Aims Pediatric Diseases and Genetic screening techniques. Lecture #32 Handout Aims Pediatric Diseases and Genetic screening techniques. Readings; Robbins, Chapter 7 pages 238-272

Accidents are the leading cause of death in ages 1-14. Diseases originating in the perinatal period account for significant morbidity and mortality. The infant mortality rate in the US has decreased from 20/1000 live births in 1970 to 6.9/1000 in 2000. Congenital anomalies, disorders relating to short gestation & low birth weight, and SIDS account for the majority of deaths in the 1st year of life. Accidents are the leading cause of death in ages 1-14. Robbins & Cotran’s Pathologic Basis of Disease Table 10-1

Congenital Anomalies These are morphologic defects that are _____________________________________. Congenital does not imply or exclude a genetic basis for the defect (not hereditary). These defects found in live births represent the least serious developmental failures during embryogenesis (approx. 20% of fertilized ova have defects so incompatible with life that implantation never occurs). There are basically 5 types of errors in morphogenesis.

Congenital Anomalies Malformations Primary errors of morphogenesis Intrinsic error in the developmental process Usually multifactorial rather than the result of a single gene or chromosomal defect. Both single & multiple organ/tissue defects can occur. Polydactyly (extra digits) & syndactyly (fusion of digits) are the malformations shown here. Robbin’s Basic Pathology 7-19

Congenital Anomalies Disruptions Result from secondary destruction of an organ or body region that was developing normally. Arise from an extrinsic disturbance in morphogenesis. Amniotic bands formed from a ruptured amniotic sac can encircle or compress part of the developing fetus (classic example of a disruption defect). Robbins & Cotran’s Pathologic Basis of Disease 10-2 & Robbin’s Basic Pathology 7-20

Congenital Anomalies Deformations Extrinsic disturbance in morphogenesis. Common problems that affect about 2% of newborn infants to varying degrees. Localized or generalized compression of the growing fetus by abnormal biomechanical forces leading to a variety of structural abnormalities. Most common is uterine constraint Both maternal (1st pregnancy, small uterus, malformed uterus) & fetal (multiple fetuses, oligohydramnios) factors can contribute to deformation.

Congenital Anomalies Sequence Multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis (Example is oligohydramnios). Oligohydramnios results from decreased amniotic fluid due to renal agenesis, amniotic leak, or maternal influences (hypertension or toxemia). Results in fetal compression. Robbin’s Basic Pathology 7-21

Congenital Anomalies Syndromes The presence of several defects that cannot be explained by a single error in morphogenesis. Most often caused by a single causative factor (viral infection or chromosomal abnormality) that simultaneously affects multiple tissues.

Causes of Congenital Anomalies 3 major categories of known causes (50% are unknown) Genetic Chromosomal Single gene defects Environmental Multifactorial Robbins Basic Pathology Table 7-9

Causes of Congenital Anomalies Genetic Causes (Chromosomal) Virtually all of the chromosomal syndromes are associated with congenital malformations. Down syndrome, Klinefelter syndrome, Turner syndrome, Patau syndrome The great majority of these arise as defects in gametogenesis and are therefore not familial. 80-90% of fetuses with abnormal chromosome # (aneuploidy) die in utero at very early stages of gestation.

Causes of Congenital Anomalies Genetic Causes (Single Gene Defects) Of those that result in congenital anomalies, 90% are inherited in an autosomal dominant or recessive pattern while the remainder are X-linked. Many of the defects that arise involve genes responsible for normal organogenesis and development. Polydactyly and syndactyly result from a defect in the protein GLI3 (a downstream target of sonic hedgehog).

Causes of Congenital Anomalies Environmental Causes Influences to which the mother was exposed during pregnancy may cause fetal malformations. Viruses (Rubella) Drugs & other chemicals (thalidomide, alcohol-leading to fetal alcohol syndrome, androgens, 13-cis-retinoic acid [Accutane]) Radiation Maternal Diabetes-diabetic embryopathy

Causes of Congenital Anomalies Multifactorial Causes The inheritance of certain mutant genes requires an interaction with the environment to fully express themselves as congenital anomalies. Dietary intake of folic acid has reduced the incidence of many neural tube defects because the lack of folic acid in the mother’s diet (environmental factor) resulted in certain genes not being expressed in development (genetic factor)

Pathogenesis of Congenital Anomalies The timing of the prenatal insult has an important effect on both the occurrence and type of malformation produced. Embryonic period (1st 9 weeks) & Fetal period (week 10 to birth) Robbins & Cotran’s Pathologic Basis of Disease 10-5

Pathogenesis of Congenital Anomalies Embryonic Period In the 1st 3 weeks an injurious agent damages either enough cells to cause death & abortion or only a few cells from which recovery and normal development occur. Between weeks 3-9 (organogenesis) the embryo is extremely susceptible to teratogens causing major morphological abnormalities (peak is during weeks 4 & 5). Fetal Period Follows organogenesis and is marked by further growth and maturation of the organs with greatly reduced susceptibility to teratogens. The fetus is susceptible to growth retardation or injury to the already formed organs. Robbins & Cotran’s Pathologic Basis of Disease 10-5

Pathogenesis of Congenital Anomalies Genes that regulate morphogenesis may be the target of teratogens. There is a complex interplay between environmental teratogens and intrinsic genetic defects. Vitamin A (retinol) derivitive all-trans-retinoic acid is essential for normal development, but retinoic acid itself (taken for acne) is a known teratogen causing retinoic acid embryopathy. Robbins & Cotran’s Pathologic Basis of Disease 10-6

Prematurity & Fetal Growth Restriction Infants born before completion of normal gestation. Prematurity is the 2nd most common cause of neonatal mortality (congenital anomalies is 1st). It is defined by a gestational age of less than 37 weeks.

Prematurity & Fetal Growth Restriction Major Risk Factors for Prematurity Preterm premature rupture of placental membranes (PPROM) Accounts for 30-40% of preterm deliveries. Single most identifiable cause of prematurity. 3 most common risk factors for PPROM are: Maternal smoking Prior history of preterm delivery Vaginal bleeding at any time during the pregnancy

Prematurity & Fetal Growth Restriction Major Risk Factors for Prematurity Intrauterine infections Major cause of premature labor with or without intact membranes. Present in about 25% of all preterm births with the frequency increasing as the gestational age decreases. Histologically there is inflammation of the placental membranes (chorioamnionitis) & inflammation of the fetal umbilical cord (funisitis). The most common organisms associated with intrauterine infections are Ureaplasma urealyticum, Mycoplasma hominis, Trichomonas, gonorrhea, & Chlamydia. Inflammatory cells recruited to the site of infection initiate the preterm labor by the release of collagenases and elastases resulting in ROM or release of prostaglandins to induce uterine contractions.

Prematurity & Fetal Growth Restriction Major Risk Factors for Prematurity Uterine, cervical, and placental structural abnormalities Uterine fibroids are an example Multiple gestation (twins)

Prematurity & Fetal Growth Restriction Many of the causes of prematurity can also result in Fetal Growth Restriction (FGR). Also called Intrauterine Growth Retardation (IUGR).

Prematurity & Fetal Growth Restriction 3 Classes of Risk Factors for FGR Fetal Factors that impair growth despite adequate utero-placental blood and nutrient exchange. They include chromosomal disorders, congenital malformations, & congenital infections. When these factors are involved, the FGR is said to be symmetrical (affects all organ systems equally).

Prematurity & Fetal Growth Restriction 3 Classes of Risk Factors for FGR Placental Any factor that compromises the utero-placental blood and nutrient exchange. May result from placenta previa (low implantation), placental infarction (loss of blood supply to placenta), multiple gestations or other causes. FGR from these factors is asymmetric (the brain is spared compared to the viscera).

Prematurity & Fetal Growth Restriction 3 Classes of Risk Factors for FGR Maternal The most common cause. Factors include vascular diseases like preeclampsia (“toxemia of pregnancy”) & chronic hypertension. Additionally, narcotic abuse, alcoholism, malnutrition, and heavy smoking can adversly affect fetal growth.

Immaturity of Organ Systems Vital Organs affected in Preterm Births Lungs Incomplete alveolar development Kidneys Incomplete formation of glomeruli Brain Brain is smooth and devoid of the involutions & there is poorly developed myelination Liver Lack of physiologic maturity (jaundice is evident)

Apgar Score The Apgar score is a method to evaluate the physiologic condition & responsiveness of newborns and thus their chances of survival. 5 parameters of the newborn are evaluated at 1 min. and 5 min. with a score of 10 being the best possible condition. Infants with a 5 min. Apgar score of 0-1 have a 50% mortality in the 1st month of life and it drops to 20% with a 4 and almost 0% with a 7 or better. Robbins & Cotran’s Pathologic Basis of Disease Table 10-4

Perinatal Infections Infections of the fetus and neonate may be acquired transcervically (ascending infections) or transplacentally (hematologic infections).

Perinatal Infections Transcervical (Ascending) Infections Involve the spread of infection from the cervicovaginal canal and can be acquired in utero or during birth. Most bacterial (streptococcus) and a few viral (herpes simplex) infections are acquired this way. The fetus acquires the infection by inhaling infected amniotic fluid into the lungs or by passing through an infected birth canal. The infection is usually associated with inflammation of the placental membranes (chorioamnionitis) and the umbilical cord (funisitis).

Perinatal Infections Transplacental (Hematologic) Infections These infections are usually caused by viruses, parasites, and some bacteria. The infecting microbes gain access to the fetal bloodstream through the placenta. The most important organisms go by the acronym TORCH Toxoplasma, Rubella virus, Cytomegalovius, Herpesvirus, & a number of Other microbes These organisms cause similar symptoms including fever, encephalitis, chorioretinitis, pneumonia, myocarditis, & hemolytic anemia.

Neonatal Respiratory Distress There are many causes of respiratory distress in the newborn including excessive sedation of the mother, fetal head injury during delivery, aspiration of blood or amniotic fluid, & intrauterine hypoxia caused by coiling of the umbilical cord around the neck. The most common cause is Respiratory Distress Syndrome (RDS) which is also called hyaline membrane disease. Formation of membranes in the peripheral airspaces of the infant.

Neonatal Respiratory Distress Robbin’s Basic Pathology 7-22

Neonatal Respiratory Distress Pathogenesis of RDS Its a disease of prematurity. It affects 15-20% of infants born between weeks 32-36 & the rate increases to 60% in those born before 28 weeks. The fundamental defect is the inability of the immature lung to synthesize sufficient surfactant. Without sufficient surfactant the alveoli collapse (atelectasis). This leads to hypoxemia & and CO2 retention that lead to a cascade of events culminating in necrosis and fibrin deposition and the formation of hyaline membranes in the lungs. Robbin’s Basic Pathology 7-22

Neonatal Respiratory Distress Infants with RDS usually appear normal at birth, but within minutes to hours develop a labored, grunting respiration that progressively worsens. If this labored breathing goes uncontrolled by immediate therapy, death will occur. RDS is the major cause of death in the neonatal period.

Necrotizing Enterocolitis (NEC) NEC is predominantly a complication of prematurity and is associated with a high perinatal morbidity & mortality. The cause is multifactorial and includes: Intestinal ischemia This is a prerequisite and may result from general hypoperfusion or selective reduction of blood flow to the intestines. Bacterial colonization of the gut Formula feeding

Necrotizing Enterocolitis (NEC) NEC mostly involves the terminal ileum, cecum, and rt. colon. The involved segment is distended (leaving very thin walls), brittle, and congested or it can even be gangrenous & necrotic. NEC is associated with a high perinatal mortality and infants who survive often develop post-NEC strictures from fibrosis caused by healing. Robbin’s Basic Pathology 7-24

Objectives Describe the 5 types of congenital anomalies and the 3 main causes. Describe the pathogenesis of congenital anomalies. Timing (embryonic & fetal period) Vitamin A deficiency & Retinoic acid embryopathy. Describe prematurity and fetal growth restriction. Major risk factors Classes of risk factors Describe perinatal infections. Transcervical and Transplacental Describe neonatal respiratory distress and necrotizing enterocolitis.