Diseases of

I n f a n c y

&

C h i l d h o o d

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 period



first four weeks of life



Infancy



the first year of life



Age 1 – 4 years (preschool)



Age 5 – 14 years (school age)

MORTALITY by TIME SPAN



NEONATE (0-4 WEEKS):

CONGENITAL, PREMATURITY 

UNDER ONE YEAR:

CONGENITAL, PREMATURITY/WEIGHT, SIDS 

1-4 YEARS:

TUMORS ACCIDENTS, CONGENITAL, 

5-14 YEARS:

HOMICIDES ACCIDENTS, TUMORS, 

15-24 YEARS:

ACCIDENTS, HOMICIDE, SUICIDE ( NONE ARE “NATURAL” CAUSES )

Cause of Death Related with Age Causes 1 Rate 2

Under 1 Year: All Causes 1 –4 Years: All Causes 5 –14 Years: All Causes 15 –24 Years: All Causes 727.4 32.6 18.5 80.7 1 Rates are expressed per 100,000 population 2 Excludes 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

fluid) – Renal agenesis – Amniotic leak (decreased amniotic

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 Malformation Frequency per 10,000 Total Births

Clubfoot without central nervous system anomalies 25.7 Patent ductus arteriosus Ventricular septal defect Cleft lip with or without cleft palate Spina bifida without anencephalus 16.9 10.9 9.1 5.5 Congenital hydrocephalus without anencephalus Anencephalus Reduction deformity (musculoskeletal) 4.8 3.9 3.5 Rectal and intestinal atresia 3.4

Adapted from James LM: Maps of birth defects occurrence in the U.S., birth defects monitoring program (BDMP)/CPHA, 1970 –1987. Teratology 48:551, 1993.

#2 #1 #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 Cause

Genetic

Chromosomal aberrations Mendelian inheritance

Frequency (%)

10–15 2–10

Environmental

Maternal/placental infections 2–3 Maternal disease states Drugs and chemicals Irradiations 6–8 1 1

Multifactorial (Multiple Genes ? Environment)

20–25

Unknown

40–60

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 (

during embryogenesis

apoptosis

)

, which, as we have seen, allows orderly organization of tissues and organs •

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 90 th age percentile for gestational  Small for gestational age (

SGA

) , <10%  Large for gestational age (

LGA

) , >90% 

Preterm

 born before

37

weeks (<2500 grams) 

Post-Term

 delivered after

42

weeks

Prematurity

 Defined as gestational age

< 37

weeks  Second most common cause of neonatal mortality (after congenital anomalies)  Risk factors for prematurity  Preterm

P

remature

R

upture

O

f fetal

M

embranes (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

age) (small for gestational  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 (

T

oxoplasmosis,

O

ther,

R

ubella,

C

ytomegalovirus,

H

erpes)  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 7 th month  surfactant deficiency 

Kidneys

 glomerular differentiation is incomplete 

Brain

 impaired homeostasis of temperature  vasomotor control unstable 

Liver

 inability to conjugate and excrete bilirubin

APGAR

( A ppearance, P ulse, G rimace, A ctivity, R espiration) Evaluation Of The Newborn Infant Sign

Heart rate Respiratory effort Muscle tone

0

Absent Absent

1

Below 100 Slow, irregular

2

Over 100 Good, crying Response to catheter in nostril (tested after oropharynx is clear) Limp No response Some flexion of extremities Grimace Active motion Cough or sneeze Color Blue, pale Body pink, extremities blue Completely 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 • HIV—at delivery with maternal to fetal transfusion • TORCH • parvovirus B19 (Fifth), erythema infectiosum – bacterial • Listeria monocytogenes

Fetal Lung Maturation

Neonatal Respiratory Distress Syndrome (RDS) (HMD)

• 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 

3)

Cesarean delivery  normal delivery process stimulates surfactant secretion

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 ↑

V

ascular

E

ndothelial

G

rowth

F

actor ( VEGF ) and angiogenesis  Oxygen Rx suppresses VEGF and causes endothelial apoptosis Bronchopulmonary “dysplasia”   oxygen suppresses lung septation at the saccular stage mechanical ventilation  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 (α-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, ( C horionic V illi S ampling) 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)



P

henyl

K

eton

U

ria (

PKU

)



Galactosemia



C

ystic

F

ibrosis (

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) Harrison’s Internal Med, 16 th Ed

CFTR Gene: Normal

    C ystic F ibrosis T ransmembrane Conductance R egulator ( 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 Respiratory and Intestinal epithelium   CTFR activation increases active luminal secretion of chloride ENaC is inhibited

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  Liver  plugging of bile canaliculi with portal inflamation  biliary cirrhosis may develop  Genitalia  Absence of vas deferens and azoospermia  Sweat glands  normal histology

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

S

udden

I

nfant

D

eath

S

yndrome (

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

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

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 factors)

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

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

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 5 to 9 Years 10 to 14 Years

Leukemia Leukemia Retinoblastoma Neuroblastoma Wilms tumor Retinoblastoma Neuroblastoma Hepatoblastoma Hepatocarcinoma Soft tissue sarcoma (especially rhabdomyosarcoma) Soft tissue sarcoma Teratomas Central nervous system tumors Central nervous system tumors Hepatocarcinoma Soft tissue sarcoma Ewing sarcoma Lymphoma Osteogenic sarcoma Thyroid carcinoma Hodgkin disease

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

*

*Neuropil Neuorblastoma

**

**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 Amplification of N-myc oncogene  present in 25-30% of cases and is unfavorable  up to 300 copies on N-myc has been observed Risk Stratification  low risk: 90% cure rate  high risk 20% cure rate

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