General Pathology - Diseases of Infancy and Childhood PDF

General Pathology INTRODUCTION THE DIFFERENT STAGES Each stage of development of the infant and child involves OF DEVELOPMENT AND a different group of disorders: THEIR RELATED (1) Neonatal period – first 4 weeks of life DISORDERS (2) Infan...

General Pathology INTRODUCTION THE DIFFERENT STAGES Each stage of development of the infant and child involves OF DEVELOPMENT AND a different group of disorders: THEIR RELATED (1) Neonatal period – first 4 weeks of life DISORDERS (2) Infancy – first year of life (3) Age 1 to 4 years (4) Age to 5 to 14 years Leading causes of death in infancy: o congenital anomalies o disorders related to short gestation (prematurity) o low birth weight o sudden infant death syndrome Leading cause of death in childhood (1 to 9 years) o injuries from accidents CONGENITAL ANOMALIES WHAT ARE CONGENITAL ➔ anatomic defects that are mostly present at birth ANOMALIES? ➔ some may not be clinically apparent until years later (e.g., cardiac defects and renal anomalies) ➔ “congenital” = “born with” ➔ most common cause of mortality in the first year ➔ may represent less serious developmental failures in embryogenesis that are compatible with live birth DEFINITIONS Morphogenesis o Refers to the process of organ and tissue development o Can be impaired by a variety of errors: - represent primary errors of morphogenesis - involves an intrinsically abnormal developmental process - can be result of: (1) o single gene or chromosomal defect Malformations o multiple genetic loci (multifactorial) → more common - present in several patterns o some may involve single body systems (e.g., congenital heart defects, anencephaly) o some may involve many organs Polydactyly = one or more extra digits Cleft left lip (with or without cleft Example of stillbirth = midface Syndactyly = fusion of digits palate) = compatible with life when it structures are fused or ill-formed + Have little functional consequence occurs in isolation internal anomalies (maldevelopment when they occur in isolation Malformation syndrome (trisomy 13) of brain, cardiac defects) Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology - d/t secondary destruction of an organ or body region that was (2) previously normal in development Disruptions - arise from an extrinsic disturbance in morphogenesis - may be caused by a variety of environmental agents - not heritable → not associated with risk of recurrence in subsequent pregnancies Amniotic bands - classic example of disruption - rupture of amnion with resultant formation of “bands” that encircle, compress, or attach to parts of the developing fetus - the image shows a band of amnion extending from the top portion of the amniotic sac to encircle the leg of the fetus - also arise from an extrinsic disturbance in morphogenesis - involve localized or generalized compression of the growing fetus by abnormal biomechanical forces Uterine Constraint - serve as the most common underlying factor - between the 35th-36th week of gestation, rapid increase in the size of the fetus outpaces the growth of the uterus (3) Factors that increase the likelihood of excessive compression: Deformations (1) Maternal factors o first pregnancy o small uterus o malformed (bicornuate) uterus o leiomyomas (2) Fetal or placental factors o oligohydramnios o multiple fetuses o abnormal fetal presentation Example of deformation: clubfeet (component of Potter sequence) - cascade of anomalies triggered by 1 initiating aberration (4) - may occur singly or in multiples Sequence - may be explained by a single localized aberration in organogenesis (malformation, disruption, deformation) → cause secondary effects in other organs Oligohydramnios (Potter) Sequence - classic example of sequence - decreased amniotic fluid - caused by a variety of unrelated maternal, placental, and fetal abnormalities Causes: o chronic leakage of amniotic fluid d/t rupture of amnion o uteroplacental insufficiency d/t maternal hypertension or severe toxemia o renal agenesis (because fetal urine is a major constituent of amniotic fluid) Consequences: o flattened facies o positional abnormalities of hands and feet o breech presentation; dislocation of hips o hypoplastic lungs → usual cause of fetal demise o amnion nodosum (nodules in the amnion) Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology - constellation of congenital anomalies that cannot be explained on the (5) basis of a single, localized, initiating defect Malformation Syndrome - most often caused by a single etiologic agent (e.g., viral infection, chromosomal abnormality) which simultaneously affects several tissues Other organ-specific terms: o Agenesis: complete absence of an organ and its associated primordium o Aplasia: absence of an organ that occurs d/t failure of growth of the existing primordium o Atresia: absence of an opening of a hollow visceral organ (e.g., trachea, intestine) o Hypoplasia: incomplete development or decreased size of an organ with decreased number of cells o Hyperplasia: enlargement of an organ d/t increased number of cells o Hyper- or hypotrophy: increase or decrease in the size of individual cells o Dysplasia: abnormal organization of cells CAUSES OF ANOMALIES GENETIC CAUSES (12-25%) Chromosomal aberrations (10-15%) o Arise from gametogenesis (not familial) o Examples: - Down Syndrome and other trisomies - Turner Syndrome - Klinefelter syndrome o Exception: transmissible Down Syndrome associated with a Robertsonian translocation in the parent o 80-90% of fetuses with aneuploidy die in utero, the majority in the earliest stages of gestation Single-gene mutations (2-10%) o underlie major malformations o characterized by mendelian inheritance Holoprosencephaly - most common developmental defect of the forebrain and midface in humans - loss-of function mutations in Hedgehog signaling pathway (which plays a critical role in the morphogenesis of the said structures) Achondroplasia - most common form of short limb dwarfism - gain-of-function mutations in fibroblast growth factor receptor 3 (which is a negative regulator of bone growth) ENVIRONMENTAL CAUSES (8-13%) Maternal/placental infections (2-3%) o Rubella, Cytomegalovirus, Herpes simplex, varicella-zoster, influenza, mumps, HIV, and enterovirus Rubella - lead to rubella embryopathy - infection extends from shortly before conception to the 16 th week of gestation - Hazard greater in the first 8 weeks than in the second 8 weeks - Congenital rubella syndrome: cataracts, heart defects, deafness, mental retardation Cytomegalovirus - most common fetal viral infection - highest at risk period: 2nd trimester of pregnancy - congenital malformations occur less frequently than in rubella - Features: CNS involvement, metal retardation, microcephaly, deafness, hepatosplenomegaly Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology Maternal diseases states (6-8%) o include diabetes, phenylketonuria, endocrinopathies Diabetes mellitus - cause maternal hyperglycemia-induced fetal hyperinsulinemia or diabetic embryopathy - results in fetal macrosomia (organomegaly + increased body fat and muscle mass) - others: cardiac anomalies, neural tube defects, CNS malformations Drugs and chemicals (1%) o include thalidomide, folate antagonists, androgenic hormones, alcohol, anticonvulsants, warfarin, 13-cis- retinoic acid Thalidomide - used as a tranquilizer - causes 50-80% of limb abnormalities in exposed fetus - MOA: downregulation of WNT signaling pathway through the upregulation of endogenous WNT repressors Alcohol - Most widely used teratogen - Cause structural anomalies + subtle cognitive and behavioral defects in the fetus - Fetal alcohol syndrome: growth retardation, microcephaly, atrial septal defect, short palpebral fissures, maxillary hypoplasia - MOA: disruption of retinoic acid signaling pathway and Hedgehog signaling pathway Smoke-derived nicotine - high incidence of spontaneous abortions, premature labor, placental abnormalities - low birth weight - prone to SIDS Irradiations (1%) o mutagenic, carcinogenic, teratogenic o cause malformations such as microcephaly, blindness, skull defects, spina bifida MULTIFACTORIAL INHERITANCE (20-25%) o most common cause of congenital malformations o implies the interaction of environmental influences with 2 or more genes of small effect o result of inheritance of multiple genetic polymorphisms that confer a “susceptibility phenotype” o interaction with environment is required before the disorder becomes manifested o decreased incidence of neural tube defects by intake of folic acid Congenital dislocation of the hip - genetic factor: shallow acetabular socket - environmental factor: frank breech position in utero UNKNOWN (40-60%) PATHOGENESIS OF Two general principles: CONGENITAL ANOMALIES (1) The timing of the prenatal teratogenic insult has an important impact on the occurrence and the type of anomaly produced Early embryonic period (first 3 weeks after fertilization) o if injurious agent damages enough cells → cause death and abortion o if only a few cells are damaged → allow embryo to recover without developing defects Late embryonic period (between the 3rd and 9th week) o organs are being crafter out of the germ cell layers o embryo is extremely susceptible to teratogenesis o peak sensitivity: between 4th and 5th weeks Fetal period o marked by further growth and maturation of the organs o greatly reduced susceptibility to teratogenic agents o susceptible to growth retardation or injury to already formed organs Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology (2) Features of dysmorphogenesis caused by environmental insults can often be recapitulated by genetic defects in the pathways targeted by these teratogens Cyclopamine o Plant teratogen (California Lily) o Effects: severe craniofacial abnormalities - holoprosencephaly - cyclopia (single fused eye) o MOA: inhibits hedgehog signaling in the embryo o Genetic counterpart: mutations in hedgehog signaling cause holoprosencephaly Valproic acid o an antiepileptic o recognized teratogen during pregnancy o MOA: disrupts expression of homeobox (HOX) proteins, which are implicated in the patterning of limbs, vertebrae, and craniofacial structures o Genetic counterpart: mutations in HOX cause same features in valproic acid embryopathy All-trans-retinoic acid o vitamin A (Retinol) derivative o absence during embryogenesis - malformations affecting multiple organ systems - essential for normal development and differentiation o excessive exposure - retinoic acid embryopathy - CNS, cardiac, craniofacial defects (e.g., cleft lip and cleft palate) - MOA: mediate deregulation of components of TGF-β signaling (involved in palatogenesis) - Genetic counterpart: mutations in Tgfb3 gene cause cleft palate PREMATURITY & FETAL GROWTH RESTRICTION WHAT IS PREMATURITY? ➔ gestational age less than 37 weeks ➔ 2nd most common cause of neonatal mortality Appropriate for gestational age (AGA) Birthweight between 10th and 90th percentile Small for gestational age (SGA) Birthweight below 10th percentile Large for gestational age (LGA) Birthweight above 90th percentile Preterm Born before 37 weeks Post-term Born after 42nd week Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology WHAT ARE THE MAJOR (1) Preterm premature rupture of placental membranes (PPROM) RISK FACTORS FOR o complicates about 3% of pregnancies PREMATURITY? o responsible for 1/3 of all preterm deliveries o described as the spontaneous rupture of membrane before 37 weeks gestation - if after 37 weeks: PROM - after 37 weeks, the associated risk to the fetus is considerably decreased Pathophysiology of PPROM: Inflammation of placental membranes Enhanced collagen degradation by MMPs What are the clinical risk factors for PPROM? a) Prior history of preterm delivery b) Preterm labor c) Vaginal bleeding during current pregnancy d) Maternal smoking e) Low socioeconomic status f) Poor maternal nutrition g) Polymorphisms in genes associated with: Immune regulation – Tumor Necrosis Factor (TNF) Collagen breakdown – Matrix metalloproteinases (MMP 1, 8, 9) (2) Intrauterine infection o the major cause of preterm labor with and without intact membranes o present in ~25% of all preterm births o earlier gestational age at delivery = higher frequency of intra-amniotic infection Histologic correlates: Chorioamnionitis = inflammation of the placental membranes Funisitis = inflammation of the fetal umbilical cord Most common microorganisms implicated: a) Ureaplasma urealyticum b) Mycoplasma hominis c) Gardnerella vaginalis (dominant organism in bacterial vaginosis) d) Trichomonas e) Gonorrhea f) Chlamydia Pathophysiology: - Endogenous Toll-like receptors (TLRs) serve as key players - Bind bacterial components as natural ligands (activated by bacterial LPS) - Deregulates prostaglandin expression → induces uterine smooth muscle contractions (3) Uterine, cervical, and placental structural abnormalities o Uterine distortion (e.g., uterine fibroids) o Cervical incompetence = compromised structural support of the cervix o Placenta previa o Abruptio placentae (4) Multiple gestation (twin pregnancy) THE HAZARDS OF ➔ Neonatal respiratory disease syndrome (“hyaline membrane disease”) PREMATURITY ➔ Necrotizing enterocolitis ➔ Sepsis ➔ Intraventricular and germinal matrix hemorrhage ➔ Long-term complications (e.g., developmental delay) Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology FETAL GROWTH o Preterm infants RESTRICTION (FGR) - Have low birth weights - Birth weight often become appropriate once adjusted for their gestational age o Small-for-gestational-age (SGA) infants - Refer to some infants (1/3) who weigh less than 2500 gm despite being born at term - undergrown rather than immature - suffer from fetal growth restriction (aka intrauterine growth retardation) Causes of fetal growth restriction: Fetal Abnormalities Maternal Abnormalities Placenta Abnormalities - intrinsically reduce growth potential - most common factor associated - uteroplacental insufficiency despite an adequate supply of with SGA infants: maternal - result in asymmetric or nutrients conditions that result in decreased disproportionate growth retardation - characterized by symmetric growth blood flow with relative sparing of the brain restriction (proportionate FGR) → 1) Vascular diseases - viewed as downregulation of growth all organ systems are similarly ▪ preeclampsia (toxemia of in late half of gestation d/t limited affected pregnancy) availability of nutrients and oxygen 1) Chromosomal disorders ▪ chronic hypertension ▪ triploidy ▪ thrombophilias (e.g., acquired Causes of insufficiency: ▪ trisomy 18, 21, and 13 antiphospholipid antibody ▪ umbilical-placental vascular ▪ deletions & translocations syndrome) anomalies ▪ inherited diseases of ✓ single umbilical artery 2) Fetal infections ✓ abnormal cord insertion ▪ should be considered in all hypercoagulability ✓ placental hemangioma infants with FGR 2) Maternal malnutrition ▪ placenta abruption ▪ most commonly responsible: ▪ prolonged hypoglycemia ▪ placenta previa TORCH (Toxoplasmosis, affects fetal growth ▪ placental thrombosis & infarction Rubella, Cytomegalovirus, 3) Avoidable factors ▪ placental injection Herpes) + others ▪ narcotic abuse ▪ multiple gestations 3) Congenital anomalies ▪ alcohol intake ▪ some do not have any detectable ▪ heavy cigarette smoking cause 4) Drugs ▪ classic teratogens (e.g., chemotherapeutic agents) ▪ commonly administered therapeutic agents (e.g., phenytoin – Dilantin) Chromosomal mosaicism: o recently discovered cause of FGR o results from viable genetic mutations occurring after zygote formation o most frequently documented: chromosomal trisomies (trisomy 7) Types of constitutional chromosomal mosaicism (1) Generalized constitutional mosaicism - occur at the time of the 1st and 2nd postzygotic division (2) Confined placental mosaicism - occurs later and within dividing trophoblast or extraembryonic progenitor cells of the inner cell mass - limited to placenta (3) Confined to the embryo NEONATAL RESPIRATORY What are the causes of respiratory distress in the newborn? DISTRESS SYNDROME ➔ Respiratory distress syndrome (RDS) – most common ➔ Excessive sedation of the mother ➔ Fetal head injury during delivery ➔ Aspiration of blood or amniotic fluid ➔ Intrauterine hypoxia d/t coiling of umbilical cord around neck What is RDS? o aka hyaline membrane disease o deposition of a layer of hyaline proteinaceous material in the peripheral airspaces of infants Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology What are the characteristic clinical findings in RDS? o Infant is almost always preterm (but has weight appropriate for gestational age or AGA) o Strong associations with: a) male gender b) maternal diabetes c) delivery by cesarean section Clinical course: Birth: resuscitation may be necessary First few minutes: reestablished rhythmic breathing and normal color Within 30 minutes: breathing becomes more difficult Within a few hours: - cyanosis becomes evident - rales heard over both lung fields - CXR reveals uniform minute reticulogranular densities → “ground-glass picture” In full-blown RDS - respiratory distress persists - cyanosis increases - administration of 80% oxygen fails to improve the situation Pathogenesis of RDS o Immaturity of the lungs is the most important substrate o Incidence is inversely proportional to gestational age - Born less than 28 weeks of gestation → 60% - Born between 28 to 32 weeks → 30% - Born after 34 weeks → 5% o Fundamental defect: deficiency of pulmonary surfactant Composition of the pulmonary surfactant: - Dipalmitoyl phosphatidylcholine (lecithin) - Phosphatidylglycerol - Surfactant-associated proteins: Group 1: hydrophilic SP-A and SP-D Group 2: hydrophobic SP-B and SP-C Function or roles of the pulmonary surfactant: - SP-A and SP-D play a role in pulmonary host defense (innate immunity) - SP-B and SP-C are involved in reduction of surface tension at the air-liquid barrier - Reduced surface tension = less pressure required to keep alveoli patent - Mutations in SFTPB and SFTBC → severe respiratory failure in neonates Production of surfactant: - by type II alveolar cells - accelerated after 35th week of gestation o High inspiratory pressure at birth → lungs retain 40% of residual air volume Normal levels of surfactant after first breath → subsequent breaths require far lower inspiratory pressures o High inspiratory pressure at birth → lungs collapse with each successive breath → infant must work as hard as in the first breath In deficiency of surfactant o Problem of stiff atelectatic lungs is compounded by the soft thoracic wall that is pulled as the diaphragm descends o Progressive atelectasis + reduced lung compliance → protein-rich, fibrin- rich exudation into the alveolar spaces and formation of hyaline membranes o Hyaline membranes act as barriers to gas exchange → CO2 retention + hypoxemia → impair surfactant synthesis → cycle repeats Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology Factors affecting surfactant synthesis: - Modulation by hormones and growth factors → cortisol, insulin, prolactin, thyroxine, TGF-β - Glucocorticoids ➔ particularly important role ➔ increased corticosteroid release (d/t intrauterine stress and FGR) → lower risk of RDS - Compensatory high levels of insulin in infants of diabetic mothers ➔ counteracts the effects of steroids ➔ higher risk of RDS - Labor ➔ increase surfactant synthesis ➔ increased risk of RDS in cesarean section Morphology Gross - normal size - solid, airless, reddish purple (color of liver) - usually sink in water Microscopic: - poorly developed alveoli; those present are collapsed - alternating atelectasis and dilation of alveoli - presence of thick eosinophilic hyaline membranes lining the dilated alveoli - upon death: necrotic cellular debris can be seen in the terminal bronchioles and alveolar ducts - Membranes are largely made up of fibrin admixed with cell debris derived from necrotic type II pneumocytes Clinical features o Major thrust in the control of RDS focuses on prevention via: (1) Delaying labor until the fetal lung reaches maturity (2) Inducing maturation of the lung in the fetus at risk o Analysis of amniotic fluid phospholipids → good estimate of level of surfactant in alveolar lining o Once infant is born, treatment consists of: - delivery of surfactant replacement therapy - oxygen therapy o Therapy can result in oxygen toxicity caused by oxygen-derived free radicals o ↑ Concentrations of oxygen administered for prolonged periods cause two well-known complications: - Retrolental fibroplasia (aka retinopathy of prematurity) - Bronchopulmonary dysplasia Retrolental fibroplasia Bronchopulmonary dysplasia Hyperoxic phase - diagnosis: at least 28 days of O2 therapy - expression of VEGF is markedly decreased - decrease in alveolar septation + dysmorphic - cause endothelial cell apoptosis capillary configuration Hypoxic phase - d/t potentially reversible impairment in - VEGF levels rebound to hypoxic room air development of septation at saccular stage ventilation → retinal vessel proliferation - Increased levels of proinflammatory cytokines in (neovascularization) the alveoli → TNF, IL-1B, IL-6, IL-8 - cause lesions in the retina Contributing factors: hyperoxemia, hyperventilation, prematurity, inflammation, vascular maldevelopment Infants who recover from RDS are at an increased risk of: - Patent ductus arteriosus - Intraventricular hemorrhage - Necrotizing enterocolitis Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology NECROTIZING ➔ Most common in premature infants ENTEROCOLITIS (NEC) ➔ Incidence = inversely proportional to gestational age o Occurs in 1 out 10 very low birth weight infants ( 1 mL of Rh+ fetal RBCs) (3) Initial exposure to Rh antigen evokes the formation of IgM antibodies ➔ First pregnancy: exposure evokes formation of IgM (do not cross the placenta) → no RH disease ➔ Subsequent pregnancy: formation of IgG (can cross the placenta) → risk of immune hydrops o Incidence of Rh isoimmunization has decreased significantly since the use of Rhesus immune globulin (RhIg) containing anti‐D antibodies. o Administration of RhIg at 28 weeks and within 72 hrs of delivery to Rh negative mothers o RhIg is also administered following abortions Fetal hemolysis by maternal-fetal ABO incompatibility - ABO incompatibility: occurs in 20-25% of pregnancies, but hemolysis occurs only in 1 out 10 - Severe enough to require treatment in only 1 out 200 - Several factors account for this: a) Most anti-A and anti-B antibodies are of the IgM type and do not cross the placenta b) Neonatal red cells express blood group antigens A and B poorly c) Many cells other than red cells express A and B antigens and thus absorb some of the transferred antibody - Hemolytic disease occurs almost exclusively in infants of group A/B with group O mothers - Certain Group O women possess IgG antibodies directed against A or B antigens even without prior sensitization → firstborn may be affected, but lysis of infant’s RBC is minimal - No effective protection against ABO reactions Two consequences of excessive destruction or red cells in neonates: Anemia Jaundice o Direct result of red cell loss o Hemolysis produces unconjugated bilirubin o May result in hypoxic injury to the heart and liver o Bilirubin passes through infant’s poorly o Liver injury → decreased plasma protein developed blood brain barrier → binds to synthesis → levels drop to 2 to 2.5 mg/dL lipids in the brain → CNS damage termed o Cardiac hypoxia → decompensation and failure kernicterus o ↓ plasma oncotic pressure + ↑ hydrostatic pressure = edema and anasarca culminating in hydrops fetalis NON-IMMUNE HYDROPS Major causes: o Include both structural and functional defects (1) Cardiovascular o Cause intrauterine cardiac failure and hydrops o Malformations and tachyarrhythmia o Turner Syndrome (45,X) (2) Chromosomal - abnormalities of lymphatic drainage from the neck → lead to anomalies postnuchal fluid accumulation or cystic hygromas o Trisomy 21, 18 Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology o Homozygous a-thalassemia (3) Fetal anemia - deletion of all four a-globin genes - most common cause of nonimmune hydrops o Parvovirus B19 - gains preferential entry into erythroid precursors (normoblasts) → viral replication → apoptosis of red cell progenitor + red cell aplasia (4) Monozygous twin o Cause 10% of cases of nonimmune hydrops pregnancies and twin-twin transfusion MORPHOLOGY OF FETAL Morphology HYDROPS Hydrops fetalis - most severe and generalized manifestation Lesser degrees of edema - isolated pleural, peritoneal, or post-nuchal fluid collections In hydrops associated with chromosomal abnormality: - dysmorphic features are seen In hydrops associated with fetal anemia: - Both fetus and placenta are pale - Enlarged liver and spleen d/t cardiac failure and congestion - Bone marrow: compensatory hyperplasia of erythroid precursors (except in parvovirus-associated aplasia) - Extramedullary hematopoiesis in liver, spleen, lymph nodes → presence of large numbers of reticulocytes, normoblasts, and erythroblasts in the peripheral circulation - Erythroblastosis fetalis Kernicterus (CNS damage) - Most serious threat in fetal hydrops - Brain is enlarged and edematous - Bright yellow color - Neural damage: bilirubin level of >20 mg/dL CLINICAL FEATURES OF Minimally affected infants FETAL HYDROPS o pallor o hepatosplenomegaly Gravely ill neonates o intense jaundice o generalized edema o signs of neurologic injury Management: o Phototherapy o Total exchange transfusion INBORN ERRORS OF METABOLISM & OTHER GENETIC DISORDERS WHAT ARE INBORN ➔ Well-characterized genetic abnormalities that give rise to metabolic disorders ERRORS OF ➔ Most are inherited as autosomal recessive or X-linked traits METABOLISM? Abnormalities suggesting inborn errors of metabolism: Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology PHENYLKETONURIA ➔ Autosomal recessive disorder (PKU) ➔ Caused by biallelic mutations of the gene encoding phenylalanine hydroxylase (PAH) → severe deficiency ➔ Result: hyperphenylalaninemia - degree and clinical phenotype = inversely related to amount of residual enzyme activity Biochemical abnormality o Inability to convert phenylalanine → tyrosine o Minor shunt pathways come into play → formation of intermediates o Intermediates are excreted in large amounts in the urine and sweat → strong musty odor o Lack of tyrosine → lack of melanin → light color of hair and skin Clinical features of PKU Normal [Phe] = 600 μm o At birth: normal o Within a few weeks: rising plasma phenylalanine level → impairs brain development o By 6 months of life: severe mental retardation becomes evident - 50 or 60 - 1/3 never able to walk, 2/3 cannot talk - accompanied by seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema o In female patients: - asymptomatic and reach childbearing age if treated with dietary restriction in early life - most have marked hyperphenylalaninemia d/t discontinuation of dietary treatment in adulthood Maternal PKU: - the offspring of these patients (even heterozygotes) may exhibit: a) mental retardation and microcephaly (75 to 90%) b) congenital heart disease (15%) - Result from teratogenic effects of phenylalanine or its metabolites that cross the placenta → affect specific fetal organs during development - Presence and severity of anomalies = maternal Phe levels Benign hyperphenylalaninemia: o mutations that result in only modest elevations of blood phenylalanine o without the associated neurologic damage o may develop false positive screening test Other causes of PKU: o Abnormalities in synthesis and recycling of cofactor tetrahydrobiopterin (BH4) - essential cofactor in PAH and also required for tyrosine and tryptophan hydroxylation - Defects in BH4 recycling disturb the synthesis of neurotransmitters - In patients with BH4 deficiency, neurologic damage is not reversed despite dietary control of phenylalanine levels ➔ Autosomal recessive disorder of galactose metabolism GALACTOSEMIA ➔ Normal metabolism: o Lactose is split into glucose + galactose in the intestinal microvilli by lactase o Galactose is converted to glucose in 3 steps: Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology Two variants of galactosemia: (1) Lack of galactose-1-phosphate uridyl transferase (GALT) → reaction 2 (2) Deficiency of galactokinase → reaction 1 In GALT deficiency: o Galactose-1-phosphate accumulates in liver, spleen, lens of eye, kidneys, heart muscle, cerebral cortex, and erythrocytes o Activation of alternative metabolic pathways lead to production of metabolic intermediates that may be toxic if in excess - galactitol (polyol metabolite) - galactonate (oxidized byproduct of excess galactose) Clinical picture - Hepatomegaly d/t fatty change or scarring - Opacification of the lens (cataract) d/t increased osmotic pressure by galactitol accumulation - Nonspecific alterations in CNS ✓ loss of nerve cells, gliosis, and edema in dentate and olivary nuclei - Failure to thrive almost from birth - Vomiting and diarrhea → appear within a few days of milk ingestion - Mental retardation (within 6-12 months) - Aminoaciduria in kidney d/t accumulation of galactose and galactose-1-phosphate that impairs amino acid transport - E. coli septicemia d/t depressed neutrophil bactericidal activity - Hemolysis and coagulopathy In Galactokinase deficiency: o Milder form o not associated with mental retardation Diagnosis: o Demonstration in the urine of a reducing sugar other than glucose o Antenatal: - assay of GALT in cultured amniotic fluid - determination of galactitol level in the amniotic fluid supernatant Management o Early removal of galactose from diet for at least the first 2 years of life o However, older patients may still have: ✓ speech disorder ✓ gonadal failure (premature ovarian failure) ✓ ataxic condition CYSTIC FIBROSIS ➔ Inherited disorder of ion transport (MUCOVISCIDOSIS) ➔ Affects fluid secretion in exocrine glands and epithelial lining of respiratory, gastrointestinal, and reproductive tract ➔ Abnormally viscous secretions obstruct organ passages and lead to: a) Chronic lung disease e) Pancreatic insufficiency b) Steatorrhea f) Malnutrition c) Hepatic cirrhosis g) Intestinal obstruction d) Male infertility Cystic fibrosis gene o Autosomal recessive pattern o Primary defect in epithelial chloride channel protein encoded by cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q31.2 CFTR function: In sweat ducts: o Chloride-conductance channel o Mutated CFTR gene causes abnormal or absent channel → inhibiting ENaC (epithelial sodium channel) function in sodium uptake across the apical membrane o Hypertonic fluid with high sodium chloride (the sine qua non of classic cystic fibrosis) is formed. o This is the basis for the “salty” sweat Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology In airways: o Normal: - CFTR inhibits ENaC activity in sodium uptake across the apical membrane - CFTR drives Cl- and HCO3- secretion and regulates Na+ absorption by inhibiting ENaC. - Positively regulates the Cl- channels ANO1, SLC26A9 and SLC26A4, increasing Cl− and HCO3− secretion therefore increasing ASL hydration and pH o Mutations result in loss or reduction of chloride secretion into the lumen and active luminal sodium absorption is increased due to loss of inhibition of ENaC activity. o Mutated CFTR inhibits secretion of HCO3 in the lumen producing acidic fluid causing: (1) Increased mucin precipitation and plugging of ducts (2) Increased binding of bacteria to plugged mucins Mutational Spectra: Class I – Defective protein synthesis o complete lack of CFTR protein at the apical surface Class II – Abnormal protein folding, processing, and trafficking o Protein does not become fully folded and glycosylated o Degraded before it reaches cell surface → also lead to complete lack of CFTR o Most common mutations: deletion of 3 nucleotides coding for phenylalanine at amino acid position 508 Class III – Defective regulation o Prevent activation of CFTR by abrogating ATP binding and hydrolysis o Normal amount of CFTR but nonfunctional Class IV – Decreased conductance o Typically occur in the transmembrane domain o Normal amount but reduced function → milder phenotype Class V – Reduced abundance o Affect intronic splice sites of the CFTR promoter → reduced amount of normal protein o Milder phenotype Class VI – Altered function in regulation of ion channels o Affect regulatory role of CFTR Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology Clinical manifestations: Genetic and environmental modifiers: Genetic modifiers Environmental modifiers Polymorphism of: o Infection by Pseudomonas aeruginosa o Mannose Binding Lectin 2 (MBL2) o Alginate producing bacteria o Transforming Growth Factor B1 o Concurrent viral infections o Interferon-Related Developmental Regulator 1 (IFRD1) Gross Morphology Microscopic Nose o Nasal polyps Nose - Single or Multiple o Polyps covering: - Soft and Edematous - Respiratory epithelium “pseudostratified columnar ciliated” Lungs - Non-thickened basement membrane o Enlarged, dilated bronchi o Core: o Dilated bronchi extending to pleural surface - Loose edematous o Filled with yellow-green mucopurulent secretions - Large cystic mucous glands with inspissated secretion in their lumina - Mixed inflammatory cells Pancreas - Chronic cases → Fibrotic cores o Cystic changes Lungs o Multiple, small cysts (1-3 mm in diameter) o Bronchiectasis o Filled with thick, tenacious secretions - Ectatic, dilated airways - Chronic inflammatory cells and fibrosis Hepatobiliary - Ulceration o Bile duct obstruction - Squamous metaplasia o Enlarged, dilated bile ducts o Follicular bronchiolitis o Filled with thick, tenacious secretions - Lymphoid hyperplasia with germinal centers o End-stage: Cirrhosis Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology Pancreas o Cystic changes - Ectatic, dilated ducts filled with eosinophilic material - Obstruction-related changes: ✓ Exocrine acinar atrophy ✓ Replacement of atrophic lobules by interstitial fibrosis ✓ Scattered islets of Langerhans o Grading: Grade I: Accumulation of secretion Grade II: Exocrine atrophy Grade III: Atrophy with lipomatosis Grade IV: fibrosis with total obliteration of the exocrine glands and ducts with scattered islets Hepatobiliary o Ductular reaction - Portal tracts expansion by inflammation and increased number of bile ductules - Bile ductules are dilated and contain plugs of light eosinophilic material o Portal fibrosis, bridging fibrosis and cirrhosis Special studies: Laboratory tests: o Elevated sweat chloride (>60 mEq/L) o Sweat glands are morphologically unaffected but produces high salt-containing sweat. Abnormal nasal trans-epithelial potential difference o Useful in cases with low sweat chloride o Milder CFTR Mutations Azoospermia on semen analysis o Obstructive type (due to structural abnormalities of the vas deferens) o Bilateral absence of vas deferens linked with CFTR mutation ➔ Remember that cystic fibrosis is an autosomal recessive disease o Mutation of one allele → carrier o Mutation of both alleles → disease ➔ Type of mutation plays a role in the overall phenotype o If two “severe” mutations (e.g. class I, II, III) → Severe clinical picture o If one “severe” and one “mild” mutation (e.g. class IV, V, VI) → Less severe o If two “mild” mutations → Very mild Therapy: ▪ Increase the function of CFTR channels Potentiators ▪ Example: increases probability of Gly551Asp-CFTR (Ivacaftor) channel opening Correctors ▪ improve the intracellular processing and delivery of (Lumacaftor) mutant CFTR → reach the cell surface ▪ example: lumacaftor in Phe508del-CFTR Production ▪ Promote read-through of premature termination Correctors codons in mRNA → generate more CFTR (Ataluren) ▪ Example: Ataluren in class I mutations Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology SUDDEN INFANT DEATH SYNDROME DEFINITION IF SIDS ➔ Sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation (performance of complete autopsy, examination of the death scene, and the clinical history) ➔ Also referred to as crib death or cot death (because the infant usually dies while asleep) ➔ Sudden unexpected infant death (SUID) o have an unexpected anatomic or biochemical basis discernable at autopsy EPIDEMIOLOGY OF SIDS o 3rd leading cause of death in infancy o ~90% occur during the first 6 months of life, most between 2 and 4 months o Most infants die at home, usually during the night after a period of sleep o Despite the decline in SIDS and SUID: ➔ The rate in all American Indian/Alaskan Native (77 per 100,000 live births) infants was more than double that of non-Hispanic white infants (35 per 100,000 live births) in 2017. ➔ SIDS rates for Asian/ Pacific Islander and Hispanic infants were much lower than the rate for non- Hispanic white infants. ➔ After postmortem examination, the death rates from SIDS range from 10 per 100,000 live births in the Netherlands to 80 per 100,000 in New Zealand. RISK FACTORS & Morphology POSTMORTEM FINDINGS ASSOCIATED WITH SIDS o Most common finding: multiple petechiae on the thymus, visceral and parietal pleura, and epicardium o Congested lungs + vascular engorgement with or without pulmonary edema o Evidence of recent infection in the upper respiratory tract (not sufficiently severe to account for death) o Astrogliosis of brainstem and cerebellum o Hypoplasia of arcuate nucleus o Hepatic extramedullary hematopoiesis o Periadrenal brown fat PATHOGENESIS OF SIDS o Accepted as a multifactorial condition, with a variable mixture of contributing factors o Triple-risk model → intersection of the following factors: a) vulnerable infant b) critical developmental period in homeostatic control c) exogenous stressor o Most compelling hypothesis in SIDS: - delayed development of arousal and cardiorespiratory control - abnormalities in serotonin-dependent signaling o It is a diagnosis of exclusion (require careful examination of the death scene + complete postmortem examination) Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology TUMORS AND TUMOR-LIKE LESIONS OVERVIEW o Only 2% of malignant tumors occur in infancy and childhood o However, cancer accounts for 9% if deaths in the US in age 4 to14 years o Only accidents cause significantly more deaths o Benign tumors: more common, may sometimes cause serious complications d/t their location or rapid increase in size o Most common neoplasms of childhood: soft tissue tumors of mesenchymal derivation CATEGORIES OF TUMOR- Heterotopia or Choristoma Hamartoma LIKE LESIONS o Microscopically normal cells or tissues that are o Excessive focal overgrowth of cells native to the present in abnormal locations organ in which it occurs. o Usually of little significance, but they can be o Cellular elements are mature and identical to confused clinically with neoplasms. those found in the remainder of the organ. o Rarely, they are sites of origin of true neoplasms. o They do not reproduce the normal architecture of the surrounding tissue Examples: Pancreatic tissue in the wall of the stomach A small mass of adrenal cells in the kidney BENIGN TUMORS AND (1) HEMANGIOMA TUMOR-LIKE LESIONS o Most common tumor of infancy o Do not differ from those encountered in adults o Classified as: (1) Cavernous hemangioma → a subset occurs in familial setting (mutations in CCM genes) (2) Capillary hemangioma → more cellular than in adults o Most are located on the skin (face and scalp) → produce elevated, irregular, red-blue masses o Port-wine stains: refer to flat, larger lesions that may represent vascular ectasias o May enlarge along with the growth of the child, but mostly spontaneously regress o Represent one facet of von Hippel-Lindau disease (2) LYMPHATIC TUMORS o Of lymphatic origin Lymphangiomas - hamartous or neoplastic - characterized by cystic and cavernous spaces - may occur in the skin but more often encountered in deeper regions of neck, axilla, mediastinum - increase in size after birth d/t accumulation of fluid and budding of preexisting spaces Lymphangiectasis - abnormal dilations of pre-existing lymph channels - presents as diffuse swelling of part or all of an extremity - lesion is not progressive (3) FIBROUS TUMORS Fibromatosis - sparsely cellular proliferations of spindle-shaped cells Congenital-infantile fibrosarcoma - richly cellular lesions indistinguishable from fibrosarcomas in adults - excellent prognosis - chromosomal translocation t(12;15)(p13;q25) → ETV6-NTRK3 fusion transcript Myofibroma - nodular proliferates of fibroblast and myofibroblast cells Karrel L. Collantes CHAPTER 10: Diseases of Infancy and Childhood MD 2023  General Pathology (4) TERATOMAS o Occur as either: (1) mature teratomas → benign, well-differentiated cystic lesions (2) immature teratomas → lesions of indeterminate potential (3) unequivocally malignant teratomas → usually admixed with another germ cell tumor o Two peaks of incidence: 2 years of age: congenital neoplasms Late adolescence or early adulthood: may also be prenatal origin but are more slowly growing Sacrococcygeal teratoma - most common teratoma in childhood (40% of cases) - occurs with a frequency of 1 in 20,000 to 40,000 livebirths - four times more common in girls than in boys - most benign teratomas are encountered in younger infants (