Diseases of

Infancy & Childhood

Diseases of Infancy and Childhood

Congenital Anomalies Birth Weight and Gestational Age Birth Injuries Perinatal Infections Respiratory Distress Syndrome (RDS) Necrotizing Enterocolitis Intraventricular Hemorrhage Hydrops Inborn Metabolic/Genetic Errors Sudden Infant Death Syndrome (SIDS) Tumors

INFANT MORTALITY
USA 1970: 20 USA 2000: 7 USA WHITE: X USA BLACK: 2X

SWEDEN 3 INDIA 82

Major Time Spans

Neonatal
first

period

four weeks of life

Infancy
the

first year of life

1 4 years (preschool) Age 5 14 years (school age)

Age

MORTALITY by TIME SPAN

NEONATE (0-4 WEEKS): CONGENITAL,

PREMATURITY

UNDER ONE YEAR: CONGENITAL,

PREMATURITY/WEIGHT, SIDS 1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS 5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES 15-24 YEARS: ACCIDENTS, HOMICIDE, SUICIDE (NONE ARE NATURAL CAUSES)

Cause of Death Related with Age Causes1 Rate 2 Under 1 Year: All 727.4 Causes 14 Years: All 32.6 Causes 514 Years: All 18.5 Causes 1524 Years: All 80.7 Causes
1Rates 2Excludes

are expressed per 100,000 population congenital heart disease

Congenital Anomalies
Definitions

Causes
Pathogenesis

 Malformations
primary errors of morphogenesis, usually multifactorial e.g. congenital heart defect

Disruptions
secondary disruptions of previously normal organ or body region e.g. amniotic bands

Deformations
extrinsic disturbance of development by biomechanical forces e.g. uterine constraint

Sequence
a pattern of cascade anomalies explained by a single localized initiating event with secondary defects in other organs e.g. Oligohydramnios (Or Potter) Sequence

Syndrome
a constellation of developmental abnormalities believed to be pathologically related e.g Turner syndrome

Malformations

Polydactyly & syndactyly

Cleft Lip

Severe Lethal Malformation

Disruption by an amniotic band

Oligohydramnios (Or Potter) Sequence

Oligohydramnios (decreased amniotic fluid)
Renal agenesis Amniotic leak

Fetal Compression
flattened facies club foot (talipes equinovarus)

Pulmonary hypoplasia
fetal respiratory motions important for lung development

Breech Presentation

The Oligohydramnios Sequence

Infant with oligohydramnios sequence

Organ Specific Anomalies

Agenesis: complete absence of an organ Atresia: absence of an opening Hypoplasia: incomplete development or
under- development of an organ with decreased numbers of cells Hyperplasia: overdevelopment of an organ associated with increased numbers of cells Hypertrophy: increase in size with no change in number of cells Dysplasia: in the context of malformations (versus neoplasia) describes an abnormal organization of cells

Implantation and the Survival of Early Pregnancy

Only 50-60% of all conceptions advance beyond 20 weeks Implantation occurs at day 6-7 75% of loses are implantation failures and are not recognized Pregnancy loss after implantation is 25-40%

NEJM 2001; 345:1400-1408

Approximate Frequency of the More Common Congenital Malformations in the United States Frequency per 10,000 Total Births 25.7 16.9 10.9 9.1 5.5 4.8 3.9 3.5 3.4

Malformation Clubfoot without central nervous system anomalies Patent ductus arteriosus Ventricular septal defect Cleft lip with or without cleft palate Spina bifida without anencephalus Congenital hydrocephalus without anencephalus Anencephalus Reduction deformity (musculoskeletal) Rectal and intestinal atresia

Adapted from James LM: Maps of birth defects occurrence in the U.S., birth defects monitoring program (BDMP)/CPHA, 19701987. Teratology 48:551, 1993.

#1 #2 #3

CAUSES OF ANOMALIES
Genetic
karyotypic aberrations single gene mutations

Environmental
infection maternal disease drugs and chemicals irradiation

Multifactorial

Unknown

Causes of Congenital Anomalies in Humans Frequency Cause (%) Genetic Chromosomal aberrations 1015 Mendelian inheritance 210 Environmental Maternal/placental infections Maternal disease states Drugs and chemicals Irradiations Multifactorial (Multiple Genes ? Environment) Unknown 23 68 1 1 2025 4060

Adapted from Stevenson RE, et al (eds): Human Malformations and Related Anomalies. New York, Oxford University Press, 1993, p. 115.

Embryonic Development

Embryonic period
weeks 1- 8 of pregnancy organogenesis occurs in this period

Fetal period
weeks 9 to 38 marked by further growth and maturation

Critical Periods Of Development

Genetic Causes

Karyotypic abnormalities
80-90% of fetuses with aneuploidy die in utero trisomy 21 (Down syndrome) most common karyotypic abnormality (21,18,13) sex chromosome abnormalities next most common (Turner and Klinefelter) autosomal chromosomal deletion usually lethal karyotyping frequently done with aborted fetuses with repeated abortions

Single gene mutations

covered in separate chapters

Maternal Viral Infection

Rubella (German measles)
at risk period first 16 weeks gestation defects in lens (cataracts), heart, and CNS (deafness and mental retardation) rubella immune status important part of prenatal workup

Cytomegalovirus
most common fetal infection highest at risk period is second trimester central nervous system infection predominates

Drugs and Chemicals

Drugs
13 cis-retinoic acid (acne agent) warfarin angiotensin converting enzyme inhibitors (ACEI) anticonvulsants oral diabetic agents thalidomide

Alcohol Tobacco

Teratogen Actions

Proper cell migration to predetermined locations that influence the development of other structures Cell proliferation, which determines the size and form of embryonic organs Cellular interactions among tissues derived from different structures (e.g., ectoderm, mesoderm), which affect the differentiation of one or both of these tissues Cell-matrix associations, which affect growth and differentiation Programmed cell death (apoptosis), which, as we have seen, allows orderly organization of tissues and organs during embryogenesis Hormonal influences and mechanical forces, which affect morphogenesis at many levels

Diabetes Mellitus

Fetal Macrosomy (>10 pounds)

maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with growth hormone effects

Diabetic Embryopathy
most crucial period is immediately post fertilization malformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNS

Oral agents not approved in pregnancy Diabetics attempting to conceive should be placed on insulin

Birth Weight and Gestational Age

Appropriate for gestational age (AGA)

between 10 and 90th percentile for gestational age

Small for gestational age (SGA) , <10% Large for gestational age (LGA) , >90% Preterm

born before 37 weeks (<2500 grams) delivered after 42 weeks

Post-Term

Prematurity

Defined as gestational age <

37 weeks

Second most common cause of neonatal mortality (after congenital anomalies) Risk factors for prematurity
Preterm Premature Rupture Of fetal Membranes (PPROM) Intrauterine infection Uterine, cervical, and placental abnormalities Multiple gestation

Fetal Growth Restriction

At least 1/3 of infants born at term are < 2.5kg Undergrown rather than immature Commonly underlies SGA (small for gestational age) Prenatal diagnosis: ultrasound measurements Classification Fetal Placental

Maternal

Fetal FGR

Chromosomal abnormalities
17% of FGR overall up to 66% of fetuses with ultrasound malformations

Fetal Infection

Infection: TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes)

Characterized by symmetric growth restriction head and trunk proportionally involved

Placental FGR

Vascular
umbilical cord anomalies (single artery, constrictions, etc) thrombosis and infarction multiple gestation

Confined placental mosaicism

mutation in trophoblast trisomy is common

Placental FGR tends to cause asymmetric growth with relative sparing of the head

Maternal FGR

Most common cause of FGR by far Vascular diseases

preeclampsia (toxemia of pregnancy) hypertension

Toxins
ethanol narcotics and cocaine heavy smoking

Organ Immaturity

Lungs
alveoli differentiate in 7th month surfactant deficiency

Kidneys

glomerular differentiation is incomplete

Brain
impaired homeostasis of temperature vasomotor control unstable

Liver

inability to conjugate and excrete bilirubin

APGAR (Appearance, Pulse, Grimace, Activity, Respiration)

Evaluation Of The Newborn Infant
Sign Heart rate Respiratory effort Muscle tone Response to catheter in nostril (tested after oropharynx is clear) Color 0 Absent Absent Limp No response 1 Below 100 Slow, irregular 2 Over 100 Good, crying

Some flexion of Active motion extremities Grimace Cough or sneeze

Blue, pale

Body pink, Completely extremities blue pink

Data from Apgar V: A proposal for a new method of evaluation of the newborn infant. Anesth Analg 32:260, 1953.

Apgar Score and 28 Day Mortality

Score

may be evaluated at 1 and 5 minutes 5 minute scores

0-1,

50% mortality 4, 20% mortality 7, nearly 0% mortality

Perinatal Infection
Transcervical (ascending)
inhalation of infected amniotic fluid
pneumonia, sepsis, meningitis commonly occurs with PROM

passage through infected birth canal

herpes virus caesarian section for active herpes

Transplacental (hematogenous)
mostly viral and parasitic
HIVat delivery with maternal to fetal transfusion TORCH parvovirus B19 (Fifth), erythema infectiosum

bacterial
Listeria monocytogenes

Fetal Lung Maturation

Neonatal Respiratory Distress Syndrome (RDS)

60,000 cases / year in USA with 5000 deaths Incidence is inversely proportional to gestational age The cause is lung immaturity with decreased alveolar surfactant
surfactant decreases surface tension first breath is the hardest since lungs must be expanded without surfactant, lungs collapse with each breath

RDS Risk Factors

1)

Prematurity

by far the greatest risk factor affected infants are nearly always premature

2) Maternal diabetes mellitus

insulin suppresses surfactant secretion normal delivery process stimulates surfactant secretion

3) Cesarean delivery

RDS Pathology
Gross
solid and airless (no crepitance) sink in water appearance is similar to liver tissue*

Microscopic
atelectasis and dilation of alveoli hyaline membranes composed of fibrin and cell debris line alveoli (HMD former name) minimal inflammation

V/Q Mismatch

RDS Prevention and Treatment

Delay labor until fetal lung is mature

amniotic fluid phospholipid levels are useful in assessing fetal lung maturity

Induce fetal lung maturation with antenatal corticosteriods Postnatal surfactant replacement therapy with oxygen and ventilator support

Treatment Complications

Oxygen toxicity

oxygen derived free radicals damage tissue

Retrolental fibroplasia hypoxia causes Vascular Endothelial Growth Factor

(VEGF) and angiogenesis Oxygen Rx suppresses VEGF and causes endothelial apoptosis oxygen suppresses lung septation at the saccular stage mechanical ventilation

Bronchopulmonary dysplasia

epithelial hyperplasia, squamous metaplasia, and peribronchial and interstitial fibrosis were seen with old regimens of ventilator usage and no surfactant use, but are now uncommon lung septation is still impaired

Necrotizing Enterocolitis

Incidence is directly proportional to prematurity, like RDS

approaches 10% with severe prematurity

2000 cases yearly in USA Pathogenesis

not fully understood intestinal ischemia inflammatory mediators breakdown of mucosal barrier

Necrotizing Enterocolitis

Hydrops Fetalis

Chromosomal abnormalities
Turner syndrome with cystic hygromas other

Cardiovascular with heart failure

anemia with high output failure

immune hemolytic anemia hereditary hemolytic anemia (-thalassemia) parvovirus B19 infection twin to twin in utero transfusion

congenital heart defects

Hydrops Fetalis

Immune Hydrops

Fetus inherits red cell antigens from the father that are foreign to the mother Mother forms IgG antibodies which cross the placenta and destroy fetal RBCs Fetus develops severe anemia with CHF and compensatory hematopoiesis (frequently extramedullary) Most cases involve Rh D antigen

mother is Rh Neg and fetus is Rh Pos

ABO and other antigens involved less often

Pathogenesis of Sensitization

Fetal RBCs gain access to maternal circulation largely at delivery or upon abortion Since IgM antibodies are involved in primary response and prior sensitization is necessary, the first pregnancy is not usually affected Maternal sensitization can be prevented in most cases with Rh immune globulin (Rhogam) given at time of delivery or abortion (spontaneous or induced)

Treatment of Immune Hydrops

In utero
identification of at risk infants via blood typing by amniocentesis, (Chorionic Villi Sampling) CVS, or fetal blood sampling fetal transfusions via umbilical cord early delivery

Live born infant

monitoring of hemoglobin and bilirubin exchange transfusions

Kernicterus

Pathogenesis of Immune Hydrops

Inborn Errors of Metabolism (Genetic)

PhenylKetonUria (PKU)
Galactosemia

Cystic

Fibrosis (CF)

(Mucoviscidosis)

PHENYLKETONURIA (PKU)
Ethnic distribution
common in persons of Scandinavian descent uncommon in persons of African-American and Jewish descent

Autosomal recessive Phenylalanine hydroxylase deficiency leads to hyperphenylalaninemia, brain damage, and mental retardation Phenylananine metabolites are excreted in the urine Treatment is phenylalanine restriction Variant forms exist

GALACTOSEMIA
Autosomal recessive Lactose glucose + galactose Galactose-1-phosphate uridyl transferase (GALT)
GALT is involved in the first step in the transformation of galactose to glucose absence of GALT activity galactosemia

Symptoms appear with milk ingestion

liver (fatty change and fibrosis), lens of eye (cataracts), and brain damage involved (mechanism unknown)

Diagnosis suggested by reducing sugar in urine and confirmed by GALT assay in tissue Treatment is removal of galactose from diet for at least the two first years of life

Cystic Fibrosis
Normal

Gene Mutational Spectra Genetic/Environmental Modifiers Morphology Clinical Course

Cystic Fibrosis (Mucoviscidosis)

Autosomal recessive Most common lethal genetic disease affecting Caucasians (1 in 3,200 live births in the USA)
2-4% of population are carriers Uncommon in Asians and African-Americans

Widespread disorder in epithelial chloride transport affecting fluid secretion in

exocrine glands epithelial lining of the respiratory, gastrointestinal, and reproductive tracts

Abnormally viscid mucus secretions

Cellular Metabolism Of The Cystic Fibrosis Transmembrane Regulator (CFTR)

Harrisons Internal Med, 16th Ed

CFTR Gene: Normal

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) CTFR epithelial chloride channel protein

agonist induced regulation of the chloride channel interacts with epithelial sodium channels (ENaC)

Sweat gland

CTFR activation increases luminal Cl resorption ENaC increases Na+ resorption sweat is hypotonic
CTFR activation increases active luminal secretion of chloride ENaC is inhibited

Respiratory and Intestinal epithelium

CFTR Gene: Cystic Fibrosis

Sweat gland

CTFR absence decreases luminal Cl resorption ENaC decreases Na+ resorption sweat is hypertonic

Respiratory and Intestinal epithelium

CTFR absence decreases active luminal secretion of chloride lack of inhibition of ENaC is opens sodium channel with active resorption of luminal sodium secretions are decreased but isotonic

Chloride Channel Defect and Effects

CFTR Gene: Mutational Spectra

More than 800 mutations are known These are grouped into six classes

mild to severe

Phenotype is correlated with the combination of these alleles

correlation is best for pancreatic disease genotype-phenotype correlations are less consistent with pulmonary disease

Other genes and environment further modify expression of CFTR

Clinical Manifestations Of Mutations In The Cystic Fibrosis Gene

Organ Pathology

Plugging of ducts with viscous mucus and loss of ciliary function of respiratory mucosa Pancreas

atrophy of exocrine pancreas with fibrosis islets are not affected plugging of bile canaliculi with portal inflamation biliary cirrhosis may develop Absence of vas deferens and azoospermia normal histology

Liver

Genitalia

Sweat glands

Lung Pathology in CF
More than 95% of CF patients die of complications resulting from lung infection Viscous bronchial mucus with obstruction and secondary infection
S. aureus Pseudomonas Hemophilus

Bronchiectasis
dilatation of bronchial lumina scarring of bronchial wall

Cystic Fibrosis Clinical Manifestations

CF Diagnosis

Clinical criteria
sinopulmonary gastrointestinal

pancreatic intestinal

salt loss male genital tract

Sweat chloride analysis Nasal transepithelial potential difference DNA Analysis

gene sequencing

Clinical Course and Treatment

Highly variable median life expectance is 30 years 7% of patients in the United States are diagnosed as adults Clearing of pulmonary secretions and treatment of pulmonary infection Transplantation
lung liver-pancreas

Sudden Infant Death Syndrome (SIDS)

Epidemiology

Morphology
Pathogenesis

Sudden Infant Death Syndrome

NIH Definition

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 another name based on the fact that most die in their sleep

Crib death

Epidemology of SIDS

Leading cause of death in USA of infants between 1 month and 1 year of age 90% of deaths occur 6 months age, mostly between 2 and 4 months In USA 2,600 deaths in 1999 (down from 5,000 in 1990)

Risk Factors for SIDS

Parental Young maternal age (age <20 years) Maternal smoking during pregnancy Drug abuse in either parent, specifically paternal marijuana and maternal opiate, cocaine use Short intergestational intervals Late or no prenatal care Low socioeconomic group African American and American Indian ethnicity (? socioeconomic factors) Infant Brain stem abnormalities, associated defective 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 Environment Prone sleep position Sleeping on a soft surface Hyperthermia Postnatal passive smoking

Morphology of SIDS

SIDS is a diagnosis of

exclusion

Non-specific autopsy findings

Multiple petechiae Pulmonary congestion pulmonary edema These may simply be agonal changes as they are found in non-SIDS deaths also

Subtle changes in brain stem neurons Autopsy typically reveals no clear cause of death

Pathogenesis of SIDS

Generally accepted to be multifactorial Triple risk model

Vulnerable infant Critical development period in homeostatic control Exogenous stressors

Brain stem abnormalities, associated defective arousal, and cardio-respiratory control

Prevention of SIDS

Maternal factors

attention to risk factors previously mentioned redress problems in medical care for underprivileged avoid prone sleeping

Environmental

back to sleep program: infant should sleep in supine position no pillows, comforters, quilts, sheepskins, and stuffed toys Sleeping clothing (such as a sleep sack) may be used in place of blankets. no excessive blankets set thermostat to appropriate temperature avoid space heaters

Avoid sleeping on soft surfaces

Avoid hyperthermia

Diagnosis of SIDS

SIDS is a diagnosis of

exclusion

Complete autopsy Examination of the death scene Review of the clinical history Differential diagnosis
child abuse intentional suffocation

TUMORS
Benign Malignant

BENIGN
Hemangiomas
Lymphatic

Tumors Fibrous Tumors Teratomas (also can be malignant)

Hemangioma

Benign tumor of blood vessels Are the most common tumor of infancy Usually on skin, especially face and scalp Regress spontaneously in many cases

Congenital Capillary Hemangioma

At birth

At 2 years After spontaneous regression

Teratomas

Composed of cells derived from more than one germ layer, usually all three Sacrococcygeal teratomas
most common childhood teratoma frequency 1:20,000 to 1:40,000 live births 4 times more common in boys than girls

Aproximately 12% are malignant

often composed of immature tissue occur in older children

Sacrococcygeal Teratoma

MALIGNANT
Neuroblastic

Tumors Wilms Tumor Incidence and Types

TABLE 10-9 -- Common Malignant Neoplasms of Infancy and Childhood 0 to 4 Years Leukemia Retinoblastoma Neuroblastoma Wilms tumor Hepatoblastoma Hepatocarcinoma Hepatocarcinoma Soft tissue sarcoma Soft tissue sarcoma (especially Soft tissue sarcoma rhabdomyosarcoma) Teratomas Central nervous system tumors Central nervous system tumors Ewing sarcoma Lymphoma Osteogenic sarcoma Thyroid carcinoma Hodgkin disease 5 to 9 Years Leukemia Retinoblastoma Neuroblastoma 10 to 14 Years

Small

Round Blue Cell Tumors

Frequent in pediatric tumors Differential diagnosis

Lymphoma Neuroblastoma Wilms tumor Rhabdomyosarcoma Ewings tumor

Diagnostic procedures
immunoperoxidase stains electron microscopy chromosomal analysis and molecular markers

Neuroblastomas

Second most common malignancy of childhood (650 cases / year in USA) Neural crest origin
adrenal gland 40 % sympathetic ganglia 60%

In contrast to retinoblastoma, most are sporadic but familiar forms do occur Median age at diagnosis is 22 months

Neuorblastoma Morphology

Small round blue cell tumor

neuorpil formation rosette formation immunochemistry neuron specific enolase EM secretory granules (catecholamine)

Usual features of anaplasia

high mitotic rate is unfavorable evidence of Schwann cell or ganglion differentiation favorable

Other prognostic predictors are used by pathologists and oncologists

Neuorblastoma

**

*Neuropil

**Homer-Wright Rosettes

Clinical Course and Prognosis

Hematogenous and lymphatic metastases to liver, lungs and bone 90% produce catecholamines, but hypertension is uncommon Age and stage are most important prognostically

< 1 year age: good prognosis regardless of stage present in 25-30% of cases and is unfavorable up to 300 copies on N-myc has been observed low risk: 90% cure rate high risk 20% cure rate

Amplification of N-myc oncogene

Risk Stratification

Wilms Tumor

Most common primary renal tumor of childhood Incidence 10 per million children < 15 years Usually diagnosed between age 2-5 5 10 % are multi-focal, i.e., bilateral
synchronous metachronous

Clinical Features

Most children present with a large abdominal mass Treatment

nephrectomy and combination chemotherapy

two

year survival up to 90% even with spread beyond the kidney

Pathogenesis of Wilms Tumor

10% of Wilms tumors arise in one of three congenital malformation syndromes with distinct chromosomal loci

Familial disposition for Wilms is rare, and most of these patients have de novo mutations

Nephrogenic rests of adjacent parenchyma

present in 40% of unilateral tumors, 100% of bilateral tumors if found in one kidney, these rests predict an increased risk for tumor in the contralateral kidney

Pathology of Wilms Tumor

Gross
well circumscribed fleshy tan tumor areas of hemorrhage and necrosis

Microscopic: triphasic appearance Blastema: small blue cells Epithelial elements: tubules & glomeruli Stromal elements Anaplasia

correlates with p53 mutation and poor prognosis and resistance to chemotherapy

Wilms Tumor