Lecture 6: Diseases of Infancy & Childhood

Neonatal period

1st month

Infancy

1st year

Childhood

2 - 12 years

Adolescents

12 - 18 years

Leading cause of death under 1 year

Congenital anomalies

Prematurity & low birth weight & complications of prematurity

Sudden Infant Death Syndrome (SIDS)

Malformations

intrinsic error in fetal development

Deformations

Extrinsic disturbance (outside force) causing abnormal shape or position of a normally developed fetal structure

e.g. small uterus causing compression of parts of the fetus

Disruptions

extrinsic event causing secondary destruction of a normally developing fetal structure

Sequence

Cascade of anomalies explained by a single localized initiating event with secondary defects in other organs

can be due to malformation, disruption, or deformation

Malformation Syndrome

group of developmental abnormalities occurring simultaneously believed to be pathologically related however, can not be explained by a single, localized initiating defect

Most often is caused by single etiologic agent

Potter sequence

Oligohydramnios causing Potter sequence

Results in fetal Compression with classic phenotype in the infant:

Flattened facies; prominent infraorbital folds; retrognathia (abnormal posterior placement of mandible)

Positional abnormalities of hand & feet

Hip dislocation

Growth of chest wall & lungs compromised → pulmonary hypoplasia → fetal demise occasionally

Nodules in the amnion (amnion nodosum - fetal squamous cells aggregates on amnion)

What are the three main causes of congenital malformations?

Genetic, environmental, Teratogens

First trimester fetal loss is likely due to genetic causes whereas congenital infections will cause fetal loss later in pregnancy

What are the two major routes for perinatal infections?

In utero

During birth

Transplacental infections (TORCH)

Fever

Encephalitis, chorioretinitis, pneumonitis, myocarditis

Hepatosplenomegaly

Hemolytic anemia

Hydrops of fetus

Vesicular or hemorrhagic skin rashes

Toxoplasma gondii

protozoa

Chorioretinitis → vision loss

CNS involvement - microcephaly

Focal cerebral calcifications

Syphilis

(Treponema pallidum)

acquired in 3rd trimester; Gummas in fetal organs

Zika virus

Microcephaly & brain damage

Rubella virus

Rubella embryopathy/Congenital Rubella Syndrome (CRS): developing baby contracts rubella from mother in first trimester (3- 9 weeks of gestation) when organogenesis is occurring)

Triad of birth defects:

Occular: congenital cataracts

Congenital Cardiac defects:

patent ductus arteriosus/PDA

Heart murmur

CNS: Microcephaly

Also deafness, skin rash at birth, hepatosplenomegaly

Cytomegalo virus (CMV)

CNS involvement

Microcephaly, intellectual disability

Deafness

Chorioretinitis → vision loss

Hepatosplenomegaly

Herpes Simplex Virus (HSV)

acquired via passage through birth canal

Vitamin A (retinol/retinoic acid) used for treatment of acne

causes deregulation of TGF-beta signaling pathways & expression of homeobox (HOX) gene leading to Retinoic acid embryopathy

CNS, cardiac & craniofacial defects (cleft lip & cleft palate)

FETAL ALCOHOL SYNDROME

1st trimester

physical features tend to become less apparent with age

Prenatal & postnatal growth retardation (symmetric)

Microcephaly

Characteristic facial anomalies/features:

short palpebral fissures, maxillary hypoplasia, thin upper lip, low-bridge nose, frontal bossing

Psychomotor disturbances – emotional instability, impulsiveness

Intellectual disability

Hepatomegaly (fatty liver) with elevated serum transaminases

cigarette smoke-derived nicotine

Smoking is the most common cause of Low birth weight due to intrauterine growth retardation

May be prone to SIDS (sudden infant death syndrome)

maternal Diabetes

Fetal Macrosomia (↑ body fat + muscle mass with organomegaly):

Maternal hyperglycemia causes ↑ insulin secretion by fetal pancreas due to hyperplasia of fetal pancreatic islets & growth promoting effects of insulin causes fetal macrosomia

Diabetic Embryopathy: Cardiac anomalies; neural tube defects & other CNS abnormalities; kidney, gut & skeletal system anomalies

Diabetes can also cause health problems in baby after birth:

RDS (respiratory distress syndrome)

Obesity later in life

Diabetes later in life

Timing of intrauterine injury

Early embryonic period (first 9 weeks): organs are crafted from germ cell layers

3 to 9 weeks embryo susceptible to teratogens → malformations

Peak sensitivity between 4th and 5th week – period of organogenesis

Fetal period (terminating at birth): Period of growth & maturation of organs

Greatly reduced susceptibility to teratogenic agents

Fetus susceptible to growth restriction & injury to already formed organs → CNS injury, gonadal injury

Full term

37 to 42 weeks

Post-Term

delivered after 42 weeks

Appropriate for gestational age (AGA)

infants with birth weight between 10th and 90th percentile for gestational age

Small for gestational age (SGA)

infants with birth weight <10 TH percentile for gestational age

at risk for CNS dysfunction, learning disabilities, sensory (visual/hearing) impairment

Large for gestational age (LGA)

infants with birth weight >90th percentile for gestational age

Prematurity

< 37 weeks

Risk factors for prematurity

Preterm Premature Rupture Of fetal Membranes (PPROM)

Intrauterine infections

Uterine, cervical & placental structural abnormalities

Multiple gestations

Fetal Growth Restriction (FGR)

FGR may result from three groups of abnormalities:

Fetal: proportional FGR (head & trunk proportionally involved)

Placental: disproportional FGR (relative sparing of the brain)

Maternal: disproportional FGR

Neonatal Respiratory Distress Syndrome or Hyaline Membrane Disease (HMD)

Preterm

deposition of a layer of hyaline proteinaceous material in peripheral airspaces (alveoli) of infants

deficiency of pulmonary surfactant

Surfactant is synthesized & secreted by type II alveolar lining cells & stored in lamellar bodies

Fetuses begin to produce surfactant around 24-week gestation. By 34-35 weeks have enough surfactant to keep the alveoli from collapsing

replacement surfactant therapy

Surfactant ↓ the surface tension of fluid in alveoli of lungs → keeps alveoli from collapsing when an individual exhales

Synthesis of surfactant is regulated by:

Cortisol, Insulin, Prolactin, Thyroxin & TGF-beta

Corticosteroids induce the formation of surfactant in fetal lung & insulin suppress surfactant synthesis

Neonatal Respiratory Distress Syndrome Risk Factors

Preterm

Maternal Diabetes mellitus: Insulin suppresses surfactant synthesis

Male

C-section delivery

Untreated Neonatal Respiratory Distress Syndrome

Few minutes after birth infant breathing well

Within 30 minutes breathing becomes difficult

retraction of lower ribs & sternum on inspiration; expiratory grunt

Next few hours respiratory distress worsens

cyanosis develops & fine rales can be heard on both lung fields

Chest X-ray of infant:

uniform minute reticulogranular densities (‘ground glass picture’)

diffuse opacification of lung fields

What is the characteristic microscopic lung findings in RDS?

Atelectasis & alveoli poorly developed or collapsed

Hyaline membranes composed of fibrin & cell debris line alveoli

Minimal inflammation

After 48 hours reparative changes appear in lungs

Neonatal Respiratory Distress Syndrome

Eosinophilic thick hyaline membranes line alveoli

Complications of oxygen therapy in NRDS

Sustained high dose oxygen therapy delivered with positive pressure ventilation can cause injury to immature lungs due to oxygen derived free radicals

Retrolental fibroplasia (retinopathy of prematurity)

Bronchopulmonary dysplasia: chronic lung disease

What are three major complications an infant who recovers from RDS at risk for?

Necrotizing enterocolitis

Perinatal infection & sepsis

Intraventricular hemorrhage

Necrotizing enterocolitis

Multifactorial - Associated with prematurity

Apoptosis of enterocytes induced by platelet-activating-factor (PAF)

Strong association with enteral feeding/introduction of formula feeds → introduction of bacteria in gut → bacterial overgrowth → inflammation → tissue injury → mucosal necrosis of gut → gangrene/necrosis of small/large bowel → perforation → sepsis and shock

symptoms usually do not appear until after first oral feeding

Bloody stools, Abdominal distension, Hypotension, Circulatory collapse

Elevated PAF

Abdominal X-ray: Gas within the intestinal wall (pneumatosis intestinalis); free abdominal air

Terminal ileum, cecum and right colon shows distension, congestion & may get gangrenous with perforation & peritonitis leading to sepsis and shock

Mucosal or transmural necrosis, ulceration, bacterial colonization & submucosal gas bubbles

What are the two major ways to control RDS in an at-risk fetus?

Corticosteroids given to mothers in premature labor

Surfactant administered to infants

Ventilator support

Sudden Infant Death Syndrome (SIDS)

Sudden death of an infant under 1 year of age in which cause remains unexplained after a thorough case investigation

most die at home while asleep in the crib mostly in prone or side position

90% of deaths occur ≤ 6 months age, mostly between 2 & 4 months

Sudden Unexpected Infant Death (SUID)

all sudden deaths in infants due to known or unknown causes

What is the most common nonspecific finding at autopsy in SIDS?

Non-specific subtle autopsy findings

Multiple petechiae of thymus, pleura & pericardium

Pulmonary congestion ± pulmonary edema

Subtle changes in brain stem: hypoplasia of arcuate nucleus or ↓ in brain stem neuron population

What are the three factors of the triple risk hypothesis?

Vulnerable infant: Infant + Parent factors

Critical development period: First 6 months of life

One or more exogenous stressors: Environmental

Parental Risk Factors

Young maternal age (age <20 years)

Maternal smoking during pregnancy

Drug abuse in either parent, specifically paternal marijuana and maternal opiate, cocaine use

Short inter-gestational intervals

Late or no prenatal care

Low socioeconomic group

African American and American Indian ethnicity

Infant: vulnerable infant Risk Factors

Brain stem abnormalities (medulla oblongata) associated with defective arousal, and cardiorespiratory control

Prematurity and/or low birth weight

Male sex

Product of a multiple birth

SIDS in a prior sibling – genetic predisposition

Antecedent respiratory infections

Environment Risk Factors

Prone or side sleep position → hypoxia, hypercarbia

Sleeping on a soft surface

Sleeping with parents in first 3 months

Hyperthermia

Postnatal passive smoking

Phenylketonuria (PKU)

Autosomal recessive (AR)

Disorder is due to severe deficiency of enzyme phenylalanine hydroxylase (PAH) → Hyperphenylalaninemia → brain damage & intellectual disability

Inability to convert phenylalanine to tyrosine

without this enzyme, intermediate products phenylacetic acid are excreted in urine & sweat & imparts strong mousy or musty odor to infants

phenylalanine & its metabolites contribute to brain damage

By 6 months severe intellectual disability

Seizures

pigmentation of hair & skin & eczema

restricting phenylalanine intake early in life

Maternal PKU

marked phenylalanemia

intellectually disabled & microcephalic

congenital heart disease

It is imperative that maternal dietary restriction of phenylalanine be initiated before conception & be continued throughout the pregnancy

Galactosemia Deficiency

Autosomal Recessive (AR) disorder of galactose metabolism resulting in accumulation of galactose-1-phosphate in blood & tissues

Lactose is converted to glucose + galactose in the intestinal microvilli by lactase

Galactose-1-phosphate uridyl transferase (GALT) is involved in the first step in the transformation of galactose to glucose

GALT enzyme deficiency/absence → galactosemia

Galactosemia Presentation

Liver (fatty change and fibrosis), lens of eye (cataracts), cerebral cortex, spleen, kidney (aminoaciduria & E. Coli sepsis), heart muscle & RBC

Symptoms usually manifest after birth as soon as infant starts on milk

Vomiting & diarrhea within few days of milk ingestion → failure to thrive

Jaundice & hepatomegaly in first week → liver failure

Cataracts in first few weeks

Intellectual disability in 6 to 12 months

Hemolysis & coagulopathy

suggested by finding reducing sugar other than glucose in urine & confirmed by GALT assay in leukocytes/erythrocytes

removal of galactose from diet for at least first two years of life can prevent some of the severe complications

Older patients inspite of dietary restrictions can have speech disorder & gonadal failure & rarely ataxia

Cystic Fibrosis (CF)/Mucoviscidosis

Autosomal Recessive

Inherited disorder of epithelial ion transport causing thick secretions in exocrine glands & in epithelial lining of respiratory, gastrointestinal & reproductive tracts causing blockage & severe damage to multiple organs to include: Lungs, Pancreas, Liver, GIT, Reproductive system

Due to mutation of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene (located on chromosome 7q31.2) there is ↓ production or abnormal function of CFTR, an epithelial chloride & bicarbonate channel protein

Most common mutation is a deletion of 3 nucleotides coding for phenylalanine that causes misfolding of CFTR

Cystic Fibrosis Pathogenesis

Sweat gland: function of CFTR gene is to reabsorb Cl & augment reabsorption of Na

CFTR gene mutation → ↑ sodium & chloride (salt) in the sweat (hypertonic sweat)

Respiratory, intestinal epithelium & reproductive tracts:

CFTR mutation → ↓ chloride secretion in the lumen, ↑ sodium & water reabsorption leads to dehydrated mucus layer, defective mucocilliary action & mucus plugging with obstruction of organ passages

Airway surface fluid deficient in antibacterial activity

Cystic Fibrosis Clinical Manifestations

Sino-pulmonary:

chronic persistent cough with thick sputum

recurrent lung infections- Staph aureus, H. influenza, Pseudomonas aeruginosa

recurrent sinusitis, nasal polyps

Gastrointestinal: thick mucus can block tubes that carry digestive enzymes from pancreas to small bowel

Pancreatic insufficiency due to inflammation & fibrosis → ↓ pancreatic enzymes (lipase, insulin)

protein, fat malabsorption → Large foul-smelling greasy stools

hyperglycemia/diabetes due to loss of islets of Langerhans (not till adults)

Deficiency of fat-soluble vitamins D, E, A, K

poor weight gain & growth

Intestinal blockage at birth present with meconium ileus → distended abdomen

Distal intestinal obstruction → rectal prolapse

Liver – jaundice; fatty liver; Biliary cirrhosis

Male genital tract abnormalities → infertility due to obstructive azoospermia due to congenital bilateral absence of vas deferens due to bi-allelic CFTR mutations

Morphology in CF

Plugging of ducts with viscous mucus in various organs:

Pancreas:

ducts plugged with mucus

atrophy of exocrine pancreas with fibrosis

islets initially are not affected

Liver:

Hepatomegaly with steatosis

plugging of bile canaliculi with mucinous material & portal inflammation

biliary cirrhosis may develop

Genitalia:

azoospermia & infertility in males who go on to adulthood

congenital absence of bilateral vas deferens

Sweat gland- normal histology

Intestines: small intestine may have mucus plugs causing obstruction & meconium ileus

Lungs:

Pneumonia, bronchiectasis

Mucus creates hypoxia & production of alginate which forms a capsule around bacteria preventing antibiotics to act

What is the single most common cause of death in CF?

Cardiorespiratory complications

CF Diagnosis

New-born screening:

Measurement of immunoreactive trypsinogen (IRT) in blood of newborn babies: ↑ IRT

positive IRT test should be confirmed with sweat test because of high false positives

Sweat test:

Persistently elevated sweat chloride concentration

Infant sweat tastes salty & diagnosis is usually made by mother

Gene sequencing: Gold standard for diagnosis

What are the current treatment options for CF?

Clearing of pulmonary secretions & treatment of pulmonary infection

Transplantation

bilateral lung transplant, liver, pancreas

Gene therapy