Pathology (Disorders of childhood1)

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

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 sleep
• Apparent life-threatening event and SIDS have different RF (ALTE--> premature apnea or respiratory obstruction)

• Maternal smoking
• Age of the mother under 20 years

• 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

• Prone or side sleep position 
•  Sleeping on a soft surface  
• Hyperthermia  
• Co-sleeping in first 3 months of life

• Vital signs
• Apnea of prematurity
• Recent upper respiratory infection
• Immunizations

Breast feeding

Multiple petechia

• 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

• (1) a vulnerable infant
• (2) a critical developmental period in homeostatic control
• (3) an exogenous stressor

delayed development of “arousal” and cardiorespiratory control

• a delayed development of “arousal” and cardiorespiratory control.
• Abnormalities in serotonin dependent signaling in the BS particularly in medulla

Those with a positive history in the sibling

• 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

serotonergic signaling and autonomic innervation

the supine sleeping position

Infections (e.g., viral myocarditis or bronchopneumonia) followed by unsuspected congenital anomalies.

fatty acid oxidation disorders

Congenital anomalies, disorders relating to short gestation (prematurity) and low birth weight, and sudden infant death syndrome (SIDS)

Accidents

congenital anomalies and malignant neoplasms assume major significance

Congenital

• 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

• Polydactyly
• Syndactyly
• CHD
• Anencephaly
• Cleft lip
• 

• 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
• 

• Like disruptions, an extrinsic disturbance of development.
• Common
• 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
• Clubfeet

uterine constraint.

• sequence is a cascade of anomalies triggered by one initiating aberration
• 

• 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.

• 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).

potter sequence

• 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

Agenesis

complete absence of an organ and its associated primordium

Aplasia

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

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.

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

describes an abnormal organization of cells

• Unknown (50%)
• Multifactorial (25%)
• Chromosomal aberrations (10-15%)

Trisomy 21

True

Early in utero death

Robertsonian translocation

Down> cleft lip without palate

SHH

gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3)

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.

rubella, cytomegalic inclusion disease, herpes simplex, varicella-zoster infection, influenza, mumps, human immunodeficiency virus (HIV), and enterovirus

shortly before conception to the sixteenth week of gestation

cataracts, heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia or stenosis, ventricular septal defect, tetralogy of Fallot), deafness, and mental retardation

CMV

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

downregulation of the developmentally important wingless (WNT) signaling pathway through upregulation of endogenous WNT repressors

growth retardation, microcephaly, atrial septal defect, short palpebral fissures, and maxillary hypoplasia

retinoic acid and Hedgehog

ntaneous abortions, premature labor, and placental abnormalities, SIDS, LBW

Maternal hyperglycemia-induced fetal hyperinsulinemia results in increased body fat, muscle mass, and organomegaly (fetal macrosomia); cardiac anomalies, neural tube defects

VSD

Cleft lip/palate/Congenital hip dislocation

• 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.

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.

mutation in SHH pathway causing holoprosencephaly

• Homeobox (HOX)
• Binds to DNA
• Patterning of limbs, vertebrae, and craniofacial structures

• 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

deregulation of components of the transforming growth factor-β (TGF-β) signaling pathway

CNS (beginning of W3)> heart (mid of W3)> ear (mid of W4)

Genitalia (mid W7)> teeth and palate (mid W6)

CNS/genitalia/Ear

AGA 10th to 90th percentile for weight

Prematurity, defined by a gestational age less than 37 weeks

Preterm premature rupture of placental membranes (PPROM)

Intrauterine infection

37th week

• 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

inflammation of placental membranes and enhanced collagen degradation by matrix metalloproteinases

the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection

inflammation of the placental membranes (chorioamnionitis) and inflammation of the fetal umbilical cord (funisitis)

Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, Trichomonas, gonorrhea, Chlamydia.

malaria and HIV

LPS activates TLR-4 which deregulate prostaglandin expression, which in turn induces uterine smooth muscle contractions

• PPROM
• 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).

• Hyaline membrane disease (Neonatal respiratory distress syndrome)  
• Necrotizing enterocolitis
• Sepsis  
• Intraventricular hemorrhage  
• Long-term complications, including developmental delay.

• Fetal
• Placental
• Maternal

chromosomal disorders (triploidy mc followed by trisomy 18), congenital anomalies, and congenital infections (TORCH)

symmetric

• 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

maternal conditions that result in decreased placental blood flow

• 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)

Neurodevelopmental abnormalities

• hypothermia
• respiratory abnormalities
• cardiovascular abnormalities
• intracranial hemorrhage
• hypoglycemia
• necrotizing enterocolitis
• infection
• retinopathy of prematurity

increases in insulin resistance and blood pressure, and a decrease in reproductive rate

RDS

The infant is almost always preterm and AGA, and there are strong,associations with male gender, maternal diabetes, and delivery by cesarean section

• 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

Lung immaturity

deficiency of pulmonary surfactant

• Predominantly of dipalmitoyl phosphatidylcholine (lecithin),
• Smaller amounts of phosphatidylglycerol,
• Two groups of surfactant-associated 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

Type II pneumocytes

• 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
• 

Hypoxia and acidosis induced pulmonary vasoconstriction and pulmonary hypoperfusion

Reduces

Increased

• 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.
• 

48 hours

• 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

Type II pneumocyte

24 to 34 weeks' gestation

extremely premature infants (gestational age ∼26 to 28 weeks)

the delivery of surfactant replacement therapy and oxygen

within 3 or 4 days

• BPD
• 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).

at least 28 days of oxygen therapy in an infant who is beyond 36 weeks'post-menstrual age

VLBW

The major abnormalities in “new” BPD are a striking decrease in alveolar septation (manifested as large, simplified alveolar structures) and a dysmorphic capillary configuration

a potentially reversible impairment in the development of alveolar septation at the saccular stage

hyperoxemia, hyperventilation, prematurity, inflammatory cytokines, and vascular maldevelopment

• patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis
• Long-term--> pulmonary HTN and upper airway disease

<1500 gr

• 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 junctions
• 4) 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

PAF

• 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

• 
• 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

• Short bowel
• Stricture

• 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

• 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.

• 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
• 

• 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

GBS