of SIDS?
- Incidence is decreasing
- during the first 6 months of life, most between ages 2 and 4 months
- infants who die of SIDS die at home, usually during the night after a period of sleepApparent life-threatening event and SIDS have different RF (ALTE--> premature apnea or respiratory obstruction)
What are the major maternal RF for SIDS?
- Maternal smoking
- Age of the mother under 20 years
What are the infantile RF for SIDS?
- Brain stem abnormalities, associated with delayed development of 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
- Germline polymorphisms in autonomic nervous system genes
What are the environmental RF for SIDS?
- Prone or side sleep position
- Sleeping on a soft surface
- Co-sleeping in first 3 months of life
What are not RF for SIDS?
- Vital signs
- Apnea of prematurity
- Recent upper respiratory infection
....................Decreased the risk of SIDS
What is the mc pathological finding in SIDS?
What are the pathological findings in SIDS?
- Multiple petechiae are the most common finding (∼80% of cases) on the thymus, visceral and parietal pleura, and epicardium
- Vascular engorgement and pulmonary edema
- Astrogliosis of the brain stem and cerebellum
- Hypoplasia of the arcuate nucleus or a decrease in brain-stem neuronal populations
- Hematopoiesis and periadrenal brown fat
What is the triple-risk model for SIDS?
- (1) a vulnerable infant
- (2) a critical developmental period in homeostatic control
- (3) an exogenous stressor
most compelling hypothesis is that SIDS reflects a ...............................
delayed development of “arousal” and cardiorespiratory control
What are the pathophysiologic changes in SIDS?
- a delayed development of “arousal” and cardiorespiratory control.
- Abnormalities in serotonin dependent signaling in the BS particularly in medulla
traumatic child abuse must be carefully excluded under which circumstances in infants with SIDS?
Those with a positive history in the sibling
What is the role of laryngeal chemoreceptors in SIDS?
- Most SIDS babies have an immediate prior history of a mild respiratory tract infection, but no single causative organism has been isolated.
- These infections may predispose an already vulnerable infant to even greater impairment of cardiorespiratory control and delayed arousal.
- In this context, laryngeal chemoreceptors have emerged as a putative “missing link” between upper respiratory tract infections, the prone position (see below), and SIDS.
- When stimulated, these laryngeal chemoreceptors typically elicit an inhibitory cardiorespiratory reflex.
- Stimulation of the chemoreceptors is augmented by respiratory tract infections, which increase the volume of secretions, and by the prone position, which impairs swallowing and clearing of the airways even in healthy infants.
- In a previously vulnerable infant with impaired arousal, the resulting inhibitory cardiorespiratory reflex may prove fatal
What is the genetic RF for SIDS?
serotonergic signaling and autonomic innervation
..............................is the only safe position that reduces the risk of SIDS
the supine sleeping position
What are the most common causes of sudden “unexpected” death?
Infections (e.g., viral myocarditis or bronchopneumonia) followed by unsuspected congenital anomalies.
Which metabolic disorders can cause sudden unexpected death commonly?
fatty acid oxidation disorders
.............................................................................................. represent the leading causes of death in the first 12 months of life
Congenital anomalies, disorders relating to short gestation (prematurity) and low birth weight, and sudden infant death syndrome (SIDS)
Among the children 1-15 years ........... is the mcc of death
Among the children 1-15 years ........... among the natural causes are the mcc of death
congenital anomalies and malignant neoplasms assume major significance
What is the mcc of death in infants?
What is malformation?
- Primary errors of morphogenesis, in which there is an intrinsically abnormal developmental process
- Multiple genetic loci (multifactorial)
- Not the result of a single-gene or chromosomal defect
- CHD, anencephaly
What are some malformations?
- Cleft lip
What is disruptions?
- Result from secondary destruction of an organ or body region that was previously normal in development
- In contrast to malformations, disruptions arise from an extrinsic disturbance in morphogenesis
- Amniotic bands, denoting rupture of amnion with resultant formation of “bands” that encircle, compress, or attach to parts of the developing fetus, are the classic example of a disruption
- Not heritable
- Associated with environmental cause
What are deformations?
- Like disruptions, an extrinsic disturbance of development.
- Pathogenesis--> is localized or generalized compression of the growing fetus by abnormal biomechanical forces, leading eventually to a variety of structural abnormalities.
- The most common underlying factor responsible for deformations is uterine constraint. Between the 35-38 weeks of gestation, rapid increase in the size of the fetus outpaces the growth of the uterus, and the relative amount of amniotic fluid (which normally acts as a cushion) also decreases.
- Several factors increase the likelihood of excessive compression of the fetus resulting in deformations.
- Maternal factors include first pregnancy, small uterus, malformed (bicornuate) uterus, and leiomyomas.
- Fetal or placental factors include oligohydramnios, multiple fetuses, and abnormal fetal presentation
The most common underlying factor responsible for deformations is .........................
What is a sequence?
- sequence is a cascade of anomalies triggered by one initiating aberration
What is potter sequence?
- The fetal compression associated with significant oligohydramnios, in turn, results in a classic phenotype in the newborn infant, including
- flattened facies and positional abnormalities of the hands and feet, hip dislocation, lung and chest hypoplasia
- Nodules in the amnion (amnion nodosum) are frequently present.
What are the causes of oligohydramnios?
- Chronic leakage of amniotic fluid because of rupture of the amnion
- Uteroplacental insufficiency resulting from maternal hypertension or severe toxemia,
- Renal agenesis in the fetus (because fetal urine is a major constituent of amniotic fluid).
Amnion nodosum is seen in........
What is a syndrome?
- A syndrome is a constellation of congenital anomalies, believed to be pathologically related, that, in contrast to a sequence, cannot be explained on the basis of a single, localized, initiating defect.
- Syndromes are most often caused by a single etiologic agent, such as a viral infection or specific chromosomal abnormality, which simultaneously affects several tissues
....................refers to the complete absence of an organ and its associated primordium.
complete absence of an organ and its associated primordium
........... refers also to the absence of an organ but one due to failure of development of the primordium
is the absence of an organ but one due to failure of development of the primordium
the absence of an opening, usually of a hollow visceral organ, such as the trachea and intestine
What are hypo and hyperplasia?
Hypoplasia refers to incomplete development or decreased size of an organ with decreased numbers of cells, whereas hyperplasia refers to the converse, that is, the enlargement of an organ due to increased numbers of cells.
What are hypo and hypertrophy?
An abnormality in an organ or a tissue as a result of an increase or a decrease in the size (rather than the number) of individual cells defineshypertrophy or hypotrophy, respectively
Dysplasia in the context of malformation.....................................
describes an abnormal organization of cells
What are the mcc of congenital anomaly ?
- Unknown (50%)
- Multifactorial (25%)
- Chromosomal aberrations (10-15%)
What is the only karyotype abnormality that is present at birth with > 10/10000 incidence?
True, false Most chromosomal abnormality are not familial because they arise as defects in gametogenesis
What is the mc consequence of chromosomal abnormalities?
Early in utero death
What is the type of Down syndrome which is inherited?
What are the mcc of birth defect in US?
Down> cleft lip without palate
Holoprosencephaly involves the loss of ....... function
achondroplasia, which is the most common form of short-limb dwarfism, is caused by ................................
gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3)
Why is gain-of function mutation in FGFR3 cause achondroplasia?
The FGFR3 protein is a negative regulator of bone growth, and the activating FGFR3 mutations in achondroplasia are thought to exaggerate this physiologic inhibition, resulting in dwarfism.
What are the viruses that cause congenital malformation?
rubella, cytomegalic inclusion disease, herpes simplex, varicella-zoster infection, influenza, mumps, human immunodeficiency virus (HIV), and enterovirus
The at-risk period for rubella infection extends from .................................................................
shortly before conception to the sixteenth week of gestation
What are the symptoms of CRS?
cataracts, heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia or stenosis, ventricular septal defect, tetralogy of Fallot), deafness, and mental retardation
What is the mc fetal viral infection?
What is the difference between CMV and CRS?
In CMV because organogenesis is largely completed by the end of the first trimester, congenital malformations occur less frequently than in rubella; nevertheless, the effects of virus-induced injury on the formed organs are often severe. Involvement of the central nervous system is a major feature, and the most prominent clinical changes are mental retardation, microcephaly, deafness, and hepatosplenomegaly
The mechanism of thalidomide teratogenicity involves .............................................................................
downregulation of the developmentally important wingless (WNT) signaling pathway through upregulation of endogenous WNT repressors
What is the feature of FAS?
growth retardation, microcephaly, atrial septal defect, short palpebral fissures, and maxillary hypoplasia
Alcohols disrupts which pathways during embryogenic period?
retinoic acid and Hedgehog
What are the association of smoking?
ntaneous abortions, premature labor, and placental abnormalities, SIDS, LBW
What are the manifestations of diabetic embryopathy?
Maternal hyperglycemia-induced fetal hyperinsulinemia results in increased body fat, muscle mass, and organomegaly (fetal macrosomia); cardiac anomalies, neural tube defects
What is the mcc of CHD?
What are the examples of multifactorial cause of congenital anomaly?
Cleft lip/palate/Congenital hip dislocation
What is the importance of the timing of the prenatal teratogenic insult?
The fetal period that follows organogenesis is marked chiefly by the further growth and maturation of the organs, with greatly reduced susceptibility to teratogenic agents. Instead, the fetus is susceptible to growth retardation or injury to already formed organs. It is thereforepossible for a given agent to produce different anomalies if exposure occurs at different times of gestation.
- In the early embryonic period (first 3 weeks after fertilization), an injurious agent damages either enough cells to cause death and abortion or only a few cells, presumably allowing the embryo to recover without developing defects.
- Between the third and the ninth weeks, the embryo is extremely susceptible to teratogenesis, and the peak sensitivity during this period occurs between the fourth and the fifth weeks. During this period organs are being crafted out of the germ cell layers.
Cyclopamine (California lily) acts similar to ...........
mutation in SHH pathway causing holoprosencephaly
Valproic acid disrupts expression of a family of highly conserved developmentally critical transcription factors known as..................
- Homeobox (HOX)
- Binds to DNA
- Patterning of limbs, vertebrae, and craniofacial structures
What is the relation vitamin A to embryogenesis?
- The vitamin A (retinol) derivative all-trans-retinoic acid is essential for normal development and differentiation, and its absence during embryogenesis results in a constellation of malformations affecting multiple organ systems, including the eyes, genitourinary system, cardiovascular system, diaphragm, and lungs
- Conversely, excessive exposure to retinoic acid is also teratogenic. Infants born to mothers treated with retinoic acid for severe acne have a predictable phenotype (retinoic acid embryopathy), including central nervous system, cardiac, and craniofacial defects, such as cleft lip and cleft palate
Vitamin A causes cleft palate through ....................
deregulation of components of the transforming growth factor-β (TGF-β) signaling pathway
The system that might be amenable to teratogens earlier than the others is......................
CNS (beginning of W3)> heart (mid of W3)> ear (mid of W4)
The system that might be highly amenable to teratogens later than the others is......................
Genitalia (mid W7)> teeth and palate (mid W6)
The system that remains amenable to teratogens until the childbirth are...............
What are SGA, AGA, LGA?
AGA 10th to 90th percentile for weight
................is the second most common cause of neonatal mortality
Prematurity, defined by a gestational age less than 37 weeks
What is the mcc of prematurity?
Preterm premature rupture of placental membranes (PPROM)
What is the second mcc of prematurity?
What is the difference between PPROM and PROM?
What are the RF for PROM?
- prior history of preterm delivery, preterm labor and/or vaginal bleeding during the current pregnancy, maternal smoking, low socioeconomic status, and poor maternal nutrition.
- Polymorphisms in genes associated with immune regulation (e.g., tumor necrosis factor [TNF]) or collagen breakdown (e.g., matrix metalloproteinases 1, 8, and 9) have been identified as possible risk factors for PPROM association
the pathophysiology of PPROM typically includes .............
inflammation of placental membranes and enhanced collagen degradation by matrix metalloproteinases
What is the relation of gestational age at delivery and intrauterine infection?
the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection
The histologic correlates of intrauterine infection are ..................................and ...............................
inflammation of the placental membranes (chorioamnionitis) and inflammation of the fetal umbilical cord (funisitis)
What are the mcc of intrauterine infection leading to preterm labor?
Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, Trichomonas, gonorrhea, Chlamydia.
In developing countries, .................and .......... are significant contributors to the burden of preterm labor and prematurity.
malaria and HIV
inflammation-induced preterm labor is caused by what pathophysiology?
LPS activates TLR-4 which deregulate prostaglandin expression, which in turn induces uterine smooth muscle contractions
What are the RF for prematurity?
- Intrauterine infection
- Uterine, cervical, and placental structural abnormalities: Uterine distortion (e.g., uterine fibroids), compromised structural support of the cervix (“cervical incompetence”), placenta previa, and abruptio placentae are associated with an increased risk of prematurity.
- Multiple gestation (twin pregnancy).
What are the consequences of prematurity?
- Hyaline membrane disease (Neonatal respiratory distress syndrome)
- Necrotizing enterocolitis
- Intraventricular hemorrhage
- Long-term complications, including developmental delay.
What are the causes of fetal growth restriction (FGR)?
What are the fetal causes of FGR?
chromosomal disorders (triploidy mc followed by trisomy 18), congenital anomalies, and congenital infections (TORCH)
Fetal FGR is usually..........
What are the placental causes of FGR?
- UPI--> umbilical-placental vascular anomalies (such as single umbilical artery, abnormal cord insertion, placental hemangioma),placental abruption, placenta previa, placental thrombosis and infarction, placental infection, or multiple gestations
- Genetic mosaicism confined to the placenta (confined placental mosaicism) --> MC mutation occurs after second postzygotic division and within dividing trophoblast or extraembryonic progenitor cells of the inner cell mass --> mc Chromosomal trisomies, in particular trisomy 7
What is the mcc of FGR?
maternal conditions that result in decreased placental blood flow
What are the maternal causes of SGA?
- maternal conditions that result in decreased placental blood flow
- Inherited thrombophilia (also associated with recurrent early pregnancy losses)
- narcotic abuse, alcohol intake, and heavy cigarette smoking
- classic teratogens and Maternal malnutrition (particularly hypoglycemia)
What is the major cause of long-term morbidity in premature infants?
What are the short-term complications of prematurity?
- respiratory abnormalities
- cardiovascular abnormalities
- intracranial hemorrhage
- necrotizing enterocolitis
- retinopathy of prematurity
What is the consequence of prematurity in adulthood?
increases in insulin resistance and blood pressure, and a decrease in reproductive rate
What is the mcc of respiratory distress in neonates?
What are the epidmiological features of RDS?
The infant is almost always preterm and AGA, and there are strong,associations with male gender, maternal diabetes, and delivery by cesarean section
What is the usual presentation of RDS?
- Resuscitation may be necessary at birth, but usually within a few minutes rhythmic breathing and normal color are re-established.
- Soon afterward, often within 30 minutes, breathing becomes more difficult, and within a few hours cyanosis becomes evident.
- Fine rales can now be heard over both lung fields. A chest x-ray film at this time usually reveals uniform minute reticulogranular densities, producing a so-called ground-glass picture.
- In the full-blown condition the respiratory distress persists, cyanosis increases, and even the administration of 80% oxygen by a variety of ventilatory methods fails to improve the situation. If therapy staves off death for the first 3 or 4 days, however, the infant has an excellent chance of recovery
What is the most important RF for RDS?
The fundamental defect in RDS is a .................
deficiency of pulmonary surfactant
What are the components of surfactant?
- Predominantly of dipalmitoyl phosphatidylcholine (lecithin),
- Smaller amounts of phosphatidylglycerol,
- Two groups of surfactant-associated proteins.
What is the function of pulmonary surfactant proteins?
- The first group is composed of hydrophilic glycoproteins SP-A and SP-D, which play a role in pulmonary host defense (innate immunity).
- The second group consists of hydrophobic surfactant proteins SP-B and SP-C, which, in concert with the surfactant lipids, are involved in the reduction of surface tension at the air-liquid barrier in the alveoli of the lung.
- Severe respiratory failure in neonates with congenital deficiency of surfactant caused by mutations in the SFTPB or SFTBC
Surfactant is produced by..................
Type II pneumocytes
What is the pathogenesis of RDS?
- With normal levels of surfactant, the lungs retain up to 40% of the residual air volume after the first breath; thus, subsequent breaths require far lower inspiratory pressures.
- With a deficiency of surfactant, the lungs collapse with each successive breath, and so infants must work as hard with each successive breath as they did with the first.
- The problem of stiff atelectatic lungs is compounded by the soft thoracic wall that is pulled in as the diaphragm descends.
- Progressive atelectasis and reduced lung compliance then lead to a train of events, resulting in a protein-rich, fibrin-rich exudation into the alveolar spaces with the formation of hyaline membranes. The fibrin-hyaline membranes constitute barriers to gas exchange, leading to carbon dioxide retention and hypoxemia. The hypoxemia itself further impairs surfactant synthesis, and a vicious cycle ensues
What causes endothelial and epithelial cell damage in the setting of RDS?
Hypoxia and acidosis induced pulmonary vasoconstriction and pulmonary hypoperfusion
What are the pathological features of RDS?
- Lung are of normal size, solid, airless, and reddish purple, similar to the color of the liver, and they usually sink in water.
- Microscopically, alveoli are poorly developed, and those that are present are collapsed.
- When the infant dies early in the course of the disease, necrotic cellular debris can be seen in the terminal bronchioles and alveolar ducts. The necrotic material becomes incorporated within eosinophilic hyaline membranes lining the respiratory bronchioles, alveolar ducts, and random alveoli. The membranes are largely made up of fibrin admixed with cell debris derived chiefly from necrotic type II pneumocytes.
- There is a remarkable paucity of neutrophilic inflammatory reaction associated with these membranes.
- The lesions of hyaline membrane disease are never seen in stillborn infants
- In infants who survive more than 48 hours, reparative changes occur in the lungs. The alveolar epithelium proliferates under the surface of the membrane, which may be desquamated into the airspace, where it may undergo partial digestion or phagocytosis by macrophages.
If alveolar epithelium proliferates under the surface of the membrane in a lung of patients with RDS, he has survived for at least............
What is the composition of hyline membrane in RDS?
- The membranes are largely made up of fibrin admixed with cell debris derived chiefly from necrotic type II pneumocytes.
- There is a remarkable paucity of neutrophilic inflammatory reaction associated with these membranes
Major cells in the hyaline membrane is................................
Type II pneumocyte
Antenatal corticosteroids decrease neonatal morbidity and mortality when administered to mothers with threatened premature delivery at
24 to 34 weeks' gestation
Prophylactic administration of exogenous surfactant at birth to .................................. and administration of surfactant to older premature infants who are symptomatic have been shown to be extremely beneficial
extremely premature infants (gestational age ∼26 to 28 weeks)
Once the infant with RDS is born, the cornerstone of treatment is ...............................
the delivery of surfactant replacement therapy and oxygen
In uncomplicated cases with RDS, recovery begins to occur .......................
within 3 or 4 days
What are the two most important side effects of hyperoxia?
What is the pathogenesis of ROP?
- During the initial hyperoxic phase of RDS therapy (phase I), VEGF is markedly decreased, causing endothelial cell apoptosis;
- VEGF increases after return to relatively hypoxic room air ventilation, inducing the retinal vessel proliferation (neovascularization) characteristic of the lesions in the retina (phase II).
What is BPD?
at least 28 days of oxygen therapy in an infant who is beyond 36 weeks'post-menstrual age
..............infants comprise most of the cases with BPD
What are the pathological findings in BPD?
The major abnormalities in “new” BPD are a striking decrease in alveolar septation (manifested as large, simplified alveolar structures) and a dysmorphic capillary configuration
BPD is caused by ........................
a potentially reversible impairment in the development of alveolar septation at the saccular stage
What are the contributing factors to BPD?
hyperoxemia, hyperventilation, prematurity, inflammatory cytokines, and vascular maldevelopment
What are the other risky conditions in those who have recovered from BPD?
- patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis
- Long-term--> pulmonary HTN and upper airway disease
What is the most important underlying condition of NEC?
What is the pathophysiology of NEC?
- 1) In addition to prematurity, most cases are associated with enteral feeding, suggesting that some postnatal insult (such as introduction of bacteria) sets in motion the cascade culminating in tissue destruction.
- 2) Infectious agents
- 3) Platelet activating factor (PAF), has been implicated in increasing mucosal permeability by promoting enterocyte apoptosis and compromising intercellular tight junctions4) Ultimately, breakdown of mucosal barrier functions permits transluminal migration of gut bacteria, leading to a vicious cycle of inflammation, mucosal necrosis, and further bacterial entry, eventually culminating in sepsis and shock
Levels of.......... is more in NEC than healthy controls
What is the clinical course of NEC?
- Onset of bloody stools, abdominal distention, and development of circulatory collapse.
- X ray--> gas within the intestinal wall (pneumatosis intestinalis).
- Typically involves the terminal ileum, cecum, and right colon
What is the morphology of NEC?
- The involved segment is distended, friable, and congested, or it can be frankly gangrenous; intestinal perforation with accompanying peritonitis may be seen. Microscopically, mucosal or transmural coagulative necrosis, ulceration, bacterial colonization, and submucosal gas bubbles may be seen.
- Reparative changes, such as the formation of granulation tissue and fibrosis, may begin shortly after the acute episode
What are the complications of NEC?
What are the features of transcervical infection?
- Most common route
- Fetus acquires the infection either by inhaling infected amniotic fluid into the lungs shortly before birth or by passing through an infected birth canal during delivery.
- Preterm birth is often an unfortunate consequence and may be related either to damage and rupture of the amniotic sac as a direct consequence of the inflammation or to the induction of labor associated with a release of prostaglandins by the infiltrating neutrophils.
- Inflammation of the placental membranes and cord are usually demonstrable, although the presence or absence and severity of chorioamnionitis do not necessarily correlate with the severity of the fetal infection.
- In the fetus infected by inhalation of amniotic fluid, pneumonia, sepsis, and meningitis are the most common sequelae
What are the features of transplacental infection?
- Most parasitic (e.g., toxoplasma, malaria) and viral infections and a few bacterial infections (i.e., Listeria, Treponema) gain access to the fetal bloodstream transplacentally via the chorionic villi.
- This hematogenous transmission may occur at any time during gestation or occasionally, as may be the case with hepatitis B and HIV, at the time of delivery via maternal-to-fetal transfusion.
What are the features of Parvovirus infection?
- Parvovirus B19, which causes erythema infectiosum or “fifth disease of childhood” in immunocompetent older children, can infect 1% to 5% of pregnant women, and the vast majorityhave a normal pregnancy outcome.
- Adverse pregnancy outcomes in a minority of intrauterine infections include spontaneous abortion (particularly in the second trimester), stillbirth, hydrops fetalis and congenital anemia.
- Parvovirus B19 has a particular tropism for erythroid cells, and diagnostic viral large homogeneous intranuclear inclusions and a surrounding peripheral rim of residual chromatin can be seen in early erythroid progenitor cells in infected infants
What are the features of neonatal sepsis?
- Perinatal sepsis can also be grouped clinically based on early onset (within the first 7 days of life) versus late onset (from 7 days to 3 months).
- Most cases of early-onset sepsis are acquired at or shortly before birth and tend to result in clinical signs and symptoms of pneumonia, sepsis, and occasionally meningitis within 4 or 5 days of life. Group B streptococcus is the most common organism isolated in early-onset sepsis and is also the most common cause of bacterial meningitis.
- Infections with Listeria and Candida follow a latent period between the time of microorganism inoculation and the appearance of clinical symptoms and present as late-onset sepsis
What is the mcc of neonatal sepsis?
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