Paediatrics

Water Soluble Vitamins

Vitamin Source Deficiency
B1 (thiamine) Whole grains, meat, fortified cereals, Beriberi (dry – peripheral neuropathy, wet – dilated
legumes, nuts cardiomyopathy & heart failure)
Wernicke-Korsakoff syndrome
B2 (riboflavin) Dairy, eggs, meat, green vegetables Angular cheilosis, stomatitis, glossitis
Normocytic anemia
Seborrheic dermatitis
B3 (niacin) Meat, whole grains, legumes Pellagra = 4 D’s
o Dermatitis – symmetric reddish rash on exposed
areas
o Diarrhea / vomiting
o Delusions/dementia, insomnia, anxiety,
disorientation, encephalopathy
o Glossitis
o Death if untreated
B6 (pyridoxine) Meat, whole grains, legumes, nuts Cheilosis, stomatitis, glossitis
Irritability, confusion, depression
B9 (folate, folic acid) Green leafy vegetables, fruit, meat, Megaloblastic anemia
fortified cereal / grains Neural Tube Defects (fetus)
B12 (cobalamin) Meat, dairy Megaloblastic anemia
Neurologic deficits (confusion, paresthesias, ataxia)
C (ascorbic acid) Citrus fruits, strawberries, tomatoes, Scurvy (punctate perifollicular hemorrhage,
potatoes, broccoli hyperkeratosis, gingivitis, corkscrew hair)

Pediatric Traumatic Brain Injury (PECARN rule)

High–risk features  Altered mental status (fussy behaviour)
(age < 2)  Loss of consciousness
 Severe mechanism of injury (fall > 0.9m [3 ft], high impact, motor vehicle collision
 Non–frontal scalp haematoma – large (i.e. > 3 cm) parietal and temporal hematomas have the
highest risk
 Palpable skull fracture
High–risk features  Altered mental status (e.g. somnolence, agitation)
(age ≥ 2 – 18)  Loss of consciousness
 Severe mechanism of injury (fall > 1.5 m [5 ft], high impact, motor vehicle collision)
 Vomiting, severe headache
 Basilar skull fracture signs (e.g. CSF otorrhea, rhinorrhea, mastoid or postauricular ecchymoses
[Battle signs], periorbital haematomas [racoon eyes])
Management  Head CT scan without contrast
o Assess for skull fractures &/or intracranial injury when high – risk features are present
 Alternatively, observation for 4 – 6 hours in emergency department may be an option for
patients with isolated or intermediate–risk / improved high–risk features (e.g. brief LOC,
resolved vomiting, small / isolated scalp hematoma) but normal mental status and no signs of a
basilar skull fracture. Head CT is warranted if symptoms worsen during this observation period
Anaphylaxis
Pathogenesis Severe IgE–mediated Type 1 hypersensitivity reaction
Massive degranulation of mast cells and basophils
Triggers Food (e.g. nuts, shellfish)
Medications (e.g. β –lactam, antibiotics)
Insect stings
Clinical Allergic symptoms affecting ≥ 2 organ systems or hypotension after exposure to an allergen
Manifestations Cardiovascular
o Vasodilation → hypotension & tissue edema
o Tachycardia
Respiratory
o Upper airway edema → stridor & hoarseness
o Bronchospasm → wheezing
Cutaneous (absent in 20% of cases)
o Urticarial rash, pruritus, flushing
Gastrointestinal
o Nausea, vomiting, abdominal pain
Management IM epinephrine
o Beta 2 agonist effect causes bronchodilation and decreases the systemic release of
inflammatory mediators
o Alpha 2 agonism vasoconstriction (which increases blood pressure and reduces edema)
Airway management & volume resuscitation
Adjunctive therapy (e.g. H1 antihistamines [diphenhydramine], glucocorticoids)

Nonaccidental Trauma
Injury inconsistent with developmental stage
Delay in seeking medical care
Red Flags
Conflicting historical details
Siblings or pets are often commonly blamed for the injury
Clinical Bruises: patterned appearance (e.g. belt buckle), occurring in non–mobile child or over non–injury
Features prone area (e.g. ear, trunk)
Burns: linear; well demarcated
Fractures:
o Multiple & in various stages of healing
o Femur fracture in non-ambulatory child
o Posterior rib fractures
 o Metaphyseal corner fractures (“bucket handle” fractures)
o Multiple digital fractures concerning for inflicted injury by door slamming
Head trauma: retinal & subdural hemorrhages
Disposition: ensure immediate safety of the child (e.g. inpatient management, child protective
Management services)
Evaluation: complete skeletal survey, CT scan of the head, fundoscopy

Abusive Head Trauma

(previously “Shaken Baby Syndrome”)
 Blunt force to the head or repeated / forceful shaking –
o Repeated acceleration–deceleration forces as the brain collides inside the cranium
o Axonal injury & venous shearing
Etiology & o Secondary Hypoxic–ischemic injury
Pathophysiology o Infants are particularly prone due to large head – to – body ratio and weak neck
muscles, making their heads vulnerable to coup–counter coup injuries. Additionally
the infant’s brain is incompletely myelinized, making it more susceptible to
shearing forces
 Child age < 1
Risk Factors  Young / single parents
 Unstable home environment, parental drug / alcohol abuse
 Non–specific irritability, vomiting, feeding difficulty
 Apnea, seizures, altered mental status e.g. lethargy
 Bulging fontanelle
Clinical Features  Retinal hemorrhages on fundoscopy – often multi–layered and bilateral
 Diffuse brain injury
 Delayed presentation to medical care following injury, and a vague inconsistent
history of events is suspicious
 Emergency CT scan of the head
o Subdural hemorrhage – due to shearing of bridging veins; appear as crescents
overlying the brain
 Typically have mixed density pattern (i.e. acute on chronic subdural
appearance) due to varying stages of injury, compared to homogenous
Evaluation
hyperdense pattern seen in accidental head trauma
o Cerebral edema
 In a situation that is not time – sensitive, and patient asymptomatic → MRI can
provide more detail regarding extent, and timing of the injury while avoiding
radiation exposure
 Benign vs. Pathologic Murmurs
Benign Pathologic
History Normal appetite, energy, activities & growth Diaphoresis & fatigue with feeding or exercise, poor weight
No significant family history gain, chest pain, dizziness, syncope, shortness of breath
Family history of sudden cardiac death, heart defects etc.
Murmur Early or mid-systolic Harsh, holosystolic, diastolic
Features Grade I or II intensity that decreases on standing ≥ Grade III intensity
& Valsalva maneuver Increases with standing & Valsalva maneuver
N.B. maneuvers that decrease venous return E.g. murmur of hypertrophic cardiomyopathy increases with
(e.g. standing, Valsalva) typically reduces the decreased venous return & preload due to consequent
intensity of innocent murmurs increased obstruction of flow (turbulent flow against a
Low-pitched, musical, pure, or squeaky tone at narrow orifice)
LLSB (Still’s murmur) or high-pitched at LUSB
(pulmonary flow murmur)
Other None Loud, fixed split, or single S2
Findings Decreased or absent femoral pulses
Workup None indicated ECG – assess hypertrophy
Echocardiogram – to assess structural abnormalities
Cardiology referral

 Ventricular Septal Defect

o Range from small and asymptomatic, to large with significant left-to-right shunting
o Holosystolic murmur at LLSE with no variation in intensity with respiration
o Small or moderate VSDs → II-VI/VI holosystolic murmurs due to turbulence
o Large VSDs are quieter due to lower resistance (and less turbulence) through a larger orifice.
 ± apical diastolic rumble from increased flow across the mitral valve (from increased left-
to-right shunting across the VSD)
 As RV pressure increases due to increased flow, S2 will become more prominent due to
increased pressure closing the pulmonary valve
 If significant or prolonged left-to-right shunting → pulmonary over-circulation &
pulmonary hypertension, growth failure, diaphoresis, easy fatigability, and congestive
heart failure
 Unrepaired, large VSDs leads to permanent pulmonary hypertension and
Eisenmenger syndrome (cyanosis from right–to–left shunting)
o Treatment – Medications (e.g. diuretics) + defect closure
 Atrial Septal Defect
o Congenital heart defect often remains asymptomatic until adulthood but can subsequently
develop decreased exercise tolerance (fatigue, dyspnea), atrial arrhythmias (atrial fibrillation or
flutter), stroke due to paradoxical embolization or cerebral abscess.
 Eventually, severe pulmonary hypertension and right heart failure can develop
o Cardiac auscultation
 Widened and fixed splitting of 2nd heart sound (S2)
 Characteristic pattern due to enlarged right ventricle’s prolonged emptying →
delayed closure of the pulmonic valve (widened S2), with no difference between
inspiration and expiration (fixed S2)
 Mid-systolic or ejection murmur over the left upper sternal border
 Resulting from increased flow across the pulmonic valve. The low-velocity left-to-
right shunt flow across the ASD itself does not produce any audible murmur
 Mid-diastolic rumble – resulting from increased flow across the tricuspid valve
o ASD can progress to severe pulmonary hypertension and right-to-left shunting; this usually does
not occur until adulthood and is associated with cyanosis and clubbing (i.e. Eisenmenger
syndrome)
Cyanotic Congenital Heart Diseases of New born
Diagnosis Examination X–ray Findings
D-Transposition of the Single S2 (absent pulmonary component of S2 because the aorta is “Egg–on–a–string” heart (narrow mediastinum)
Great Arteries anterior to the pulmonary artery) Mixing of deoxygenated and oxygenated blood necessary for
± VSD murmur (N.B. no murmur associated with PFO) survive (e.g. PDA, VSD patent foramen ovale)
Two parallel circuits of blood flow (pulmonary circulation isolated from Prostaglandin E1 to keep PDA open & optimize inter-
systemic circulation) circulatory mixing
o Aorta arising from the right ventricle and a pulmonary artery arising Associated with maternal DM
from the left ventricle
Tetralogy of Fallot Harsh pulmonic stenosis murmur – harsh systolic ejection murmur at the “Boot shaped” heart (right ventricular hypertrophy)
mid to left upper sternal border Associated with 22q11 syndromes and prenatal alcohol
4 components VSD murmur Management of tet spells
 RVH Severity of RVOT obstruction determines clinical presentation (may o Knee–chest positioning, Squatting: ↑ SVR, ↓ right–to-left
 VSD develop severe infundibular spasm with agitation or exertion, e.g. shunt, improves cyanosis.
 RV outflow tract feeding, crying, hyperventilation → near-complete RVOT obstruction) o Supplemental O2 – stimulates pulmonary vasodilation
obstruction o Severe RVOT – central (perioral) cyanosis shortly after birth (decreased PVR) and systemic vasoconstriction
(infundibular / o Moderate RVOT – subtle symptoms during infancy; instead presents o IV fluids improve right ventricle filling and pulmonary flow
pulmonic stenosis) during childhood with sudden hypoxic / hypercapnic “Cyanotic Tet (increases systemic venous return, i.e. preload)
 Over–riding aorta over spells” due to right-to-left shunting across VSD
Right and left ventricles o Exertional dyspnea, syncope
o Squatting / Knee-chest Positioning may reduce cyanosis & increase
murmur intensity
 this manuevre increases SVR (afterload) by kinking femoral arteries
& decreases right-to-left shunting across VSD → increasing flow
across RVOT
Tricuspid Atresia Single S2 Minimal pulmonary blood flow
VSD murmur
Truncus Arteriosus Single S2 Increased pulmonary blood flow, edema
(1 vessel) Systolic ejection murmur (increased flow through truncal valve) Tx – prostaglandin E1; emergent corrective surgery
Signs of heart failure (e.g. respiratory distress, poor feeding) due to
excessive pulmonary blood flow
Associated with DiGeorge Syndrome
Total anomalous Severe cyanosis Pulmonary edema, “snowman” sign (enlarged supracardiac
pulmonary venous return Respiratory distress veins & SVC)
with obstruction (TAPVR) Pulmonary veins drain into right heart circulation ↑ pulmonary vasculature
ASD or PDA allows for right–to–left shunting to maintain cardiac output Tx – prostaglandin E1; emergent corrective surgery in severe
cases
Ebstein Anomaly Characterized by a downardly displaced tricuspid valve → enlarged right CXR – cardiomegaly, ↓ pulmonary vasculature
atrium Treatment –
 Increased right atrial pressure shunts blood to the left heart via the o Prostaglandin E1
foramen ovale or ASD, leading to cyanosis o Corrective surgery
Tricuspid regurgitation – holosystolic murmur
Right heart failure
Associated with lithium exposure in utero
Hypoplastic Left Heart Ductal – dependent congenital heart defect (along with reliance on right CXR – enlarged cardiac silhouette and signs of pulmonary
Syndrome ventricle) venous hypertension.
o Underdeveloped left ventricle & atretic mitral valve (&/or atretic aortic Tx – Immediate administration of prostaglandin E1 in
N.B. for the right side of vavle) + patent ductus arteriosus suspected HLHS (required to maintain patency and, in turn,
the heart to adequately o Atrial septal defect systemic perfusion)
oxygenate & perfuse the o Ascending aorta hypoplasia (Narrow ascending aorta) Uniformly fatal without surgical correction
body, oxygenated blood Cyanosis at birth – Mixing of oxygenated & deoxygenated blood in the
must be delivered to the right atrium
right atrium (via an ASD or o As pulmonary vasculature resistance physiologically decreases & PDA
PDA) and blood must flow closes around day 1 of life
from the pulmonary artery No murmurs
to the aorta via a PDA Oxygen saturations rapidly decrease (< 80 – 90% in all extremities)
Respiratory distress
Cardiogenic shock – symmetrically low BP in all extremities, cold
peripheries with diminished pulses, tachycardia, acidosis
± Single S2 (may indicate an absent aortic valve or developing pulmonary
HTN
 Centor Score (Modified/McIsaac) for Streptococcal Pharyngitis
N.B. Criteria not recommended for children and/or preadolescents (AAP, Centre for Disease Control & Prevention)
Streptococcal pharyngitis is rare in individuals < 3 years and does not progress to rheumatic fever
Testing should only be performed in patients who have a sore throat with concomitant tonsillar exudates or swelling,
palatal petechiae, and have no viral symptoms (e.g. rhinorrhea)
Criteria Points Cumulative Risk of GABHS Treatment
Score pharyngitis
 Absence of cough 1 ≤0 1– 2.5% Score ≤ 1: No testing or treatment
 Swollen, tender anterior cervical 1 1 5– 10% for streptococcal infection
nodes May perform throat culture or
RADT for score = 1
 Temperature > 100.4°F (38°C) 1 2 11– 17% Score 2 – 3 → Throat Cx or RADT
 Tonsillar exudates or swelling 1 3 28– 35%  RADT – highly specific but limited
sensitivity (70-90%); all negative
RADT in children must be
followed up with throat culture
 Always need throat Cx in children
irrespective of score
 Age ≥4 51– 53% Empiric treatment with antibiotics
(penicillin or amoxicillin) or RADT
o 3 to 14 years 1 Treatment Options
o 15 to 44 years 0  Oral penicillin V; intramuscular penicillin G benzathine; oral
o 45 years or older –1 amoxicillin is as effective as penicillin and has better palatability in
children
 If Penicillin allergy
o 1st gen cephalosporin (e.g., cephalexin [Keflex]) for patients with
type IV HSR to penicillin;
o clindamycin, clarithromycin (Biaxin), or azithromycin (Zithromax) for
patients with type I HSR to penicillin
o GABHS = group A beta-hemolytic streptococcal; RADT = rapid antigen detection testing

Streptococcal Tonsillopharyngitis
Group A streptococcus – most common in children age 5 – 15
Microbiology
Occurs in late fall, winter, and early spring
Abrupt onset of sore throat
Fever
Signs & symptoms Absence of cough and viral symptoms (N.B. viral pharyngitis typically
presents with upper respiratory symptoms such as rhinorrhea, cough)
Abdominal Pain & Vomiting
Palatal petechiae
Examination Tonsillar erythema & exudates
Tender anterior cervical lymphadenopathy
Throat culture
Diagnosis
Rapid streptococcal antigen test
1st line Penicillin or amoxicillin
o Inappropriate Rx of broad spectrum amoxicillin – clavulanic acid
may lead to emerging resistance of bacterial strains in general
Treatment Cephalosporin if penicillin allergic
Adjunctive symptomatic treatment – NSAIDs, hydration
Goals of treatment – to reduce symptom severity and duration,
decrease spread to close contacts, and prevent acute rheumatic fever
Complications Peritonsillar abscess
 Cervical lymphadenitis
Rheumatic Fever
Post – streptococcal glomerulonephritis

Diphtheria
Epidemiology Toxigenic strains of Corynebacterium diphtheriae
o Aerobic, gram positive bacilli
o Produces diphtheria exotoxin, which inactivates elongation factor (EF–2) via ADP–ribosylation
 Inhibits protein synthesis, causing necrosis in respiratory, cardiac and CNS tissue
 Affects mucous membranes, especially the respiratory tract
o Exotoxin is encoded by β–prophage
o Transmission via respiratory droplets
Children age < 15
Diphtheria toxoid vaccine significantly decreases risk; also limits asymptomatic carriage of toxigenic
strains (causing population–wide declines in prevalence)
Manifestations Toxic Appearance – Low Grade Fever, malaise, sore throat; may have croup–like cough
Tachycardia out of proportion with fever
Pseudomembranous Pharyngitis – grey – white tenacious exudate or patches adherent to posterior
pharynx(‘pseudomembrane’ – bleeds when scrapping; leaves focal hemorrhagic raw surface when
removed)
Cervical lymphadenopathy – “Bull neck”
Toxin – mediated myocarditis (66%), arrhythmias (e.g. complete heart block) & heart failure in severe
cases,
Neuritis (peripheral or cranial neuropathies), kidney disease
Diagnosis CBC - leukocytosis
Culture from respiratory secretions
o GPB with blue & red granules (metachromically) seen on
 Culture cysteine–tellurite agar (appears as black colonies)
 Löffler medium positive
Toxin assay (to prove toxigenic) – Elek test for diphtheria toxin
Management Droplet precautions
Antibiotics for 14 days duration
o Erythromycin 20mg/kg/day divided every 6 hours IV or
o Penicillin G 50,000 U/kg up to 1.2 MU/day IV every 12 hours, then transition to Penicillin VK
when able
o Culture and treat contacts

Diphtheria antitoxin (if severe; Equine serum from CDC)
Complications Airway compromise from soft tissue swelling
Heart failure from myocarditis
Secondary bacterial infection (i.e., pneumonia)
Prevention DTaP vaccine (Diphtheria–Tetanus–Acellular pertussis)
o Components
 Diphtheria toxoid, Tetanus toxoid
 Conjugated pertussis antigen (pertactin)
o 5 doses before school–age, completed by 4–6 years of age
 2, 4, & 6 months
 15 – 118 months
 4 – 6 years
o Absolute Contraindications
 Encephalopathy after previous dose (within 7 days) – due to pertussis component, thus
children can still receive Td vaccines
 Anaphylaxis to any vaccine component, immediately after vaccination
o Relative Contraindication / Caution if:
  Extremely high fever (≥ 40.6 OC [105 F]) or seizures following previous DTaP vaccination or
ongoing evaluation for neurologic condtion
Tdap vaccine
o Booster vaccine at 11–12 years of age
o Should also be given to pregnant mothers and those around them
Td vaccine
o Tetanus and diphtheria toxoid vaccine at 10-year intervals

 Infantile Vitamin K Deficiency Bleeding

o Vitamin K is essential cofactor of gamma-carboxylation & activation of factors II, VII, IX, X, and
protein C & S
o Deficiency increases the risk of spontaneous bleeding
o Newborns are vitamin K deficient due to poor placental transfer, absent gut flora to synthesize
vitamin K, and immature liver function (i.e. poor vitamin K use)
o Patients who do not receive vitamin K are at increased risk for VKDB, particularly if exclusively
breastfed because breast milk has insufficient vitamin K
o Clinical Features
 Classically presents in 1st week (day 2 – 7) of life
 Easy bruising
 Umbilical, mucosal & GI bleeding
 Late-onset VKDB occurs between 2 weeks and 6 months and is more commonly associated
with intracranial hemorrhage
 ICH may block CSF flow leading to obstructive hydrocephalus
 Signs of increased ICP – irritability, vomiting, bradycardia, hypertension, bulging
fontanelle and/or a rapidly enlarging head circumference
 Pressure on midbrain may also cause upward gaze impairment (i.e. persistent
downward gaze)
o Investigations
 ↑ PT, ↑ PTT (if severe), normal platelet count
 CT Brain – layered, hyperdense fluid collection is located in posterior ventricles due to supine
positioning; enlarged ventricles due to obstructive hydrocephalus
o Prevention
 Intramuscular vitamin K at birth
 Hemorrhagic Stroke in Children
o Risk Factors
 Vascular malformations
 AVM (isolated or multi-organ associated with hereditary hemorrhagic
[mucocutaneous] telangiectasia)
 Aneurysm
 Hematologic abnormalities (e.g. hemophilia, sickle cell disease)
o Clinical Features
 Headache, vomiting
 Seizure
 HTN (Cushing’s reflex)
 Focal neurologic deficits (e.g. contralateral hemiparesis)
 Altered mental status (e.g. stupurous with decerebrate rigidity)
o Imaging
 CT Brain – intraparenchymal, intraventricular, or subarachnoid hyperdense fluid collection
with irregular margins
o Management
 Supportive – antiepileptics
 Reduction of intracranial pressure (e.g. elevated head of bed, surgical decompression)
 Breath–Holding Spells
o Usually benign and occur most commonly in children age 6 months to 5 years
o Types
 Cyanotic – crying followed by breath-holding in forced expiration, cyanosis, & loss of
consciousness
 Pallid – minor trauma followed by breath-holding, pallor, diaphoresis, & loss of
consciousness
 Episode last < 1minute with subsequent confusion and sleepiness for a few minutes
o Diagnosis – based on clinical history and normal physical examination
o Management – reassurance, treatment generally unnecessary
 Some patients develop recurrent episodes that usually stop at age 5. Others develop
vasovagal syncope later in life
 Rashes that affect the palms & soles (“Kawasaki CARS”)
o Kawasaki
o Cocksakie A – Hand Foot & Mouth Disease
o Rocky Mountain Spotted Fever
o Secondary Syphilis
 Maculopapular rash on palms and soles, snuffles, periostitis

Hand–Foot–Mouth Disease (HFMD)

Pathogenesis  Coxsackievirus infection
 Direct contact with respiratory, oral, or vesicular secretions
o Typically occurs in infants and young children during the
summer
o Can spread quickly through daycare centres, schools, and
camps
 Fecal – Oral Transmission (Virus is shed in the stool; e.g. diaper
changes)
Clinical  Fever, malaise, poor oral intake
Features  Oral enanthem – Painful vesicles on anterior oral mucosa (e.g.
tongue, buccal mucosa) → rupture to form oral ulcers
 Exanthem – Non – pruritic, macules / papules / vesicles on palms,
soles, &/or buttocks
Managemen  Supportive – Hydration, Pain control
t  Oral and skin lesions typical self – resolve within a week
 Handwashing is extremely important as the virus can be
contagious for several weeks after rash resolution

 HIV in infancy
o Risk Factors
 High maternal Viral Load (most important)
 Transplacental route or, more commonly, during delivery
 Breastfeeding by HIV positive mother
o Clinical Features
 Failure to Thrive (FTT)
 Chronic Diarrhea
 Lymphadenopathy
 Pneumocystis jirovecii pneumonia
o Diagnosis
 DNA PCR testing
  Persistence of HIV antibody after age 18 months (N.B. maternal antibody may be present in
HIV-negative children up to 18 months)
o Treatment
 Immediate combination antiretroviral therapy
 Hypoketotic Hypoglycemia / Nonketotic Hypoglycemia
o Etiology – fatty acid oxidation disorders
 Primary carnitine deficiency
 MCAD Deficiency – medium-chain acyl-CoA dehydrogenase)
o Primary Carnitine Deficiency
 Autosomal recessive inheritance
 Pathophysiology
 Carnitine acyltransferase (CAT)–1 deficiency → impaired entry of long-chain fatty
acids into mitochondria from cytoplasm as acyl-carnitine via carnitine-dependent
shuttle → impaired fatty acid metabolism via beta-oxidation (mitochondria unable to
β –oxidize fatty acids into acetyl CoA, the carbon substrate in citric acid cycle)
o Cardiac and skeletal myocytes unable to synthesize ketone bodies
 ↓ Energy production from fatty acids (↓ gluconeogenesis ) and ↓ production of
ketones → hypoketotic hypoglycemia
 Accumulation of fat (long-chain fatty acids ) in the cytosol of the liver and cardiac and
skeletal muscle cells → toxicity
 Clinical Features – onset in early childhood
 Lethargy, irritability, failure to thrive
 nonketotic / hypoketotic hypoglycemia
 triggered by catabolic states (e.g., fasting or illness)
 Muscle weakness, hypotonia
 Dilated Cardiomyopathy, Congestive Heart Failure
 Elevated muscle triglycerides
 Liver dysfunction
 Encephalopathy
 Rhabdomyolysis (can cause renal failure )
 Diagnostics
 Part of newborn screening
 Absent ketones on urinalysis
 ↓ Glucose and ↓ ketones in serum (hypoketotic hypoglycemia),
 hyperammonemia , ↑ ALT , ↑ AST
 Very low plasma carnitine levels; Low carnitine content on muscle biopsy
 Tx –
 Avoid fasting states
 Oral carnitine supplementation
 Acute hypoketotic hypoglycemic encephalopathy: administer IV carnitine and 10%
dextrose in water
o Myopathic CAT deficiency
 carnitine acyltransferase (CAT)-2 deficiency
 presentation
 myoglobinuria
 muscle aches/weakness
 ↑ TG content in muscles (unable to use as energy)
 provoked by prolonged use of muscle (may ambulate normally initially but rapidly
becomes weak and tired
o MCAD Deficiency (medium-chain acyl-CoA dehydrogenase)
 Autosomal recessive inheritance
  Pathophysiology
 Deficiency of medium-chain acyl-CoA dehydrogenase → defective breakdown of
medium-chain fatty acids into acetyl-CoA → elevated concentrations of fatty acyl-CoA
in the blood → hypoketotic hypoglycemia
 C8-C10 acyl carnitines in blood – liver unable to break FAs down further than C8-C10
 Liver unable to produce ketones from β-oxidation and unable to produce enough
energy from β-oxidation to supply gluconeogenesis
 Clinical Features – onset within first years of life
 Dehydration, poor feeding, vomiting
 Hypoketotic Hypoglycemia, Encephalopathy, Seizures
 Fatty liver and impaired hepatic function
 Sudden Death (cardiopulmonary collapse)
 Symptoms often precipitated by prolonged fasting, increase metabolic demand (e.g.
infection, stress, exercise)
 Diagnostics
 Part of newborn screening
 Hypoglycemia
 ↓ Ketones in blood and urine
 Hyperammonemia , hyperuricemia
 Metabolic acidosis
 ↑ AST and ALT
 Prolonged PT and aPTT
 Plasma acylcarnitine profile
 Treatment – Avoid fasting states; low fat diet with frequent meals of high carbs
 IV administration of 10% dextrose during acute decompensation
 Galactosemia
o AR inheritance; Galactose accumulation after lactose or galactose inheritance
o Deficient enzyme:
 Galactose–1–phosphate uridyl transferase deficiency (GALT; classic galactosemia)
 Galatokinase deficiency (rare)
 more benign disorder of galactose metabolism
 cataract formation (only association)
o Clinical Features – classic galactosemia
 ↑ galactose → damages kidney, liver and brain
 neonatal jaundice (direct hyperbilirubinemia)
 cataracts (33%)
o accumulated galactitol deposits in the lens
o either present at birth or develop during 1st few weeks of life
 hepatomegaly
 Increased risk for Escherichia coli sepsis
 Mental retardation
 Vomiting, feeding intolerance, death if untreated
 Poor feeding can lead to lethargy, hypotonia, dehydration (e.g. sunken fontanelle)
 Hypoglycemia may lead to seizures
 Breastfeeding contraindicated
 Symptoms start soon after breastfeeding is initiated
o Investigations
 RBG – Hypoglycemia
 Conjugated &/or unconjugated Hyperbilirubinemia, increased AST, ALT
 Conjugated suggest hepatic involvement
  May have unconjugated hyperbilirubinemia due to accumulation of galactose-1-
phospate in RBCs, thereby promoting hemolysis (Haemolytic anemia)
 Metabolic acidosis
 Widespread screening in newborns often leads to early diagnosis. Screen for
 ↓ RBC concentrations of galactose 1-phosphate uridyltransferase
 ↑ galactose / galactose-1-phosphate (in serum and urine - galactosuria)
o + Non–glucose Urine reducing substance suggesting galactosuria
o Tx – dietary restriction of galactose & lactose (disaccarhide of glucose and galactose) for life
 Soy–based formula
 End-organ dysfunction and symptoms including cataracts typically resolve
 Good prognosis
Breastfeeding Contraindications
 Active untreated tuberculosis
 HIV infection* (in developed countries, where formula is readily available)
 Herpetic breast lesions
 Active varicella infection
 Chemotherapy or radiation therapy
Maternal
 Active substance use disorder (e.g. cocaine, phencyclidine)
o Cocaine passes into breast milk and may cause infant intoxication and
withdrawal symptoms (e.g. irritability, tremors)
o Additionally, cocaine may cause long-term neurobehavioural problems
(e.g., hyperactivity, cognitive delay)
Infant  Galactosemia

 Aldolase B deficiency (Hereditary fructose intolerance) – life–threatening

o Autosomal recessive; chromosome 9q gene defect
o Pathophysiology
 Accumulation of fructose-1-phosphate due to deficient aldolase B → decrease in available
phosphates → inhibition of glycogenolysis and gluconeogenesis → hypoglycemia
 Fructose rapidly absorbed in proximal small bowel by hexose transporter GLUT-5
 Intracellular accumulation of fructose-1-phosphate and depletion of inorganic
phosphate, which inhibits glycogenolysis and gluconeogenesis
o Clinical Features
 Vomiting and hypoglycemia 30 minutes after fructose ingestion
 Diaphoresis, bloating
 Symptoms of hypoglycemia in infancy: seizures, hypotonia, poor feeding, cyanosis, irritability
 Typically present when fructose containing foods are introduced to diet (within first 6
months of life)
 Failure to thrive, hepatomegaly and jaundice may occur
 Undiagnosed individuals may eventually develop liver failure (cirrhosis) and renal
failure (proximal tubular dysfunction)
 Bleeding tendency
o Diagnostics
 Detection of reducing substances (fructose) in urine
 Urine dipstick only tests for glucose and will, therefore, be negative.
 Definitive diagnosis
 Enzyme assay in a liver biopsy sample
 DNA testing for the genetic defect
 Abnormal LFTs: ↑ AST and ALT, hypoalbuminemia , ↓ PT/INR
o Tx –
  Lifelong adherence to a fructose-free, sorbitol-free, and sucrose-free diet (results in
symptom improvement and good long – term prognosis)
 Essential fructosuria – Benign
o Autosomal recessive; chromosome 2p gene defect
o Pathophysiology – deficiency in fructokinase
 Increased conversion of fructose to fructose-6-phosphate by hexokinase (hexokinase
becomes the main pathway for turning fructose to fructose-6-phosphate)
 Unphosphorylated fructose does not get trapped in cells → remaining excess fructose →
excretion of fructose in urine
o Diagnostics – Detection of reducing substances (fructose) in urine
o Asymptomatic. No treatment indicated
 Maple Syrup Urine Disease
o Autosomal recessive
o Pathophysiology
 Branched chain alpha-ketoacid dehydrogenase requires several coenzymes: Thiamine,
Lipoate, Coenzyme A, FAD, NAD (Mnemonic: Tender Loving Care for Nancy)
 Absent or deficient branched-chain alpha-ketoacid dehydrogenase → impaired degradation
of branched-chain amino acids (valine, leucine, isoleucine) → elevated α-ketoacid formation
o Clinical Features
 infantile onset
 normal for first week
 progressive onset of symptoms
 lethargy, vomiting, poor feeding
 weight loss
 Dystonia (hyper/hypotonia)
 mental retardation / Intellectual disability
 Sweet-smelling urine (smells of maple syrup or burnt sugar)
 Damage to the CNS can be severe (elevated leucine level leads to brain injury)
 Death if dietary intake of Val, Leu, Ile is not restricted
o Diagnostics
 Part of newborn screening
 Serum:
 Increased levels of alpha-ketoacids (especially leucine alpha-ketoacids)
 Increased levels of leucine , isoleucine , and valine
 Hypoglycemia
 Urine: presence of abnormal branched-chain hydroxy acids and ketoacids
o Tx –
 Lifelong restriction of branched chain amino acids (leucine, isoleucine, valine)
 Thiamine supplementation
 Phenylketonuria (PKU)
o 1/10,000 births
o AR mutation in phenylalanine hydroxylase
o Pathophysiology
 Phenylalanine hydroxylase deficiency (classic PKU) or Deficiency in tetrahydrobiopterin
(BH4), a cofactor in phenylalanine metabolism
 Accumulation of phenylalanine due to impaired conversion to tyrosine
 Excess of phenylalanine → transformed into phenylketone neurotoxic byproducts
and metabolites (e.g., phenylpyruvate, phenylacetate, and phenyl lactate) →
excretion of metabolites in the urine
 Tyrosine deficiency → decreased neurotransmitter, melanin, and thyroxine synthesis
o Clinical Features
  Untreated patients develop:
 Severe intellectual disability, psychomotor delays (as early as 4 – 6 months)
 Seizures
 Signs
 Hypopigmentation of hair, eyes, skin & brain nuclei – fair complexion & fair hair
 Blue eyes, albinism
 Eczema
 “Musty Odour”
 Maternal PKU: in pregnant women with PKU who do not follow proper diet during
pregnancy; infant is at risk of microcephaly, growth restriction, facial dysmorphisms,
congenital heart defects, intellectual disability
o Investigations
 Newborn screening (tandem mass spectrometry): direct measurement of serum
phenylalanine levels on the 2nd–3rd day after birth
 If screening test is positive: oral tetrahydrobiopterin loading test
 Performed to differentiate between PKU and tetrahydrobiopterin deficiency
 In the case of BH4 deficiency, phenylalanine levels decrease; in the case of PAH
deficiency, they remain unchanged.
 Quantitative amino acid analysis (↑ Phenylketones in urine: phenylacetate, phenyl lactate,
phenylpyruvate)
o Treatment – low Phe diet
 ↓ phenylalanine and ↑ tyrosine in diet, tetrahydrobiopterin supplementation
 Cereal, starches, fruits, vegetables and phenylalanine–free milk formulas
 Phenylalanine levels should not rise above 20 mg/dL; phenylalanine levels should also
not fall below 1 mg/dL because phenylalanine is an essential amino acid.
 BH4 deficiency: supplementation of tetrahydrobiopterin
 Homocystinuria
o AR inheritance, inherited enzyme deficiency – defect in cystathionine –synthase
 Cystathionine β-synthase deficiency leads to accumulation of homocysteine in blood & urine
 Can also be caused by decreased affinity for vitamin B6, B6 deficiency, or B12 deficiency
 Effects
 Intimal fibrosis and Fibre destruction
o Destroys arterial elastic fibers
o Destroys Zonular fibers of the lens
 Fatty Liver infiltration
 Gliosis and focal necrosis of the Midbrain
o Etiology
 Cystathionine B-synthase deficiency
 Methylene Tetrahydrofolate reductase deficiency
 Methionine synthase defect
 Vitamin B12 transport or coenzyme defect
o Elevated levels of homocysteine and methionine
 affects the methionine degradation pathway as an amino acid metabolism disorder
presenting in adolescents and young adults.
o Exhibits pleiotropy (i.e. one gene influences two or more seemingly unrelated phenotypic traits)
 Other examples of pleiotropy include sickle cell anemia and phenylketonuria
o Clinical features
 Marfanoid habitus (tall, long limbs, arachnodactyly, and hyperflexibility)
 Ectopia lentis (downward lens subluxation) + intellectual disability
 C.f. Marfan Syndrome – subluxation of lenses (superior & temporal) + no mental
retardation
 Predisposition to atherosclerosis, deep venous thrombosis (DVT), cerebrovascular accident,
and myocardial infarction (MI) before age 20 years.
o Diagnosis
 Elevated Homocysteine and Methionine Levels (Present in CSF, Plasma and Urine)
o Treatment
 Vitamin B6, Folate and Vitamin B12 to lower homocysteine levels
 Additionally antiplatelets or anticoagulation should be considered for thromboembolism
prophylaxis

Differential Diagnosis of Marfanoid Body Habitus

Diagnosis Overlapping Features Distinguishing Features
 Pectus Deformity  Autosomal Dominant
 Tall stature  Normal Intellect
Marfan Syndrome o ↑ Arm:height ratio  Aortic Root Dilatation
o ↓ Upper:Lower Segment ratio  Ectopia Lentis – Superior & temporal lens
 Arachnodactyly dislocation
 Joint Hyperlaxity  Autosomal Recessive
 Skin Hyperelasticity  Intellectual Disability
Homocystinuria
 Scoliosis  Venous Thromboembolism / Thrombosis,
Cerebrovascular Accident
(↑ Homocysteine,
 Ectopia Lentis – Downward lens Dislocation
methionine levels)
 Megaloblastic Anemia
 Fair complexion, Blue Eyes

 Noonan Syndrome
o Autosomal Dominant in 40% of cases (Sporadic in 60% of cases)
o M=F
o Pathophysiology
 Genetic mutation affecting RAS/mitogen–activated protein kinase (MAPK)
 Protein tyrosine phosphatase non – receptor type 11 gene mutation (PTPN11) is
causative in 50% of cases
 Affects cell cycle
 Normal karyotype in Noonan’s Syndrome (c.f. Turner’s Syndrome – 45,XO)
o Prenatal (USS & Labs)
 Increased Nuchal translucency
 Polyhydramnios
 Hydrothorax
 Abnormal maternal triple screen
o Clinical Features
 Short stature (50 – 70%)
 Broad Forehead
 Coarse, wispy hair
 Facial Dysmorphism
 Flat nasal bridge
 Ocular hypertelorism (wide spaced eyes)
 Eyes prominent with droopy eyelids
 Small receding chin
 Sad facial expression
 High arched palate
 Dental anomalies with malocclusion / cleft uvula
 Mental retardation
 Webbed Neck
  Congenital heart disease
 Pulmonary stenosis
 Atrial septal defect
 Hypertrophic cardiomyopathy

Delayed Puberty in Boys

 Primary hypogonadism (Gonadal failure)
o Klinefelter’s Syndrome (Karyotype = [47, XXY])
 Secondary hypogonadism (due to impaired GnRH → hypogonadotropic hypogonadism)
o Constitutional delay
 Late maturation of HPG axis resulting in delayed bone age and short stature (< 3rd
percentile) but normal growth velocity
Causes
 Typically associated family history of “late bloomers”
o Functional – Chronic illness, malnutrition, stress
o Hypothyroidism, hyperprolactinemia – increased levels of TSH & prolactin interfere
with GnRH secretion
o Genetic – Kallmann Syndrome
o Hypothalamic / Pituitary pathology – Craniopharyngioma
Clinical  Absent testicular enlargement (< 4 mL) by age 14
Features  Delayed growth splurt
 FSH, LH, testosterone
o Primary (elevated FSH / LH)
Initial Workup o Secondary (low to normal FSH / LH)
 TSH, prolactin
 Bone age radiography – assess remaining growth potential
 Congenital adrenal hyperplasia (CAH)
o Encompasses a group of autosomal recessive defects in the enzymes that are responsible for
cortisol, aldosterone, and, in very rare cases, androgen synthesis.
o Three subtypes of CAH:
 21β–hydroxylase (∼ 95% of CAH)
 11β–hydroxylase (∼ 5% of CAH)
 17α–hydroxylase (rare)
o Low levels of cortisol → lack of negative feedback to the pituitary → increased ACTH → adrenal
hyperplasia and increased synthesis of adrenal precursor steroids
o Clinical Features:
Enzyme deficiency BP XX (female) genotype XY (male) genotype
21β–hydroxylase deficiency
Female pseudohermaphroditism:
Most common HYPOtension clitoromegaly &/or male external
Presents in infancy (salt (↓ BP) genitalia along with a uterus &
wasting) or childhood ovaries  Normal male external genitalia at
(precocious puberty) Precocious puberty birth
11β–hydroxylase deficiency Virilization in females (deepening  Precocious puberty
voice, clitoromegaly, male pattern
Presents in infancy (severe baldness)
hypertension) or childhood Irregular menstrual cycles, infertility
(precocious puberty)
HYPERtension
(↑ BP)  Male pseudohermaphroditism:
Normal female external genitalia at
female external genitalia with a
birth
blind–ending vagina and intra–
17α-hydroxylase deficiency Delayed puberty (primary
abdominal testes at birth
amenorrhea) or sexual infantilism
 Delayed puberty or sexual
XX: lacks 2° sexual development
infantilism
N.B. If deficient enzyme starts with 1, it causes hypertension; if deficient enzyme ends with 1, it causes
virilization in females
All congenital adrenal enzyme deficiencies are autosomal recessive disorders and most are characterized by
skin hyperpigmentation (see below).
 Hypoglycemia
 Adrenal crisis → vomiting and diarrhea → dehydration
 Failure to thrive
 Hyperpigmentation in areas that are not exposed to sunlight (e.g., palm creases, mucous
membranes of the oral cavity, genitalia) is a common feature in all forms of CAH
 Due to ↑ MSH production, which is co–produced and secreted with ACTH) and
bilateral adrenal gland enlargement (due to ↑ ACTH stimulation).
 Different types of mutations on the CYP21A2 gene (which codes for 21β-hydroxylase ) are
associated with different levels of disease severity:
Classic CAH Non–classic CAH
21β-hydroxylase deficiency  Severe  Mild
Detection on neonatal screening  Yes  No
Prevalence  Less common  More common
Onset of symptoms  Early onset (during the neonatal  Late onset (manifests during late
period or early infancy) childhood, adolescence, or
adulthood)
Clinical Manifestations  Salt–wasting type  Normal glucocorticoids &
o ∼ 67% of all classic forms mineralocorticoids, ↑ Androgens
o 7–14 days after birth, males  Normal external genitalia at birth in
present with FTT, dehydration, both genotypes
vomiting, and shock  Precocious puberty – early pubic /
o Ambiguous genitalia in females axillary hair growth
  Non–salt-wasting type (simple  Severe Acne
virilizing)  Infertility
o ∼ 33% of all classic forms  Hirsutism & oligomenorrhea in girls
o No signs of shock  ↑ growth velocity & bone age
o Males present with precocious  May even be asymptomatic
puberty at age 2–4.  ↑ 17–hydroxyprogesterone level on
o Ambiguous genitalia in females ACTH stimulation test
Ethnic predisposition  Inuit and Alaska native populations  Ashkenazi and white populations
o Investigations
 Screening is conducted by measuring 17–hydroxyprogesterone (also for newborns)
 ↑ 17–hydroxyprogesterone in 21β–hydroxylase & 11β–hydroxylase deficiency
o Urine for 17–hyrdroxycorticoids
 ↑ 17–OH = 11β–hydroxylase deficiency
 ↓ 17–OH = 21β–hydroxylase deficiency
 ↓ 17–hydroxyprogesterone in 17α–hydroxylase deficiency
 Hypocortisolism is seen in all forms of CAH
 Low Cortisol levels even after administration of Cosyntropin (synthetic ACTH)

Enzyme deficiency Cortisol Aldosterone 11–Deoxycorticosterone (DOC) Androgens

21β–hydroxylase ↓
↑
11β–hydroxylase ↓ ↓
↑
17α–hydroxylase ↓

Adrenal enzyme deficiencies
Laboratory findings 21β–hydroxylase 11β–hydroxylase 17α–hydroxylase

17–Hydroxyprogesterone ↑↑ ↑ ↓

11–Deoxycorticosterone (DOC) ↓ ↑↑ ↑
 weak mineralocorticoid activity (↑ BP) (↑ BP)
↓
Corticosterone ↓ ↑↑
(↓ BP; ‘salt loser’)
↓
Sodium ↑ ↑
(Hyponatremia)
↑
Potassium ↓ ↓
(Hyperkalemia)
Metabolic acidosis Metabolic alkalosis Metabolic alkalosis
Acid–base disorders

o Treatment
 Glucocorticoid replacement therapy is indicated in all forms of CAH.
 Lifelong daily regimen
o Hydrocortisone in neonates and children
o Prednisolone or dexamethasone in adolescents and adults
 Steroid stress dosing
 Specific treatment
 21β–hydroxylase deficiency
o Lifelong fludrocortisone therapy (aldosterone substitution)
o NaCl (salt) supplements, especially during infancy and childhood
 11β–hydroxylase deficiency
 o Spironolactone to block mineralocorticoid receptors
o Reduced dietary sodium intake
 17α–hydroxylase deficiency
o Spironolactone to block mineralocorticoid receptors
o Estrogen replacement therapy for female genotype; may be started in
early puberty
o Reduced dietary sodium intake
 Salt–wasting CAH
o Fluid resuscitation with intravenous normal saline
o Intravenous dextrose in patients with significant hypoglycemia
o Immediate administration of glucocorticoid replacement therapy
 Non–classic CAH
o Symptomatic children: hydrocortisone replacement therapy until 2–3
years postmenarche for girls and early to mid-puberty for boys
o Women: combined oral contraceptives are first-line treatment
(alternatively glucocorticoid therapy)
o Men: usually no treatment required
 Additional considerations
 Intersex medical intervention may be considered in children with ambiguous
genitalia
 Patients that experience gender dysphoria may benefit from counseling.
 Precocious Puberty
 Appearance of pubertal development in children at a younger age than is considered normal (around 8 years for girls and 9 years for boys)
 10x more common in females than males
 1 in 5,000–10,000 children
 Due to premature activation of hypothalamic–pituitary–gonad axis
o Onset of puberty is caused by the pulsatile release of GnRH by the hypothalamus → ↑ in LH & FSH levels, which stimulate production of sex steroids
 Androgens and estrogens cause the physical changes of puberty in boys and girls, as well as a growth spurt and enlargement of the gonads
Bone Age Advanced bone age Normal Bone Age
(> 1 year difference between bone age & chronological age)
Classification Central precocious puberty Peripheral precocious puberty isolated premature isolated premature
(gonadotropin-dependent precocious (gonadotropin-independent thelarche adrenarche
puberty, true precocious puberty) precocious puberty, peripheral
pseudo-puberty, Precocious pseudo- Isolated breast development Isolated pubic hair
puberty, peripheral precocity) development
Biochemistry high FSH and LH, elevated GnRH levels low FSH and LH, low GnRH levels

Pathophysiology Early activation of the hypothalamo- Due to ↑ peripheral synthesis of sex

hypophyseal axis → abnormally early
initiation of pubertal changes → early
development of 2O sexual characteristics exposure to sex hormones
Etiology  Idiopathic (most common cause)
 CNS lesions
o Intracranial tumors (e.g.,
hamartoma, glioma,
craniopharyngioma)
o Trauma
o Infections (e.g., encephalitis,
meningitis)
o Hydrocephalus
 Obesity–related precocious sexual
development
 Systemic conditions: tuberous
sclerosis, neurofibromatosis
 Radiation
Clinical features  Premature sexual development
typically follows the normal pattern of
puberty, except that it is early.
hormones (from ovaries, testes, or
adrenal glands) or exogenous
↑Androgen production
o Congenital adrenal hyperplasia
o Virilizing ovarian and
adrenocortical tumors (e.g.,
Sertoli–Leydig cell tumor, Leydig–
cell tumor)
 ↑ Estrogen production
o McCune–Albright syndrome
↑ β–hCG production (HCG–secreting
germ cell tumors)
o Dysgerminoma
o Malignant embryonal cell
carcinoma
o Choriocarcinoma
Primary hypothyroidism
Exogenous steroid use
Obesity–related precocious sexual
development
May not follow the normal
developmental pattern (signs of
estrogen or androgen excess)
  Symmetric development of 2O sexual May exhibit possible features of an
characteristics or, occasionally, as underlying condition (e.g., café–au–
isolated premature, adrenarche, or lait spots in McCune–Albright
menarche syndrome, testicular mass in Leydig–
 Increased growth velocity: Children cell tumor)
tend to be taller than their peers during
adolescence, but are of shorter stature
by the time they reach adulthood (due
to early closure of the epiphyseal plate)
Investigations &  Serum LH and FSH
Diagnosis  GnRH stimulation test
 Serum testosterone /estradiol – increased (depending on the tumour)
Imaging:
 X–Ray of the left hand and wrist: allows comparison between skeletal maturation and chronological age
o Bone age is within 1 year of a child's age: Puberty likely has not started.
o Bone age is > 2 years of the child's age: Puberty has been present for a year or longer
MRI /CT of the brain with contrast:  TFTs
indicated if ↑ LH is confirmed  Serum DHEA-S and 17-
o Perform in girls ≤ 6 years of age, all hydroxyprogesterone : in cases of
boys, and children with neurologic hyperandrogenism
symptoms.  Corticotropin stimulation test :
o Rule out intracranial causative suspicion of congenital adrenal
pathology. hyperplasia or an adrenal tumor
 ABD Pelvic USS – ovaries, testicles,
ABD (cases of ↑ ovarian &/or uterine
volume than expected for age,
diagnostic uncertainty)
 CT ABD – Adrenal imaging
Treatment  GnRH agonist (e.g., leuprolide ,  Surgical removal of hormone–
buserelin, goserelin): to prevent producing tumour
premature fusion of growth plates,  Precocious puberty caused by CAH:
downregulate LH & FSH, thereby cortisol replacement
slowing progression of pubertal  Ovarian cysts: no intervention is
development necessary (spontaneous resolution
 Treat underlying illness is common)
 Close monitoring of therapy
 4 – 6 monthly follow up to assess
progression
 McCune-Albright Syndrome is characterized by triad of:
o Polyostotic Fibrous dysplasia – typically unilateral
o Autonomous endocrine hyperfunction
 Gonadotropin–independent precocious puberty
 Breast development
 Axillary & pubic hair
 Girls typically have premature vaginal bleeding and breast development
o Irregular café au lait macules (‘Coast of maine’)
 Neonatal Displaced Clavicular Fractures
o Risk Factors
 Fetal Macrosomia (maternal diabetes, post-term pregnancy)
 Instrumental delivery (vacuum or forceps)
 Shoulder dystocia
o Clinical Features
 Crying / pain with passive motion of affected extremity
 Crepitus over clavicle
 Asymmetric Moro Reflex
o Investigations – X-Ray
o Treatment
 Reassurance (usually heal rapidly, within 7 – 10 days, with no long-term sequelae)
 Gentle Handling
 Analgesics
 Place affected arm in long-sleeved garment & pin sleeve to chest with elbow flexed at 90
degrees
o C.f. traumatic clavicular fractures in older children are less likely to heal spontaneously and may
require treatment
 Displaced fractures are often surgically reduced, and non-displaced fractures are typically
managed with a figure-of-8 splint
 Neonatal Polycythemia
o Hematocrit (Hct) > 65% in term neonates (> 2 SD above the mean) or Hb > 22 g/dL
 Affects 5% of newborns
o Etiology
 Increased erythropoiesis from intrauterine hypoxia:
 Maternal diabetes, Hypertension, or smoking
 IUGR
 Erythrocyte transfusion:
 Delayed cord clamping
 Twin–twin transfusion
 Genetic/metabolic disease:
 Hypothyroidism, or hyperthyroidism
 Genetic trisomy (13, 18, 21)
 Dehydration (can be a source and outcome of polycythemia)
o Clinical Presentation
 Asymptomatic (most common)
 Hct values decline to baseline levels within the first 24 hours of life
 Hyperviscosity → hypoperfusion, Tissue hypoxia
 Ruddy/Plethoric skin
 Metabolic Derangements – Hypoglycemia, Hyperbilirubinemia, Hypocalcemia
 Respiratory distress, cyanosis, apnea
 Hypotonia
 Irritability, jitteriness, lethargy, drowsiness
 Abdominal distension, Poor Feeding
 Hct > 65% on heel prick should be confirmed by rechecking a sample from peripheral venous
blood, which is more reliable, unaffected by changes in temperature and blood flow, and
often up to 15% lower than Hct taken from a capillary sample
o Treatment
 1st line – Oral hydration or IVF + Glucose–containing parenteral feeds
 2nd line – Partial exchange transfusion
 Bilirubin Physiology
o Reticuloendothelial system
→ →
 Heme Heme Oxygenase Biliverdin Bilirubin Reductase Unconjugated Bilirubin
o Unconjugated bilirubin bound to albumin and transported in the blood to the liver
o UDP–Glucoronyltransferase conjugates Bilirubin in the liver (now Bilirubin + Glucouronic acid)
o Secreted in the biliary system via bile
→
o In intestine, Conjugated Bilirubin via Gut Bacteria urobilnogen which can now either be:
 Urobilinogen reabsorbed via enterohepatic pathway
 Converted to Urobilin in the kidney and renally excreted (yellow colour of urine)
 Converted to stercobilin in the colon and excreted in stool (brown colour)
 Neonatal Jaundice (Congenital Hyperbilirubinemia)
o Etiology
 Day 1 – ALWAYS Pathologic
 Rh iso, ABO incomp, TORCH, Sepsis
 Next best test – Direct Coombs
o Positive = ABO or Rh incompatibility
o Negative = twin/twin or mom/fetus transfusion, Infant of DM mother, TORCH,
sepsis
 Pathologic jaundice is seen in first 24 hours, persists beyond one week, can be
conjugated or unconjugated, with total bilirubin peaking > 15 mg/dL + conjugated
bilirubin > 10% of total bilirubin
o Bilirubin increases > 0.5mg/dl/hour
 Day 2
 Day 1 causes + G6PD, PKD, membranopathies (hereditary spherocytosis, heridatary
elliptocytosis etc.)
 Day 3
 Day 1,2 causes + physiologic
 Physiologic Jaundice
o At birth, fetal RBCs are increased (↑ Hematocrit 50 – 60%) with shortened life
span (90 days) → high RBC turnover and increased bilirubin production
o Hepatic bilirubin clearance is decreased as uridine diphosphogluconurate
glucuronosyltransferase (UGT) activity does not reach adult levels until age 2
weeks → decreased hepatic conjugation of bilirubin
 East Asian newborns have ↓ UGT compared to other ethnicities
o Enterohepatic recycling is increased because low bacterial load in the
newborn gut results in slower conversion of bilirubin to urobilinogen for fecal
excretion
o Peaks at 3 days, and resolves over 1–2 weeks; Bilirubin peaks at < 15 mg/dL,
large component of unconjugated bilirubin (N.B. typically conjugated bilirubin
< 10% of total bilirubin)
o Bilirubin increases < 5mg/dl/day
 Day 4
 As day 3 + breast feeding jaundice
 Persistent indirect hyperbilirubinemia beyond 2 weeks suggests:
 Hemolysis
 Hereditary glucuronyl transferase deficiency (e.g. Gilbert Syndrome)
 Breast milk jaundice
 Hypothyroidism
 Intestinal obstruction
 Worst complication of Hyperbilirubinemia = Kernicterus
  Presents with lethargy, poor feeding, a high–pitched cry, hypertonicity, and seizures
 Jaundice may follow a cephalocaudal progression as bilirubin concentration increases
 Typically requires bilirubin level > 20 mg/dL
o Investigations
 CBC & Blood Smear – may show hemolysis → indirect hyperbilirubinemia
 Coombs test
 Used to distinguish immune–mediated hemolytic disorders (e.g. ABO incompatibility)
from non – immune (e.g. G6PD, hereditary spherocytosis)
 LFTs, ALP, Bile acids, and sweat test (Cystic fibrosis)
 May identify diagnosis if direct hyperbilirubinemia
 Help rule out amino acid–opathies and alpha – 1 – antitrypsin deficiency
 Sepsis work up – Blood Cx, Urine Cx, LP & CSF Cx
 Indicated if fever, hypotension, and tachycardia
 Maternal–Fetal ABO and Rh incompatibilities
 May identify immune – mediated hyperbilirubinemia
o Treatment / Management
 No treatment for physiologic jaundice (breastfeeding mothers can continue to breastfeed)
 Phototherapy
 Indicated when bilirubin levels > 15–20 mg/dl regardless of cause
 Specific nomograms exist to govern when blue–light therapy is indicated
 Complications
o Retinal damage, dehydration, dermatitis, and diarrhea all related to UV
exposure
 Exchange transfusion
 May be indicated in very severe cases of hyperbilirubinemia
Differential Diagnosis of Neonatal Jaundice
Unconjugated Hyperbilirubinemia Conjugated Hyperbilirubinemia
(Direct bilirubin < 15% of Total Bili) (Direct Bilirubin > 15 – 20% of Total Bili)
 Physiologic jaundice  SEPSIS!
o Breastfeeding failure jaundice (1st week)  UTI, TORCH infections
 Relative caloric deprivation in 1st few days of life due to decreased  Extrahepatic biliary obstruction (dark urine, pale acholic
feeding (suboptimal breastfeeding – E.G. inadequate milk supply, stool)
poor latch, &/or infrequent feeding) & resulting in dehydration ( ↓ o Biliary atresia – bx reveals bile plugs in bile and canalicular
urine output, excessive weight loss) ducts, portal tract edema, and fibrosis
 ↓ bilirubin elimination & Increased enterohepatic circulation:  Symptoms develop at age 2 – 8 weeks
retained meconium with delayed stooling → reabsorption of o Choledochal cysts
deconjugated bilirubin & increased enterohepatic circulation o Alagille Syndrome – autosomal dominant
 ↓ bilirubin delivery to the liver and ↓ conjugation  Error in development of bile ducts, heart, CNS, and
face
 N.B. Frequent feeding promotes gut colonization and fecal excretion
 Neonatal intrahepatic cholestasis and
 Maternal factors: Delayed milk production or inadequate milk
hepatosplenomegaly with xanthomas with tetralogy of
supply; infrequent feeding; cracked / clogged nipples
Fallot, and coarctation of aorta
 Infant Factors: Poor latch (e.g. due to breast engorgement);
 Unusual butterfly shape of bones in spinal column
ineffective suck; falling asleep
 Broad prominent forehead, deep – set eyes, & small
o Breastmilk jaundice (starts at age 3 – 5 days; peaks at 2nd week)
pointed chin
 High levels of β –glucuronidase in breast milk deconjugates
 Supplementation with Vitamin ADEK, and
intestinal bilirubin & increases enterohepatic circulation by
ursodeoxycholic acid
promoting intestinal absorption
 Liver transplant in select cases
 Adequate breastfeeding & normal physical exam (no signs of
o Tumors/masses
dehydration or feeding difficulty)
o Neonatal sclerosing cholangitis
 N.B. Kernicterus from breast milk jaundice is very rare
 Metabolic/genetic diseases
 Tx – continue breastfeeding exclusively; spontaneous resolution by
o Congenital Hypothyroidism
3 months
o Hypopituitarism
 Autoimmune Hemolysis (Coombs positive)
o ABO incompatibility o Galactosemia
o Rh incompatibility o Tyrosinemia
o Alagille syndrome
 RBC enzymopathy /membranopathy (Coombs negative hemolytic anemia)
 o G6PD deficiency o Alpha–1 antitrypsin deficiency
o Pyruvate kinase deficiency o Cystic fibrosis
o Hereditary spherocytosis o Maternal diabetes
o Hereditary elliptocytosis  Toxins / Drugs
 Conjugation defects o Aspirin, acetaminophen, rifampin, alcohol, corticosteroids
o Gilbert disease (relatively benign)  Cholestasis associated with TPN
 Autosomal recessive; 3.7% prevalence  Neonatal hepatitis
 UGT1A1 Gene Defect → Mildly ↓ UDP–glucuronosyltransferase  Dubin–Johnson Syndrome
conjugation & impaired bilirubin uptake o MRP2 protein defect → Defect in cannanicular cationic
 Mild jaundice usually with stress, illness, or fasting transport protein (Decreased hepatocellular bilirubin
 Typically manifests in adolescence as periodic asymptomatic excretion) → ↑ conjugated bilirubin
jaundice from unconjugated hyperbilirubinemia; rarely presents o Black liver pigmentation due to impaired excretion of
before puberty and is less common in girls epinephrine metabolites (pigment deposition in
o Crigler–Najjar syndrome (type 1 = total deficiency in UDP– lysosomes).
glucuronosyltransferase)  Liver Biopsy – dark, coarsely granular melanin – like
 Jaundice, ↑ unconjugated bilirubin pigment in the centrilobular hepatocytes
 Kernicterus (type 1 only; bilirubin encephalopathy with neurotoxic o Rare autosomal recessive; benign
lesions in the basal ganglia) o Oral Contraception is contraindicated (involved in
 Liver transplant curative (type 1 only) estrogen/progesterone metabolism)
 Type 2 (less severe UDP–glucuronosyltransferase deficiency) - treat  Rotor Syndrome
with phenobarbital o Autosomal recessive; benign
 Other o OATP1B1 & OATP1B3 defective → ↓ uptake and excretion
o Other causes of Increased enterohepatic circulation – Pyloric stenosis, of conjugated bilirubin → ↑ conjugated bilirubin
ileus or intestinal obstruction o Milder presentation to Dubin–Johnson
o Cephalohematoma or bruising o No black liver
o PC 2/2 delayed cord clamping o Oral Contraception is contraindicated (involved in
estrogen/progesterone metabolism)
o Hepatic storage disorder – due to impaired hepatic uptake
& excretion
 N.B. Threshold for phototherapy in a full-term, healthy, 4-day old infant is a total bilirubin level ≥ 20 mg/dL.
Exchange transfusion is reserved for infants with levels ≥ 25 mg/dL or those with bilirubin–induced neurologic
dysfunction

Gilbert Syndrome Congenital Hypothyroidism

Epidemiolog  M > F  Familial or sporadic
y  Most common inherited disorder of bilirubin
glucoronidation
Pathogenesis  AR or AD mutation in UGT1A1 gene  Thyroid dysgenesis (i.e. aplasia, hypoplasia,
 ↓ UDP-glucuronosyltransferase activity → or ectopic gland) – 85%
unconjugated hyperbilirubinemia  Inborn errors of thyroxin synthesis (AR
inheritance) – 10%
 Transplacental maternal thyrotropin-
receptor blocking antibodies – 5%
Clinical  Intermittent episodes of mild jaundice  Normal at birth initially
Features  Provoked by stress (e.g. infection, fasting, vigorous  Symptoms develop after maternal T4
exercise, surgery) wanes
o apathy, weakness, hypotonia
o large protruding tongue
o sluggish movement
o abdominal bloating, constipation
o umbilical hernia
o Enlarged fontanelle
o Poor feeding, hoarse cry
o Dry skin
o Pathologic jaundice
o Difficulty breathing
o Noisy respiration
o Hypothermia
 o Refractory macrocytic anemia
Diagnosis  Unconjugated hyperbilirubinemia on repeat testing  Serum: ↓ T4 & ↑ TSH
 Normal CBC, blood smear, reticulocyte count  Newborn screening
 Normal AST, ALT, alkaline phosphatase
Treatment  No specific treatment indicated  Levothyroxine 10 mcg/kg initially, then
 Educate about benign nature of the disease titrated accordingly

Trisomy 21 (Down Syndrome) Trisomy 18 (Edwards Trisomy 13 (Patau Syndrome)

Syndrome)
Epidemiology  Increased risk with advanced maternal age; this  2nd most common autosomal  occurs in 1:10000 birth
however does not apply to translocation trisomies trisomy after Down Syndrome  M > F (3:1)
 Most common genetic cause of intellectual  Frequency: ∼ 1:6,000
disability children
 Associated development of multiple comorbidities  F > M (3:1)
o Early–onset Alzheimer’s / Alzheimer’s–like
dementia ( 3rd and 4th decade)
o Acute lymphocytic leukemia
o Autism
o ADHD
o Depressive Disorder
o Seizure Disorder
Etiology /  Meiotic non–disjunction (~95%) → full trisomy 21  Karyotype: 47, XX or XY, +18  Karyotype: 47, XX or XY, +13
Pathophysiology (47 XX or XY + 21)  Non–disjunction (in meiosis)  Non–disjunction (in meiosis)
o 70% Meiosis I; 20% Meiosis II
o ~5% paternal non–disjunction during
spermatogenesis
 Translocation trisomy 21 (3 – 4%) –
o Occurrence independent of maternal age
o Balanced Robertsonian translocation – 45,XX or
XY, t(21;14)
 Mother who is a carrier of chromosome 21
Robertsonian translocation has ~10% risk of
having a child with Down Syndrome
o Unbalanced translocation – 46, XX or XY, +21,
t(21;14)
 Mosaicism (1 – 2%) – 46, XX/ 47, XX, +21 or 46,
XY/47, XY, +21
Clinical Features  Delayed motor development, Muscle hypotonia,  Severe Intellectual Disability  Midline Defects
flat occiput  Prominent occiput, oMicrocephaly /
 Variable intellectual disability (average IQ 50) – microcephaly holoprosencephaly
developmental milestones achieved at twice the  Low–set ears (malformed oCleft lip and/or palate
normal age auricle) oMicrophthalmia (unilateral
 Increased risk of obesity  Micrognathia (congenital or bilateral), ocular
 Reduced growth & shortening of long bones mandibular hypoplasia) hypertelorism
 Craniofacial dysmorphia  Cleft Lip & palate opossibly coloboma
o Eyes – upward slanting eyelids, epicanthal folds,  Clenched fist with flexion  Low–set malformed ears,
hypertelorism, Brushfield spots (aggregation of contracture of fingers (3rd & bulbous nose, small chin
connective tissue in iris inner & outer periphery, 4th fingers overlap with the 2nd Polydactyly, primarily
visible as white or grayish-brown spots) and 5th fingers) hexadactyly, flexed fingers
 Refractive errors e.g. myopia, astigmatism;  Rocker – bottom feet: convex  Congenital heart defects
strabismus deformity of plantar side of (particularly VSD, PDA)
 Cataracts (congenital, infantile, juvenile) foot, with vertical talus, and  Rocker–bottom feet
o Mouth – high arched palate, small oral cavity, prominent calcaneus  Visceral and genital
tongue protrusion anomalies, especially of the
o Brachycephaly  Frequent screening kidneys and ureter
o Hypoplastic nasal bones, broad and flat nasal o Yearly eye exam in infancy  Severe intellectual disability
bridge, flat facial profile o Hearing test q6-12 monthly  Cutis aplasia / Aplasia cutis
o Ear – small, low–set ears, adherent earlobes o Dental exam q6-monthly congenita: (“punched out”
 Extremities, soft tissue, and skeletal features o Cervical spine x-rays at 3 – 5 scalp lesion) – congenital
o Single transverse palmar crease years absence of skin in an area
 o Sandal gap o TFTs q12monthly that may extend to the bone
o Clinodactyly, Hypoplastic (shortened) incurved or the dura
5th digit  Capillary hemangioma
o Atlantoaxial instability – usually asymptomatic
o Increased risk of umbilical and inguinal hernias
o Marked hyperextension of joints may occur
Organ  Heart (50%) – endocardial cushion defects (AVSD >  Congenital Heart Disease 
Manifestations VSD > ASD >Tetralogy of Fallot) (>50%) – particularly VSD,
and Associated  GI tract – Duodenal atresia, Hirschsprung’s disease ASD, TOF
Complications  GU – hypogonadism, cryptorchidism, decreased  Malformation of internal
fertility in men organs –
 ALL, early-onset Alzheimer’s (75% affected by age  Horseshoe Kidneys
40), Hypothyroidism, celiac disease, ↑ risk of
epilepsy, susceptibility to recurrent infections
Investigations  Chromosomal Analysis
(Postnatal)  Screening for associated conditions e.g. Echocardiogram, ECG
Prenatal Integrated test (detection rate 85% & false positive  Associated USS findings: T1 Screening – Sonographic
Diagnosis rate 1.2%): o Polyhydramnios Nuchal Translucency &
 Nuchal translucency thickness at 10 weeks o Enlarged uterus maternal serum:
 Maternal serum markers: o Small Placenta  ↓ ↓ PAPP-A, ↑ NT
o 1st trimester – ↓ PAPP-A T1 (11 – 13 weeks):  cffDNA testing ≥ 10/40 GA –
o 2nd trimester – Quad screen  Sonographic Nuchal Identifies chromosomal
 ↓ AFP & estriol Translucency – ↑ NT aberrations (high specificity
 ↑ β –hCG & inhibin A  Maternal serum and sensitivity for trisomy 21
o ↓ ↓ PAPP-A > trisomy 18 > trisomy 13);
o ↓β –hCG Determine the gender of the
T1 (11 – 13 weeks):
fetus
 Nuchal translucency on USS (thickened nuchal fold  T2 Quad screening –
> 95 centile) at 10 weeks o ↓ AFP
 Maternal serum o ↓ ↓ β-HCG
o ↓ PAPP-A (Pregnancy–associated plasma o ↓ ↓ free estriol
protein–A; measured in 1st trimester) o ↓ Inhibin A
o ↑ β –hCG
 cffDNA testing (≥ 10/40 GA)
T2 (15 – 20 weeks):
 Quad screen
 Risk of aneuploidy is
o ↓ alpha-fetoprotein (AFP) & estriol
evaluated based on maternal
o ↑ β –hCG & inhibin A age, lab results, and
 Cell–free fetal DNA testing (cffDNA) – 10 weeks ultrasound.
gestation onwards; fetal DNA isolated from
maternal blood specimen for genetic testing
 Diagnostic fetal karyotyping
o Indicated for positive screening test, previous
trisomy 21 pregnancy, parent with known
chromosomal translocation or aberration
o Chorionic Villus Sampling (T1 – 10 – 13 weeks) or
o Amniocentesis (T3 or > 15 weeks)
o Risk – bleeding, infection, fetal injury or loss,
PROM, transverse limb abnormality
Prognosis  Life expectancy ~ 50 years Most affected die in 1st month  Only 5% of infants survive
Surgical repair of VSD improves past 6 months of age.
survival
Only 5 – 10% survive past 12
months of age
 Atlantoaxial instability in Down’s Syndrome
o Usually asymptomatic but symptoms can develop due to compression of the spinal cord
 Weakness, gait changes
 Urinary / Fecal incontinence
 Vertebrobasilar symptoms – dizziness, vertigo, imbalance, diploplia
 Upper motor neuron findings – spasticity, hyperreflexia, Babinski sign
 May have no effect on the low tone of Down Syndrome or cause hypertonicity
o Diagnosis
 Lateral C–Spine X-Rays in flexion, extension, and in neutral position
 Open – mouth X-rays (Odontoid view)
o Management – fusion of C1 and C2
o Duodenal Atresia
o Incomplete or partial recanalization of duodenum in gestational weeks 8 – 10
o Often associated with other malformations such as GI, cardiac, renal, vertebral
 25% of newborns with atresia have Down’s Syndrome
o Clinical Features
 Typically presents early, while in newborn nursery
 Gastric distention and vomiting (possibly bilious)
 Vomiting typically begins within first few hours of first feeding
 Abdominal distention may or may not be present
 Maternal history of polyhydramnios is helpful
 C.f. Distal Small Bowel atresia (jejunum, ileum)
 Symptom onset delayed 12 to 24 hours after first feeding
 Bilious Emesis
 Abdominal Distention more prominent
 No meconium passage in first 24 hours in 80% of children
o Investigations
 Diagnosis can be postnatal Dx using AXR and ABD USS
 Often also detected during antenatal USS exam
 Distal lesions tend to be diagnosed after birth
 AXR
 Double Bubble Sign in Duodenal Atresia (large Stomach air filled bubble, smaller
duodenal air filled bubble)
 Double-Bubble is also seen in Midgut Volvulus
 Abdominal USS findings – dilated loops of bowel, polyhydramnios
 Differentiates atresia from meconium ileus and Intestinal Malrotation
 Water soluble enemas
 Differentiates atresia from meconium ileus and Hirschsprung Disease
 Colon contracted in Intestinal Atresia (obstruction prior to ileocecal valve)
o Management
 Surgical optimization followed by surgical correction
  NPO, NG tube, electrolytes corrected
 Broad Spectrum antibiotics
 IVF hydration

o Hirschsprung Disease (Congenital Aganglionic Megacolon)

o Epidemiology
 ~10% associated with chromosomal abnormality (e.g. Down Syndrome)
 Up to 25% of cases have another congenital anomaly (e.g. renal)
o Pathophysiology
 Failure of neural crest cell migration during fetal intestinal development
o Clinical Features
 Delayed meconium passage (> 48 hours after birth)
 N.B. c.f. 99% of full term infants pass stool within 48 hours
 Abdominal distension, poor feeding, bilious emesis
 DRE – tight anal canal (failure of internal anal sphincter relaxation), relieves an explosion of
gas and greenish, foul–smelling stool (positive squirt sign)
o Investigations
 AXR – distended loops of bowel + no air in rectum (absent rectal gas); also rule out free
intraperitoneal air
 Contrast enema – Transition zone between normally innervated, but markedly dilated
descending colon [megacolon] and a normal or narrow caliber rectosigmoid [aganglionic
segment]
 Typical Level of obstruction – rectosigmoid junction
 Rectal mucosal suction biopsy (Diagnostic Gold Standard)
 Absence of ganglion cells on rectal mucosa
 ± Anorectal manometry (if biopsy inconclusive)
 Measures anal sphincter pressure, anorectal inhibitory reflex, and rectal compliance
& sensation
 Less accurate (especially in neonates, infants ≤ 1 month)
 Lacks sensitivity of rectal biopsy
 o Treatment – surgical resection of aganglionic segment and anastomosis of normal bowel to anus
o Meconium Ileus
o Misnomer – true bowel obstruction and not a paralytic ileus
o Associated with Cystic Fibrosis (virtually diagnostic of CF)
o Typical Level of obstruction – inspissated, distal small bowel obstruction
o Negative “squirt” sign
o Erect CXR and Abdominal X–ray for meconium ileus if neonate stable
 Dilated loops of bowel (delineate level of obstruction); identify pneumoperitoneum for
perforated bowel
 After pneumoperitoneum is excluded → Contrast enema with hyperosmolar enema (e.g.
Gastrograffin)
 Gastrograffin can potentially break up inspissated meconium and dissolve obstruction
o Microcolon on contrast enema; underused, contracted colon is the result of
viscous meconium accumulation and obstruction in the terminal ileum

Primary Ciliary Dyskinesia versus Cystic Fibrosis

Primary Ciliary Dyskinesia Cystic Fibrosis
(Immotile Cilia Syndrome; Kartagener Syndrome)
Pathophysiology DNAL1 & DNAH5 gene autosomal recessive defect (Dynein Autosomal recessive CFTR gene on
light chain 1 + Dynein heavy chain 5) chromosome 7
o Mutation in ciliary dynein arms lead to absent or Inspissated bronchial & pancreatic
dysmotile cilia & poor mucociliary clearance secretions
Abnormal ciliary function
Respiratory Chronic sinopulmonary infections (recurrent rhinosinusitis, Chronic sinopulmonary infections
Tract Features otitis media, Bronchiectasis) Nasal polyps (40%)
Nasal polyps Bronchiectasis
Digital clubbing Digital clubbing
Extrapulmonary Situs inversus (50% of cases) – dextrocardia Pancreatic insufficiency
Features o N.B. normal ciliary motion is needed in embryogenesis for Infertility in males only due to
proper thoracoabdominal orientation congenital absence of Vas Deferens
Infertility in males &/or females (azoospermia)
o immotile spermatozoa Failure to thrive
o immotile fimbriae of fallopian tube (increased risk of Meconium ileus
ectopic pregnancy)
Normal growth
 ± Conductive hearing loss (sequelae of recurrent otitis
media)
Diagnosis Low nasal nitric oxide levels Sweat chloride test diagnosis
Bronchoscopy & electron microscopic visualization or ciliary Nasal transepithelial potential
abnormalities difference test
Genetic testing Neonatal screening
o ↑ immunoreactive trypsinogen
o DNA assay [prenatal or postnatal]

o Pediatric Obstructive Sleep Apnea

o Pathophysiology – Adenotonsillar Hypertrophy
o Clinical Manifestations
 Night symptoms
 Loud snoring, pauses in breathing, gasping
 Enuresis, parasomnias (e.g. sleepwalking, sleep terrors)
 Day Symptoms
 Inappropriate naps or falling asleep during school
 Irritability, inattention, learning problems, behavioural problems
  Mouth breathing, nasal speech
o Complications
 Poor growth (i.e. failure to thrive)
 Poor school performance
 Cardiopulmonary (e.g. hypertension, structural heart changes) – also seen in adult OSA
o Management
 Tonsillectomy & Adenoidectomy
o Intraventricular Haemorrhage
o Pathophysiology – Rupture of fragile germinal matrix vessels in periventricular area, resulting in
haemorrhage with possible extension into lateral ventricle
 Prematurity & VLBW are at increased risk as vasculature is fragile and more susceptible to
changes in cerebral perfusion (e.g. hypotension, hypoxia, hypo-or hyperventilation)
o Risk Factors
 Prematurity (specifically < 32 weeks)
 Very low birth weight (< 1500g)
o Clinical Findings
 Often asymptomatic (up to 50%)
 Typically occurs in first 3 – 4 days of life
 Seizures or apnea
 Bulging or Full fontanelle, rapid increase in head circumference
 Acute Anemia, tachycardia or bradycardia (Cushing’s reflex)
o Diagnosis
 Cranial Ultrasonography*
 Performed if symptomatic or as a routine screening if < 32 weeks gestational age at
age 1 – 2weeks
 Hyperechoic material (blood) within germinal matrix ± extension to ventricles or
parenchyma
o Management
 Symptomatic & supportive (e.g. blood pressure stabilization, antiseizure medication,
oxygenation/ventilation, nutrition)
 Early detection and monitoring for complications (e.g. post–hemorrhagic ventricular
dilatation)
o Prognosis: Neurodevelopmental conditions such as cerebral palsy and intellectual disability
o Fetal Hydantoin Syndrome
o Orofacial clefts. (cleft lip, cleft palate), microcephaly, Hypoplastic fingers/nails, cardiac defects,
dysmorphic facial features
o Given it’s known teratogenicity, phenytoin should be discontinued via slow taper in women of
reproductive age who are considering becoming pregnant and have a low risk of seizure recurrence
 Rapid withdrawal may result in seizure recurrence
 Other dose-dependent ADRs of phenytoin – drowsiness, diplopia, ataxia
o Pregnant women on phenytoin during their last trimester often receive prophylactic vitamin K to
prevent neonatal bleeding as phenytoin may increase the rate of fetal vitamin K degradation
o Familial Dysautonomia (Riley-Day Syndrome)
o Autosomal recessive
o Primarily children of Ashkenazi Jews
o Clinical Manifestations
 Presents at birth with feeding problems + low muscle tone
 Gross dysfunction in autonomic nervous system (e.g. no tears) with severe orthostatic
hypotension (swings from severe hypotension to postural hypotension)
o Investigations
 AXR – dilated loops of bowel
  Contrast enema – microcolon (narrow, underused colon)
Food Protein–Induced Allergic Proctocolitis
 Non–IgE-mediated reaction
Pathophysiology  Eosinophilic inflammation of rectosigmoid colon
 Common triggers: cow’s milk & soy proteins
 Eczema
Risk Factors
 Family history of food allergies
 Age 1 – 4 weeks (up to 6 months)
Clinical Features  Well appearing
 Blood– &/or mucus–streaked stools (positive Hemoccult)
 Clinical Diagnosis confirmed by symptom resolution after protein elimination
o Breastfed infants: restrict dairy (± soy) from maternal diet
Diagnosis &
o Formula–fed infants: switch to hydrolyzed formula
Treatment
o If no symptom resolution, consider evaluation for alternate diagnosis (e.g. flexible
sigmoidoscopy)
Prognosis  Tolerance of offending protein by age 1

o Neural Tube Defects

o Types –
 Anencephaly
 Encephalocele
 Spina Bifida, Myelomeningocele
o Risk Factors
 Prenatal maternal folate deficiency
 Low Folic Acid Intake (i.e. inadequate supplementation)
 Antifolate drugs – Methotrexate, antiepileptics
 Pre–gestational Diabetes mellitus
 Prior pregnancy with neural tube defect
 Maternal fever in the first trimester
 Maternal obesity
 Genetic factors
o Prenatal screening
 2nd trimester ultrasound
 Maternal serum alpha–fetoprotein
o Prevention
 Average risk – 0.4mg folic acid daily’
 High risk (e.g. HbSS [not related to NTD risk], NTD in prior pregnancy, antiepileptic drugs) –
4mg folic acid daily
o Myelomeningocele (Spina Bifida)
o Pathophysiology
 Most common Neural tube defect
 Caused by failure of the caudal neuropore to close properly during fetal development
 Defect of the lower vertebral column that exposes the meninges and spinal cord due to
failure of neural tube closure –
 Lumbosacral protrusion consisting of a membranous sac containing meninges,
cerebrospinal fluid & spinal cord through skin
 Exposed spinal cord is generally dysplastic
 Increased risk with maternal folate deficiency
o Clinical Features
 Membranous sac over lumbosacral region
 Severe neurologic deficits distal to lesion (Motor / sensory dysfunction)
 paralysis, sensory loss
  Neurogenic bladder / bowel (bowel / bladder incontinence or retention)
o Recurrent urinary tract infections
o Potential renal dysfunction
 Scoliosis
o Investigations
 Usually prenatal diagnosis on USS or MRI
 Elevated Maternal serum alpha–fetoprotein screening is suspicious
o Associated abnormalities
 Hydrocephalus
 Chiari II malformation
 Inferior displacement of medulla & cerebellum through foramen magnum
 Obstructive hydrocephalus – obstruction of CSF flow through the 4th ventricle with
lateral ventricular dilatation; enlarged head circumference & full fontanelle
o Treatment
 Immediately after birth, the defect is wrapped in a moist, sterile dressing and covered with
plastic wrap to prevent infection and heat loss
 Neurosurgery – Surgical closure of the NTD must be done during the first 24 – 48 hours after
birth in order to prevent the occurrence of CNS infections
 Pre-operative imaging rarely performed due to the urgency of the condition. Imaging
is used in the follow – up examination after surgical repair
 Unlike other spinal disorders, myelomeningocele is an exception to the rule of relying
on imaging for pre surgical evaluation. MRI used in pre–surgical evaluation in most
spinal disorders otherwise
 Surgical repair may result in hydrocephalus, requiring a ventriculoperitoneal shunt in
over half of infants
 Clean intermittent catheterization – prevents urinary stasis
 Scheduled laxatives / enemas
 Orthopedic evaluation – bracing, correcting of deformities, preservation of adequate
posture, and promote ambulation, if possible
o Choanal atresia
o Congenital blockage (bony or membranous obstruction) of the posterior nasal aperture, present
shortly after birth
o Clinical Findings
 Unilateral (most common)
 Chronic nasal discharge & obstruction
 Symptomatic during childhood
 Bilateral
 Cyanosis at rest, or that worsens with feeding and improves with crying
o Recall neonates are obligate nasal breathers
o Resultant hypercapnia triggers neonates to cry and temporarily relieve
obstruction
 Noisy breathing (stertor)
 Symptomatic shortly after birth
 May be associated with CHARGE syndrome
 Coloboma (missing eye tissue; hole in one of the eye structures)
 Heart defects (e.g. TOF, VSD)
 Atresia choanae
 Retardation of growth / development
 Genitourinary abnormalities (e.g. cryptorchidism)
 Ear abnormalities (e.g. hearing loss, dysplastic ears [for instance short and wide ears
with no earlobes])
 o Additional key findings in CHARGE syndrome – Anosmia, cleft lip / palate,
Hypotonia
o Clinical diagnosis; CHD7 gene testing
o Diagnosis
 Inability to pass catheter past nasopharynx
 Confirmation with CT scan or direct visualization via nasal endoscopy
o Treatment –
 Maintain airway – oral airway, intubation
 Orogastric tube feedings until corrective surgical repair
o VACTERL Syndrome – anomalies include:
o Vertebral
o Anal Atresia
o Cardiac
o Tracheoesophageal fistula
o Renal
o Limb
o Tracheoesophageal fistula with Esophageal Atresia
o 1 in 3500 births
o Up to 50% of patients have additional anomalies →
Work up for VACTERL association
o Less commonly associated with CHARGE syndrome
(Coloboma, Heart Defects, Atresia choanae,
Retardation of growth, Genitourinary anomalies, and
Ear abnormalities)
o Pathogenesis
 Improper formation during the 4th & 5th
gestational weeks
 Defective division of foregut into esophagus
& trachea
 Most commonly results in proximal esophageal pouch & fistula between distal trachea &
esophagus
o Most common defective arrangement is proximal esophageal atresia with fistula between the
trachea and distal esophagus
o Clinical Features
 Prenatal USS – polyhydramnios (unable to swallow amniotic fluid)
 Excessive drooling / secretions
 Choking, coughing, and regurgitation / vomiting with initial feeding attempts are seen
immediately after birth
 Tracheoesophageal fistula permits air entry into the gastrointestinal tract. Stomach and
intestines can become quite distended with each breath, especially in a ventilated patient
 Additionally, gastric fluid can reflux into the distal esophagus (atretic pouch) through the
fistula and into the trachea and lungs, causing aspiration pneumonia (crackles and Infiltrates,
more commonly right lower lobe)
o Diagnosis
 Presence of the enteric tube coiled up in the proximal esophagus on X-ray
 inability to pass a feeding tube into the stomach is extremely suggestive of esophageal
atresia
 Esophagography, if performed, may show pooling of water-soluble contrast in the
esophageal pouch
o Management
 Surgical correction
  VACTERL screening: echocardiography, renal ultrasound
o Transient tachypnea of the newborn (wet lung disease)
o Reversible respiratory disorder
o Risk Factors – N.B. typically resorptive mechanisms are activated at term and during labor
 Most commonly occurs in full-term neonates delivered by cesarean section
 Prematurity
 Maternal Diabetes
o Pathophysiology
 Inadequate alveolar fluid clearance at birth (retained amniotic fluids) results in mild
pulmonary edema
o Clinical Features
 Tachypnea & increased work of breathing (retractions, nasal flaring); shortly after birth &
resolves by day two of life
 Clear Breath Sounds; may hear crackles
 CXR – fluid in the lung fissures and increased lung volumes (hyperinflation with flattened
diaphragm).
 Prominent bilateral perihilar streaking in the interlobular fissures
 Mild Cardiomegaly
 Prominent vascular markings
o Treatment:
 Supportive care (e.g., supplemental oxygen, neutral thermal environment, adequate
nutrition)
 Self – resolution in 1 – 3 days with no long term complications
o Meconium aspiration syndrome
o usually post-term rather than preterm infants
o An unresponsive neonate and green amniotic fluid establish the diagnosis and serve as indications
for suctioning, emergency intubation and endotracheal drainage.
o Other signs include:
 CXR – shows coarse, irregular infiltrates and hyper-expansion
 Increased lung volume
 Asymmetric, patchy opacities
 Pleural effusion
o Permanent neurocognitive impairment a severe complication of birth asphyxia due to meconium
aspiration syndrome
o Neonatal Respiratory Distress Syndrome
o Most common form of respiratory failure in preterm infants
o Observed in 65% of preterm infants born at 28-30 weeks of gestation
o Results from surfactant deficiency causing decreased lung compliance and atelectasis
 Pulmonary surfactant is a mixture of phospholipids and proteins produced by lamellar bodies
of type II alveolar cells. These phospholipids reduce alveolar surface tension and thereby
prevent the alveoli from collapsing.
 Surfactant production occurs early, at around 20 weeks' gestation. However, its distribution
throughout the lungs begins around weeks 28–32 and does not reach sufficient
concentration until week 35. Thus, any infant born before term is vulnerable to surfactant
deficiency.
 Surfactant deficiency → little or no reduction of alveolar surface tension → reduced
pulmonary unfolding → atelectasis → decreased lung compliance and functional
residual capacity → hypoxemia and hypercapnia
o males > females
o RDS incidence is inversely proportional to gestational age
o Risk Factors
  2nd born of twins
 Caesarean delivery without labour (intrauterine stress is thought to increase stimulate early
fetal lung maturity)
 maternal diabetes
 Causes fetal hyperglycemia & compensatory hyperinsulinism → high levels of
circulating insulin antagonizes cortisol and blocks maturation of sphingomyelin
 Prematurity
 Small for Gestational Age; VLBW (< 1.5 kg [3.3] lbs)
 Introduction of feeding (withholding feeds delays NEC onset but cannot prevent NEC—thus
no need to delay feeds)
 Intrauterine hypoxia (maternal HTN, placental abruption)
 Other congenital disorders (i.e. congenital heart disease, respiratory distress, polycythemia
sepsis, seizures, hypoglycemia, hypercoagulable state, gastroschisis)
o Ways to reduce risk:
 Breast feeding
 Slow enteral feeds
 Enteral supplementation of probiotics (optimal dosage and specific species remains under
investigation)
o Clinical Features
 Hypoxia/Hypoxemia, Cyanosis (reflects significant atelectasis)
 tachypnea (RR > 60/min)
 Intercostal recessions (intercostal muscles contract to pull in compliant chest wall)
 Nasal flaring (decreases nasal airway resistance)
 expiratory grunting (to increase end-expiratory pressure)
o Investigations
 Prenatal testing for NRDS:
 Amniocentesis. Markers of fetal lung immaturity:
o Lecithin-sphingomyelin ratio < 2
Foam stability index < 0.48
o Low surfactant-albumin ratio
 CXR
 bilateral atelectasis & low lung volumes
 air bronchograms
 diffuse reticulogranular (classic "ground glass") appearance
o Management
 Ventilation
 Nasal CPAP with a PEEP of 3–8 cm H2O
 If respiratory insufficiency persists, intubation with mechanical ventilation and O2
inhalation
 Endotracheal administration of exogenous / artificial surfactant within 2 hours postpartum
 Supportive measures: IV fluid replacement; stabilization of blood sugar levels and
electrolytes
o Prevention
 pretreat mothers at high risk of preterm birth (34 weeks gestation or less) with
corticosteroids (betamethasone)
o Complications
 Persistent wheezing and steroid dependence can occur if subsequently develop chronic lung
disease after respiratory distress syndrome
o Persistent Pulmonary Hypertension
o Typically term or post-term neonates
o Pathophysiology – high pulmonary vascular resistance results in right-to-left shunting through
foramen ovale & ductus arteriosus, and hypoxia
 o Clinical Features – Tachypnea & severe cyanosis
o CXR – Clear lungs with decreased pulmonary vascularity
o Necrotizing Enterocolitis
o Most common cause of acute abdomen in neonates
o Common in premature infants
o Peak incidence: 2nd–4th week after birth (not during the first week!)
o M>F
o Risk factors
 Prematurity (≤ 35 weeks gestation) & VLBW (i.e. < 1.5 kg [3.3 lb])
 Particularly vulnerable due to decreased mobility, increased intestinal permeability,
and immature host defenses
 early-onset neonatal sepsis
 mechanical ventilation
 5-minute APGAR < 7
 Enteral feeding (formula > breast milk; exposure to bacteria in enteral feeds)
 Term infants with reduced mesenteric oxygen delivery from cyanotic congenital heart
disease and/or hypotension
o Pathophysiology
 Condition caused by bowel ischemia with super imposed bacterial invasion of the bowel wall
 Although the pathogenesis is unclear, it is believed to be due to an exaggerated
inflammatory response to some sort of insult (e.g., enteral feeds in a premature infant)
that injures immature intestinal epithelial cells
o Clinical Features
 Vital sign / Temperature instability (e.g. hypothermia < 36.5 OC [97.7 OF])
 Feeding intolerance (e.g., bilious emesis)
 lethargy, apnea, dyspnea
 may require ventilatory support
 Abdominal distension, bloody stool
Bell staging criteria
Stage Diagnosis Symptoms
Stage I Suspected NEC Lethargy, distended and shiny abdomen, gastric retention, vomiting, diarrhea, rectal bleeding
Stage II Proven NEC Stage I symptoms + abdominal tenderness, visible intestinal loops lacking peristalsis
Stage III Advanced NEC Intestinal perforation, symptoms of sepsis, flank redness 
If left untreated: rapid progression to disseminated intravascular coagulation (DIC) and shock
o Investigations
 CBC –
 Leukocytosis
 Neutrophil counts < 1500/μL are associated with a poor prognosis.
 Degree of thrombocytopenia correlates with the severity of NEC.
 ↑ Inflammatory markers
 Check for signs of DIC (disseminated intravascular coagulation)
 ABG: Metabolic acidosis (reflects intestinal ischemia) associated with advanced NEC
 Blood culture
 Abdominal X-ray
 Pneumocystis intestinalis (air in bowel wall)
 Portal venous gas (pneumatosis hepatis)
 Increased intestinal wall thickness
 Dilated intestinal loops
 Air-fluid levels
 Pneumoperitoneum (intestinal perforation)
  Abdominal USS if AXR is inconclusive
o Treatment
 NPO, IVF, parenteral nutrition (TPN) if necessary, antibiotics and resection of necrotic bowel
 Supportive care & Bowel Rest:
 Stop enteral feeding → parenteral feeding and substitution of fluids
 Gut decompression via nasogastric tube
 IV broad–spectrum antibiotics
 Radiographic monitoring: plain supine abdominal radiographs every 6–12 hours in the initial
phase of the disease
 Surgery: primary peritoneal drainage and/or laparotomy with necrotic bowel excision
 Indications: perforation, peritonitis and/or clinical worsening despite medical therapy
o Prognosis
 Poor, high rate of mortality due to sequelae of bowel perforation, sepsis, shock
 Long term complications – strictures, short gut syndrome

Neonatal Varicella–Zoster Infection Perinatal Hepatitis B Virus Infection (HBV)

Epidemiolog   90% risk of vertical transmission without prophylaxis
y  < 5% risk after prophylaxis
 Chronic infection in 90% of perinatally infected infants
 Risk Factors
o High maternal viral load (primary risk factor)
o Maternal HBeAg positive
Clinical  Aerosolized droplets, extremely  Transmission
Features contagious o Perinatal exposure to genital secretions during delivery
 IP 2 – 3 weeks (most common)
 Fever o Transplacental (rare) – particularly in women with high
 Vesicular eruption (chickenpox) HBV viral loads or acute 3rd trimester infection
 Systemic involvement (e.g. o Not transmitted by breastfeeding
pneumonia, hepatitis,  Infected Newborns usually immune–tolerant (normal or
meningoencephalitis) mildly elevated liver enzymes & asymptomatic);
 IUGR o but up to 90% risk of developing chronic infection and
 premature birth significant risk of cirrhosis and progression to
 Chorioretinitis, cataract hepatocellular carcinoma if left untreated
 Encephalitis  High viral load & HBeAg positive
 Pneumonia
 CNS abnormalities
 Hypoplastic limbs
Diagnosis  Direct fluorescent antigen test  Obtaining serologic status &/or LFTs is unnecessary prior to
(DFA) administering prophylaxis. Confirm serology after prophylaxis,
 PCR for VZV and those with confirmed infection should have LFTs
 DNA Serology (IgM antibodies)  Serum – normal or slightly elevated transaminases; high viral
replication rate
o HBV is not cytopathic itself and neonates lack mature
cytotoxic T cells that mediated damaged hepatocytes →
very limited hepatic tissue damage
Treatment  Acyclovir, VZIG 
 Breastfeeding
Prevention  Isolate infant from varicella  HBV vaccine AND immunoglobulin within 12 hours of
contact birth(i.e. active & passive immunization)
 Administer Varicella–Zoster o Administered within 12 hours of birth regardless of
immunoglobulin (VZIG) to infant if infant’s birth weight or clinical condition
maternal infection developed 5  Completion of routine immunization (at age 0, 2, & 6 months)
days before or 2 days after  Breastfeeding allowed as long as passive–active post–
delivery exposure prophylaxis was given
  VZV vaccine is a live vaccine &
contraindicated if < 1 year old
 Management of HBsAg–positive mothers
 Serology ~3 months after 3rd dose of vaccine (i.e. usually at 9
months well child visit)
o Early serology may be falsely positive (HBsAg remains
positive for up to a month after immunization, and the
immunoglobulin persist for 6 – 8 months)
o However, as anti–HBs decreases over time, serology
obtained after 12 months may incorrectly identify children
as vaccine non–responders even if their anti–HBs levels
were appropriate at age 9 – 112 months
o Mild disease &/or low HBV DNA levels – may delay therapy
till after birth
o In severe disease (e.g. cirrhosis) &/or high HBV DNA levels
– maternal antiviral therapy with nucleoside/nucleotide
analogs (esp. tenofovir)
o Delivery – spontaneous vaginal delivery possible
o Interferon contraindicated in pregnancy

Cervical Lymphadenitis in Children

Pathogen Key Clinical Finding
Acute Enlarged, erythematous, tender
Staphylococcus
Most common cervical node
aureus
Children < 5 years ±
 Fever, Abscess formation
Streptococcus
Suppuration common – needle aspiration & Empiric antibiotic therapy –
pyogenes
Cx o Clindamycin (coverage against
Acute MRSA, S. pyogenes & anaerobes)
History of Periodontal disease or dental o Amoxicillin-clavulanate (if low
Anaerobic caries (local spread of normal flora from MRSA prevalence)
bacteria (e.g. oropharynx) o 1st gen cephalosporin (if low
Prevotella spp) Children < 5 years likelihood of periodontal disease
or dental carries)
Incision & drainage if abscess present
Unilateral Acute 
History of contact with infected animal (e.g.
Francisella
rabbit, rodent)
tularensis
Non–specific prodrome (fever, malaise)
(Tularemia)
Localized lymphadenopathy adjacent to an
ulcerated papule
Children < 5 years Rifampin + azithromycin
Mycobacterium
Chronic
avium
Non-tender, violaceous
Fastidious gram negative bacilli Diagnosis – usually clinical ± serology
Bartonella
Chronic Azithromycin
henselae (Cat
Papule at site of cat scratch / bite Generally self-limiting
Scratch Disease)
 ± Fever of Unknown Origin (≥ 14 days)
Acute (e.g. adenovirus) associated with self- 
limiting URI (cough, sore throat)
o Adenovirus causes marked fever,
Bilateral Viral
pharyngitis & conjunctivitis
Subacute / Chronic (e.g. EBV, CMV),
associated with mononucleosis symptoms
 Bronchiolitis
Epidemiology  Age < 2 years, peak age = 6 months
 RSV (most common causative agent)
 Less commonly Rhinovirus, influenza virus,
parainfluenza virus
 Nasal swab for hospital epidemiology in
order to cohort RSV+ patients in hospital
Clinical  Upper Respiratory prodrome of nasal
Presentation congestion / discharge & cough
 Wheezing / crackles & respiratory distress
(e.g. tachypnea, retractions, nasal flaring)
 Infants < 2 months, or those with history of
prematurity, congenital heart disease, and
chronic lung disease are most – susceptible
to life – threatening apnea
 Absence of fever
 Symptoms of RSV bronchiolitis typically peak
around day 3 – 5 of illness
 Serology unreliable in infants age < 6 months
due to passively acquired maternal
antibodies.
 Serology is generally not helpful in acute
illness as it can take weeks for antibody titres
to rise
Treatment  Hospitalized – contact & droplet precautions
 Supportive, symptomatic Care
o IV fluids
o Nasal bulb suctioning
o Humidified oxygen, Chest Physiotherapy
o N.B. inhaled bronchodilators no longer
recommended (does not reduce illness
duration, admission rates or length of
hospital stay); nebulized hypertonic saline
can induce bronchospasm and is not
routinely recommended
 Trial of beta agonists (e.g. albuterol) if
severe
 Steroids ineffective
 Inpatient admission if high risk:
o Age <3 months, ill appearing
o SpO2 <95%, tachypnea >70 breaths/min,
o Significant atelectasis on CXR
 Ribavirin for congenitally ill children:
o Preterm birth < 29 weeks' gestation
o Chronic lung disease of prematurity
o Hemodynamically significant congenital
heart disease
Prevention  Pavlivizumab for infants with the following
conditions:
o Preterm birth < 29 weeks gestation
o Chronic lung disease of prematurity
o Haemodynamically significant
congenital heart disease
Complications  Apnea (especially infants < 2months)
 Respiratory failure (esp. if < 2 months)
Croup (Laryngotracheitis)
 6 months – 3 years
 Fall / early winter
 Parainfluenza viral infection of the larynx & trachea
 Symptoms develop due to narrowing of subglottic
space from viral inflammation (classically steeple sign
on radiographs of neck)
 Initially brief prodrome with non–specific URTI (e.g.
rhinorrhea, congestion)
 Fever
 Inspiratory stridor
 Barking, seal–like cough
 Hoarseness
 CXR & Neck X–Ray, soft tissue (in uncertain cases) –
Steeple sign (‘subglottic narrowing’)
 Generally self – limiting illness and usually resolves
within a week
 Mild (no stridor at rest) – humidified air ±
corticosteroids (e.g. dexamethasone)
o Decrease airway edema
 Moderate / severe (stridor at rest) – corticosteroids +
nebulized epinephrine
o Nebulized epinephrine constricts mucosal arteries
in the upper airway and alters capillary hydrostatic
pressure → decreased airway edema + reduced
secretions
o Criteria for admission – severe symptoms: –
 Hypoxic (SpO2 < 92%)
 if condition worsens (respiratory distress)
 if condition does not improve despite repeated
doses of nebulized epinephrine (after a 4–hour
interval period of observation)
 Difficulty swallowing
 Intubation with mechanical ventilation indicated if
failed treatment with corticosteroids & epinephrine
and/or have signs of impending respiratory failure
(e.g. altered mental status, poor respiratory effort)
 If bacterial infection suspected, add 2nd gen
cephalosporin (e.g. Cefotetan)
 Handwashing
 Decontamination of surfaces
 Proper ventilation

  Increased risk of Acute otitis media (10%)
 Recurrent wheezing in childhood (30%)

Key respiratory tract infections in children

Diagnosis Classic Presentation Treatment
Pathogen
Laryngotracheobronchitis  Parainfluenza  Age 6 months to 3 years  Clinical diagnosis
(Croup) virus  Initially brief prodrome with non–  Corticosteroids (e.g.
specific upper respiratory symptoms dexamethasone) are useful
(e.g. rhinorrhea, congestion) for mild cases (e.g. stridor
 Fever with agitation)
 Harsh ‘seal–like’ Barking cough  Nebulized racemic
 Stridor, hoarseness epinephrine for severe
 Inspiratory Stridor (due to upper cases (e.g. stridor at rest)
airway edema), which worsens with
agitation (e.g. crying) or excitement;
Biphasic stridor if severe
 Steeple sign on CXR – subglottic
edema
Epiglottitis  H. influenza  Unvaccinated children  Secure airway
type b  Toxic–appearing (high fever, drooling, (endotracheal intubation)
(Haemophilus severe respiratory distress)  Minimize possible agitators
influenzae  Sore throat, dysphagia, drooling (e.g. detailed oropharynx
type b)  Tripod position (leaning forward with examination) to decrease
hands on knees and neck risk of laryngospasm
hyperextended)  May require surgical airway
 “Thumb sign” on lateral C–spine X–ray if intubation attempts fail
 N.B. Cough is absent in epiglottis  Broad-spectrum antibiotics
(i.e. ceftriaxone +
vancomycin)
 Oxygen
Bacterial Tracheitis  S. aureus  Rare, life-threatening disease of 
(may be childhood
bacterial  Most common in children under age 3
superinfection  Ill-appearing child
of preceding  Can mimic croup but more toxic, high
viral infection) fever
 H. influenza  Clinically similar to epiglottis
 Strep  Acute onset fever, stridor and
significant respiratory distress (severe
inspiratory and expiratory wheezes)
 Purulent secretions
 Airway obstruction
Bronchiolitis  Respiratory  Age < 2, peak age = 6 months  Supportive, symptomatic
Syncytial virus  Wheezing, coughing Care
(RSV) – most  Presents like URI-triggered asthma  Trial of beta agonists if
common exacerbation in small children severe
 Nasal swab  Clinical diagnosis  Steroids ineffective
for hospital  Ribavirin for congenitally ill
epidemiology children
 Causes of Stridor in Infants & Toddlers
Acute
 Croup  Parainfluenza virus, most cases in fall / winter
 Inspiratory or biphasic stridor, “barky” cough, infectious symptoms
 Foreign Body  ± Preceding choking episode
Aspiration  Inspiratory stridor&/or localized wheeze with focally diminished breath sounds
Chronic
 Laryngomalacia  “Floppy” supraglottis, prominent age 4 – 8 months
 Inspiratory stridor worsens with feeding, crying or supine positioning; improves when prone
 Vascular Ring  Great Vessels encircle & compress trachea
 Biphasic stridor that improves with neck extension
 May have esophageal compression by abnormal secondary arch leading to vomiting and
solid–food predominant dysphagia
 Diagnosis – CT Scan (delineate precise anatomy forming the vascular ring and evaluate any
associated tracheal abnormalities)
 Direct laryngoscopy, bronchoscopy & echocardiography for concurrent cardiac and airway
abnormalities
 Airway  Hemangiomas enlarge in the first few weeks of life
hemangioma  Worsening biphasic stridor, concurrent skin hemangiomas (“bread distribution”)

 Pertussis
o Microbiology – Bordetella Pertussis
o Clinical phases
 Catarrhal (10 – 14 days): mild cough, rhinitis / rhinorrhea, malaise
 Significantly longer prodrome of URTI symptoms c.f. bronchiolitis & croup
 Paroxysmal (2 – 6 weeks):
 Several bouts of coughing (coughing paroxysms) with inspiratory whoop (particularly in
young children), post–tussive emesis;
 Infants: relentless coughing fits, gagging, gasping, cyanosis, life–threatening apnea
 Intercostal muscle tenderness may also occur due to forceful bouts of coughing episodes
 Convalescent (weeks to months): symptoms resolve gradually
 Fever uncommon
o Diagnosis
 Nasopharyngeal Bordetella Pertussis culture or nasopharyngeal PCR
 Lymphocyte–predominant leukocytosis (> 20,000/mm 3 with ≥ 50% lymphocytes)
o Treatment – Macrolides (e.g. azithromycin, clarithromycin)
 Reduces transmission risk and if initiated early (within the first week of symptoms), may shorten
illness duration
o Prevention – acellular pertussis vaccine
 However lifelong immunity is not conferred from vaccination or prior pertussis infection
 Acquired immunity wanes 5 – 10 years post–vaccination, thereby allowing even fully
immunized individuals to be susceptible to infection

Herpangina Herpetic gingivostomatitis (‘cold sore’)

Etiology Coxsackie A virus Herpes simplex virus type 1
Age 1 – 7 years 6 months – 5 years
Seasonality Late summer / early fall None
Clinical Sudden onset Fever Prodrome of Fever, anorexia, irritability in
Features Pharyngitis children, adenopathy (may precede lesions by 3
Gray vesicles / ulcers on posterior oropharynx on days)Pharyngitis
the posterior soft palate, anterior palatine pillars, Erythematous gingiva
tonsils and uvula. Clusters of vesicles on anterior oral mucosa/lips
Lesions spare buccal mucosa, gingiva, and tongue (buccal mucosa, tongue, gingiva, hard palate)
Last 7 – 10 days Recurrent herpetic lesions in 1/3 of cases
(herpes labialis)
Treatment Supportive (hydration, analgesia); symptoms Oral Acyclovir
typically resolve in a week Supportive (hydration, analgesia)

 Coxsackievirus is the most common cause of pediatric myocarditis

o Presents with fever, LV dysfunction and heart failure
Urinary Tract Infection in Children (age < 2)
Risk Factors  Female sex
 Uncircumcised male infants
 Vesicoureteral reflux, anatomic defects (e.g. posterior urethral valves in boys – urethra
obstructed by congenital posterior urethral membrane; ADPKD)
o Posterior urethral valve is most common cause of chronic renal insufficiency / failure in
children
 Dysfunctional Voiding
 Constipation
Clinical Features  Dysuria
 Fever
 Suprapubic pain (cystitis) &/or flank/back pain (pyelonephritis) – may be difficult to elicit in
children
 Non – specific symptoms – poor feeding, irritability
 Recurrent and/or chronic pyelonephritis can lead to blunting of calices (calyceal clubbing) and
focal parenchymal scarring
Laboratory Findings  Pyuria (≥ 5 WBCs/hpf on microscopy)
 Bacteriuria on urine culture
o ≥ 50,000 CFUs/mL in clean voided mid–stream urine specimens of uropathogen, ideally on 2
seperate samples
 ≥ 10,000 CFUs/mL in clean voided mid–stream urine specimens in Male Adults
 ≥ 100,000 CFUs/mL in clean voided mid–stream urine specimens in Female Adults
o ≥ 100 CFUs/mL from catheterized specimen of uropathogen
o Any growth on Suprapubic aspirate
o N.B. presence of ≥ 3 bacterial species in the urine &/or >20 squamous cells/hpf suggests
contamination and a new specimen should be obtained if a UTI is suspected
 Positive nitrites (specific for Enterobacteriaceae infection) and leukocyte esterase (produced
by WBCs) support the diagnosis
 ± Haematuria
Management  Antibiotic therapy (1 – 2 weeks of 3rd gen cephalosporins)
o N.B. Daily prophylactic antibiotics can be considered in patients with recurrent UTIs or
evidence of high-grade vesicoureteral reflux. They are generally not indicated in children
with first febrile UTI.
 ± Renal & bladder Ultrasound
o Evaluate for anatomic abnormalities (e.g. urinary obstruction, vesicoureteral reflux) that
might predispose to UTIs
o Performed after fever and symptoms have resolved to minimize false positive results from
acute inflammation
 o If patient has persistent or worsening symptoms, an ultrasound should be performed
immediately to assess for renal abscess
o Children age > 2 and adults generally do not need further evaluation for first–time UTI due
to lower likelihood of predisposing anatomic issues, lower risk of complications, and lower
risk of recurrent UTI
 ± Voiding cystourethrogram
o Indicated if scarring or hydronephrosis seen on USS
o also indicated in children with recurrent UTIs (2 or more febrile UTIs)
o 1st Febrile UTI (Fever ≥ 39 OC) & bacteria other than E. coli
o Signs of chronic kidney disease (i.e. poor growth, hypertension)
 If high – grade VUR (e.g. grade IV or V) is detected on renal ultrasound → daily antibiotic
prophylaxis is considered to prevent further UTIs and renal damage
 Renal scintigraphy with dimercaptosuccinic acid is preferred modality for long–term
evaluation of renal scarring
 Serial Renal function testing
 Patients with vesicoureteral reflux should be monitored for complications of chronic renal
insufficiency, such as hypertension and anemia

 Posterior Urethral Valve (PUV)

o Aka congenital obstructing posterior urethral membranes (COPUM)
o Most common congenital obstructive lesion of the urethra and a common cause of obstructive uropathy
in male infancy.
o Estimated incidence is at ~1 in 10,000-25,000 live births with a higher rate of occurrence in utero.
o Pathology
 Posterior urethral valves result from the formation of a thick, valve–like membrane from a tissue
of Wolffian duct origin (failure of regression of the mesonephric duct) that courses obliquely from
the verumontanum to the most distal portion of the prostatic urethra. This is thought to occur in
early gestation (5-7 weeks).
 The valve is a diaphragm with a central pinhole, however as it is more rigid along its line of fusion
it gradually distends and becomes distended into a bilobed sail-like or windsock-like structure
o Clinical Features – depends on the severity of obstruction
 In severe obstruction – usually an antenatal diagnosis on USS
 small for gestational age fetus
 Oligohydramnios
 Associated abnormalities – (not typically seen before 26 weeks gestation)
o Marked distention and hypertrophy of the bladder
o Bilateral hydronephrosis and hydroureter may or may not be present
o Renal Dysplasia
o Keyhole sign may be seen on ultrasound due to the distention of both the
bladder and the urethra immediately proximal to the valve (dilated proximal
urethra)
o Potter’s Sequence (pulmonary hypoplasia, flattened facies)
 In less severe cases, the diagnosis is often not apparent until early infancy.
 Urinary tract infections are common in this group
 Weak urinary stream, strained voiding
 Incontinence
o Investigations
 Renal / KUB USS – Initial test for genitourinary malformations
 Very sensitive for hydronephrosis
 Less sensitive for distal obstructions; cannot definitively differentiate uteropelvic junction
obstruction, vesicoureteral reflux, and PUVs
 Voiding Cystourethrogram (VCUG) - Confirmatory
 Performed by catheterizing the patient, injecting radiopaque dye, and obtaining images
during voiding.
 Findings:
 o dilatation and elongation of the posterior urethra (Dilated proximal urethra when
catheter is removed before end of imaging; equivalent to the ultrasonographic
keyhole sign)
o linear radiolucent band corresponding to the valve (only occasionally seen)
o vesicoureteral reflux (VUR) & ureteral dilatation due to severe outflow
obstruction from PUV: (~ 25 – 50% of patients)
o bladder trabeculation / diverticula
o Management
 After confirmation of PUV on VCUG, placement of foley catheter to temporarily relieve the
obstruction.
 When infants condition has stabilized, cystoscopy allows direct visualization and ablation of the
valve (curative)

 Infectious Mononucleosis
o Etiologic agent – EBV
 N.B. CMV, HHV6 causes Heterophile antibody (Monospot) negative mononucleosis-like
syndrome
o Clinical Features
 Fever
 Tonsillitis / pharyngitis +/- exudates
 Posterior or diffuse cervical lymphadenopathy
 Significant fatigue
 +/- Hepatomegaly
 +/- rash after Amoxicillin (beta-lactam antibiotic); typically 2-10 days after exposure & resolves
within days of drug discontinuation
 Theorized delayed-type drug hypersensitivity reaction due to virus-induced immune
modification; not considered a true drug allergy & most patients able to received
antibiotic subsequently without reaction
o Diagnostic findings
 Positive heterophile antibody (Monospot) test – 25% false-negative rate during 1 st week of illness
 > 10% Atypical Lymphocytes, lymphocytosis
 Transient hepatitis
o Management
 Avoid sports for ≥ 3 weeks (contact sports ≥ 4 weeks) due to risk of splenic rupture
o Complications
 Acute Airway Obstruction – tx with corticosteroids to decrease airway edema
 Autoimmune hemolytic anemia & thrombocytopenia
 Splenic rupture
 Cerebral Palsy
o Non-progressive motor dysfunction characterized by abnormal tone, movement, and development,
usually result from prenatal insults to the brain (e.g. prematurity)
 o Risk Factors
 Prematurity (greatest risk factor)
 Low Birth Weight
 Perinatal hypoxic-ischemic encephalopathy (underlying etiology is often unknown)
o Clinical Features
 Delayed gross motor milestones (E.g. commando crawl – pulling self by the arms while dragging
legs behind her)
 Abnormal tone, hyperreflexia predominantly involving the lower extremities
 Spastic diplegia, contractures, equinovarus deformity (feet point down and inward)
 Comorbid seizures, intellectual disability
o Diagnosis
 Clinical (usually by age 1 – 2)
 Brain MRI (e.g. periventricular leukomalacia [white matter necrosis from ischemia/infarction],
basal ganglia lesions, intraventricular haemorrhage [germinal matrix bleeding due to fragile
vasculature])
o Management
 Physical, occupational, and speech therapy
 Nutritional support
 Antispastic medications
 Acute Bacterial Rhinosinusitis
o Etiology
 Nontypeable Haemophilus influenzae (~40 – 50%)
 Streptococcus pneumoniae (~20 – 25%)
 Since PCV13, S. pneumoniae has become less prevalent
 Moraxella catarrhalis (~25%)
 Chronic sinusitis (>12 weeks) – Staphylococcus aureus (rarely a causes in children)
o Clinical Features
 Cough, Nasal Discharge
 Fever
 Face Pain / headache
o Diagnostic Criteria (1 of 3)
 Persistent symptoms ≥ 10 days without improvement
 Severe onset (fever ≥ 39 OC [102.2 OF]) ≥ 3 days
 Worsening symptoms following initial improvement
o Treatment – Amoxicillin +/- clavulante
 Bacterial Meningitis
o Common Pathogens
 Neonates < 1 month
 Group B Strep (early onset; ≤ 7 days), E. coli (& other gram negatives), Listeria
monocytogenes
 Gram Positive Enteric Organism
 HSV (viral meningitis)
 1 – 3 months
 Group B strep (late onset), Streptococcus pneumoniae, Neisseria meningitidis
 GNBs, Listeria, Haemophilus Influenza type B (rare), salmonella
 Three months to three years of age
 S. pneumoniae, N. meningitidis, H. influenzae (rare due to immunity)
 Three to 12 years of age
 S. pneumoniae, N. meningitidis, H. influenzae (rare due to immunity)
 12 years to adult:
 S. pneumoniae (~70% of cases of community-acquired bacterial meningitis)
o Usually secondary to hematogenous dissemination (bacteremia); may occur with
or without concurrent pneumococcal pneumonia
 N. meningitidis (~12%)
 Group B strep
 H. influenzae
o Clinical Features
 Fever (usually ≥ 38 OC [100.4 OF])
 Increased ICP (e.g. nausea, vomiting, headache, altered mental status, irritability, lethargy, poor
feeding, bulging fontanelle)
 Meningeal Irritation (e.g. nuchal rigidity, Brudzinski, Kernig’s Sign) – less reliable in neonates
 If Meningococcal meningitis, within 12 – 24 hr, petechiae/purpura, meningeal signs, altered
mental status; tx – ceftriaxone
 Complications of Meningococcus – Shock & multiorgan failure, DIC, Adrenal
Haemorrhage (Waterhouse-Friderichsen Syndrome)
 Prevention – droplet precautions & chemoprophylaxis for close contacts (Rifampin,
ciprofloxacin, or ceftriaxone)
 Neonatal sepsis – hypothermia or hyperthermia, lethargy & irritability, high or low WBC with left
shift (i.e. bandemia), apnea
o Investigations
 CBC – leukocytosis, U&E, serum Glucose
 Blood Cx
 UA & Urine Cx & sensitivity
 LP – CSF Cx & sensitivity, CSF glucose, CSF protein, CSF cell count
 Typical CSF findings in bacterial meningitis:
o WBC count – neutrophilic leukocytosis >1000/mm 3
o high protein (ranges from 100-500 mg/dL; > 200 mg/dL)
o low glucose (<40 mg/dL)
o high opening pressure (often 20 – 75 cm H 2O; > 350 mm H2O)
o positive gram stain
o Treatment
 Neonates
 Ampicillin & gentamicin
 Infants to 18 months
 IV vancomycin & 3rd gen cephalosporin (e.g. ceftriaxone or cefotaxime)
o Vancomycin offers coverage for S. pneumoniae resistant to penicillin
 ± Dexamethasone (always used for H. influenza type B; consider with other pathogens)
 Reduces the risk of sensorineural hearing loss & focal deficits
 Adults (Age 2 – 50) – S. pneumoniae, Neisseria meningitidis
 IV vancomycin & 3rd gen cephalosporin ± Dexamethasone
 Adults > 50 – S. pneumoniae, N. meningitidis, Listeria (ampicillin)
 IV Vancomycin + 3rd gen cephalosporin + Ampicillin ± Dexamethasone
o Add ampicillin if age > 50 years or those who are immunocompromised due to
increased risk of Listeria monocytogenes
 Immunocompromised (e.g. chronic glucocorticoids) – S. pneumoniae, N. meningitidis, Listeria,
GNBs
 Vancomycin + cefepime (4th gen cephalosporin) + ampicillin
 Neurosurgery / penetrating skull injury – Gram-negative rods, MRSA, coagulase-negative
staphylococci
 Vancomycin + cefepime (4th gen cephalosporin)
o Vancomycin offers coverage against cephalosporin-resistant pneumococci
o Cefepime covers most organisms causing bacterial meningitis (e.g. Streptococcus
pneumoniae, Neisseria meningitidis, group B streptococci, Haemophilus
influenzae) as well as Pseudomonas aeruginosa
 Adolescents should receive quadrivalent meningococcal vaccine at age 11–12, and booster at 16
years of age
 Additionally, the meningococcal serogroup B vaccine can be considered for ages 16 – 18
 Alternatives to ampicillin: trimethorprim-sulphamethoxazole for Listeria
 Alternatives to cefepime: ceftazidime or meropenem
o Complications
 Hearing loss
 Intellectual / behavioural disabilities (ADHD, low IQ, MR, cognitive impairment, behavioral issues)
  Vision deficits, including cortical blindness
 Neurologic deficits (seizures / epilepsy, motor deficits, cerebral palsy)

Neisseria Meningitidis Prophylaxis

Recommended N. meningitidis has a high risk of epidemic spread and most secondary cases develop within 10 days
populations of the initial patient’s diagnosis. Risk of transmission occurs from 7 days prior to symptom onset until
24 hours after initiating appropriate antibiotic therapy. Therefore antimicrobial chemoprophylaxis
given to asymptomatic close contacts, irrespective of vaccination status, who had exposure during
this period
o Household members
o Roommates or inmate contacts
o Childcare centre workers
o Persons directly exposed to respiratory or oral secretions
o Person seated next to affected person for ≥ 8 hours (e.g. airline traveler)
Prophylaxis options Antibiotics given as soon as possible after exposure, ideally < 24 hours of diagnosis, but can be up to
two weeks
Rifampin
3rd generation cephalosporin (e.g. Ceftriaxone) – indicated if symptoms of invasive disease
Ciprofloxacin (adults only)

Antibiotics in Paediatric Sepsis

Age Most common organisms Empiric antibiotics
 Group B Streptococcus  Ampicillin (GBS & Listeria coverage) + Gentamicin* (E. Coli coverage)
 Escherichia coli o N.B. * Gentamicin can be replaced with cefotaxime or ceftazidime for cases of
≤ 28 days
 Listeria monocytogenes suspected meningitis due to superior CSF penetration
(age < 7 days)
 Streptococcus  Ceftriaxone
pneumoniae o Not preferred in 1st month of life because it can displace albumin – bound
¿ 28 days  Neisseria meningitidis bilirubin → thus increased risk of kernicterus, particularly in patients with
sepsis – related hemolysis & indirect hyperbilirubinemia
 ± Vancomycin (if meningitis or suspected MRSA e.g. concomitant skin infection)

 Neonatal Sepsis
o Age ≤ 28 days (immunologically deficient and predisposed to serious infections)
o Associated with 10–40% mortality & significant morbidity, especially neurologic sequelae of meningitis
o Risk Factors / Predisposing factors
 Premature rupture of membranes (>24 hours)
 Premature labor
 Maternal fever
 UTI
 foul lochia, chorioamnionitis
 IV catheters (in infant)
 Intrapartum asphyxia
 Intrauterine monitoring (pressure catheter or scalp electrode).
o Microbiology
 Early infection (0 to 4 days of age) –
 Group B streptococci and Escherichia coli (60 – 70%) of infections.
 Also Listeria (rare in United States), Klebsiella, Enterococcus, Staphylococcus aureus
(uncommon), Streptococcus pneumoniae, group A streptococci.
 Late infection (>5 days of age) –
 Staph. Aureus, Group B streptococci, E. coli, Klebsiella, Pseudomonas, Serratia, Staph.
epidermidis, Haemophilus influenzae.
o Clinical Features – signs and symptoms may be subtle
 Temperature instability / Poor temperature control (fever or hypothermia < 36 OC [96.8 OF])
 Any febrile neonate must have a septic work-up. Fever may be absent
 Poor feeding, vomiting
 Mild Jaundice – due to transient conjugation deficiency
  May progress to respiratory distress, poor perfusion, abdominal distension, jaundice, bleeding,
petechiae, or seizures.
 CNS signs (lethargy, irritability, apnea / apneic spells)
 ± hypotonia, full anterior fontanelle
 Bulging fontanel is a very late sign of neonatal meningitis, and Brudzinski's sign or
Kernig's sign is rarely found.
 Abnormal WBC (high or low)
 Left shift (bandemia)
o Diagnosis
 CBC (recall neutropenia or thrombocytopenia are also suggestive of infection)
 U&Es, RBG, Urinalysis, C-Reactive Protein
 Associated lab findings. Hypocalcemia, hypoglycemia, hyponatremia, and DIC
 CXR
 Blood Cx, Urine Cx
 Lumbar Puncture for CSF cell count, protein, glucose, and CSF Cx
 Latex agglutination test for pneumococcus, E. coli, H. influenzae, group B streptococci,
and meningococcus in blood, urine, and CSF is done even though the usefulness is
questionable. Negative latex agglutination tests do not rule out infection, but positive
results may help guide therapy.
o Treatment
 Empiric parental antibiotics (ampicillin & gentamicin) after cultures, then culture-directed
 However, those who are critically ill ((e.g. septic shock, status epilepticus) or who cannot
immediately undergo LP should receive antibiotics first
 Empiric early (0 to 4 days old).
o Ampicillin 50 mg/kg/day (100 mg/kg/day in meningitis) IV BD plus Gentamicin 5
mg/kg/day IV BD.
 Empiric late (>5 days old).
o Depends on cause (for example, methicillin-resistant Staph. aureus outbreak
requires vancomycin)
o Ampicillin 100 to 200 mg/kg/day IV Q8h plus (ceftriaxone 100 mg/kg/day IV Q12h
or cefotaxime 150 mg/kg/day IV Q8h), or ampicillin-gentamicin as above usually
adequate.
 Repeat cultures in 24 to 48 hours. In meningitis, repeat LP every day until clear.
 There are isolates of Streptococcus pneumoniae that are resistant to penicillin and
cephalosporins. Depending on your institution, vancomycin plus rifampin should be
added to the above regimens until sensitivities are known.
 Other. Hemodynamic, respiratory, hematologic, metabolic, and nutritional support and
surveillance are critical. Shock may require volume expansion (FFP preferred) or respiratory
depression may require supplemental oxygen or artificial ventilation
 Colic
o Crying for no apparent reason ≥ 3 hours/day (usually evening) for ≥ 3 days per week
o Otherwise healthy infant < 3 months old
 Symptoms peak at 6 weeks and typically resolve by 3 – 4 months
o Diagnosis of exclusion
o Soothing techniques – pacifier, holding, rocking, or swaddling the baby
 Minimize environmental stimuli (e.g. dark room)
 Use of swings, carriers, and strollers can also be calming and allow parents to rest from active
soothing
 Adjusting feeding techniques (e.g. upright feeding position in bottle-fed babies) may help reduce
air swallowing and relieve colic
 Tourette Syndrome
o Comorbidities such as OCD and ADHD are common
 5–7% of OCD pts have full blown Tourette Syndrome
o Clinical Features
 Both multiple motor & ≥ 1 vocal tics (not necessarily consistent, > 1 year), (c.f. Chronic Tic
Disorder which involves either motor or vocal tics, but not both, for ≥ 1 year)
  Motor –
o Simple motor tics (e.g. facial grimacing, blinking, head/neck jerking, shoulder
shrugging, tongue protrusion, sniffing)
o Complex tics (e.g. body gyrations, odd gait, obscene gestures)
 Vocal – grunting, snoring, throat clearing, barking, yelling, coprolalia (obscenities &
profane language)
 Onset age < 18
 Tics are usually preceded by irresistible urges and followed by feelings of relief; exacerbated by
stress and fatigue
 Although experienced as involuntary, tics can be suppressed voluntarily for some time
o Treatment
 Behavioural therapy (habit reversal training)
 Antidopaminergic agents
 Tetrabenzine (dopamine depleter)
 Antipsychotics (dopamine receptor blockers / antagonists)
o E.g. risperidone (2nd gen antipsychotic)
o N.B. although 1st gen antipsychotics (such as haloperidol, fluphenazine, pimozide)
have demonstrated efficacy and are FDA – approved, 2 nd gen antipsychotics are
preferred due to 1st gen side effect profile (e.g. extrapyramidal symptoms, QTc
prolongation with pimozide)
o Indications – severe tics that interfere with social and academic functioning
o As a group, antipsychotics reduce frequency and intensity of tics by 60 – 80%
 Alpha–2–adrenergic receptor agonists
 E.g. guanfacine, clonidine
 If comorbid OCD, impulse control problems, and rage attacks in Tourette’s patients → SSRI such
as fluoxetine
 Provision Tic Disorder (formerly known as transient tic disorder)
o Tics present for < 1 year
o Tics occur in ~25% of normal children and typically remit spontaneously in a few weeks or months

Routine Adolescent Screening

Category Screening Method (annually unless otherwise indicated)
Mental Health  Validated depression questionnaire
o Suicide is the leading cause of death in this age group with depression being the greatest risk
factor
o Prevalence of clinical depression ~10%
Sexual Health  Confidential discussion about sexual activity
 Gonorrhea & chlamydia testing in sexually active women age < 25, as well as those with other
risk factors (e.g. multiple sexual partners, illicit drug use)
o If positive, all sexual partners from preceding 2 months should also be test and treated
 HIV testing (once at age < 18)
Substance Use  Confidential discussion about exposure, use, abuse
Dyslipidemia  Lipid panel once between 17 & 21
Safety  Inquiry about bullying
 Inquirey about seatbelt & helmet use

Febrile Seizures
Definition & Seizure with fever (Temperature >100.4 OF) in neurologically healthy child without CNS
Epidemiology Infection
Most common seizure in childhood
Occurs in 3-5% of children before age 5 years
M:F = 2:1
Most common in winter and early spring – corresponding to increased frequency of
respiratory and gastrointestinal infections
Risk Factors Fever from mild viral illness (e.g. HHV–6, influenza, adenovirus, parainfluenza)
 o High fever also is associated, raising Neuronal excitability and decreasing Seizure
threshold
Family History
Classification / Simple Febrile Seizure (65-90%)
Types of Febrile o Generalized Seizure
Seizure o Seizure duration <15 minutes
o Occurs once in 24 hour period
o No prior neurologic conditions
o Normal Neurologic Exam
Complex Febrile Seizure (20-25%)
o Focal Seizure (most common reason for classifying as complex Seizure)
o Seizure duration >15 minutes
o Occurs more than once in a 24 hour period
o Known neurologic condition (e.g. Cerebral Palsy)
o Postictal neurologic abnormality (Todd's Paralysis)
o May also be associated with prolonged postictal state
Febrile Status Epilepticus (5%)
o Generalized Febrile Seizure lasting >30 minutes
Diagnostic Criteria Typically age 3 months to 6 years (peak at age 2 years)
o Likely due to nervous system immaturity
No previous afebrile seizure
No meningitis or encephalitis
o I.e. no abnormal neurologic findings (e.g. no nuchal rigidity, no bulging fontanelles)
No acute metabolic cause
Associated Clinical Febrile seizures typically have a benign course, and do not require therapy
Features Seizures usually occur during the first day of viral illness, and are frequently the initial
manifestation of infection
Findings consistent with infections (e.g. rhinorrhea, tachycardia, tachypnea)
Typically generalized, jerky movements that are short–lived (most last < 7 minutes), with
minimal post–ictal lethargy
Investigations Workup is generally unnecessary as it is not cost – effective and is typically normal
o Well appearing children with simple Febrile Seizures do not require lab testing
o In addition, well appearing children even with complex Febrile Seizures are unlikely to
have abnormal labs
GMR / RBG
Consider Urinalysis
Consider U&Es (BMP) if indicated by history
o E.g. Diarrhea or Vomiting
o However lab testing is not routinely indicated (not recommended by AAP)
o Consider basic chemistry panel (Serum Glucose, Na +, Ca2+, Mg2+)
 Consider Lumbar Puncture if:
o Petechiae
o Nuchal Rigidity (or Kernig Sign or Brudzinksi Sign)
o Prolonged Altered Mental Status (i.e. post – ictal period > 10 min)
 Decreased Level of Consciousness or Coma
 E.g. response only to painful stimuli 1 hour after seizure
o Prolonged (> 30 min) or recurrent seizures without return neurologic baseline are
associated with a higher risk of an underlying CNS infection
o Signs of raised intracranial pressure (e.g. morning headaches, vomiting, bulging
fontanelle)
o Hypotension
o Focal neurologic deficit
o Seizure in a premature infant with an underlying neurologic condition (e.g.
ventriculoperitoneal shunt) that increases the risk for CNS infection
o Children 6–12 months of age with unknown or incomplete Vaccination series –
 Haemophilus Influenzae type B, Streptococcus Pneumoniae (Prevnar)
 Consider MRI Brain / Head only if:
o Persistent neurologic deficits or Altered Mental Status
o Cerebral Abscess risk
o Increased Intracranial Pressure signs
o Head Trauma
o Suspected structural defect (e.g. Microcephaly)
o Status Epilepticus
o Complex Febrile Seizure associated with other neurologic findings
Management Left lateral decubitus position during episode and ensure unobstructed airway
Abortive therapy (if ≥ 5 minutes)
Antipyretics
Management of Seizure duration >15 – 30 minutes
Febrile Status Approach
Epilepticus o Treated the same regardless of fever presence
o Consider initiating Benzodiazepines for Seizure >5 minutes (as these are unlike to stop
spontaneously)
o ABC Management
o Supplemental Oxygen, monitor and airway management
o Benzodiazepines (Lorazepam, Diazepam, Midazolam) followed by Fosphenytoin,
Levetiracetam or Phenobarbital
Emergency department
o Lorazepam
 Preferred agent for acute tonic-clonic pediatric
 Seizures Dose: 0.1 mg/kg IV up to 4 mg
o Diazepam
 Consider rectal form (diastat) when no IV Access available
 Dose: 0.2 to 0.5 mg/kg IV (or rectally) q15 minutes
 Maximum cumulative dose: 5 mg for age <5 years
o Midazolam
 Consider when no IV Access available (use IM)
 Dose: 0.2 mg/kg IM of the IV formulation up to 10 mg
o Fosphenytoin (preferred over Phenytoin)
 Indicated for Seizure refractory to Benzodiazepine
Prognosis Normal development / intelligence
~30% risk of at least one recurrence
< 5 % risk of epilepsy

 Indications for neuroimaging in a child with a headache

o History of coordination difficulties
o Presence of numbness, tingling, or focal neurologic signs
o History of headache that causes awakening from sleeping
o History of increasing headache frequency
 Juvenile Myoclonic Epilepsy
o Genetic epilepsy syndrome that affects otherwise healthy adolescents
o Clinical Features
 Adolescents – late onset of absence seizures with myoclonic activity, and is associated with life –
long seizures
 In ~ 33% of cases, JME begins as absence seizures (e.g. staring spells) in childhood, up to
5 years before other seizure types
 Morning myoclonus (limb–jerking)
 Generalized Tonic–Clonic Seizures (typically occurring in the morning)
 Postictal state (e.g. confusion), urinary incontinence
 Occurs late in the disease course in almost all patients
 May be triggered by sleep deprivation
  Up to 50% of patients can have a concurrent psychiatric diagnosis (e.g. anxiety disorder)
o Diagnosis
 Interictal Electroencephalogram (EEG): bilateral polyspike & slow wave activity
o Management
 Anticonvulsants – Valproic acid (1st –line)
 Successfully suppresses seizures in 80% of patients
 ADRs Valproic Acid
o Potentially teratogenic – linked with neural tube defects
o Life-threatening hepatotoxicity, and pancreatitis
o Dose – related thrombocytopenia
 Monitor with CBC at treatment initiation and followed periodically
 N.B. Gabapentin is contraindicated in these patients as it may exacerbate seizures
 Avoid triggers (e.g. alcohol, sleep deprivation)
 Lennox–Gestault Syndrome
o Age < 5 years
o Various, severe seizure types accompanied by intellectual disability
 Psychogenic, non-epileptic seizures
o Mimic seizures, but not associated with abnormal neural activity
o Generally witnessed events that occur during wakefulness
o Followed by immediate return to baseline neurologic status
o Urinary incontinence is uncommon
 Primary Nocturnal Enuresis
o Definition:
 Nighttime Urinary incontinence age ≥ 5 without additional urinary tract symptoms (i.e. no
dysuria, daytime incontinence etc.)
 No prior prolonged period of overnight dryness
o High rate of spontaneous resolution over time
o Pathogenesis

o Risk Factors
o Evaluation
 Urinalysis to rule out secondary causes
 Voiding dairy
o Management
 Lifestyle changes
 Minimize fluid intake before bedtime
 Avoid sugary / caffeinated beverages
 Void before bedtime
 Motivational therapy – Institute reward system (e.g. “gold star” chart)
 Enuresis alarm (can take 3 – 4 months to be effective)
 Best long – term outcome & Low risk of relapse
 Indicated if continued enuresis after institution of lifestyle changes and measures for 3 –
6 months
 Sensor in patients bed pad or underwear detects moisture and triggers an auditory or
vibratory alarm that wakes the patient, thereby inhibiting further bladder emptying
 With consistent use, conditions patient to wake up prior to voiding
 Patient adherence and motivation required, as the child is responsible for responding to
the alarm
 Desmopressin therapy (1st line pharmacotherapy for immediate results)
 Counsel patients to minimize fluid intake in the evening to prevent hyponatremia with
therapy
 High rate of relapse after discontinuation of desmopressin therapy
 TCAs can be considered for refractory cases – anticholinergic effect of urinary retention
 Secondary Nocturnal Enuresis
o New–onset bed–wetting in a child age ≥ 5 who had previously achieved overnight dryness for a
prolonged period (≥ 6 months)
 o Secondary enuresis in an adolescent for instance should raise suspicion for a psychological stressor (e.g.
parent’s divorce) or an underlying medical condition:
 Constipation
 Infrequent & hard stools, Encoporesis
 ± Palpable stool mass
 Bladder Dysfunction
 Daytime incontinence
 Weak stream, urgency, straining
 ± Recurrent UTIs
 UTI
 Dysuria, urinary frequency, abdominal pain
 Positive Urine Culture
 CKD
 Daytime incontinence
 Weight loss, fatigue
 HTN, proteinuria, haematuria
 Diabetes Mellitus
 Polyuria, polydipsia, polyphagia
 Weight loss, fatigue
 Glucosuria
 Diabetes Insipidus
 Polyuria, polydipsia
 Low urine specific gravity
 Obstructive Sleep Apnea
 Snoring
 Hyperactivity, inattention
 Adenotonsillar hypertrophy
o Investigations
 Urinalysis – to exclude medical causes (e.g. UTI); glucosuria suggestive of DM
 U&Es, RBG
 DM (≥ 200 mg/dL on random testing or ≥ 126 mg/dL if fasting)
 Hyponatremia & hypokalemia may be associated with hyperglycemia
 Beckwith–Wiedemann Syndrome
o Pathogenesis – Deregulation of imprinted gene expression in chromosome 11p15, which includes genes
that encode insulin–like growth factor 2 (IGF–2)
o Clinical Features
 Fetal macrosomia, rapid growth until late childhood
 Medial abdominal wall defects – Omphalocele or umbilical hernia
 Macroglossia
 Hemihyperplasia
 ± Hypoglycemia due to fetal hyperinsulinemia
 ± Visceromegaly
o Complications
 Increased risk of embryonal tumours such as Wilms tumour, hepatoblastoma, neuroblastoma
o Surveillance
 Serum AFP q3–monthly from birth to age 4
 Abdominal / renal ultrasound q3–monthly from age 4 – 8 years
 Those with isolated hemihyperplasia are also at risk of Wilm’s and hepatoblastoma and should
undergo frequent surveillance
 Wilms Tumour (Nephroblastoma)
o Epidemiology
 Most common renal malignancy in children
 Peak age 2 – 5
 Deletion of WT1 gene within affected chromosome
 Usually sporadic but may be associated with:
  WAGR Syndrome / 11p deletion Syndrome – Gene deletion on chromosome 11p13 →
deletion of WT1 gene and other genes such as PAX6
o Wilms tumour (occurs ~ 50% of WAGR syndrome)
 Often bilateral & presents earlier (age 1 – 3) in the syndrome than in
isolation
o Aniridia [absent iris]
o Genitourinary abnormalities
 Epispadias
 Pseudohermaphroditism, undescended testes in males (due to gonadal
dysgenesis)
 Early–onset nephrotic syndrome
o Intellectual Disability [mental Retardation])
 Beckwith–Wiedemann syndrome (mutations of WT2 gene)
 Denys–Drash syndrome
o Point mutation in WT1 gene, which encodes a zinc finger transcription factor
o Wilms tumor
o Pseudohermaphroditism, undescended testes in males (due to gonadal
dysgenesis)
o Early–onset nephrotic syndrome
o Clinical Features
 Unilateral, often PAINFUL, abdominal mass
 ± Abdominal pain, hypertension, hematuria (25%)
 ABD USS followed by Contrast–enhanced CT or MRI ABD – evaluate extent of mass
 Lungs are common site of metastatic spread but children rarely have pulmonary symptoms
 CT Chest – pulmonary metastases
o Treatment
 Surgical excision
 Chemotherapy
 ± Radiation therapy
o Prognosis – 90% survival rate with treatment
 Neuroblastoma
o Most common extra – cranial solid tumour of childhood
o Pathogenesis
 Neural crest origin (derived from primitive sympathetic ganglia) and secrete catecholamines (e.g.
epinephrine, norepinephrine) → may contribute to ↑ blood pressure, flushing and diaphoresis
 Involves adrenal medulla (most common site), sympathetic chain
o Clinical Features
 Median age < 2 years
 PAINLESS, palpable abdominal mass with systemic features (e.g. fever, weight loss)
 Less commonly, mass may have compressive symptoms – constipation, urinary
retention / incontinence, compression of renal artery (RAAS activation → HTN)
 ± ↑ BP (HTN), flushing and diaphoresis (sympathetic stimulation from excess catecholamines)
 Periorbital ecchymoses (“racoon eyes”; orbital metastases that obstruct palpebral blood vessels)
 Spinal cord compression from epidural invasion (“dumbbell tumour”)
 Opsoclonus–myoclonus syndrome (rapid eye movements; rare autoimmune paraneoplastic
finding)
 Ipsilateral Horner’s syndrome – tumor involvement of cervical paravertebral sympathetic chain
o Diagnostic Findings
 Elevated Urine & serum catecholamine metabolites (vanillymandelic acid and homovanillic acid)
 Biopsy (confirmatory) – Small, round blue cells on histology
 N–myc gene amplification
 Craniopharyngioma
o Epidemiology
 Benign, slow growing tumour derived from epithelial remnants of Rathke pouch (within pituitary
stalk); tumour found in suprasellar region, adjacent to the optic chiasm
 Bimodal age distribution (age 5 – 14 & 50 – 75)
 o Clinical Features
 Due to slow growth, often cause subtle symptoms for years prior to diagnosis
 Optic chiasm compression → bitemporal hemianopsia
 Due to peripheral vision loss, patients often bump into the corners of walls, furniture etc.
 Pituitary stalk compression → endocrinopathies (panhypopituitarism)
 Growth failure in children (↓ TSH or ↓ GH) – most common manifestation
 Hypogonadism → Pubertal delay in children or sexual dysfunction in adults ( ↓ LH & FSH)
 Diabetes insipidus (↓ ADH)
 Adrenal insufficiency (due to corticotropin deficiency)
 Headache, obstructive hydrocephalus
 Papilledema
o Investigations / Diagnosis
 MRI / CT Scan: Calcified &/or cystic suprasellar mass
 Diabetes insipidus – high-normal serum sodium, dilute urine (low specific gravity)
o Treatment
 Surgical resection ± radiation therapy
 Medulloblastoma
o Epidemiology
 Most common malignant pediatric brain tumour
 Other common posterior fossa tumour in kids is pilocytic astrocytoma
 Posterior fossa tumour
 Originates in cerebellar vermis
 Often compresses fourth ventricle
 Potential for leptomeningeal spread
o Clinical Features
 Cerebellar Dysfunction
 Truncal / gait ataxia (cerebellar vermis)
 Dysmetria, intention tremor (cerebellar hemispheres)
 Obstructive Hydrocephalus (↑ ICP)
 Headache, vomiting
 Papilledema
 Abducens nerve palsy
o Treatment – resection, craniospinal radiation, chemotherapy
 Choroid Plexus Papilloma (CPP)
o CPP most common in infants
o Rare, slow-growing, benign overgrowth of the choroid plexus that results in increased CSF production
 Choroid plexus, a highly vascular, neuroepithelial tissue found within the ventricles, produces CSF
o Accumulation of excess CSF (i.e. hydrocephalus) causes enlarging head circumference and signs of
increased intracranial pressure (e.g. poor feeding, bulging fontanelle, irritability, vomiting on walking)
o Developmental Delay (e.g. inability to sit with support at age 6 months)
o Headache often occur in older children, and adults
o With increasing tumour size, obstruction of CSF flow can occur →increased intracranial pressure→
Ventriculomegaly and intraventricular mass on Cranial USS
o MRI confirms diagnosis
o Management – treatment for large or symptomatic CPP is resection
o Recurrent is rare
 Werdnig–Hoffman Syndrome
o Autosomal recessive
o Involves degeneration of anterior horn cells and cranial nerve nuclei
o It is a cause of “floppy baby syndrome” (infant botulism is the other cause)
 Dandy Walker Syndrome
o Congenital atresia of the foramina of Luschka and Magendie prevents CSF outflow into the subarachnoid
space, causing hydrocephalus
 Rett Syndrome
o Key Features – “Rett causes Regression”
 Rare neurodevelopmental disorder, most often caused by mutations of MECP2 gene
  Onset 6 – 18 months
 X – linked dominant
 Greater incidence in girls, (possibly because the mutations are most often of paternal
origin)
 No male to male transmission
 Initially Girls have normal development (with no dysmorphic features at birth) until 6 months of
age followed by developmental regression:
 Regression of speech and motor function (Loss of communicative and fine motor skills
follows around age 12 – 18 months)– usually slow but may occur rapidly
o Loss of purposeful hand use (inability to feed or dress oneself)
 Purposeless squeezing of hands
o Loss of speaking skills
 Development of stereotypical hand movements (e.g. wringing, pill–rolling, twisting,
kneading, hand clapping, hand-to-mouth licking)
 Gait abnormalities (e.g. lurching)
o Additional Findings
 Head growth deceleration – microcephaly
 Seizures / Epilepsy – majority of patients and are increasingly prevalent with age
 Periodic breathing abnormalities (alternating episodes of hyperventilation and hypoventilation or
apnea); tend to occur during periods of heightened emotions
 Sleep disturbance (e.g. waking up crying or screaming)
 Autistic features (lack of eye contact and social reciprocity, restricted interests)
o Etiology
 X–linked MECP2 gene mutations that affect neuronal development (possibly including
abnormalities in cortical dendrites and in neuromodulation in CNS respiratory centres)

Prader Willi Syndrome Angelman Syndrome

(“Floppy Baby with undescended testicles”) (Happy Puppet Syndrome)
Etiology  Mutation or absence of expression of paternally  Deletion of maternal chromosome 15q11-q13
active gene region of chromosome 15q  Paternal uniparental disomy
o Deletion of paternal chromosome 15q11-  Rarely defects in imprinting centre
q13 (65 – 75%) – detected on FISH
o Maternal uniparental disomy (20 – 30%)
o Rarely defects in imprinting centre
 Methylation “turns off” genes
Clinical  Short Stature
Features  Intellectual Disability
 Hypotonia  Frequent smiling or inappropriate laughter
 Weak suck / feeding problems in infancy (Happy disposition)
 Hypogonadism e.g. cryptorchidism  Jerky gait / ataxia
 Hyperphagia & Obesity  Hypermotoric behaviours – Hand–flapping
 Dysmorphic features  Truncal & limb hypotonia, hyperreflexia
o Narrow forehead  Hyperexcitability, short attention span
o Almond–shaped eyes  Epileptic Seizures (80%)
o Down–turned mouth  Speech Delay
Diagnosis  Deletion on Paternal chromosome 15q11-q13  Deletion of Maternal chromosome 15q11-q13
 Karyotype (FISH or chromosomal microarray;  Karyotype (FISH – Fluorescence in situ
detects deletion), Methylation studies hybridization), Methylation studies
Complications  Sleep apnea (70%)  Life expectancy typically normal
 Type 2 Diabetes Mellitus (25%)
 Gastric distention / rupture
 Death by choking (8%)
 Normal life expectancy if extreme obesity is
avoided

 Lesch–Nyhan Syndrome
 o Pathophysiology
 X–linked recessive
 Defect in hypoxanthine–guanine phosphoribosyltransferase (HGPRT) enzyme, involved in purine
metabolism → Hypoxanthine & uric acid accumulation in urine, serum and CNS
o Clinical Features
 Delayed milestones & hypotonia in infancy
 Early childhood (by age 3)
 Intellectual Disability, Mental retardation
 Extrapyramidal symptoms (e.g. dystonia, choreathetosis)
 Self–mutilating behaviour
 Late, Untreated Disease
 Marked hyperuricemia, Gouty arthritis in late, untreated disease
 Nephrolithiasis, obstructive nephropathy
o Diagnostics
 Hyperuricemia
 ↓ HGPRT activity
 Makrocytosis (megaloblastic anemia may occur)
o Treatment
 There is no treatment for the underlying enzyme defect.
 Reduce uric acid levels: Allopurinol (first-line), Febuxostat (second-line), Low-purine diet
o Prognosis: high mortality if the infant is not treated within the first year of life
 Lennox-Gestault Syndrome
o Severe seizures of multiple types
o Typically presents in children age 3 – 5
o Associated with intellectual disability, and a slow, generalized spike-and-wave pattern on EEG

Acute causes of hemiplegia in children

Cause Historical clues Key Findings
 Prothrombotic disorder (e.g. ATIII deficiency
 Congenital Heart disease (e.g. patent foramen
ovale, ASD → paradoxical embolic stroke via right-
to-left shunting)
Ischemic Stroke  Focal infarct on brain imaging
 Vasculopathy (e.g. Sickle Cell Disease)
 Homocystinuria – predisposition to venous and
arterial thrombi, intellectual disability, Marfinoid
Habitus, ectopia lentis
 Recent trauma
 Bleeding disorder (e.g. Haemophilia)
Intracranial
 Signs of increased ICP (e.g. vomiting, Cushing  Haemorrhage on brain imaging
haemorrhage
reflex – bradycardia, increased BP, irregular
breathing)
Seizure (Todd  Symptoms preceded by limb jerking or LOC  Symptoms self-resolve within 36
Paralysis)  Presence of post-ictal confusion hours
 Onset in adolescence
 Positive family history
Hemiplegic migraine  Symptoms self-resolve
 History of migraine headaches preceded by aura
with motor weakness; No LOC

Botulism
(Infant, Foodborne or Wound)
Etiology &  Flaccid neuropathy occurring in
Pathophys children < 1 year following ingestion of
Clostridium botulinum spores (infant
botulism) or performed botulinum
toxins (foodborne botulism)
o Infants with immature digestive
Clostridium Tetani
 Gram positive, obligate anaerobic, spore-forming rod
 Normally found in soil
 Enters the body through break in skin (e.g. puncture wound,
lower extremity lacerations / abrasions)
 Toxin-mediated neuromuscular blockade
o Tetanoplasmin & tetanolysin → retrograde axonal transport
 system that lacks protective enteric
microbiota; therefore spores are
able to colonize GI tract and produce
toxin in situ
o This neurotoxin inhibits presynaptic
ACh release at NMJ (motor synapse),
thus causing dysfunction of skeletal
and smooth muscles; N.B. therefore
sensory abnormalities are rare
 Sources
o Infantile botulism – Improperly
canned foods (e.g. fruits, vegetables)
or honey, as well as environmental
dust / soil, particularly in rural or
farm areas where the soil is
frequently disturbed
o Aged seafood (e.g. cured fish)
o C. botulinum spores contaminate
puncture wound (e..g IV drug use),
germinate in anaerobic
environment, and generate
botulinum toxin in vivo
Clinical  Acute onset within 36 hours ingestion:
Features  Prodromal symptoms include GI
discomfort (constipation & poor
feeding), dry mouth, sore throat
 Bilateral cranial neuropathies
(oculobublar palsies)
o CN III, IV & IV – Blurred vision,
diplopia, ptosis, mydriasis
o CN VII – Facial weakness
o CN IX & X – dysarthria, dysphagia,
poor suck, absent gag reflex
 Symmetric descending muscle
weakness or paresis (Symmetric
hypotonia), diminished DTRS,
decreased strength
 Areflexia, Diaphragmatic weakness
with respiratory failure
 Autonomic dysfunction (e.g. ileus,
orthostatic hypotension, urinary
retention)
 In contrast to infant botulism, wound
botulism is often associated with fever
and leukocytosis, and generally
presents ~ 10 days (rather than hours)
after transmission
Complications
Investigations  Clinical Diagnosis
 Confirmation by stool C. botulinum or
toxins
o Serum analysis for toxin
o Isolation of C. Botulinum in culture
Management  Equine serum hepatavalent botulinum
antitoxin
 Intravenous Botulism immune globulin
to CNS
o Exocytosis proteins (i.e. synaptobrevin, a SNARE protein)
cleaved, inhibiting release of inhibitory neurotransmitters
GABA, & glycine from Renshaw cells across the synaptic cleft
→ uninhibited activation of alpha motor neurons → muscle
spasms, rigidity, autonomic instability
Groups at higher risk
o Non-immunized individuals
o Diabetes
o Neonates
o IV drug abusers
o Certain patient groups (i.e. post-surgical, obstetric, dental)
 IP 3 – 21 days (average ~ 10 days)
o Symptoms occur a few days to several weeks following
inoculation
 Generalized tetanus – painful muscle spasms and rigidity
o Trismus
o Risus Sardonicus – grinning caused by cramps of facial
muscles
o Neck stiffness
o Opisthotonus
o Abdominal rigidity
o Life-threatening complications
 Laryngospasm, respiratory muscle spasm → respiratory
failure
 Autonomic dysfunction → labile blood pressure,
tachycardia, diaphoresis → circulatory arrest and shock
 Dysphagia
 Neonatal Tetanus – occurs in infants of unimmunized mothers
after unsterile management of umbilical stump
o Typically 5 – 8 days after birth (axonal length in infants are
shorter than in adults)
o Difficulty opening the mouth and feeding due to trismus and
risus sardonicus
o Muscle stiffness & opisthotonus
o Clenched hands
 Clinical diagnosis
 Debridement of infected wound
 Antibiotics – Metronidazole (1st line), Penicillin G (alternative)
 Active and passive immunization
 (BIG–IV)
 Supportive care – respiratory support,
laxatives for constipations, NG feeds
for poor suck
o Infants often require
hospitalization for a few months,
however a full recovery is
expected with BIG–IV
 Wound debridement for wound
botulinism
Prevention   Vaccination schedule
 Prophylaxis after injury
o IM Tetanus Immunoglobulin + Tetanus toxiodi (Tdap, DT, Td,
DTap depending on age, previous immunity, allergies
o Children < 7 years old
 DTaP (diphtheria toxoid, tetanus toxoid, acellular
pertussis [conjugated pertussis antigen, pertactin])
 DT – if unable to tolerate pertussis vaccine
o Adolescents & Adults
 Tdap if 11 – 64 years old
 Td > 11 years
o Initial immunization recommendations:
 Children < 7 years old → 5 doses of DTaP (2,4, & 6
months, 15–18 month, 4–6 years)
o Contraindications to vaccine
 Unstable neurologic disorders (e.g. infantile spasms,
uncontrolled epilepsy), and Encephalopathy (i.e. coma,
decreased level of consciousness, prolonged seizures)
after previous dose
 Anaphylaxis to vaccine component
o Booster recommendations
 Children 11 – 12 years of age: single dose of Tdap
 Adults 19 – 64 year of age: single dose of Tdap
 Adults ≥ 19 years of age: Td every 10 years
o If Unknown Vaccination history or < 3 tetanus toxoid doses:
 Tetanus toxoid (Td or Tdap; active immunization) for
clean, minor wounds
 Tetanus toxoid + Tetanus immunoglobulin for all other
wounds (dirty, contaminated)
o If ≥ 3 tetanus toxoid doses, Tetanus toxoid with Td or Tdap
indicated if:
 last immunization ≥ 10 years & clean, minor wound
 last immunization ≥ 5 years & wound is dirty or
contaminated

 Sleep Tremors
o Form of parasomnia during non-rapid eye movement (NREM) sleep
o Most commonly seen children age 2 – 12 (peak incidence 5 – 7)
o Clinical Features
 Abrupt arousals from sleep (panicked scream, terror, autonomic arousal, unresponsive to
comfort)
 Flushed face, tachycardia, diaphoresis
 Child inconsolable during period and cannot be fully awakened
 Little or no dream recall
 Amnesia for episodes
o Management
 Reassurance; Usually resolve within 1 – 2 years
  Low-dose BZDs at bedtime if episodes are frequent, persistent & distressing, and interfere with
daytime functioning
 Autism Spectrum Disorder
o Clinical Features
 Deficits in social communication& interactions with onset in early development
 Sharing emotions or interests
 Non-verbal communication
 Developing & understanding principles
o Lack of interest in shared social play and impaired joint attention (e.g. lack of
pointing or bringing objects to others)
 Restricted, repetitive patterns of behaviour
 Repetitive stereotypical movements or speech (e.g. head banging)
 Insistence on sameness/routines (e.g. lining up toys, distress over small changes)
 Intense fixated interests
 Adverse responses to sensory input
 May occur with or without language & intellectual impairment (range from complete lack of
speech to language delays and odd, stilted speech)
o Assessment and management principles
 Early diagnosis & intervention
 Comprehensive, multimodal treatment (speech, behavioural therapy, educational services)
 Adjunctive pharmacotherapy for psychiatric comorbidities
 Hereditary angioedema
o Autosomal dominant
o Pathophysiology
 C1 inhibitor deficiency / dysfunction
 Excessive bradykinin
o Clinical Features
 Recurrent edema / Swelling (e.g. face, extremities, genitalia) without urticaria
 c.f. IgE mediated type I HSR, as seen with anaphylaxis which has associated pruritus and
urticaria
 Usually after a dental procedure, periods of stress, or trauma
 Laryngeal edema → laryngospasm & airway obstruction
 Bowel wall edema – Colicky abdominal pain, vomiting, diarrhea
o Diagnosis
 Low C4 level (due to exaggerated cleavage of C4 by C1 complex)
 Low C1 inhibitor protein or function
o Management
 C1 inhibitor concentrate
 A bradykinin antagonist (e.g. icatibant) or kallikrein inhibitor (e.g. ecallantide) may be effective in
resistant cases
Congenital Immunodeficiencies
Disease Etiology & Pathophysiology
 Aside N.B. Decreased B cells associated with:
o Bacteria – Encapsulated (Please SHINE my SKiS): Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus Influenzae type b, Neisseria meningitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae,
Group B Streptococcus
 Bordetella pertussis (whooping cough; perihilar infiltrates on CXR) can cause severe illness in vaccinated patients with B – cell disorders (impaired humoral immunity) due to decreased responsiveness
o Viruses – Enteroviral encephalitis, poliovirus (live vaccine contraindicated)
o Fungi / Parasites – GI giardiasis (no IgA)
X–linked (Bruton) Defect in BTK, bruton
Agammaglobulinemia tyrosine kinase gene
expressed in B cells → no
B–cell maturation
Selective IgA Unknown
Deficiency Most common congenital
immunodeficiency
Common Variable Defect in B-cell
Immunodeficiency differentiation.
Cause unknown in most
cases
Phenotypically normal B
cells are unable to
differentiate into plasma
cells → low
immunoglobulins of all
classes
Inheritance Clinical Features Diagnostic Findings Treatment
B–cell Disorders
X–linked Recurrent severe pyogenic infections (bacterial Absent or ↓ B cells (CD19+) in  IVIG (long–term therapy)
recessive ( and enteroviral), especially encapsulated peripheral blood  Prophylactic antibiotics
↑ in Boys) organisms after 6 months (↓ maternal IgG in ↓ immunoglobulins (Ig) of all  N.B. other vaccines (i.e. not live vaccines) are not
fetal serum) classes contraindicated but are incapable of generating a
Hypoplasia of lymphoid tissue and tonsils (1°  Normal T–cell count meaningful antibody response in patients with XLA
follicles and germinal centers absent) → live
vaccines contraindicated
 Often Asymptomatic  ↓ IgA  Treatment of infections
May manifest with respiratory infections, and/or  normal IgG, IgM levels  Prophylactic antibiotics
chronic diarrhea  Normal B cell count  IV infusion of IgA is not recommended because of the
Anaphylactic reaction to blood products  Increased susceptibility to risk of anaphylactic reactions (caused by the production
containing IgA (such as pRBCs, platelets, FFP) – giardiasis of anti–IgA antibodies)
can form IgE antibodies against IgA = anti-IgA  Can cause false–positive β-  Blood products should be washed of residual plasma or
antibodies) hCG test from an IgA–deficient donor
Increased risk of Autoimmune disease (e.g.
gluten–sensitive enteropathy [celiac disease],
IBD) & Atopy (eczema)
 May present in childhood but usually diagnosed  ↓ plasma cells  IVIG (long-term therapy)
after puberty, more commonly in adulthood  ↓ immunoglobulins (low  Tx of infections
(age 20-40); IgG, and either IgA, IgM or  Prophylactic antibiotics
o Onset later than other B-cell defects (usually both)  Poor response to vaccinations
20–35 years)  Normal B- & T-cell count
o Recurrent sinopulmonary infections,  Poor response to
frequently Streptococcus pneumoniae, & immunization
Haemophilus influenzae; brochiectasis
o GI disorders
 Recurrent GI infections (e.g. Salmonella,
Campylobacter, Giardia lamblia)
 Chronic diarrhea, IBD–like conditions
o If T-cell immunity is also affected, increased
risk of enteroviral encephalitis
o ↑ risk of lymphoma, autoimmune disorders
(RA, thyroid disease), & chronic lung disease

 Aside N.B. Decreased T cells (cell – mediated immune system disorders) associated with:
o Bacteria – Sepsis
o Viruses – CMV, EBV, JC virus, VZV, chronic infection with respiratory/GI viruses (e.g. opportunistic pneumocystis jiroveci)
o Fungi / Parasites – Candida (local), PCP, Cryptococcus
 Most are associated with a low leukocyte count and lymphocyte count
Thymic Aplasia Microdeletion at 22q11.2
Defective development of
3rd & 4th pharyngeal
pouches → Hypoplastic or
absent thymus and
parathyroids & subsequent
abnormalities of the face,
neck and mediastinum
DIGEORGE SYNDROME—
triad of thymic,
parathyroid, conotruncal
cardiac defects
Velocardiofacial syndrome
— palate, facial, cardiac
defects
IL–12 Receptor Decreased IL–12 →
Deficiency impaired Th1 response →
no release of IFN-γ
Autosomal dominant Deficiency in Th17 cells due 
Hyper–IgE syndrome to STAT3 mutation →
(Job Syndrome) defective neutrophil /
macrophage chemotaxis
(e.g. asthma, bronchiectasis)
T–cell Disorders
 Variable phenotype Detection of 22q11.2 deletion Immune deficiency treatment
CATCH–22 Mnemonic for DiGeorge Syndrome via FISH Antibiotics, virostatics, and antimycotics
oConotruncal Cardiac anomalies (TOF, ↓ PTH & Ca2+ (tetany) PCP prophylaxis
persistent truncus arteriosus, interrupted ↓ Absolute T cells Consider bone marrow transplant and/or IVIG
aortic arch, septal defects less commonly) (lymphopenia) Possible thymus transplantation
oAnomalous face Rarely thrombocytopenia
 Hypertelorism, micrognathia, short philtrum CXR: absence of thymic
oThymic aplasia/hypoplasia (T–cell deficiency) shadow
 Consequent defective cellular immunity (T- Skin testing: delayed
cell deficiency) leads to recurrent infections hypersensitivity
(viral/fungal/PCP pneumonia)
 Increased susceptibility to sinopulmonary
bacterial infections as well
 Lack of T-cell dependent immunity leads to
lack of Type IV HSR
 Unable to develop significantly elevated
levels of IgE since IgE isotype-switching
depends on TH2 cytokines
oCleft palate & facial dysmorphisms (e.g. low-
set ears, micrognathia, bulbous nose)
oHypocalcemia / Hypoparathyroidism→
tetany, seizures, arrhythmias
 due to absence of parathyroid glands
oAffected chromosome 22
AR Onset varies but usually 1 – 3 years ↓ IFN-γ Antibiotics and IFN-γ therapy
Disseminated mycobacterial & fungal infections;
o may present after BCG vaccine administered
Most common cause of Mendelian susceptibility
to mycobacterial diseases (MSMD)
Remember the acronym FATED ↑ IgE Antibiotics & prophylaxis (with penicillinase–resistant
o Facies: coarse facial features; fractures from ↑ eosinophils antibiotics)
minor trauma IV immunoglobulin therapy
o Abscesses: cold, non–inflamed staphylococcal
abscesses
o Teeth: retained primary/ baby teeth

Chronic Several congenital defects
Mucocutaneous (e.g., AIRE protein
candidiasis deficiency) → T–cell
dysfunction → impaired or
absent cell–mediated
immunity against Candida
sp
IL–17 defects
IPEX syndrome FOXP3 mutation →
(Immune impaired regulatory T cells
dysregulation, → autoimmunity
Polyendocrinopathy,
Enteropathy, X-linked)
Severe Combined RAG mutation → V(D)J
Immunodeficiency – recombination defect
SCID Gene defect leading to
(“Bubble Boy Disease” failure of T–cell
– confinement to development
sterile environment) B–cell dysfunction due to
loss of helper T cells
function
Ataxia–Telangiectasia Defects in ATM gene →
failure to detect & repair
dsDNA breaks/damage →
failure to halt progression
of cell cycle → mutations
accumulate
Chromosomal breakage
syndrome – associated
o Hyper–IgE (eosinophilia)
o Dermatologic: severe eczema
 Persistent non–invasive Candida albicans Absent in vitro T-cell Antifungal therapy
infections of skin and mucous membranes proliferation in response to Treatment of associated conditions
Candida antigens
Absent cutaneous reaction to
Candida antigens
XLR Onset: early infancy Genetic testing: FOXP3 Nutritional support
Lymphadenopathy, chronic lymphoid tissue mutations Immunosuppression: tacrolimus, cyclosporine, or sirolimus
hypertrophy Low or absent CD4+CD25+ Rituximab
Eczema, Dermatitis, or other autoimmune regulatory T cells Bone marrow transplant
dermatologic conditions. Otherwise normal T-cell
Nail dystrophy populations
Autoimmune endocrinopathy (e.g., T1DM
particularly in male infants)
Chronic diarrhea
Failure to thrive (FTT)
B– & T–cell disorders
(Combined Impaired humoral immunity & Cell – mediated immune system disorders)
 XLR (most  Recurrent, severe viral, fungal (e.g. Candida  Quantitative PCR: ↓ T–cell  Bone marrow or Stem cell transplantation (definitive)
common; [thrush]) protozoal, or opportunistic (i.e. receptor excision circles  Short term management – IVIG, broad–spectrum
defective Pneumocystis jirovecii) infections (TRECs) antibiotics
IL–2R o Recurrent sinopulmonary bacterial infections  CXR – absent thymic shadow  PCP prophylaxis
gamma (e.g. pneumonia, otitis media)  Lymph Node Bx: absent  N.B. Live attenuated vaccines are contraindicated; can
chain)  Failure to Thrive (FTT) germinal centers be fatal; inactivated vaccines are not contraindicated but
 AR –  Chronic diarrhea in infancy  Flow cytometry: will not result in protective immunity due to poor
adenosine  Lymphopenia (low, dysfunctional CD19+ [B cell]; oAbsent T cells (X-linked humoral response
deaminas absent CD3+ [T cell] ) variant);
e  Fatal if untreated oabsent T cells, B cells, and
deficiency NK cells (AR variant)
(ADA)
AR Onset: early childhood MRI: cerebellar (vermis) Rehabilitation for ataxia
Gene Classic triad of 3 As atrophy For recurrent infections
defect on o Progressive Ataxia due to cerebellar atrophy ↑ AFP levels o IVIG
chr 11 o Spider Angiomas & facial telangiectasias ↓ IgA, IgG, and IgE o Antibiotics
o IgA deficiency Lymphopenia
Ocular and cutaneous telangiectasias
o Observed as capillary distortions in conjunctiva
Susceptibility to infections (e.g., ear infections,
 with increased numbers of
translocations, especially
involving the T–cell
receptor loci
Hyper–IgM Syndrome Most commonly due to XLR
defective CD40L on T-
helper cells → class
switching defect (inability
of B cell to switch from
production of IgM to other
classes of antibodies)
Wiskott–Aldrich Mutated WAS protein XLR
Syndrome (WASp) gene → leukocytes
& platelets unable to
reorganize actin
cytoskeleton → defective
antigen presentation →
impaired function of T cells
 “Some Bacteria Produce No Serious granules”: Staphylococcus, Burkholderia cepacia, Pseudomonas aeruginosa, Nocardia, Serratia
 Fungi / parasites – Candida (systemic), Aspergillus, Mucor
Leukocyte Adhesion Absence of the ß2–integrin AR
Deficiency (Type 1) leukocyte adhesion surface
molecule LFA-1 (CD18) →
Leukocytes are unable to
migrate into tissues during
infection or inflammation.
Chediak–Higashi Defect in neutrophil
Syndrome chemotaxis & microtubule
polymerization dysfunction
→ defective phagosome–
lysosome fusion
Defect in lysosomal
trafficking regulator gene
(LYST)
Chronic Defective phagocytic
granulomatous NADPH oxidase
disease Defective ROS production
by neutrophils &
sinusitis, pneumonia)
Increased incidence of malignancy (e.g.,
lymphoma and leukemia)
Increased sensitivity to radiation
Severe pyogenic, sinopulmonary (e.g. acute OM, Normal or ↑ IgM IV immunoglobulin therapy – interval administration
pneumonia, sinusitis) infections early in life; ↓ ↓ IgG, IgA, IgE Prophylactic antibiotics
Commonly opportunistic infections Normal T & B cell counts Recombinant human G-CSF
(Pneumocystis jirovecii, Cryptosporidium, Lymph Node Bx: absent Stem cell transplantation may be curative.
Histoplasma, CMV) germinal centers
 Failure to Thrive (FTT)
Triad ↓ to normal IgG, IgM IV immunoglobulin therapy
o Thrombocytopenia (bleeding diathesis e.g. ↑ IgE, IgA Prophylactic antibiotics
petechiae) Thrombocytopenia with Platelet transfusions
o Eczema smaller platelets Hematopoietic stem cell transplantation may be curative.
o Recurrent pyogenic infections (with
encapsulated organisms)
 Increased risk of autoimmune disease and
haematologic malignancies
Neutrophil & Phagocyte Dysfunction
Recurrent non–suppurative bacterial skin & Leukocytosis with marked Prevention of further infections (e.g., adequate dental
mucosal infections, impaired wound healing neutrophilia; however, hygiene)
o Wounds with minimal inflammation & no pus neutrophils are absent at the Treatment of infections
o Dysfunctional neutrophils, absent pus site of infection! → impaired Bone marrow transplant
Omphalitis (infection of umbilicus) wound healing
Severe periodontitis Flow cytometry: absent CD18,
Delayed separation of umbilical cord (> 2 weeks CD11a, CD11b, & CD11c
postpartum)
AR Recurrent pyogenic infections Peripheral smear: giant Bone marrow transplant
o May be extensive if massive infiltration occurs cytoplasmic granules in
o Pathogens include Strep. pyogenes, S. aureus, granulocytes and platelets
and Pseudomonas spp. Mild coagulation
Partial oculocutaneous albinism abnormalities
Progressive peripheral neuropathy Neutropenia, pancytopenia
Hemophagocytic lymphohistiocytosis (can occur
in the accelerated phase and is potentially fatal)
XLR (most ↑ susceptibility & recurrent severe pulmonary Neutrophil function testing: Treatment of infections
common) (pneumonia, empyema) and skin & soft tissue Abnormal dihydrorhodamine Life–long prophylactic antibiotics, e.g., TMP-SMX &
AR infections with catalase ⊕ bacterial & fungal 123 test (DHR; flow itraconazole – for catalase–positive infections
infections – cytometry) test: ↓ green Glucocorticoids for severe inflammation
 macrophages o Staphylococcus aureus fluorescence IFN–γ therapy (for patients with severe phenotypes)
↓ respiratory burst o Serratia marcescens Negative nitroblue Bone marrow transplant
(formation of superoxide o Burkholderia cepacian complex tetrazolium dye reduction Possibly gene therapy
radicals, H2O2) in o Pseudomonas aeruginosa test (obsolete; fails to turn
neutrophils → impairs o Aspergillus (most common fungal) blue)
intracellular killing of o Nocardia spp. Genotyping is confirmatory
phagocytosed bacteria and o Candida
fungi → recurrent o Enterobacter Normal Ig
infections Anemia & lymphadenopathy
Possible skin granulomas
Other common infections: Suppurative adenitis,
osteomyelitis, liver abscesses
Appropriate increase in peripheral leukocytes
(e.g. no leukopenia)
Myeloperoxidase Mutation in MPO gene → AR Often asymptomatic Positive nitroblue tetrazolium No specific treatment or prophylaxis
Deficiency partial or complete Recurrent candida infections (e.g. oral thrush, test (intact NADPH oxidase) Treatment of fungal infections
deficiency of MPO in vulvovaginal candidiasis) Absent MPO on staining
phagocytes, thus unable to Genetic analysis: MPO gene
form hypochlorous acid mutation
Respiratory burst preserved
(since NADPH oxidase is
intact)

Viral Exanthems
Erythema Infectiosum – Fifth Roseola Infantum (Exanthema
Measles Virus (Rubeola) – First Disease Scarlet Fever – 2nd disease Rubella (German “3-day” Measles)
Disease Subitum) – Sixth Disease
Transmission Airborne transmission Group A β–hemolytic streptococci direct or airborne droplet contact Parvovirus B19 HHV–6 (& HHV–7)
IP ~ 2 weeks after infection (e.g. Streptococcus pyogenes, or from nasopharyngeal secretions Contact with respiratory tract Mode of transmission
Either inhalation or via direct contact of respiratory GAS) produce erythrogenic scarlet transplacental secretions unknown (possibly from
particles with a mucosal surface (e.g. mouth, eyes) fever exotoxins (A, B, or C) – < 10%
Infectivity: 7 days prior to and 7 days Percutaneous exposure to blood nasopharyngeal secretions)
Pathogen: Morbillivirus = RNA virus of the of streptococcal tonsillopharyngitis following the appearance of an or blood products IP: 5 – 15 days
Paramyxoviridae family Previous infection does not rule out exanthem Vertical transmission from Children 6 months – 4 years
additional episodes of the disease,IP: 2–3 weeks after infection mother to fetus Most common exanthem
as there are several different types
Pathogen IP: 1–2 weeks before age 2
of exotoxins o Rubella virus, RNA virus of the Most infectious before onset of No vaccine; infection results in
Delayed–type HSR to Erythrogenic family Togaviridae the rash immunity
Toxin A o Humans are the only hosts
Transmission: aerosol
IP: 1 – 7 days
Clinical Symptoms manifest 1–3 weeks after inhalation of Initial phase – acute tonsillitis Rash & Fever concurrent Children 4–10 yrs old, but can Prodrome (Febrile phase):
Presentation infectious respiratory particles, which can remain o Fever Malaise, headache, chills, Children
airborne for hours within a closed space (e.g. and myalgias
airplane, clinic waiting room) o Tonsillopharyngitis
High fever (> 40 OC [104 OF]), Malaise  Sore throat and dysphagia
o Rash & fever concurrent  Tonsillar exudates & posterior
Prodrome – fever + ‘4 Cs’ (cough, coryza, pharyngeal erythema
conjunctivitis, Koplik spots)  Palatal petechiae, circumoral
o Most contagious during prodromal phase but pallor
may spread disease for several days after  Strawberry tongue with white
resolution of rash coating
o Coryza: “head cold” with nasal congestion,  Anterior cervical
rhinorrhea, sore throat lymphadenopathy
o Koplik spots (pathognomonic but not always  ± Associated nausea &
present) – small white lesions on buccal mucosa vomiting in children
opposite the molars  Exanthem phase (12 – 48 hours
Maculopapular exanthem (diffuse morbilliform after fever onset; 7 days duration):
rash) o Scarlet–colored maculopapular
o Cephalocaudal & centrifugal spread exanthem (rash) – Fine,
o Spares palms & soles erythematous, sandpaper–like
o Subsequently coalesces and appears texture, most prominent within
haemorrhagic (dark, reddish–brown) and non– skinfolds (e.g. axilla, groin),
blanching spares palms & soles
o Lasts ~ 1 week and patients’ other symptoms  Blanches with pressure
improve as rash resolves o Non–blanching petechiae are
 Recovery: Clinical improvement begins within 2 often additionally present
days of appearance of the rash. The rash tends to o ± Pruritus
fade after 3–4 days and will last around 6–7 days o Pastia's lines: linear, petechial
appearance; most pronounced in
the groin, underarm, and elbow
creases (i.e., flexural areas)
o Location – Starts at Neck →
disseminates to trunk and
extremities within 24 hours
o As illness resolves,
desquamation of rash results in
peeling of the hands & feet
affect all ages o Abrupt–onset High fever
o Prodrome (1–5 days) – Low- Non–specific Prodrome: low– (39-40°C)
grade fever, headache, sore grade fever, malaise, headache, o Palpebral (eyelid) edema &
throat, conjunctivitis, pruritus, coryza, myalgias, joint conjunctivitis
rhinorrhea, cough, localized pain (more common in adult o Cervical, posterior
lymphadenopathy (posterior women) auricular, &/or occipital
cervical, posterior auricular, and Exanthem: Confluent, lymphadenopathy
suboccipital & occasional erythematous, edematous Mild upper respiratory
splenomegaly) plaques on the malar symptoms (pharyngitis,
o Maculopapular Exanthem (2 – 3 eminences - “slapped cheeks” cough etc.)
days) – Cephalocaudal spread (facial flushing usually sparing o Inflamed tympanic
within 24 hours of onset of rash nasolabial fold); Erythematous membranes
(blanching, fine, pink, non– reticular eruption (lacy, o Vomiting &/or diarrhea
confluent, sparing palms & reticular rash) on the trunk and o Nagayama spots: papular
soles); does not darken like extremities, sparing palms & enanthem on the uvula
measles soles; usually lasts 5–9 days and soft palate
 Appearance of rash typically Papular Purpuric Gloves and o Child appears well. As
14–17 days after exposure Socks Syndrome – painful and fever subsides,
o Enanthem (20%): petechial or pruritic papules, petechiae, and maculopapular exanthem
erythematous papules on soft purpura of hands and feet, appears (“exanthema
palate & uvula (Forchheimer's often with fever and enanthem subitum” means “sudden
sign) (oral erosions). rash”)
Adolescents / Adults o Unlike the typical rash of Exanthem (1–3 days) after
o Same as children + arthralgia or Erythema Infectiosum, fever subsides: non–pruritic,
arthritis (particularly females) patients with this patchy, pink macules and
o Most symptoms resolve in a few presentation are viremic and papules surrounded by white
days, however joint pain can last contagious halos. Begins on trunk,
up to a month spreads to neck and proximal
extremities.
Complications Groups at increased risk for complications of
measles include immunocompromised hosts,
pregnant women, malnourished individuals, and
persons at extremes of age
Most common complications include otitis media,
pneumonia, laryngotracheobronchitis (croup), and
diarrhea. Hepatitis, thrombocytopenia, and
encephalitis occur less commonly.
o Pneumonia is the most common fatal
complication of measles in children and the most o Sinusitis
common complication overall in adults.
o Subacute sclerosing encephalitis – progresses
from personality changes to dementia, and
death over months to years
Diagnosis Serology: Measles Anti–IgM & IgG antibodies
Isolation of measles virus or identification of
measles RNA
Histologic evaluation of skin lesions or respiratory
secretions ± syncytial keratinocytic giant cells
Non–suppurative
o Poststreptococcal
glomerulonephritis
o Acute rheumatic fever (rare)
Suppurative (i.e., pus–forming)
o Cervical lymphadenitis
o Retropharyngeal or peritonsillar
abscess
o Otitis media
o Mastoiditis
Primarily a clinical diagnosis that
should be confirmed with
additional testing
Pathogen detection
Throat culture
Rapid streptococcal antigen
detection testing (rapid strep test)
Leukocytosis with a left shift;
possibly eosinophilia over the
course of disease
↑ ASO & anti–DNAase B (anti-
streptolysin O &
anti-deoxyribonuclease B titers
Thrombocytopenic purpura
Congenital Rubella Syndrome
o T1 – miscarriage, stillbirth
o Sensorineural hearing loss
o Mental Retardation
o Cataracts (cloudy cornea)
o Patent Ductus Arteriosus
(congenital heart disease)
Rare:
o Rubella encephalitis
o peripheral neuritis
o optic neuritis
o myocarditis
o pericarditis
o hepatitis
o orchitis
o bronchitis
o Haemolytic anemia
Serology – rubella–specific IgM
antibody or ≥ 4-fold rise in IgG titer
in acute and convalescent–phase
serum
Leukocytopenia with relative
lymphocytosis & increased plasma
cells
Transient aplastic crisis (pure HHV-6 is known to cause
red cell aplasia) in patients febrile seizure in children with
with chronic hemolytic infection, often without a rash
anemias (e.g. HbSS, G6PD) Febrile seizures (in up to 15%
 Parvovirus B19 can also cause of cases), usually without
arthritis in adults sequelae
If immunodeficient, chronic Meningoencephalitis (very
erythroid hypoplasia (pure red rare)
cell aplasia) with severe anemia
o ↓ Reticulocytes (0–1%)
o ↓ Hb below patient's baseline
by ≥ 2 g/dL (aplastic crisis) or
(< 8 g/dL) (severe anemia as
in pure red cell aplasia)
Pregnancy (TORCH infection) –
hydrops fetalis*, IUGR, pleural
& pericardial effusions, death
Hepatitis, myocarditis, and
aseptic meningitis/encephalitis
(rare)
Detection of serum parvovirus Clinical diagnosis
B19–specific IgM antibody;
o Positive IgM test → infection
likely occurred within the last
2–4 months
Prevention Live–attenuated measles vaccine
o 2 doses @ age 1 & 4 (generates immunity >
95% of vaccinated patients)
o For international travel, an additional dose
between age 6 – 11
Isolate known or suspected cases with airborne
precautions (negative pressure room, N95 face
mask for health care personnel)
Patients who are immunocompromised or
pregnant, at extremes of age (e.g. infants or the
elderly), or who are vitamin A deficient are at
greater risk of complications such as pneumonia,
encephalitis, or blindness
Treatment Supportive – antipyretics, fluids and rest
Vitamin A supplementation for hospitalized
patients
o Promotes antibody–producing cells and
regeneration of epithelial cells (e.g. in the
gut, lungs and retina)
o Vitamin A deficiency is associated with
increased morbidity with measles infection;
plays no role in measles prevention
 Malnutrition, immunosuppression, poor health,
and inadequate supportive care can worsen the
prognosis in any patient.
All cases of scarlet fever should be
treated with antibiotics, both to
prevent complications and to
prevent transmission
Drug of choice: oral penicillin V (or Symptomatic treatment
other penicillin e.g. amoxicillin)
Alternative antibiotics:
o Macrolides e.g. erythromycin (if
penicillin allergy)
o Cephalosporins (if recurrence
due to antibiotic resistance)
After 24 hours of antibiotic
treatment, the patient is no longer
infectious and may return to day
care or school!
Live attenuated rubella vaccine  
Droplet precautions & exclusion from
school or child care for seven days
after the onset of the rash
not necessary in most cases; Acetaminophen (lowers risk of
o Severe pruritis: antihistamines disease is often self–limiting (5– further febrile seizures)
o Severe polyarthritis: rest & 10 days) Very good prognosis; usually
NSAIDs Analgesics & NSAIDs benign and self–limiting
Short course of low–dose disease
prednisone for parvovirus B19– The virus persists lifelong in its
associated arthritis host →reactivation of latent
virus or reinfection may occur
later in life (especially if
individuals become
immunocompromised)

 In a susceptible child, a febrile maculopapular rash that begins on faces with cephalocaudal spread (i.e. spreads to trunk and extremities) is suggestive of rubeola (measles) or rubella (German
measles)
o Additional finding of Postauricular and occipital tender lymphadenopathy is suggestive of Rubella, which is caused by a togavirus
o Rubeola is a paramyxovirus
 Mumps
o Epidemiology
 sex: ♂ = ♀ for parotitis (however, males are three times more likely to have CNS complications)
 Peak incidence: 5–14 years of age
 Incubation period: 16–18 days
 Affected individuals are contagious ∼ 3 days before and up to 9 days after disease onset (when the parotid gland becomes swollen).
o Transmission
 Airborne droplets
 Direct contact with contaminated saliva or respiratory secretions
 Contaminated fomites
o Clinical Features
  Asymptomatic course in ∼ 20% of cases
 Nonspecific or predominantly respiratory symptoms in ∼ 50% of cases
 Prodrome:
 Duration: 3–4 days
 Low-grade fever, malaise, headache
 Classic course (in ∼ 30% of cases):
 inflammation of the salivary glands, particularly parotitis for ≥ 2 days (may persist > 10 days)
 May initially present with local tenderness, pain, and earache
 Swelling on one side is initially observed → progresses to bilateral salivary gland enlargement
o Possible redness in the area of the parotid duct and protruding ears
 Usually self-limiting with a good prognosis (unless complications arise)
o Chronic courses are rare
o Complications:
 Orchitis (< 10% of cases; most common complication in post-pubertal males)
 Primarily unilateral, although bilateral in ∼ 15% of cases
 Sudden onset of fever, nausea, vomiting
 swollen and tender affected testicle(s)
 May lead to atrophy and, in rare cases, infertility
 Aseptic meningitis (1–10% of cases): predominantly mild course; usually no permanent sequelae
 Encephalitis (< 1% of cases)
 Reduced consciousness, seizures
 Neurological deficits: cranial nerve palsy, hemiplegia, sensorineural hearing loss (rare)
 Acute pancreatitis (< 1% of cases)
 Vomiting, nausea, upper abdominal pain
 ↑ Lipase, ↑ amylase
 Diabetes mellitus type I (delayed complication)
o Investigations
 Positive serology confirms the diagnosis: IgG and/or IgM
 Relative lymphocytosis
 ↑ CRP, ↑ ESR ↑ amylase
o Prevention
 Primary immunization: a live vaccine in combination with measles and rubella vaccine (i.e., MMR) and, if necessary, varicella (MMRV)
 Via two doses: first dose at 12–15 months, second dose at 4–6 years
 Isolate infected patients (up to 5 days after onset of symptoms); mumps is a class 1 notifiable / reportable disease
o Treatment
 Symptomatic therapy
 Antipyretic and analgesia (e.g., acetaminophen)
 Bedrest
 Adequate fluid intake
  Avoidance of acidic foods and drinks
 Ice packs to soothe parotitis
 Isolation and post–exposure prophylaxis (as above)
LYSOSOMAL STORAGE DISORDERS
Sphingolipodoses Mucopolysaccharidoses
Metachromatic Hunter
Disease Neimann–Pick Tay–Sachs Fabry Krabbe Gaucher Hurler Syndrome
leukodystrophy Syndrome
 Sphingomyelinase  β –hexosaminaidase A  α –Galactosidase A  Arylsulfatase A  Galactocerebrosidase  Glucocerebrosidase ( β –  α –L–iduronidase  Iduronate-
deficiency deficiency (galactoslyceramidase) glucosidase) deficiency 2-sulfatase
Pathology /
 Type A (severe), B & C → Glucocerebrosidase
Deficient
are milder accumulation in
enzyme
macrophages of
different tissues
Inheritance Autosomal Recessive XR Autosomal Recessive XR
 Ashkenazi Jewish heritage     Increased prevalence in  
Ashkenazi Jews
Epidemiology  Most common
lysomomal storage
disease
 Age 2 – 6 months     Type 1 GD most  
common form
 Due to varying degrees
Onset
of severity, any time
from early childhood to
late adulthood
 Loss of motor milestones (progressive  Early – triad of episodic  Central and  Manifest prior to age <  Severe Splenomegaly  Dystosis multiplex – a range of  Mild
neurodegeneration) peripheral neuropathy, peripheral 6 months (more prominent), skeletal findings including Hurler +
 Hypotonia angiokeratomas, & demyelination  Peripheral neuropathy hepatomegaly shortened & thickened long aggressive
 Feeding difficulties hypohidrosis with ataxia,  destruction of  BM infiltration → bones behavior
 Cherry-red macula  Late – progressive renal dementia oligodendrocytes Pancytopenia – anemia,  Developmental delay  No corneal
 Hepatosplenomegaly  Hepatosplenomegaly failure, cardiovascular  Developmental delay thrombocytopenia  Coarse facial features – clouding
 Areflexia absent disease  Optic atrophy  Low bone density Gargoylism, wide nasal bridge,
 Hyperreflexia  FABRY’C  Globoid cells (osteopenia, flat midface
o Foam cells / Febrile  Microcephaly osteoporosis)  Airway obstruction
episodes predisposes to  Corneal clouding
Clinical o Alpha galactosidase A pathologic fractures  Hepatosplenomegaly
Features deficiency /  AVN of femur  Frequent infections
Angiokeratomas  Bone crises / Bony pain
o Boys / Burning pain in at night (often
hands & feet misconstrued as
(“peripheral “growing pains”)
neuropathy”)  Failure to thrive &
o Renal Failure delayed puberty
o XY genotype (XR, male)  Gaucher cells (lipid–
o Ceramide trihexidose laden macrophages
accumulation / CVS resembling crumpled
disease tissue paper)
       Tx with recombinant  
glucocerebrosidase
(slows disease
Treatment
progression & prevent
complications such as
osteonecrosis)

GLYCOGEN STOARGE DISEASE

 Incidence: 1 per 20,000 live births  Muscle involvement (muscle GSD): Cardiac (Type II); Skeletal (Types III, IV, V)
 Age of onset: presentation during infancy or  Liver involvement (liver GSD): Types I, III, IV
childhood o Hypoglycemia (typically fasting hypoglycemia) and ketosis
 Sex: ♂ = ♀  Symptoms of hypoglycemia in infancy: seizures, hypotonia, poor feeding, cyanosis, irritability
 Mode of inheritance: mostly autosomal recessive o Hepatomegaly → distended abdomen
Type I (Von Gierke disease) Type II (Pompe Type IV (Andersen
Disease Type III (Cori disease) Type V (McArdle disease) Type VI (Hers disease)
Type 1a Type 1b disease) disease)
Relative
~ 25% ~15% ~25% ~3% ~2% ~30%
Frequency
 Glucose-6-  Glucose-6-  Lysosomal acid  Glycogen debranching enzyme  Glycogen  Muscle phosphorylase  Liver phosphorylase
phosphatase phosphatase maltase deficiency deficiency (performs 2 functions: α- branching (myophosphorylase) deficiency
deficiency translocase deficiency (Acid α –glucosidase, 1,6-glucosidase and 4-α-D- enzyme deficiency
Pathology  Impaired gluconeogenesis and aka alpha-maltase, glucanotransferase) deficiency
glycogenolysis deficiency)  Limit dextrin–like structures
accumulate in cytosol.
 Gluconeogenesis intact
 Presents at age 3 – 4 months  CARDIOMEGALY /  Generalized muscle weakness and/or  Proximal  ↑ glycogen in muscle, but  Hepatomegaly
 Severe fasting HYPOGLYCEMIA, mild CARDIOMYOPATHY cramps myopathy muscle cannot break it down
ketosis  HYPERTROPHIC  Hepatomegaly  Hepatomegaly → painful Muscle cramps
 Severe hyperlipidemia → doll-like faces CARDIOMYOPATHY  Possibly cirrhosis (ascites,  Possibly cirrhosis  Easy fatiguability, exercise
with rounded cheeks, xanthomas, AND/OR splenomegaly) (ascites, intolerance
pancreatitis CONDUCTION  Mild, fasting hypoglycemia and ketosis splenomegaly)  Rhabdomyolysis →
Clinical
 Hyperuricemia (gout) BLOCKS  Hyperlipidemia  FTT Myoglobinuria (red urine)
Features
 ↑ ↑ Glycogen in liver and kidneys  Hypotonia; proximal  FTT with strenuous exercise, and
 hepatomegaly, renomegaly myopathy  Similar to Von Gierke but milder arrhythmia from electrolyte
 thin extremities, short stature  macroglossia symptoms abnormalities.
 Liver does not regulate blood glucose  FTT  Second-wind phenomenon
 Failure to thrive (FTT)  exercise intolerance noted during exercise due to
 Early death ↑ muscular blood flow.
Investigations  Hypoglycemia  ECG,  Hypoglycemia  Genetic Testing  No elevation in lactate during  Fasting hypoglycemia
 Anemia Echocardiography  Hyperlipidemia forearm exercise test (no (mild) and ketosis
 Serum  ↑ CK  Ischemic forearm test: abnormal result longer recommended)  Hyperlipidemia
o ↑ lactate (Lactic acidosis), ↑ TGs  ↑ Lactic Acid (i.e. lactate levels do not increase) in o flat venous lactate curve  Genetic Testing
(Hyperlipedemia), ↑ uric acid (Gout)  Genetic Testing type III, V with normal rise in
  Genetic testing preferred over liver biopsy  ↑ creatine kinase ammonia levels during
(PAS+ glycogen storage granules)  alpha-1,6-glucosidase deficiency exercise
 Genetic Testing  Normoglycemia
 ↑ CK (> 1000 U/L)
 Muscle Biopsy – negative
staining for
myophosphorylase
 Genetic Testing
 frequent oral glucose/cornstarch;  Enzyme replacement  Symptomatic treatment   Sucrose before exercise may  dietary therapy (e.g., corn
 avoidance of fructose and galactose therapy  dietary therapy (e.g., corn starch, improve symptoms starch, glucose
Treatment o alglucosidase alfa glucose preparations) with the aim of preparations) with the aim
prevent hypoglycemia and/or muscle of prevent hypoglycemia
symptoms
 TORCH Infections – toxoplasmosis, Other (Parvovirus B19), Rubella, CMV, HSV
Clinical Findings of Congenital infections Transmission Diagnosis Treatment
All  IGUR 
 Jaundice, Hepatosplenomegaly
 Blueberry muffin spots

CMV  Most infected neonates are asymptomatic (90%)  Causative organism – HHV–5  Viral Cx – bodily fluids  Valganciclovir or Ganciclovir can improve hearing loss
(Cytomegalovirus)  USS findings (Human herpes virus 5) (urine, saliva) and neurodevelopmental outcomes; 6mg/kg per dose
o Periventricular intracranial calcifications,  Transplacental (Vertical)  PCR testing of bodily IV x 6/52
Most common ventriculomegaly  Perinatal (contact with vagina during fluids  Supportive Care
congenital infection – o Microcephaly in severe cases vaginal delivery or breast milk after  Maternal serology  N.B. Treatment is not recommended for
CMV infection common o IUGR (Fetal growth restriction) delivery)  Amniocentesis asymptomatic individuals with isolated sensorineural
in children age 1 – 4 o Hydrops fetalis (e.g. pleural effusion, ascites)  Pregnant women – Contact with hearing loss
(especially if attending o intrahepatic calcifications bodily fluids (urine/saliva)  Maternal antiviral therapy is not indicated as it has
daycare)  Neonatal features o Maternal infection can result in not been proven to prevent fetal infection
o Jaundice, Hepatosplenomegaly either a subclinical or mild, non– Prevention:
o Petechiae & purpura (blueberry muffin rash) specific febrile illness  Frequent hand washing
o Thrombocytopenia  Transmission is possible through  Pregnant women with risk factors for TORCH infection
o Chorioretinitis, Microcephaly reactivation of latent infection should avoid potentially contaminated workplaces
 Long–term Sequelae (decreased risk of transmission) (e.g., schools, pediatric clinics
o Seizures
o Sensorineural deafness (most common sequelae; 50% of
symptomatic & 15% of asymptomatic CMV infections)
o Developmental Delay
Toxoplasmosis  1st trimester – often results in death  Transplacental (Vertical)  Definitive – isolating  Pyrimethamine + Sulfadiazine + Leucovorin
 2nd trimester  Fecal–oral route organism from o Pyrimethamine 2mg/kg (max 50mg/dose) OD x 2
o Diffuse intracerebral (parenchymal) calcifications – ring–  Oocytes excreted in cat feces, either placenta, serum, or CSF days; then 1mg/kg (max 25 mg/dose) OD x6 months;
enhancing on MRI directly (e.g. kitty litter) or indirectly  PCR for T. gondii DNA then 1 mg/kg (max 25 mg/dose) Alt days x 1 year
o Hydrocephalus (e.g. unwashed, soil–contaminated  Serology – T. gondii o Sulfadiazine 50mg/kg BD x 1 year (i.e. 100mg/kg/day
o Non–specific signs of congenital infection fruits and vegetables) specific IgM antibody in 2 divided doses)
 Found in undercooked meat, titre (N.B. IgG will be o Leucovorin (folinic acid) 10mg 3x per week during
 Hepatosplenomegaly, jaundice
contaminated water/soil, and elevated if mother is and 1x per week after pyrimethamine therapy
 Petechiae and purpura (blueberry muffin rash)
 Intrauterine Growth restriction unpasteurized goat milk infected regardless of  ± Glucocorticoids (prednisone 0.5mg BD) if CSF protein >
transmission) 1 g/dL or active chorioretinitis threatening vision
 3rd trimester – often asymptomatic at birth  Risk of fetal infection increases with
 MRI – Ring–enhancing  Tx reduces parasite burden in CNS and can relieve
 Severe chorioretinitis in adulthood due to reactivation of gestational age
obstructive hydrocephalus
infection lesions
Prevention:
 Avoidance of uncooked meat
  Avoidance of handling cat feces
 Spiramycin: prevention of fetal toxoplasmosis in acute
maternal toxoplasmosis infection

Macular scar in congenital toxoplasmosis

Congenital Syphilis  Frequently asymptomatic at birth but become symptomatic  Causative Organisms – Treponema  Dark field microscopy Penicillin
at age 1 – 3 months pallidum  FTA–Abs  <1 month old
 Clear, purulent or serosanguinous rhinorrhea (‘snuffles’)  Transplacental  RPR or VDRL o Benzathine penicillin G 50,000U/kg IM x single dose
or
 Abnormal long–bone X–Ray (e.g. metaphyseal lucencies)  Sexual activity  PCR
o Aq Penicillin G 50,000U/kg q12hrly (infants ≤ 7 days
 Diffuse maculopapular rash that involves palms and soles;
old) & q8hrly (infants > 7 days old) or
may progress to desquamating or bullous rash o Procain penicillin G 50,000 U/kg IM OD x 10 days
 Anemia  Single dose therapy C/I for infants born to women with
 Thrombocytopenia (not seen in adult syphilis) suboptimal treatment unless the infant has undergone
 Placenta is typically enlarged with an edematous umbilical appropriate evaluation (CSF quantitative VDRL, cell count,
cord protein; long–bone radiographs) & has completely normal
 Late manifestations if untreated (onset > 2 years) results
o Frontal bossing  > 1 month old (including those with late congenital syphilis
o Rhagades (perioral fissures, cracks, &/or scars, & children with acquired syphilis)
o Aq Penicillin G 50,000 U/kg IV q4-6hrly x 10 days
particularly near the corners of the mouth and nose) Pemphigus syphiliticus on plantar o ± Benzathine penicillin 50,000 U/kg IM x1 dose
o Osteoarticular destruction leading to Hutchinson triad surface of feet Prevention – Tx of mother in early pregnancy with penicillin G
(Saddle nose, Hutchinson teeth, Mulberry Molars)
o Interstitial keratitis
o Sensorineural deafness
o Saber shins
Rubella  Triad  Causative organism – togavirus Serology – IgM Ab titre  Supportive Care
o Sensorineural hearing loss  Transplacental PCR – Rubella RNA Prevention:
o Cataracts  Respiratory Secretions Viral Cx from blood,  Active immunization of mother before conception
o Heart defects (e.g. PDA, pulmonary stenosis) urine, CSF, oral / nasal  2nd immunization of mother after delivery if serologic
 Salt & Pepper retinopathy secretions titers remain negative
 Petechiae and purpura (blueberry muffin rash)  N.B. MMR vaccine is live – attenuated, and thus its
 Hepatitis administration is contraindicated during pregnancy
HSV Intrauterine HSV infection (~5%):  HSV1 & 2 PCR of CSF, IgM titres,  Acyclovir IV 20mg/kg/dose TID (i.e. 60mg/kg/day in
(Herpes Simplex Virus)  Fetal demise, preterm birth, VLBW  Perinatal (contact with vagina during HSV culture of a lesion divided doses q8hrly)
 Microcephaly, hydrocephalus, and other CNS defects delivery)  SEM disease – tx for minimum 14 days
 Microphthalmia → chorioretinitis  Contact after rupture of membranes  CNS & Disseminated disease – tx for minimum 21 days
 Vesicular skin lesions  Direct contact with affected areas & repeat LP to ensure DNA PCR is negative & all CSF
Perinatal & postnatal transmission: parameters
 SEM (Skin, Eye, Mouth) disease
o Keratoconjunctivitis, cataracts, chorioretinitis
o Ulcerative or vesicular lesions of oropharynx
(Mucocutaneous vesicles)
  CNS disease
o Meningoencephalitis (fever, lethargy, irritability, poor
feeding, seizures, bulging fontanelle, temperature
instability)
o Temporal lobe hemorrhage / edema (highly specific) –
viral transmission through olfactory bulb to temporal lobe
 Disseminated Disease
o Multiple organ involvement (CNS, skin, eye, mouth, lung,
liver, adrenal gland)
o Sepsis – fever or hypothermia, apnea, irritability, lethargy,
respiratory distress
o Hepatitis, ascites, direct hyperbilirubinemia, neutropenia,
DIC, pneumonia, hemorrhagic pneumonitis. Necrotizing
enterocolitis, skin vesicles
Parvovirus B19  Aplastic anemia  Parvovirus B19  PCR for parvovirus B19  Intrauterine fetal blood transfusion if indicated
 Non–immune Hydrops fetalis – scalp edema, peeling skin,  Vertical transmission DNA Prevention:
pleural and pericardial effusions, placental edema, high–  Serial ultrasounds to  Frequent hand washing
output heart failure → ascites & generalized skin edema rule out fetal hydrops  Pregnant women with risk factors for TORCH infection
due to 3rd spacing should avoid potentially contaminated workplaces
 IUGR, Death / Fetal Demise (e.g., schools, pediatric clinics)
Varicella Zoster (VZV)  Fever  Varicella Zoster  Direct fluorescent  Varicella–zoster immune globulin (VZIG)
 Vesicular eruption (chickenpox)  Aerosolized droplets, extremely antigen test (DFA)  Acyclovir
 Systemic involvement (e.g. pneumonia, hepatitis, contagious  PCR for VZV DNA  Breastfeeding
meningoencephalitis)  IP 2 – 3 weeks  Serology (IgM Prevention:
 IUGR, premature birth antibodies)  Isolate infant from varicella contact
 Chorioretinitis, cataract  Administer Varicella-Zoster immunoglobulin (VZIG)
 Encephalitis to infant if maternal infection developed 5 days
 Pneumonia before or 2 days after delivery
 CNS abnormalities  VZV vaccine is a live vaccine & contraindicated if < 1
 Hypoplastic limbs year old
Listeriosis  Spontaneous Ab (in utero fetal demise); premature birth  Gram–positive, non–spore–forming,  Bacterial culture  Ampicillin & gentamicin
 Meningoencephalitis, sepsis motile, facultatively anaerobic bacilli Prevention:
 Vesicular and pustular skin lesions, multiple abscesses and – Listeria monocytogenes  Pregnant women should avoid unpasteurized dairy
granulomas (granulomatosis infantiseptica) o catalase–positive & oxidase– products and cold deli meats
 Disseminated abscesses in multiple organs (liver, spleen, negative, and expresses a beta
lungs, kidneys, brain) hemolysis
 USS – dilated loops of bowel and ascites o Maternal infection – non–specific
flu–like symptoms (e.g. myalgia,
malaise)
 Contaminated food (esp. raw milk)
Zika virus  Microcephaly, craniofacial disproportion  Maternal mosquito bite (Aedes  Neuroimaging:  Supportive with continued evaluation of sequelae
 Closed anterior fontanelle (Craniosynostosis) aegypti, A. albopictus) or sexually calcifications,  Avoid travel to tropical mosquito–infested regions
  Multiple Intracerebral calcifications transmitted from infected partner ventriculomegaly, during pregnancy
 Neurologic abnormalities (e.g. spasticity, seizures)  Single–stranded RNA Flavivirus cortical thinning (i.e.
o Multiple contractures & Hypertonicity  Transplacental transmission to fetus thin cerebral cortices)
 Ocular abnormalities  Targets neural progenitor cells  Zika RT–RNA detection
in newborn serum,
urine, or CSF

 Fetal alcohol Syndrome

o Microcephaly
o Small palpebral fissures
o Low nasal bridge
o Epicanthal folds
o Upturned nose
o Thin vermillion border
o Smooth philtrum
o Flat midface
o Underdeveloped jaw
o “Railroad track” ears
o
Biostatistics & Epidemiology
 Leavell’s 3 Levels of Disease Prevention
 Primordial Prevention –
o Broad steps to prevent disease (not individual preventions)
o Prevention of Underlying conditions leading to exposure of causative agents (i.e. Prevent
emergence of risk factors)
 Primary Prevention
o Prevent disease through education and vaccination
 Secondary Prevention
o Pre–symptomatic diagnosis through early screening to reduce morbidity & impact e.g. Blood
Pressure Checks
o Tackles latent (hidden) disease stage
 Tertiary Prevention
o Treat disease and support people with disease (e.g. support groups)
o Cure or slow disease progression, prevent complications, treat/ limit disability & rehabilitate
so as to prevent death
o Limits the physical and social consequences of symptomatic disease
 Quaternary Prevention – Making sure not to repeat steps
COMMON TYPES OF SYSTEMIC ERRORS IN STATISTICAL STUDIES
Inappropriate selection (e.g. random or non–random) or poor retention of study subjects (i.e. different
attrition rates between study groups) – Randomization prevents selection bias in allocating interventions
to participants at the beginning of a study (before the outcome is ascertained)
 Allocation Bias – occurs when subjects are nonrandomly assigned to a treatment group of a clinical study
(e.g. physicians may preferentially enroll sicker patients into a specific treatment group)
 Ascertainment (sampling) bias – occurs when results of a clinical study are distorted by knowledge of
which intervention the participants are assigned to. Blinding mitigates against this bias. Can be
introduced at any stage of a clinical study by individuals who:
o Administer interventions (e.g. researchers, assistants) – study population differs from target
population due to non–random selection methods
o Receive interventions (i.e. participants)
o Ascertain the outcomes (e.g. researchers, data collectors, evaluators)
o Analyze the data (i.e. statisticians)
 Nonresponse bias – High response rate to surveys / questionnaires can cause errors if non-responders
Selection differ in some way from responders
Bias  Berkson bias – Disease studied using only hospital–based patients may lead to results not applicable to
target population
 Prevalence (Nyman) Bias – Exposures that happen long before disease assessment can cause study to
miss diseased patients that die early or recover
 Attrition bias – Significant loss of study participants may cause bias if those lost to follow–up differ
significantly from remaining subjects
 Susceptibility bias (confounding by indication) – when treatment regimen in RCT that is selected for a
patient depends on the severity of the patient’s condition i.e. may have underlying confounders that are
responsible for worsening of their disease; thus those where treatment regimen is uncontrovertibly
indicated due to clinical deterioration should not be grouped with original RCT groups as it may lead to
erroneous analysis and weaken conclusions drawn from the study
o Can be avoided with intention–to–treat analysis which bases analysis on the original intention
regardless of the eventual treatment to avoid counting crossover patients
o Conversely, as–treated analysis compares groups based on actual treatment received; performed
to gauge effectiveness of treatment itself, with less regard for potential confounders
Observation Inaccurate measurement or classification of disease, exposure or other variable
Bias  Recall bias – common in retrospective studies, subjects with negative outcomes are more likely to report
certain exposures than control subjects
  Observer bias – observers misclassify data due to individual differences in interpretation or preconceived
expectations regarding study
 Reporting bias – subjects over– or under–report exposure history due to perceived social stigmatization
 Surveillance (detection) bias – risk factor itself causes increased monitoring in exposed group relative to
unexposed group, which increases probability of identifying a disease

 Verification Bias – aka workup bias; a type of measurement bias that occurs when a study uses gold
standard testing selectively in order to confirm a positive (or negative) result in preliminary testing
o This can result in overestimates (or underestimates) of sensitivity (or specificity)
 Hawthorne effect – refers to a change in behaviour that occurs if study participants know they are
being studied. Mitigate by doing placebo control and double blinding investigators and participants.
 Lead–time Bias – Systematic error of apparent increased survival from detecting disease in an early
stage
o False impression that people are living longer after early detection of disease on screening
 Length–time bias
o Cases with longer pre-clinical period (slowly progressing disease) have greater chance of being
detected by screening;
 recall: Prevalence = Incidence x Duration (P =I x D)
o Systematic error from detecting disease with a long latency or pre–clinical period.
 Methods for controlling for confounding
o Design stage
 Matching
 Restriction
 Randomization
o Analysis stage
 Stratified analysis
 Statistical modeling (e.g. multivariate analyses)
 Confounding
 Confusion of two supposedly causal variables, so that part or all of the purported effect of one
variable is actually caused by the other.
o A third variable that can obscure a true causal relationship – distort the association between
a predictor (independent variable) and outcome (dependent variable)
 Confounder affects both exposure and outcome, but unlike effect modification, no change in
strength or direction of the effect is typically seen with stratification
o E.g. alcohol increases risk of pancreatic cancer, and smoking acts as confounder because
smokers at increased risk of both alcohol consumption and is an carcinogen
o E.g. Birth Order and risk of down’s syndrome, confounder would be mother’s age
 By convention, when a third variable masks or weakens a true association between two variables,
this is negative confounding. When a third variable produces an association that does not actually
exist, this is positive confounding. To be clear, neither type of confounding is a “good thing” (i.e.,
neither is a positive factor); both are “bad” (i.e., negative in terms of effect)
 Qualitative confounding (when a third variable causes the reversal of direction of effect).
 Use stratified analysis to reduce confounding
 Effect modification
o Occurs when an external variable positively or negatively impacts the effect of a risk factor on a
disease of interest
o Effect is real but magnitude of the effect of an exposure differs depending on a third variable
o Effect modification only affects outcome, not exposure (c.f. confounding)
 Stratification based on the modifier can help detect effect modification as it typically
shows different effects in each stratum
 Separate measures of effect should be reported for each stratum
o E.g. Risk of VTE is increased with estrogen therapy, and this effect is augmented by smoking

 Post–hoc analysis
o Performing unplanned statistical tests on patterns that are identified after the fact in data from a
completed study
 Reducing Bias
o Double Blind Study (Reduces observation bias)
o Randomization (reduces selection bias)
o Crossover study – subject / patient acts as own control
 Benefits – has smaller variance (only within–group variability present, no between–
group variability); think paired t–test versus student t–test
 Within–subjects design: Comparisons between drug and placebo are made within
each subject (or patient), rather than between different subjects. In these
designs, each patient serves as his or her own control (so the control group is a
same–subject control group).
 Also called a repeated measures study because the measurements of the
dependent variable (such as symptom severity) are repeated within each patient,
rather than a single measurement being taken, and compared between different
patients in the more common between-subjects designs.
 If there is a danger of a “carryover” effect (e.g., if the treatment is a drug that may
continue to have some effect after it is
withdrawn), there can be a washout period
between the drug and the placebo phases,
during which no treatment is given.
 →
Reliability Reproducibility & Repeatability
(corresponds to precision)
 Validity → Accuracy
o In any measurement exercise: Observed value =
true value ± error
o Extent to which a measurement/instrument
measures what it purports to measure
 Internal Validity External Validity
(Causality) (Generalizability)
Describes causality (i.e., if change in Describes generalizability (i.e. if observed
independent variable causes change in relationship applies to situations or people
Characteristics dependent variable) outside study)
↑ As study becomes more tightly controlled ↑ As study becomes more tightly controlled
↓ As study becomes more like the real world ↑ As study becomes more like the real world
Bias due to:
 Confounding
 History Bias due to:
Threats to  Maturation  Artificial research environment
Validity  Measurement  Measurement effects
 Regression toward the mean  Non–representative sample
 Repeated testing
 Selection

 Common Measures of therapeutic efficacy

o Number Needed to Treat (similar calculation for Number Needed to Harm with ARI,
attributable risk increase)
1
 NNT =
| ARR|
 ARR ( attributable risk reduction) =Control Rate−Treatment Rate
C
 Control rate = risk of disease among non –exposed ¿
C+ D
A
 Treatment rate = risk of disease among exposed (aka intervention group) ¿
A +B
C A
 ∴ ARR= −
C+ D A+ B
 Absolute risk reduction (also called the risk difference) = the difference in the risk of a
negative outcome between an exposed group and a non–exposed group (i.e. the
percentage indicating the actual difference in event rate between control & treatment
groups
o Attributable Risk Percent, ARP = percentage of disease in an exposed group that can be
attributed to the exposure (i.e. the
percentage of disease in an exposed group
that could be prevented by eliminating the
exposure [i.e. the risk factor])
 e.g. ARP =

( risk ∈exposed – risk ∈unexposed ) ( RR−1 )

×100= ×100
risk ∈exposed RR
 o Relative Risk Reduction (RRR)
 Percentage indicating relative reduction in the treatment event rate compared to the
control group
ARR
 RRR=
control rate
o Relative Risk (RR)
 Ratio of the probability of an event occurring in the treatment group compared to the
control group
a
treatment rate (a+b)
 RR= =
control rate c
(c+ d)
o Population attributable risk percent – compares risks (or incidences)
( Risk ∈total population−Risk∈unexposed )
 PARP=
Risk ∈total population

Risk ∈total population=( Risk∈exposed ) ( Proportion of exposed ) + ( Risk∈unexposed )( Proportio
( Prevalence ) ( RR−1 )
 PARP=
[ ( Prevalence )( RR−1 ) +1 ]
 Cohort studies – use Relative Risk
a
risk of event ∈treatment group (a+b)
o RR= =
Risk of event∈control group c
(c +d)
o In cohort studies, in contrast to case–control, the outcome of interest has not occurred at the
start of the investigation. People with and without the exposure of interest are followed up to
examine the proportion in each group who go on to develop the outcome of interest
o A Retrospective cohort is also called a historical prospective study, non-concurrent prospective
study or a prospective study in retrospect
 Conducted by reconstructing data about persons at time(s) in the past. Exposure
information is obtained from relevant records whereas outcome information can be
current or any other time subsequent to exposure
o Prospective cohort is also called a longitudinal study, follow up, panel, incidence or a concurrent
prospective study
 Conducted by currently determining exposure status and following up in time for
outcome assessment
o N.B. Both approaches have the key feature: Selection in the study is based on exposure status.
Difference involves calendar time
A
B A× D
 Case–control studies – use Odds Ratio (exposed vs. unexposed) = =
C B×C
D
o Retrospective study looking for the odds of a previous exposure on the development of a rare
disease manifestation
o Start with people who have the disease and look backwards at other groups that are otherwise
matched to assess for risks of exposure
o Subject to recall bias re what persons with disease may have been exposed to in the past
 Cross–sectional (Prevalence) Studies – uses Odds Ratio
o E.g. National Census
o Cross–sectional studies consist of a single examination of a population without any follow–up,
i.e. data are collected at one point in time. They provide a ‘snapshot’ of a population and can
 measure attitudes, behaviours, health conditions (past and present) or risk factors (past and
present), and can be repeated to measure change in a population. Can be conducted in:
 A specific time window - a calendar year, a specific month or specific week or
 At a fixed point in the course of events that vary in time from person to person -
before entering high school or college or at retirement
 Cross sectional studies can be conducted several times in the same population. This
allows for trends in particular characteristics or diseases to be monitored over time –
time series
 Two–sample t-test
o Determines if means of two sample populations are equal or different with statistical
significance (i.e. rule out null hypothesis if p<0.05)

Key Mechanisms
 Acting out: Expressing unacceptable feelings through actions
 Denial: Behaving as if an aspect of reality does not exist
 Displacement: Transferring feelings to less threatening object / person
 Intellectualization: Focusing on non–emotional aspects to avoid distressing feelings
 Passive Aggression: Avoiding conflict by expressing hostility covertly
Immature
 Projection: Attributing one’s own feelings to others
 Rationalization: Justifying behaviour to avoid difficult truths
 Reaction formation: Transforming unacceptable feelings / impulses into the opposite
 Regression: Reverting to earlier developmental stage
 Splitting: Experiencing a person / situation as either all positive or all negative
 Sublimation: Channeling impulses into socially acceptable behaviours
Mature
 Suppression: Putting unwanted feelings aside to cope with reality
 Crude Rate, Age-Specific Rate, Age-adjusted Rate, Infant Mortality Rate, Neonatal Mortality Rate,
Perinatal Mortality Rate, Case-Fatality Rate (Cause-Specific Death Rate)

observed number of deaths

 Standardized mortality ratio , SMR=
expected number of deaths
o Expected number of deaths calculated by age–specific rates of death in a standard reference
population (e.g. total US population)
o Ratio of the observed deaths amongst a population / cohort of interest divided by the expected
number of deaths based on a standard population
 SMR < 1 indicates that the number of observed deaths in the study group is lower than
what is expected
 SMR = 1 indicates that the number of observed deaths in the study group is equal to
what is expected
 SMR > 1 indicates that the number of observed deaths in the study group is greater than
what is expected
o SMR represents an adjusted measure of overall mortality. Mortality is often adjusted for age
(and less commonly, gender, race, or other factors)
 Rate Ratio = incidence rate of an event in the intervention group divided by the incidence rate of the
same event in the control group (e.g. placebo)
incidence rate∈the intervention group
o Rate Ratio , RR=
incidence rate∈the control group
 o Incidence rate is a measure of incidence that incorporates time, in the form of individual times
“at–risk” (person–time), directly in the denominator
 Rate ratio < 1.0: intervention has a protective effect
 Rate ratio = 1.0 (null value): incidence rate of the event is the same in intervention and
control groups
 Rate ratio > 1.0: intervention has a risk effect
 A confidence interval that includes the null value is not statistically significant, and a CI that excludes the
null value is statistically significant
 Significant difference is that PPV and NPV use the disease prevalence to determine the likelihood of a
test diagnosing that specific disease. Whereas sensitivity & specificity are independent of prevalence
 Prevalence & PPV/NPV
o ↑ Prevalence → ↑ PPV & ↓ NPV
o ↓ Prevalence → ↓ PPV, ↑ NPV
True Disease Status
Test Result Positive Condition Negative Condition
Positive Test Result TP FP PPV = TP / (TP + FP)
Negative Test FN TN NPV = TN / (FN + TN)
Result
Sensitivity = TP / (TP + FN) Specificity = TN / (TN + FP)
TP A
o Sensitivity= =
(TP+ FN ) A +C
 Ability of test to correctly identify those with a
given disease
 SNOUT – Sensitivity rules out disease → good for
screening
 Probability that a patient tests positive given that
they have the disease
 N.B. False Negative Rate = 1 – sensitivity
TN D
o Specificity= =
(TN + FP) D+ B
 Ability to test to correctly identify those without a
given disease
 SPIN – Specificity rules in disease → good
confirmatory testing
 Probability that a patient tests negative given that
they do not have the disease
 N.B. False Positive Rate = 1 – Specificity
o N.B. Sensitivity and specificity do not change based on
prevalence or rate of a disease in a community
TP A
o PPV = =
(TP+ FP) A+ B
 Positive Predictive Value (PPV) is the probability that an individual will truly have that
specific disease given that the test result is positive (i.e. probability that a positive test
result is truly positive / Pr [person has the disease given that the test result is positive])
 For any given test (i.e. sensitivity and specificity remain the same) as prevalence
decreases, PPV decreases (N.B. there will be more false positives for every true positive)
TN D
o NPV = =
(TN + FN ) D+C
 Negative Predictive Value (NPV) is the probability that an individual will truly not have
that specific disease given that the test result is negative (i.e. probability that a negative
test result is truly negative / Pr [person does not have disease given that test is negative])
  As prevalence decreases, NPV increases (N.B. there will be more true negatives for every
false negative)
o Positive Likelihood Ratio (LR+) is the ratio of the sensitivity of a test to the false–positive
error rate of the test, or [a/(a+c)] ÷ [b/(b + d)].
 ¿
 It is the probability of an individual with the disease testing positive divided by the
probability of an individual without the disease testing positive
 Represents the value of a positive test result (A ratio representing the likelihood of
having a disease given a positive result)
o Negative Likelihood Ratio (LR−) is the ratio of the false–negative error rate divided by the
specificity, or [c/(a + c)] ÷ [d/(b + d)].
 ¿
 It is the probability of an individual with the disease testing negative divided by the
probability of an individual without the disease testing negative
 Represents the value of a negative test result (A ratio representing the likelihood of
having a disease given a negative result)
o N.B. If the LR+ of a test is large and the LR− is small, it is probably a good test.
 LR values can vary from 0 to infinity. In general, the smaller the LR, the less likely the
disease is present
 An LR < 1 argues against the disease (e.g. LR = 0.1 decreases probability of disease
by ~45%)
 LR < 0.1: strong evidence to rule out disease
 LR > 10: strong evidence to rule in disease
o Just as sensitivity and specificity are independent of prevalence, LRs do not change with
prevalence of disease and additionally, LRs can be used to calculate post–test odds where:
 Post – test odds=Pre – test odds × LR , thus providing clinically useful information to
individual patients based on pre–test odds of disease
 LRs can also be used with tests that have > 2 possible test results and they can be used to
combine the results of multiple diagnostic tests
Four outcomes of making a decision. The decision can be either correct (correctly reject or retain null) or
wrong (incorrectly reject or retain null)
Truth in Population about the null hypothesis, Ho
Ho true Ho false (H1)
Type I error (False positive) Correct conclusion
Reject Ho
Decision based on test α (1 – β ) = power
results Correct conclusion Type II error (false negative)
Fail to Reject Ho
(1 – α ) β

 A p value is the probability of obtaining a sample outcome, given that the value stated in the null
hypothesis is true. The p value for obtaining a sample outcome is compared to the level of significance.
 Significance, or statistical significance, describes a decision made concerning a value stated in the null
hypothesis. When the null hypothesis is rejected, we reach significance. When the null hypothesis is
retained, we fail to reach significance.
 Researchers make decisions regarding the null hypothesis. The decision can be to retain the null (p > .05)
or reject the null (p < .05). P-values and levels of significance can also be set at higher criteria (e.g.
p=0.01, p = 0.001 etc.)
 Type II error, or beta (β) error (false negative result), is the probability of retaining a null hypothesis
that is actually false.
 Type I error (false positive result) is the probability of rejecting a null hypothesis that is actually
true. Researchers directly control for the probability of committing this type of error.
 An alpha (α) level is the level of significance or criterion for a hypothesis test. It is the largest
probability of committing a Type I error that we will allow and still decide to reject the null
hypothesis. A p-value of 0.05 means that if a study were repeated, there is a 95% chance it would
reproduce findings consistent with the current findings (conversely there’s a 5% chance that the data
is due to random factors)
a−b
o Z−score=
√ a+b
o P–value 0.10 corresponds to a Z–score of 1.65 ≡ 90% Confidence interval
o P–value 0.05 corresponds to a Z–score of 1.96 ≡ 95% Confidence interval
o P–value 0.01 corresponds to a Z–score of 2.58 ≡ 99% Confidence interval
 The power in hypothesis testing is the probability of rejecting a false null hypothesis. Specifically, it
is the probability that a randomly selected sample will show that the null hypothesis is false when
the null hypothesis is indeed false.
o Power=1 – β
o Ability of a study to demonstrate an association or causal relationship between two
variables, given that an association exists.
o By convention, 80% is an acceptable level of power
o Pooled data in meta-analysis increases power
 Standard deviation (SD) measures the amount of variation or dispersion in a set of observations. It
gives us the average distance of the values from the mean
 Standard error (SE) is a statistical term that measures the accuracy with which a sample represents a
population; measures how precisely the population mean is estimated by the sample mean.
o SE – SDsample quantifies deviation of sample mean from true population mean
o 1 SD = 68% of population falls within this range
o 2 SD = 95% of population falls within this range
o 3 SD = 99.7% of population falls within this range

PREDICTOR VARIABLE(S) OUTCOME VARIABLE

Categorical Continuous
Categorical  Chi Square (Differences in  2 sample t–test (compares 1 or 2 means)
Proportions)  ANOVA  (Analysis of Variance; ≥ 3
 Fisher’s exact test (similar Categorical) – gives the F statistic
to chi – squared but used  Linear regression
when sample size is small)
 Log linear
 Logistic
Continuous  Logistic regression  Linear regression
 Pearson correlation
Mixture of Categorical and  Logistic regression  Linear regression 
Continuous  Analysis of Covariance
  Kappa statistic – quantitative measure of inter–rater reliability (sometimes referred to as inter–rater
concordance)
o Range from – 1 (perfect disagreement) to + 1 (perfect agreement)
 Kappa = 0 suggests agreement due to chance alone
 Kappa < 0 suggests less than chance agreement (possibly intentional disagreement)
 Kappa > 0 suggests greater than chance agreement
o Following arbitrary cutoffs are often used:
 Kappa: 0 – 0.20 represents negligent improvement over chance agreement
 Kappa: 0.21 – 0.40 represents minimal improvement over chance agreement
 Kappa: 0.41 – 0.60 represents fair improvement over chance agreement
 Kappa: 0.61 – 0.80 represents good improvement over chance agreement
 Kappa: 0.81 – 1 is excellent
 Factorial study design (or fully crossed design)
o Type of experimental study design that utilizes ≥2 interventions and all combinations of these
interventions

Phases of Clinical Trials

Preclinica  Laboratory & animal models
l  Goal: Explore if & how new treatment may work
Phase I  Small number (e.g. 20 – 100) of healthy subjects
 Goal: Evaluate Toxicity, maximum tolerated dose, adverse effects, pharmacokinetics &
pharmacodynamics of new treatment (safety)
Phase II  Small number (e.g. up to a few hundred) of affected subjects
 Goal: Explore efficacy, optimal dosing & adverse effects of new treatment (expanded safety)
Phase III  Large number (e.g. 300 – 3000) of affected subjects randomly assigned to new treatment or control
 Goal: Compare new treatment to current standard of care (safety & efficacy)
Phase IV  Post–marketing surveillance
 Goal: Identify rare & long–term side effects

Root Cause Analysis

 Collect Data (mainly through interviewing individuals involved with the error)
 Create causal flow chart
 Identify root cause; ask why? – aka underlying factors leading to causal factor
 Generate recommendations and implementations
 Measure success of changes implemented (assess efficacy of changes)

Population Genetics (Inheritance Patterns and Pedigree Charts)
 Hardy–Weinberg Equations 
o Used to determine frequencies of one gene with multiple alleles (e.g. Aa, AA, ss, but not multiple
genes AB) in a population
o Allele and genotype frequencies stay constant from population to population
o Assumes absence of evolutionary forces (No mutation, no gene flow, no migration, no selective
pressure / no natural selection, random mating)
o Assumes infinite population size (No genetic drift)
o p2 +2 pq+ q2= ( p+ q )2=¿ 1; ∴ p+ q=1
 Where p2 = population frequency of homozygous dominant genotype (% of AA)
 Where q 2 = population frequency of homozygous recessive genotype (% of aa)
 Where 2 pq = population frequency of heterozygous genotype (% of Aa)
 Where p = population frequency of dominant allele (percentage of A)
 Where q = population frequency of recessive allele (percentage of a)
o If X–linked recessive condition:
 p = population frequency of healthy male genotype (percentage of XY)
 q = population frequency of affected male genotype (percentage of XdY)
 The allele frequency of male and female will be identical (i.e. the p and q values for males
will be the same in females)
 p2 = population frequency of healthy female genotype (% of XX)
 Where q 2 = population frequency of affected female genotype (% of XdXd)
 Where 2 pq = population frequency of carrier female genotype (% of XdX)
 Genetic Drift
o Founder Effect
 Group moved away from primary population, carrying certain ancestral traits from
original population with them
o Bottleneck Effect
 Certain phenotype or genotype eliminated in a population (e.g. war, death / genocide,
overhunting of species), leading to less genetic variation
 Mutation–Selection Equilibrium – balance between natural selection pressures and new de novo
mutations
 Inheritance Algorithm – Stepwise approach to identifying inheritance pattern in pedigree chart
o Determine if Disease present in every generation (i.e. Does not skip a generation)
 Mitochondrial → affected females pass disease to all offspring & male offspring do not
further pass on the disease
 Otherwise Dominant
 X–Linked Dominant –
o Affected Male passes to all female offspring and No male to male
transmission
 Autosomal Dominant –
o generally Affected Male = Affected Female + male to male transmission
o If Disease skips a generation, this implies Recessive
 X–linked Recessive –
 Only affected Males from unaffected parents
 Predominantly affected male >>> affected female (i.e. rare in females)
 Autosomal Recessive otherwise
 Male & Females equally affected
 Autosomal Dominant (AD)
o Only one copy of defective gene is required to express disease phenotype
 Affected child must receive disease from affected parent
 a homozygote dominant parent has a 100% chance of
having an affected child
 Two heterotyzgote parents with the AD disease
condition have a 75% chance of having a child with the
disease phenotype
o Males and Females equally affected
o Does not skip Generations
 if two parents without the AD disease have child with an AD disease
 possibility is reduced penetrance (i.e. have mutant gene but phenotypically
normal) – i.e. Variable Expressivity
 De novo germline mutation
o Generally defects in structural genes; usually presents after puberty
o Often pleiotropic – several organ systems affected by single genetic defect
o Examples – “Very Powerful DOMINANT Humans”
 V–
 Von Willebrand’s Disease (decrease vWF)
o Increase bleeding time, ↑ or normal PTT, defect in platelet plug formation
o Abnormal Ristocetin test – Ristocetin induces platelet agglutination by
causing vWF to bind to GP1B
o Tx – Desmopressin (ADH / vasopressin analog): releases vWF from Weibel
Palade bodies in endothelium
 Von Hippel–Lindau Disease
o Genetic disorder resulting in multiple benign and malignant tumours of
many organs
 Hemangioblastomas of retina / cerebellum / medulla
 Bilateral renal cell carcinoma
o VHL gene mutation on chromosome 3
 VHL protein may act as a tumor suppressor; however, its role in
tumorigenesis is not fully clear
 ubiquitinates hypoxia–inducible factor 1a (HIF–1a)
 Loss of VHL gene leads to increase in IGF–1 (promotes growth) and
increased HIF transcription factor (increases VEGF and PDGF)
 P – Pseudohypoparathyroidism
 D – Dystrophia Myotonica (Myotonic Dystrophy)
 O–
 Osteogenesis Imperfecta
 Osler–Weber–Rendu Syndrome (Hereditary Hemorrhagic Telangiectasia)
o Telangiectasia, Recurrent epistaxis, Skin discolorations
o Arteriovenous malformations (mainly mouth and GI tract)
 Vascular malformations in lungs may cause a number of problems.
Pulmonary AVMs bypass the capillary network in the lungs and
allow bacteremia and emboli to potentially migrate to brain
without being ‘filtered’ by lungs → brain abscesses, embolic
strokes
o Shows genetic anticipation
o Symptomatic treatment accordingly. No specific treatment
 Severe epistaxis – ablative treatment, septoplasty
 GI Bleeds – Endoscopic sclerotherapy, surgical resection
  Pulmonary AVM – embolization, surgical resection
 Hepatic AVM – embolization (to stabilize cardiac failure and
encephalopathy)
 M – Marfan’s Syndrome
 I – Intermittent Porphyria
 N – Noonan’s Syndrome (Male version of Turner’s Syndrome); AD dominant with variable
expression
 A–
 Androgenic Alopecia
 Autosomal Dominant Polycystic Disease (ADPKD)
o Always bilateral, HTN (increased renin secretion), hematuria
o Associated with
 Polycystic liver cyst (most common extra-renal manifestation),
 Berry aneurysms (most common cause of death)
 MVP
o Majority due to mutation in PKD1 (chromosome 16)
 Achondroplasia
o Congenital skeletal dysplasia associated with short limbs, but head and
trunk are normal size. Results in dwarfism
 Rhizomelic dwarfism – humerus shorter than forearm and femur
shorter than tibia
 normal trunk
 adult height ~ 50 inches
 Frontal bossing
 Extremities
 Trident Hands (fingers same length with divergent ring and
middle fingers)
 Genu varum
 Radial head subluxation
 Muscular hypotonia in infancy
 Spine – thoracolumbar kyphosis, excessive lordosis
o AD mutation in the fibroblast growth factor receptor 3 gene (on
chromosome 4P) → overexpression of FGFR3 inhibits growth
 Phenotype commonly Heterozygous ‘Aa’. Homozygous dominant
alleles ‘AA’ usually not compatible with long life expectancy
o Risk increases with advanced paternal age
o Achondroplasia affects endochondral ossification (cartilage matrix
becoming ossified particularly in long bone formation)
 Inhibition of chondrocyte proliferation in the proliferative zone of
the physis
 N.B. Achondroplasia does not affect intramembranous ossification
(bone formation without pre-existing cartilage matrix, seen in flat
bone)
 Enlarged head relative to limbs (via membranous ossification)
 N – Neurofibromatosis Type I
 T – Tuberous Sclerosis
 H–
 Hypercholesterolemia
o Xanthomas (tendons, classically Achilles), MI develops before age 20
o Elevated LDL due to defect or absent LDL receptor. If homozygous, LDL
often > 700+
  Huntington’s Disease, Hypertrophic Obstructive Cardiomyopathy, Hereditary
Spherocytosis, Hereditary Non–polyposis Coli (HNPCC Syndrome)
 Autosomal Recessive (AR)
o Must have 2 defective copies of the gene
 most often more severe than AD
 chances greatly increased with consanguinity
o Male and Female equally affected
o Generations affected
 1/4 of offspring affected when both parents are carriers
 1/2 of offspring are carriers when both parents are
carriers
 2/3 of nonaffected children are carriers
 usually 1 generation
o Pathology tends to be a defect in enzymes
o Complete penetrance, Presents early in life (infancy to childhood)
o Examples
 Albinism
 Tyrosinase deficiency (type 1 – tyrosinase gene on chromosome 11, type 2 –
defect tyrosinase transporter [chromosome 15; OCA2 gene]) impairs melanin
production, at risk of Ultaviolet–B
 Variable inheritance due to locus heterogeneity
 ARPKD (Autosomal Recessive Polycystic Kidney Disease)
 Associated with congenital hepatic fibrosis
 Renal failure in utero can lead to Potter’s sequence
 HTN
 Beta Thalassemia
 Cystic Fibrosis – deficiency in the chloride channel CFTR
 Deafness
 Emphysema (alpha–1–antitrypsin deficiency)
 Fredrich’s Ataxia
 Gaucher’s Disease
 Galactosemia
 Homocysteinuria
 Hemochromatosis
 inborn errors of metabolism
 PKU (Phenylketonuria), von Gierke's, Pompe's, glycogen storage diseases,
sphingolipidoses (except Fabry's), and mucopolysaccharidoses (except Hunter's)
 Sickle Cell Anemia
 X–Linked Recessive (XR) – “Only Males affected from unaffected parents”; Rarely female affected
o Skips generations – No male to male transmission
 Males must receive defective gene from carrier mother
 carrier mother's sons have 50% chance of having disease
 affected males give copy to all of their daughters
 Only one defective copy necessary for disease in males (hemizygous for X chromosome)
 If affected male & non–carrier female → all female progeny will be carriers
 If carrier mother & unaffected father:
 Daughters have 50% chance of becoming carriers
 Sons have 50% chance of being affected
 Two defective copies necessary for disease in females
 can be affected with just one defective copy if normal X chromosome is
inactivated to Barr body (manifesting heterozygotes)
 o Phenotype usually milder than affected males
o Pathology – defective enzymatic genes (similar to AR diseases)
o Usually presents after puberty
o Examples – “Be Wise, Fool’s GOLD Heeds Silly Hope”
 B – Bruton’s Agammaglobulinemia
 W – Wiskott Aldrich Syndrome
 F – Fabry’s Syndrome
 G – Glucose–6–phosphate dehydrogenase
(G6PD) Deficiency Chronic Granulomatosis Dx
 O – Others
 Ocular Albinism
 Ornithine Transcarbamylase Deficiency
 Red–Green Color Blindness
 Menke’s Disease
 L–
 Lesch–Nyhan Syndrome
o Deficiency of HGPRT
o Mental retardation & self–mutilation
 D – Dystrophias (Duchenne muscular dystrophy, Becker muscular dystrophy)
 H S – Hunter’s Syndrome
 H – Hemophilia A & B
 X–Linked Dominant (XD)
o “At least one parent of either sex is affected and all female
offspring of affected male have the disease”
 Does not skip generations
 only possibility is reduced penetrance
 Females of affected fathers are always affected (N.B.
male–to–male transmission not seen)
 Male or females of affected mothers can be affected
o Males and females affected at equal frequency
o Pathology – defects in structural genes
o Usually presents after puberty
o Examples
 Hypophosphataemic Ricketts
 Fragile X Syndrome
 Alport Syndrome
 Mitochondrial Inheritance
o Transmitted through Mother to all children
o Males and Females equally affected
o Does NOT skip generations
o Only transmitted from affected female
 gives to all offspring
 due to the fact that the sperm do not
contribute mitochondria to the zygote
o Pathology
 Defects in electron transport/oxidative
phosphorylation process
 Presents as neuropathies/myopathies
 Neurons and muscle cells require high amounts of energy and depend on
mitochondria
o Usually presents after puberty
o Variable expression due to heteroplasmy
 a small percentage of mitochondria within a cell are affected leading to variable severity
o Examples
 Mitochondrial Myopathy (myoclonic epilepsy with ragged red muscle fibers, MERRF
Syndrome)
 Muscle biopsy reveals Gomori trichrome stain
 Hearing loss, muscle weakness, epilepsy
 Leber’s Hereditary Optic Neuropathy
 MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke–like episodes)
 Leigh syndrome (also called Leigh disease and subacute necrotizing
encephalomyelopathy)
Ethics
Stages of Change Model
Motivational Interviewing
Stage (emphasizes development of patient’s intrinsic motivation
to change and take responsibility for recovery)
Encourage patient to evaluate consequences of current
Not ready for change: patient does
behaviour
Precontemplation not acknowledge negative
Explain & personalize the risk
consequences
Recommending action is premature
Thinking of change: patient
Encourage evaluation of pros & cons of behaviour change
Contemplation acknowledges consequences but is
Promote new, positive behaviours
ambivalent
Ready for change: patient decided Encourage small, initial steps
Preparation
to change Reinforce positive outcome expectations
Help identify appropriate change strategies & enlist social
Making change: patient makes
Action support
specific, overt changes
Promote self–efficacy for dealing with obstacles
Changes integrated: into patient’s Follow–up support; reinforce intrinsic rewards
Maintenance
life; focus on relapse prevention Develop relapse prevention strategies
Behaviour is automatic: changes
Identification Praise changes
incorporated into sense of self