Paediatrics Flashcards
What is neonatal jaundice
The yellowing discolouration of the skin and sclera of a neonate, which is caused by increased levels of bilirubin in the blood
What is a neonate
An infant in the first 28 days of life
What is the aetiology of neonatal physiological jaundice
- Increased bilirubin load secondary to increased RBC volume, decreased RBC lifespan, or increased enterohepatic circulation
- Decreased uptake by the liver because of decreased UDPGT activity
- Decreased exertion into bile
What is the aetiology of neonatal pathological jaundice with unconjugated hyperbilirubinaemia
- Haemolytic anaemias
- Extravasation of blood
- Polycythaemia
- Increased enterohepatic circulation
- Defective conjugation
- Metabolic conditions
- Breastfeeding
- Decreased binding of bilirubin to albumin
What is the aetiology of neonatal pathological jaundice with conjugated hyperbilirubinaemia
Hepatocellular disease:
- Metabolic or genetic defects
- Infection
- TPN
- Neonatal haemochromatosis
- Idiopathic neonatal hepatitis
- Shock
Intrahepatic biliary disease:
- Alagille syndrome
- Inspissate bile syndrome
Extrahepatic biliary disease
- Biliary atresia
- Choledochal cyst
- Bile duct stenosis
- Cholelithiasis
What is the pathophysiology of neonatal jaundice
When the normal process of bilirubin formation and excretion is dirupted, hyperbilirubinaemia results
What is physiological vs pathological neonatal jaundice
Physiological:
- Usually noted at postnatal day 2, peaks on days 3 to 5 and then decreases
- Serum bilirubin levels up to 205.2 micro mol/l are considered physiological in term neonates
Pathological:
- Any jaundice in the first 24hrs of life
- Bilirubin levels exceeding 95th percentile, as defined by a nomogram, are pathological
What is the epidemiology of neonatal jaundice
Jaundice is the most common condition in newborns that requires medical attention.
Around 50-70% of term babies and 80% of preterm babies develop jaundice in the first week of life.
Jaundice usually appears 2-4 days after birth and resolves 1-2 weeks later without the need for treatment
The risk of neonatal hyperbilirubinaemia is higher in males and increases progressibely with decreasing gestational age
What are the signs and symptoms of neonatal jaundice
Yellowing discolouration of the skin and sclera
Cephalocaudal progression (first appears in the face, progresses down body as total serum bilirubin rises)
Fatigue
Not want to feed or not feed as well as usual
Dark yellow pee
Pale stool
What are the risk factors for neonatal jaundice
Asian American-indian Maternal diabetes Low birth weight Decreased gestational age Decreased caloric intake and weight loss Breastfeeding
How is suspected neonatal jaundice investigated
Transcutaneious bilirubinometer Total serum bilirubin Direct Coombs' test Direct serum bilirubin Haematocrit FBC Reticulocyte count Peripheral blood smear Blood groups
Consider also:
- G6PDH screen
- osmotic fragility test
- blood culture
- LFTs
- urine for reducing substances
- plasma amino acids
- urine organic acids
- urine culture
- abdominal ultrasound
- percutaneous liver biopsy
What is an infant
Child under 1 year old
What is a newborn
Child under 28 days of age
What is the perinatal period
22nd week of gestation to 7 days after birth
What is the post partum period
first 6 to 8 weeks after birth
What is a live birth
Post natal presence of vital signs eg respiration, pulse, umbilical cord pulse
What are the types of term birth
All live births between 37-42 weeks gestation
Early term: 37+0 - 38+6
Full term: 39+0 - 40+6
Late term: 41+0 - 41+6
What are the evaluation categories for birth weight
Appropriate for gestational age: 10th-90th percentile for gestational age
Small for gestational age: <10th percentile for gestational age
Large for gestational age: >90th percentile for gestational age
Low birth weight: <2500g regardless of gestational age
How is a newborn immediately cared for when born
Wipe the newborn’s mouth and nose to clear airway secretions, use suction only if necessary.
Dry and stimulate the newborn.
Provide warmth.
Skin-to-skin contact with mother and initiation of breastfeeding
Clamp and cut the umbilical cord.
Apgar score assessment at 1 and 5 minutes after birth
Begin resuscitation if onset of respirations has not yet occurred within 30–60 seconds
What is the APGAR score
Appearance Pulse Grimace Activity Respirations
Used for standardised clinical assessment at 1 and 5 minutes after birth
Each of the five components can be given between 0 and 2 points depending on the status of the newborn
The total Apgar score is the sum of all five components
Reassuring: 7-10
Moderately abnormal: 4-6
Low: 0-3
In infants with a score below 7, the Apgar assessment is performed at 5 minute intervals for an additional 20 minutes
Persistently low Apgar scores are associated with long-term neurologic sequelae
What factors can determine a delivery as high risk and therefore needing the neonatal resus team available
Maternal factors:
- Extremes of maternal age
- Diabetes
- Hypertension
- Substance abuse
- Previous foetal loss
Foetal factors:
- Prematurity
- Postmaturity
- Congential anomalies
- Multiple gestations
Complications of pregnancy and delivery:
- Placental anomalies
- Oligohydraminos/ polyhydraminos
- Transverse/breech delivery
- Chorioamnionitis
- Meconium-stained amniotic fluid
- Abnormal foetal heart rate
- Delivery with forceps/vacuum/Caesarean
What are the neonatal resuscitation steps
Preductal pulse oximetry
Positive pressure ventilation (bag mask valve) at a rae of 40-60 per minute
- Indicated in inadequated resp effort (gasping, apnea) or a heart rate <100
- Intubation if pressure ventilation is ineffective or compressions are required
- Restrictive use of supplementary oxygen, guided by pulse oximetry
- At birth ventilation should be with room air for infants ≥35weeks
- Premature infants <35weeks can receive FiO2 21-30% initally, titrated to SpO2
Chest compressions
- Indicated if Heart rate <60bpm despite adequate ventilation for 30 seconds
- Use the two thumb encircling hands technique if two health cae providers present
- Use the two finger technique if only one health care provider is present
- 3 chest compressions followed by 1 inflation
Iv epinephrine if HR <60bpm despite adequate ventilation and chest compressions for at least 30-60 seconds
If there is no evidence of return of spontaneous circulation within 20mins, consider termination of resuscitation
What are the preventive measures which can be given directly after birth
Ophthalmic antibiotics: to prevent gonoccal conjunctivitis (erythromycin ophthalmic ointment)
Vitamin K: to prevent Vit K deficiency bleeding of the newborn
What is neonatal polycythemia
Venous Haematocrit (HCT) greatly exceeding normal values for gestational and postnatal age
How common is neonatal polycythemia
1-5% of newborns
What are the risk factors for neonatal polycythemia
Small for gestational age Large for gestational age Infants of diabetic mothers Twin to twin transfusion syndrome (recipient) Maternal tobacco use Chromosomal abnormalities Delayed umbilical cord clamping
What is the pathophysiology of neonatal polycythemia
Delayed umbilical cord clamping → erythrocyte transfusion → ↑ circulating red blood mass (HCT)
Placental insufficiency or chronic intrauterine hypoxia → increased intrauterine erythropoiesis → ↑ circulating red blood mass (HCT)
What are the clinical features of neonatal polycythemia
Respiratory distress, cyanosis, apnea Poor feeding, vomiting Hypoglycemia Plethora Lethargy and irritability Tremors or seizures
How is neonatal polycythemia diagnosed
Venous HCT > 65%
Hemoglobin > 22 g/dL
How is neonatal polycythemia treated
Monitoring
IV hydration
Partial exchange transfusion: a procedure in which part of the blood is replaced with an isotonic fluid to lower the hematocrit
-Indicated in asymptomatic patients with high hematocrit (> 75%) or symptomatic patients with hematocrit > 65%
-Increased risk of necrotising enterocolitis
What are the potential complications of neonatal polycythemia
Hypoglycaemia
Hyperbilirubinaemia
Necrotising enterocolitis
What is erythema toxicum neonatorum
A benign self limiting rash that appears within the first week of life
What are the clinical features of erythema toxicum neonatorum
Small red macules and papules that progress to pustules with surrounding erythema
Located on trunk and proximal extremities
Spares the palms of hands and soles of feet
How is erythema toxicum neonatorum diagnosed
Based on clinical appearance of rash
Biopsy or smear of pustual (rarely necessary) but would show high eosinophils
How is erythema toxicum neonatorum treated
Observation only
What is the prognosis of erythema toxicum neonatorum
Typically resolves without complications within 7-14 days
What is a congenital dermal melanocytosis
AKA Mongolian spot
A benign blue-ray pigmented lesion of newborns
What is the neonatal prevalence of congenital dermal melanocytosis
Asian and Native American: 85–100%
African American: > 60%
Hispanic: 46–70%
White: < 10%
What is the pathophysiology of congenital dermal melanocytosis
Melanocytes migrating from the neural crest to the epidermis during development become entrapped in the dermis
What are the clinical features of congenital dermal melanocytosis
Blue-gray pigmented macule (may also be green or brown)
Diameter: typically < 5 cm, may be > 10 cm
Location: most common on the back, also seen on the buttocks, flanks, and shoulders
How is congenital dermal melanocytosis diagnosed
Based on clinical appearance
It is important to document the diagnosis of Mongolian spots, as they may resemble bruises and lead to false suspicions of child abuse.
What is the prognosis of congenital dermal melanocytosis
Usually resolves spontaneously during childhood (typically by the age of 10 years)
How does a congenital melanocytic nevus clinically present
Vary in size: < 1.5 cm to > 20 cm A nevus larger than 20 cm in size is referred to as a giant congenital melanocytic nevus Light to darkly pigmented lesion Often with increased hair growth 1/20,000 births
How is congential melanocytic nevus treated
Surgical excision or laser ablation (depending on type and size of lesion)
What is the prognosis for a congential melanocytic nevus
Large nevi are at risk of degeneration for need frequent follow up
What is an infantile hemangioma
AKA strawberry hemangioma
Occurs in 3-10% of infants
Mostly affects girls
Manifests during the first few days to months of life
Progressive presentation: blanching of skin → fine telangiectasias → red painless papule or macule (strawberry appearance)
Most commonly on head and neck
Usually solitary lesions
What is the pathophysiology of an infantile hemangioma
Abnormal development of vascular endothelial cells
Rapid proliferation followed by subsequent spontaneous slow involution (occurring at the age of 5–8 years)
How is infantile hemangioma diagnosed
Based on clinical findings
The differential diagnosis of a cherry angioma is found mostly in adults
How is infantile hemangioma treated
Active nonintervention: (monitoring, parental education)
Systemic therapy with propranolol in complicated cases:
- Rapidly growing cutaneous hemangiomas
- Periorbital hemangioma: vascular anomaly in the periorbital region, most commonly the upper eyelid
- Hemangiomas in the airways, gastrointestinal tract, or liver
- Hemangiomas with high risk of complications
If unresponsive to medication:
- Cryotherapy
- Laser therapy
- Resection if necessary
What are potential complications of an infantile hemangioma
Ulceration
Disfigurement
What is the prognosis for infantile hemangioma
Usually good prognosis
Spontaneous resolution is common
Visual impairment if periorbital hemangioma is left untreated
What is milia neonatorum
Definition: tiny epidermal papules caused by the buildup of keratin and sebaceous secretions
Clinical features: pinhead-sized lesions located on the face/trunk
Treatment: not necessary
Prognosis: benign skin lesion, spontaneous resolution without scarring
What are capillary malformations
Naevus flammeus, port-wine stain, firemark
Definition: congenital, benign vascular malformations of the small vessels in the dermis
Epidemiology: may occur in association with a neurocutaneous disorder such as Sturge-Weber syndrome
Clinical features: typically unilateral, blanchable, pink-red patches that grow and become thicker and darker with age
Treatment: cosmetic laser treatment if desired (not necessary)
Prognosis: benign skin lesion
What is transient neonatal pustular melanosis
AKA TNPM
Definition: a benign, transient, idiopathic neonatal skin condition
Epidemiology:
- Incidence: ∼ 2%
- Most commonly occurs in African American infants (5 %)
Clinical features:
- Solitary or clustered pustules and vesicles on a nonerythematous base
- Hyperpigmented, erythematous macules and collarettes of fine scale
- Most commonly affects the forehead, anterior neck, and lower back
Treatment: reassurance
Prognosis: benign, self-limiting skin lesion
What is nevus anemicus
Definition: a pale patch of skin that does not create erythema in response to trauma, heat, or cold
Etiology: caused by a vascular anomaly (increased sensitivity of cutaneous blood vessels to naturally occurring catecholamines)
Treatment: not required
What is LEOPARD syndrome
AKA Noonan syndrom with multiple lentigines
Lentigines: lenticular hyperpigmentation (dark macules)
Electrocardiographic conduction abnormalities
Ocular hypertelorism
Pulmonary stenosis
Abnormalities of genitalia
Retardation of growth
Deafness
What is blueberry muffin syndrome
A descriptive term for neonates born with multiple bluish, purple marks in the skin, which can be due to extramedullary erythropoiesis, purpura, or metastases.
The differential includes various cancers (e.g., rhabdomyoscarcoma), blood disorders (e.g., hemolytic disease of the new born), and congenital viral infections (e.g., rubella)
What are the risk factors for birth trauma
Macrosomia or anatomical abnormalities Extremely premature infants; low birth weight Abnormal fetal presentation Breech presentation Shoulder dystocia Forceps-assisted delivery or vacuum delivery Prolonged or rapid labor Small maternal stature
What are the potential neonatal soft tissue injuries
Soft tissue injuries of the scalp in infants are mostly caused by shearing forces during vacuum or forceps delivery.
Head molding:
- Transient deformation of the head into an elongated shape due to external compression of the fetal head as it passes through the birth canal during labor
- Typically resolves within a few days after the birth
Caput succedaneum:
- Benign oedema of the scalp tissue that extends across the cranial suture lines
- Firm swelling; pits if gentle pressure is applied
- No treatment required; resolves within hours or days
Cephalohematoma:
- Subperiosteal hematoma that is limited to cranial suture lines
- Complications: calcification of the hematoma, secondary infection
- No treatment required; resolves within several weeks or months
Subgaleal hemorrhage:
- Rupture of the emissary veins and bleeding between the periosteum of the skull and the aponeurosis that may extend across the suture lines
- Associated with a high risk of significant hemorrhage and hemorrhagic shock
How does a birth related clavicle fracture present clinically
Epidemiology: most common fracture during birth (∼ 2% of deliveries)
Clinical features: Usually asymptomatic Possible pseudoparalysis Bone irregularities, crepitus, and tenderness over the clavicle possible on palpation Possible brachial plexus palsy
How is a birth related clavicle fracture diagnosed
Clinical diagnosis
X-ray only indicated in cases of gross bone deformation
How is a birth related clavicle fracture treated
Reassurance and promote gentle handling of the arm (e.g., while dressing)
To avoid discomfort, pin shirt sleeve to the front of the shirt with the arm flexed at 90 degrees
Consider analgesics
Follow-up 2 weeks later to confirm proper healing: via clinical findings of a callus formation, and possibly an x-ray
Usually self-resolves within 2–3 weeks without surgical intervention or long-term complications
What is infant torticollis
Twisted or rotated neck caused by contraction of the sternocleidomastoid muscle
It can be acquired or congenital
What is the pathomechanism of infant torticollis
Acquired torticollis:
- Sternocleidomastoid or trapezius muscle injury
- Cervical muscle spasm
- Cervical nerve irritation
Congenital torticollis:
- Not fully understood; likely from muscular or skeletal injury during delivery with subsequent fibrosis and contracture of the sternocleidomastoid muscle
- Associated with:
- Intrauterine constraint, which causes unilateral shortening of the sternocleidomastoid muscle
- – Oligohydramnios
- – Multiple gestation
- – Macrosomia
- Decreased fetal movement
- Breech presentation
- Assisted vaginal delivery
What are the clinical features of infant torticolis
Head noticeably tilted to one side with the chin rotated towards the opposite side
Muscular tightness; limited passive range of motion
Potentially palpable thickening of the SCM
Conditions associated with congenital torticollis:
- Developmental dysplasia of the hips
- Brachial plexus palsy
- Clubfoot
- Craniofacial asymmetry
What are the differentials for infant torticollis
Postural preference Vertebral anomalies Absence of cervical musculature Ocular anomalies Underlying conditions (e.g. spina bifida)
How is infant torticollis treated
Early initiation of physiotherapy, passive positioning
Surgery at 12 months of age if conservative management is insufficient: myotomy or bipolar release of the affected SCM
What are the potential complications of infant torticollis
Craniofacial asymmetry
Scoliosis of the cervical spine
What are the important facts about facial nerve palsy due to birth trauma
Epidemiology: most common cranial nerve injury during birth
Pathomechanism:
- Injury occurs during forceps-assisted delivery (most common)
- Prolonged birth in which the head is pressed against the maternal sacral promontory
Clinical features
Peripheral facial nerve palsy: difficulty feeding, incomplete eye closure, absent nasolabial fold
Treatment: eye care with artificial tears and ointment
Prognosis: spontaneous recovery in 90% of cases within several weeks
What are the important facts about neonatal brachial plexus palsy due to birth trauma
Excessive lateral traction on the neck during delivery → injury to the upper trunk of the brachial plexus → Erb palsy (most common iatrogenic brachial plexus injury during delivery)
Excessive traction on the arm during delivery → injury to the lower trunk of the brachial plexus → Klumpke palsy
Prognosis: approx. 25% of affected infants experience persistent functional impairment
What is Shoulder dystocia
An obstetric emergency in which the anterior shoulder of the fetus becomes impacted behind the maternal pubic symphysis during vaginal delivery
Occurs in ~0.2-3% of births
What are the risk factors for shoulder dystocia
History of shoulder dystocia Fetal macrosomia Prolonged second stage of labor Maternal diabetes mellitus Maternal obesity
What are the clinical features of shoulder dystocia
Features of arrested active phase of labor
Turtle sign: the fetal head is partially delivered but retracts against the perineum
Failed restitution of the head
How is shoulder dystocia diagnosed
Clinical diagnosis
How is shoulder dystocia treated
The patient should stop bearing down and lie supine with the buttocks on the edge of the bed.
Perform shoulder dystocia maneuvers:
- First-line: McRoberts maneuver
- Any of the other internal maneuvers may be attempted to next (Rubin maneuver, Woods maneuver, Delivery of posterior arm)
- Move to another maneuver if delivery is not accomplished within 20–30 seconds.
- If all above maneuvers fail, attempt the all fours position.
Last-resort options:
- Fracture of fetal clavicle
- Zavanelli maneuver
- Symphysiotomy
What are the potential complications of shoulder dystocia
Fetal:
- Brachial plexus injury (Erb palsy is more common than Klumpke palsy)
- Clavicle or humerus fracture
- Hypoxia over an extended period of time as a result of umbilical cord compression
Maternal:
- Perineal lacerations
- Postpartum hemorrhage
What is chorioamnionitis
An intrauterine infection of the foetal membranes, placenta and amniotic fluid most commonly caused by bacteria ascending from the vagina
What is the aetiology of chorioamnionitis
Common bacteria:
- Ureaplasma urealyticum (up to 50% of cases)
- Mycoplasma hominis (up to 30% of cases)
- Gardnerella vaginalis
- Bacteroides
- Group B streptococcus
- E. coli
What are the risk factors for chorioamnionitis
Prolonged labor or premature rupture of membranes (PROM)
Pathological bacterial colonization of vaginal tract (e.g., STDs, frequent UTIs)
Iatrogenic: multiple digital vaginal exams, invasive procedures (e.g., amniocentesis)
What are the clinical features of chorioamnionitis
Maternal:
- Fever (> 38 °C or > 100°F)
- Tachycardia > 120/min
- Uterine tenderness, pelvic pain
- Malodorous and purulent amniotic fluid, vaginal discharge
- Premature contractions, PROM
Fetal tachycardia > 160/min in cardiotocography
How is chorioamnionitis diagnosed
Chorioamnionitis is a clinical diagnosis (fever plus ≥ 1 additional symptom).
Tests support or confirm diagnosis if the clinical presentation is ambiguous (e.g., in subclinical chorioamnionitis).
Maternal blood tests:
- Leukocytosis > 15,000 cells/μL (∼ 70–90% of cases)
- ↑ CRP
Bacterial cultures:
- Urogenital secretions
- Amniotic fluid (most reliable, but rarely conducted)
- Group B Streptococcus screening: cervicovaginal and rectal swabs
How is chorioamnionitis managed
Maternal antibiotic therapy:
- Vaginal delivery: IV ampicillin plus gentamicin (broad coverage)
- Cesarean delivery: IV ampicillin and gentamicin, plus clindamycin (anaerobe coverage to minimize postcesarean complications, e.g., endometritis)
Delivery:
- Swift delivery is generally indicated to minimize both maternal and fetal complications.
- Cesarean delivery is not generally indicated, but is often necessary because of obstetrical complications (e.g., insufficient contractions).
What are the potential complications of chorioamnionitis
Maternal:
- Uterine atony
- Postpartum hemorrhage
- Endometritis
- Septic shock
- DIC
- Venous thrombosis
- Pulmonary embolism
- Death
Fetal/neonatal:
- Fetal deat
- Premature birth
- Asphyxia
- Intraventricular hemorrhage
- Cerebral palsy
- Neonatal infection
What are the two types of neonatal infection/sepsis and their causes
Early-onset infection/sepsis:
- ≤ 6 days after delivery
- Common causes:
- -chorioamnionitis
- -bacterial colonization of the maternal genital tract (pathogen transfer to the infant)
- Common pathogens:
- -group B Streptococcus (GBS, Streptococcus agalactiae) and E. coli;
- -less common are Listeria monocytogenes, Staphylococcus aureus, Enterococcus, and Haemophilus influenzae.
Late-onset infection/sepsis:
- 7–89 days after delivery
- Common causes: hospital acquired infection
- Common pathogens: group B Streptococcus (GBS, Streptococcus agalactiae) and E. coli; less common are coagulase-negative Staphylococcus, Staphylococcus aureus, Klebsiella, Pseudomonas
What are the risk factors for neonatal infection/sepsis
Maternal:
- Fever
- PROM, premature labor
- Infections (e.g., UTI)
Fetal:
- Premature birth, low birth weight, low Apgar score
- Difficult delivery
- Asphyxia
- Intravascular catheter or nasal cannula (in late-onset sepsis)
What are the symptoms of neonatal infection/sepsis
General presentation:
- Nonspecific
- Irritability, lethargy, poor feeding
- Temperature changes (fever and hypothermia both possible)
- Cardiocirculatory: tachycardia, hypotension, poor perfusion, and delayed capillary refill > 3 sec
- Respiratory: tachypnea, dyspnea (e.g., expiratory grunting), apnea (more common in preterm infants)
- Skin tone: jaundiced and/or bluish-gray (indicates poor perfusion)
Specific symptoms:
- Neonatal meningitis
- Often no signs of meningism
- Early phase: general symptoms, vomiting
- Late phase: bulging fontanelles, shrill crying, seizures, stupor
- Neonatal pneumonia
- Tachypnea with intercostal/sternal retractions and nasal flaring
- Reduced oxygen saturation with cyanosis
How is neonatal infection/sepsis diagnosed
Blood cultures or urine culture for suspected UTI
-In GBS sepsis: blood agar plate reveals β-hemolytic, gram-positive cocci that enlarge the area of hemolysis formed by S. aureus
Blood tests:
- Leukocytopenia or leukocytosis, thrombocytopenia
- ↑ CRP
Lumbar puncture:
-Test cerebrospinal fluid for possible meningitis
Chest x-ray:
-May reveal clear signs of pneumonia (e.g., segmental infiltrates) but more often nonspecific with diffuse opacities
How is neonatal infection/sepsis managed
Supportive care (cardiopulmonary monitoring and support)
Broad-spectrum antibiotics: IV ampicillin and gentamicin
-Indications: clinical suspicion, confirmed or suspected maternal infection (e.g., chorioamnionitis)
Adapt therapy according to antibiogram results
What is the prophylaxis regime for GBS infection
Indication:
- Maternal GBS colonization
- Determined via culture of vaginal and rectal swabs
- Indicated between 36 0/7 – 37 6/7 weeks’ gestation
- Anytime GBS bacteriuria occurs during pregnancy or if a previous newborn had a GBS infection
- The presence of risk factors (e.g., chorioamnionitis, fever, ↑ CRP, premature contractions, PROM)
Medication:
- Intrapartum IV penicillin G or ampicillin (readminister every 4 hours until delivery)
- If previous mild penicillin reaction: IV cefazolin
- If severe penicillin allergy: clindamycin
What is the prognosis of neonatal infection/sepsis
May cause septic shock within hours if treatment is inadequate (mortality rate up to 50%)
The longer symptoms are present, the higher the risk of developing meningitis.
What is omphalitis
Bacterial infection of the umbilical stump occurring 3–9 days after delivery
What pathogens cause omphalitis
Staphylococcus aureus
Group A Streptococcus
E. coli
Klebsiella pneumoniae
Clostridium tetani: common cause of omphalitis and neonatal tetanus in developing countries
What are the symptoms of omphalitis
Periumbilical redness, tenderness, swelling, and hardening
Purulent discharge
Signs of systemic infection
How is omphalitis diagnosed
Generally a clinical diagnosis, although cultures should be conducted
Bacterial cultures: pathogen identification and antibiogram (sample of discharge)
In systemic infection: blood and cerebrospinal fluid cultures (detection of sepsis and meningitis)
How is omphaliitis managed
Broad-spectrum IV antibiotics: antistaphylococcal penicillin (e.g., oxacillin) PLUS aminoglycoside (e.g., gentamicin)
Surgery: complete debridement if complications arise
What are the complications of omphalitis
Sepsis
Necrotizing fasciitis and myonecrosis (infectious muscle involvement): rare; associated with high mortality rates
How is omphalitis presented
Keep the navel dry (frequent diaper change)
Observe general hygiene measures
What is neonatal respiratory distress syndrome
AKA surfactant deficiency disorder
A lung disorder in infants that is caused by a deficiency of pulmonary surfactant
What is the aetiology of neonatal respiratory distress syndrome
It is caused by impaired synthesis and secretion of surfactant
What are the risk factors for neonatal respiratory distress syndrome
- Premature birth
- Maternal diabetes (leading to increased fetal insulin, which inhibits surfactant synthesis)
- Hereditary
- C section delivery (results in lower levels of fetal glucocorticoids than in vaginal delivery, in whiich higher levels are released as a response to stress from uterine contractions)
- Hydrops fettles
- Multiple pregnancies
- Male sex
What is the epidemiology of neonatal respiratory distress syndrome
Incidence:
- 1% of all newborns
- 10% of all preterm babies
The risk of developing NRDS depends on gestational age:
- < 28 weeks of gestation: > 50%
- > 37 weeks of gestation: < 5%
What is the pathophysiology of NRDS
Pulmonary surfactant is a mixture of phospholipids and proteins produced by lamellar bodies of type II alveolar cells.
These phospholipids reduce alveolar surface tension, preventing the alveoli from collapsing.
Surfactant deficiency is most likely to occur in preterm infants, because:
- Surfactant production begins at approximately 20 weeks gestation.
- Distribution throughout the lungs begins at 28-32 weeks’ gestation and does not reach sufficient concentration until 35 weeks gestation.
Surfactant deficiency → little or no reduction of alveolar surface tension → increased alveolar collapse → atelectasis → decreased lung compliance and functional residual capacity → hypoxemia and hypercapnia
Hypoxemia and hypercapnia → vasoconstriction of the pulmonary vessels (hypoxic vasoconstriction) and respiratory acidosis → intrapulmonary right-to-left shunt → increased permeability due to alveolar epithelial damage → fibrinous exudation within the alveoli → development of hyaline membranes in the lungs (hyaline membrane disease)
What are the clinical features of NRDS
- Maternal history of premature birth
- Onset of symptoms is usually immediately after birth but can occur up to 72 hours postpartum
- Signs of increased respiratory effort:
- Tachypnea
- Nasal flaring
- moderate to severe subcostal/intercostal and jugular retractions
- Characteristic expiratory grunting
- Decreased breath sounds on auscultation
- Cyanosis due to pulmonary hypoxic vasoconstriction
How is NRDS diagnosed
Physical exam
Maternal history
X ray chest:
- Interstitial pulmonary oedema with perihilar streaking
- Diffuse, fine, reticulogranular (ground-glass) densities with low lung volumes and air bronchograms
- Atelectasis
Blood gas analysis:
- Hypoxia with respiratory acidosis may lead to increased lactate levels
- Evaluate for partial respiratory failure or global respiratory failure
Amniocentesis for prenatal testing of NRDS:
- screening for markers of fetal lung immaturity
- Lecithin-sphingomyelin ratio <1.5 (≥ 2 is considered mature)
- Foam stability index <0.48
- Low surfactant-albumin ratio
Histological findings:
- Hyaline membranes lining the alveoli
- Composed of fibrin, cellular debris and red blood cells
- Eosinophilic appearance, amorphous material lining the alveolar surface
- Engorged and congested capillary vessels in the interstitium
What are the differentials for NRDS
Pulmonary hypoplasia
Congenital diaphragmatic hernia
Pneumothorax
Neonatal pneumonia
WHat is pulmonary hypoplasia
Underdevelopment of the lungs characterised by a decreased number of alveoli and small airways and reduced lung volumes in on eor both lobes
Results in impaired gas exchange and severe respiratory distress that may require intubation
Associated with congenital diaphragmatic hernia (usually left-sided), oligohydramnios, and Potter sequence
How is NRDS treated
Ventilation:
- Nasal CPAP with a PEEP of 3–8 cm H2O
- If respiratory insufficiency persists, start intubation with mechanical ventilation and O2 inhalation.
Endotracheal administration of artificial surfactant within 2 hours postpartum
Supportive measures: IV fluid replacement; stabilization of blood sugar levels and electrolytes
What is physiological O2 saturation in neonates
Around 90%
A saturation 100% is considered toxic for neonates
What are the potential complications of NRDS
- Bronchopulmonary dysplasia
- Pneumothorax
- Hypoxia
- Patent ductus arteriosus (the persistently low partial pressure of oxygen in the blood contributes to PDA)
- Cardiovascular arrest
- Neonatal sepsis
Complications of O2 inhalation: -Retinopathy of prematurity -Bronchopulmonary dysplasia -Intraventricular hemorrhage (Baby Oxen have RIBs)
What is the prognosis of NRDS
Mortality rate <10%
Most cases resolve within 3-5 days if treated promptly
How is NRDS prevented
Prevent premature birth where possible (use of tocolysis to slow down)
Antenatal corticosteroid therapy administered to the mother to stimulate infant lung maturation:
-48 hours before delivery
-2 doses of IM betamethasone 24 hours apart or 4 doses of IM dexamethasone 12 hours apart
What is a teratogen
An environmental factor that causes a permanent structual or functional abnormality, growth restriction or death of the embryo or foetus
How can the physical effects of teratogens characteritically present
VACTERL association: Vertebral, Anal, Cardiac, Tracheoesophageal fistula, Renal, and Limb abnormalities - All due to a defect during the development of embryonic mesoderm
What are the types of limb deformities due to teratogens
Syndactyly: fusion of two or more fingers or toes (most common congenital malformation of the limbs)
Polymelia/polydactyly: supernumerary limbs, fingers, or toes
Oligodactyly, adactyly: absence of one or more of the fingers or toes
Ectromelia: collective term for hypoplasia and/or aplasia of one or more long bones, resulting in limb deformity
Peromelia/perodactyly: amputation-like stump of a limb, finger, or toe
What is the pathophysiology of diabetic embryopathy
In first trimester
Hyperglycemia → inhibition of myoinositol uptake → abnormalities in the arachidonic acid-prostaglandin pathway → birth defects and spontaneous abortion
What are the effects of diabetic embryology
Congenital heart disease:
- transposition of the great vessels,
- ventricular septal defect,
- truncus arteriosus,
- tricuspid atresia,
- patent ductus arteriosus,
- dextrocardia
Neural tube defects
Caudal regression syndrome:
- Definition: rare structural anomaly of the caudal region
- Clinical features:
- Mild to severe motor function impairment, paralysis, and/or bladder incontinence
- Anorectal malformations and sacral agenesis (aplasia or hypoplasia of the sacrum and/or lumbosacral spine)
- Lower limb or foot deformities are common.
- Prognosis: severe disease in the neonatal period that often results in infant death secondary to cardiac and renal complications
Duodenal atresia
Small left colon syndrome: self-limiting inability to pass meconium
Vertebral anomalies
Cleft palate
Flexion contracture of the limbs
Renal agenesis
What is the pathophysiology of diabetic fetopathy
In the second and third trimester
Chronic fetal hyperglycemia → fetal hyperinsulinemia, islet cell hyperplasia, ↑ insulin-like growth factor, and ↑ growth hormones → ↑ metabolic effects and oxygen demand → fetal hypoxemia
What are the effects of diabetic fetopathy
Macrosomia (increased risk of birth injuries)
Polycythemia (associated with an increased risk of hyperviscosity syndrome and hyperbilirubinemia)
Neonatal hypoglycemia
Electrolyte imbalances (hypocalcemia, hypomagnesemia)
Respiratory distress (due to insufficient production of pulmonary surfactant)
Hypertrophic cardiomyopathy (polycythemia → redistribution of iron → iron deficiency in cardiac tissue and hypoxemia → impaired cardiac remodeling)
Polyhydramnios (fetal hyperglycemia → fetal polyuria)
What can be the consequence of maternal graves disease
Neonatal thyrotoxicosis Microcephaly Frontal bossing and triangular facies Craniosynostosis Developmental and behavioral problems
What can be the consequence of maternal hypothyroidism
Congenital hypothyroidism with a possible congenital iodine deficiency syndrome
What can be the consequence of maternal obesity in pregnancy
Neural tube defects
Cleft lip and cleft palate
Congenital heart disease
Limb reduction abnormalities
What can be the consequence of phenylketonuria
IUGR
Microcephaly
Intellectual disability
Congenital heart disease
What is the epidemiology of fetal alcohol syndrome
Most common cause of teratogenic damage in children (0.2–1.5 per 1,000 live births) [10]
Most common preventable cause of intellectual disability in the US
What is the pathophysiology of fetal alcohol syndrome
Failed neuronal and glial cell migration
What are the clinical features of fetal alcohol syndrome
Dysmorphic features:
- Thin upper lip
- Smooth hypoplastic philtrum (the vertical groove between the middle of the upper lip and the nose)
- Down-slanting, short palpebral fissures (the opening between the upper and lower eyelid, defined as the elliptical space between the medial and lateral canthi of the open eye)
- Hypertelorism
- Microcephaly
- Epicanthal folds
- Receding chin
Features of specific systemic defects:
- Heart defects (mainly ventricular septal defect)
- Heart-lung fistulas
- Skeletal anomalies (limb dislocations, joint contractures, pectus excavatum/pectus carinatum)
- Renal anomalies (aplastic/dysplastic kidneys) leading to hypertension
- Prenatal or postnatal growth retardation → short stature
- Holoprosencephaly: a developmental field defect, in which the forebrain fails to divide into two hemispheres resulting in fusion of ventricles (leading to the formation of monoventricle) and other bilateral cerebral structures, e.g., basal ganglia
- Typically occurring during the 3rd–4th week of pregnancy
- Potential genetic causes include:
- – Mutations in SHH gene coding for sonic hedgehog protein
- – Trisomy 13
- Associated clinical features:
- – Craniofacial abnormalities (cyclopia and/or cleft lip/palate)
- – Endocrine disorders related to pituitary dysfunction (e.g., diabetes insipidus)
- – Seizures and epilepsy
Hyperactivity, intellectual disability (e.g., impaired language development, learning disabilities, memory deficits), and subsequent problems in social interactions and school performance
What are potential differentials for fetal alcohol syndrome
Down syndrome
Fragile-X syndrome
Williams syndrome
What is the pathophysiology of smoking cigarettes during pregnancy
Nicotine:
↑ catecholamine release → vasoconstriction of uteroplacental blood vessels → compromised blood flow and oxygen delivery to the fetus
Carbon monoxide:
↑ COHb causes tissue hypoxia
What are the effects of cigarette smoking in pregnancy
Intrauterine growth restriction and low birth weight
Increased risk of preterm labor and miscarriage (e.g., due to placental abnormalities such as placental abruption)
Attention deficit hyperactivity disorder (ADHD) and conduct disorder
Sudden infant death syndrome (SIDS)
Cleft lip and palate
What can result from opioid use during pregnancy
Fetal dysgenesis
Placental abruption
Respiratory depression
Neonatal abstinence syndrome
What can result from cocaine use during pregnancy
Causes vasoconstriction in the placental vessels
Intrauterine growth retardation and low birth weight
Increased risk of preterm labor and placental abruption
What was Diethylstilbestrol used for previously
A synthetic estrogen that is primarily used to prevent miscarriages in expectant mothers
What were the adverse effects found in use of Diethylstilbestrol, leading to it’s approval being revoked
Vaginal clear cell adenocarcinoma
Congenital anomalies of the Müllerian duct
What was Thalidomide used for previously
A sedative that was used to treat nausea or vomiting in pregnant women (now administered in limited indications, e.g., multiple myeloma)
What were the adverse effects found in use of Thalidomide, leading to it’s approval being revoked for use in pregnancy
Thalidomide embryopathy:
- Symmetrical amelia (complete absence of limbs)
- Micromelia (“flipper limbs”)
- Anotia (absence of the external ear)
- Phocomelia: a teratogenic limb defect that is characterized by the absence of the proximal portion of a limb (hand or foot are directly attached to the shoulder or hip)
What are the potential effects from radiation exposure during pregnancy
Chromosomal damage or cell death leading to:
- Microcephaly
- Intellectual disability
- Growth restriction
- Malignancy
What are the potential effects of maternal lead toxicity
Spontaneous abortion
Stillbirth
Hemangiomas, lymphangiomas, hydroceles, skin tags, undescended testes
VACTERL
What are the potential effects of maternal mercury toxicity
Cerebellar atrophy
Atrophy of the visual brain cortex
Polyneuritis
What is sudden infant death syndrome
SIDS
The abrupt and unexplained death of an infant
Diagnosis requires that a forensic examination reveals no other cause of death
What is the epidemiology of SIDS
Peak incidence at 2-6 months
In rare cases during the first days of life
Male>female
Over 90% of SIDS occur during sleep
What is the aetiology of SIDS
Unclear but suggests that caused by a combination of both extrinsic and intrinsic factors which ultimately lead to acute or chronic hypoxia
Extrinsic factors (triggers):
- Sleeping in the prone position
- Exposure to nicotine during pregnancy and after birth (including 2nd-hand smoking)
- Overheating
- Unsafe sleeping environment or CO2 rebreathing: e.g., a shared blanket, stuffed animals in the crib (because of the grasping reflex, newborns tend to drag items to their faces)
- Many more correlations:
- SIDS in siblings,
- babies born prematurely,
- young mothers (< 20 years),
- low socioeconomic status, etc.
Intrinsic factors:
-Brainstem disorder that includes morphologic/ biochemical abnormalities of serotonin (known as 5-hydroxytryptamine or 5-HT), which impacts the respiratory drive, the ability to wake up, blood pressure, upper respiratory reflexes , and body temperature.
How is SIDS diagnosed
Diagnosis of exclusion.
If there is an unexplained death of an apparently healthy infant, an autopsy is required by law to rule out other causes of death.
Differentials:
- Congenital anomalies that could lead to infant death (e.g., cardiac anomalies)
- Intentional suffocation; evidence of battered child syndrome
What is an apparent life-threatening event of an infant (ALTE)
A sudden and unexpected event occurring in an infant that is considered life-threatening by the observer and is characterized by some combination of the following:
- Apnea
- Changes in skin color (usually cyanosis or pallor) and/or muscle tone (e.g., rigidity, floppiness)
- Choking/gasping
May occur when the infant is awake or asleep
Not associated with SIDS
What is the epidemiology of ALTE
Reported incidence is 0.05-6%
What is the aetiology of ALTE
Most common causes:
- seizure,
- respiratory tract infection,
- gastroesophageal reflux,
- cardiac conditions (e.g., arrhythmia)
Associated risk factors:
- age < 10 weeks,
- prematurity,
- prior ALTE,
- feeding difficulties,
- and/or symptoms of upper respiratory infection
What is the prognosis of ALTE
Recurrence is high but overall mortality is low (<1%)
How is SIDS prevented
Parents should receive information on how to prevent SIDS during prenatal care and in pediatric check-ups after birth.
During pregnancy:
- No smoking, alcohol, or recreational drugs
- Prenatal care
Protective factors after birth:
- The infant should be placed to sleep in the supine position
- Safe sleep environment:
- firm mattress;
- no:
- – pillows,
- – blankets,
- – stuffed animals,
- – bumper pads in the crib.
- In the first 6 months, co-sleeping in the same room without bed-sharing
- Second-hand smoke and overheating should be avoided
- Use of pacifier during sleep
- Breastfeeding until the 4th–6th month
- “Tummy time”
- Immunization in line with the official schedule
What causes congenital infections
Pathogens transmitted from mother to child during pregnancy (transplacentally) or delivery (permpartum)
What does the acronym TORCH stand for
Toxoplasmosis
Others:
- Syphilis (Treponema pallidum)
- Listeriosis
- Varicella zoster virus
- Parovirus B19 infection
Rubella virus
Cytomegalovirus (CMV)
Herpes simplex virus (HSV)
What are congenital TORCH infections
Vertically transmitted infections (acquired directly from the mother and transmitted to the embryo, fetus or newborn through the placenta or birth canal) that are capable of significantly influencing fetal and neonatal morbidity and mortality
Which vaccines are contraindicated in pregnancy
Live vaccines: measles, mumps, rubella and varicella
Conception should be avoided for 1 months after immunisation with live vaccines
How common is congenital toxoplasmosis
~0.5-1 : 10,000 live births per year
Which pathogen causes congenital toxoplasmosis
Toxoplasma gondii
How is toxoplasmosis transmitted to a newborn
Mother:
- Cat feces
- Raw or insufficiently cooked meat
- Unpasteurized milk (especially goat milk)
Fetus:
- Transplacental transmission
- First trimester: ∼ 15%
- Third trimester: ∼ 70%
What are the clinical features of congenital toxoplasmosis
First trimester:
- Increased risk of premature birth and spontaneous abortion
- Classic triad of toxoplasmosis
- Chorioretinitis (a form of posterior uveitis)
- Diffuse intracranial calcifications
- Hydrocephalus
- Possible other nonspecific clinical features:
- Petechiae and purpura (blueberry muffin rash)
- Fever
- Jaundice
- Hepatosplenomegaly
- Lymphadenopathy
- Pneumonitis
- Seizures
- Macrocephaly or microcephaly
- Thrombocytopenia
Second or third trimester:
-Subclinical or mild toxoplasmosis
Sequelae of congenital toxoplasmosis:
- Epilepsy
- Intellectual disability
- Visual disabilities (chorioretinitis → increased risk of retinal lesions , cataracts, and glaucoma)
- Sensorineural hearing loss
How is congential toxoplasmosis diagnosed
Fetus:
-PCR for T.gondii in amniotic fluid
Newborn:
-CT/MRI: intracranial calcifications, hydrocephalus, ring-enhancing lesions
-T. gondii-specific IgM antibodies (CSF, serum)
PCR forT. gondii DNA (CSF, serum)
-Ophthalmological evaluation: chorioretinitis
How is congential toxoplasmosis treated
Mother: immediate administration of spiramycin to prevent fetal toxoplasmosis
Fetus: When confirmed or highly suspected, switch to pyrimethamine, sulfadiazine, and folinic acid.
Newborn: pyrimethamine, sulfadiazine, and folinic acid
What are the 4 Cs pf congenital toxoplasmosis
Cerbral calcifications
Chorioretinitis
hydroCephalus
Convulsions
How can congenital toxoplasmosis be prevented
Avoid raw, undercooked, and cured meats.
Wash hands frequently, especially after touching soil (e.g., during gardening).
Avoid contact with cat litter.
How common is congenital syphilis
~23:100,000 live births per year in US
What pathogen causes congenital syphilis
Treponema pallidum
How is congenital syphilis transmitted
Mother:
-Sexual contact (contact with infectious lesion)
Fetus:
- Transplacental transmission from infected mother
- Increased risk of transmission with recent syphilis infection
- Risk of transmission increases with gestational age
Neonate:
-Perinatal transmission during birth
How does congenital syphilis present
In utero syphilis:
- Miscarriage
- Stillbirth
- Hydrops fetalis
Early congenital syphilis (onset < 2 years of age):
- Hepatomegaly and jaundice
- Rhinorrhea with white or bloody nasal discharge (also called “snuffles”)
- Maculopapular rash on palms and soles; a bullous form of the rash called pemphigus syphiliticus may be present at birth.
- Skeletal abnormalities (e.g., metaphyseal dystrophy, periostitis)
- Generalized lymphadenopathy (nontender)
Late congenital syphilis (onset > 2 years of age):
-Typical facial features:
– saddle nose,
– frontal bossing,
– short maxilla
-Dental findings:
– Hutchinson’s teeth (notched, widely spaced teeth);
– mulberry molars (poorly developed first molars)
-Eyes and ears
– Syphilitic keratitis: nonulcerative, interstitial keratitis that develops as a late complication of syphilis
(More common in patients with congenital syphilis than acquired syphilis. Causes stromal inflammation)
– Sensorineural hearing loss
-Skin: rhagades (perioral fissures, cracks, and/or scars, particularly near the corners of the mouth and nose)
-Skeletal
– Saber shins: An anterior bowing of the tibia, causing it to resemble a saber
(Other causes include rickets and Paget disease of bone.)
– Painless arthritis in knees and other joints
-Neurological:
– cranial nerve palsies (e.g., CN VIII defect causing deafness),
– intellectual disability,
– hydrocephalus
How is congenital syphilis diagnosed
Newborn and mother:
- Initial test: Rapid Plasma Reagin (RPR) or Venereal Disease Research Laboratory (VDRL) (serum)
- Confirmatory test: dark-field microscopy or PCR of lesions or bodily fluids
Fetus:
-repeated ultrasound examinations (looking for placentomegaly, hepatomegaly, ascites, and/or hydrops fetalis)
How is congenital syphilis treated
10 days IV penicillin G for both pregnant women and newborns
How is congenital syphilis prevented
Maternal screening and, if positive, antibiotic treatment: should take place in early pregnancy because placental transmission is most likely to occur after the first trimester.
Nationally notifiable condition: Congenital syphilis and syphilitic childbirth must be reported
WHat is Hutchinson triad
Triad of common symptoms of congenital syphilis
Interstitial keratitis
Sensorineural hearing loss
Hutchinson teeth
How common is congenital listeriosis
~3:100,000 live births per year in the US
Which pathogen causes congenital listeriosis
Listeria monocytogenes
How is congenital listeriosis transmitted
Mother:
- Contaminated food: especially raw milk products
- Other possible sources: fish, meat, and industrially processed vegetables (e.g., ready-made salads)
Fetus:
- Transplacental transmission from an infected mother
- Direct contact with infected vaginal secretions and/or blood during delivery
What are the clinical features of congenital listeriosis
Listeriosis of pregnancy:
- Increased risk of premature birth and spontaneous abortion
- Early-onset syndrome: granulomatosis infantiseptica
- Severe systemic infection characterized by disseminated abscesses (may develop in any organ system)
- Most common findings: respiratory distress and skin lesions
- Signs of meningitis may already develop.
Neonatal listeriosis:
-Late-onset syndrome (5 days to 3 weeks after birth): Listeria meningitis/encephalitis
How is congenital listeriosis diagnosed
Culture from blood or CSF samples (pleocytosis)
How is congenital listeriosis treated
IV ampicillin and gentamicin for both mother and newborn
How is congenital listeriosis prevented
Avoidance of soft cheese
Avoidance of potentially contaminated water and food
Notifiable condition so report to public health
How common is congenital varicella infection
Seroprevalence in the general population is ∼ 95%.
Most mothers have been vaccinated, so congenital infection is rare (< 2%).
Which pathogen causes congenital varicella infection
Varicella zoster virus
How is congenital varicella infection transmitted
Mother:
- Primary infection
- Airborne droplets
- Direct skin contact with vesicle fluid
- Reactivation: usually in immunocompromised individuals
- Chickenpox and Shingles
Fetus:
-Transplacental transmission from an infected mother
What are the clinical features of congenital varicella infection
Congenital varicella syndrome (infection during first and second trimester):
- Hypertrophic scars (cicatricial skin lesions)
- Limb defects (e.g., hypoplasia)
- Ocular defects (e.g., chorioretinitis, cataracts, microphthalmia)
- CNS defects (e.g., cortical atrophy, seizures, intellectual disability)
- Hydrocephalus
Neonatal varicella:
- Mild infection (maternal exanthem (rash) > 5 days before birth)
- Severe infection (maternal exanthem (rash) < 5 days before birth):
- hemorrhagic exanthem,
- encephalitis, pneumonia, or
- congenital varicella syndrome (mortality rate of up to 30%)
How is congenital varicella infection diagnosed
Newborn and mother:
- Usually clinical diagnosis is confirmed by appearance of skin lesions
- DFA or PCR of fluid collected from blisters or cerebrospinal fluid (CSF)
- Serology
Fetus:
-PCR for VZV DNA (in fetal blood, amniotic fluid) and ultrasound to detect fetal abnormalities
How is congenital varicella infection treated
For pregnant women or newborns with (severe) infection: acyclovir
Administer postexposure prophylaxis in newborns if mother displays symptoms of varicella < 5 days before delivery:
-IgG antibodies (varicella-zoster immune globulin, VZIG)
Cesarean delivery if lesions are present at the delivery
Breastfeeding is encouraged because of the possible protective effect of antibodies in breast milk.
How is congenital listeriosis prevented
Immunization of seronegative women before pregnancy
VZIG in pregnant women without immunity within 10 days of exposure
Nationally notifiable condition
How common is congenital parvovirus B19 infection
∼ 5% incidence in pregnant women per year in the US
Higher prevalence in daycare workers and primary school teachers
What causes congential parvovirus B19
Pathogen: parvovirus B19
Mechanism of action: infection of erythrocyte progenitor cells in bone marrow and endothelial cells by attaching to their P antigen → cell destruction → hydrops fetalis in neonates and pure RBC aplasia in adults
How is congential parvovirus B19 transmitted
Mother
- Mainly via aerosols
- Rarely hematogenous transmission
- See “Fifth disease.”
Fetus: transplacental transmission from infected mother
How does congential parvovirus B19 present
Severe anemia and possibly fetal hydrops
Fetal demise and miscarriage/stillbirth in approximately 10% of cases (Risk is highest in the first and second trimesters.)
Most intrauterine infections do not result in fetal developmental defects.
What is fetal hydrops
A fetal condition characterized by generalized edema and accumulation of fluid in serous cavities (e.g., pleural effusion, pericardial effusion, ascites).
Diagnosed via ultrasound.
Aetiologies include severe fetal anemia (e.g., hemolytic disease of the newborn, hemorrhage), congenital infections (e.g., parvovirus B19), chromosomal abnormalities, and congenital heart defects.
Associated with a high rate of perinatal mortality.
How is congential parvovirus B19 diagnosed
Mother:
Serologic assays for IgG and IgM against parvovirus B19
Fetus:
- PCR for parvovirus B19 DNA (amniotic fluid or blood)
- Doppler ultrasound of fetal vessels in suspected hydrops fetalis (every 1–2 weeks)
- In cases of suspected anemia according to Doppler ultrasound, fetal hemoglobin levels are determined via the umbilical vein.
How is congential parvovirus B19 treated
Intrauterine fetal blood transfusion in cases of severe fetal anemia
Additional platelet transfusion if thrombocytopenia is also present
How is congential parvovirus B19 prevented
Hand hygiene (frequent hand washing)
Pregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics).
How common is congenital rubella infection
Most mothers have been vaccinated so congenital infection is very rare
What pathogen causes congenital rubella infection
Rubella virus
How is congential rubella infection transmitted
Mother:
Mainly via airborne droplets
Fetus:
- Transplacental from infected mother
- Risk of fetal infection is high in the first trimester, decreased in the second trimester and then increased again in the third trimester.
- Risk of congenital rubella syndrome:
- 1–12 weeks gestation (period of organogenesis): highest risk
- 12–20 weeks gestation: very low
- > 20 weeks gestation: no documented cases
How does congenital rubella infection present
Intrauterine rubella infection:
- miscarriage,
- preterm birth,
- fetal growth restriction (especially likely if infection occurs during the first trimester)
Congenital rubella syndrome:
- Triad of symptoms:
- Cardiac defect: most common defect (e.g., patent ductus arteriosus, pulmonary artery stenosis)
- Cataracts: Other eye manifestations may also occur later in life, including glaucoma and salt and pepper retinopathy (abnormal retinal pigmentation)
- Cochlear defect: bilateral sensorineural hearing loss
- Early features:
- Hepatosplenomegaly, jaundice
- Hemolytic anemia, thrombocytopenia
- Petechiae and purpura, i.e., blueberry muffin rash (due to extramedullary hematopoiesis in the skin)
- Transient meningitis and/or encephalitis
- Pneumonia
- Late features
- CNS defects: microcephaly, intellectual disability, panencephalitis
- Skeletal abnormalities
- Endocrine disorders (e.g., diabetes, thyroid dysfunction)
- Vascular disease
- Immune defects
How is congenital rubella infection diagnosed
Newborn and mother:
- PCR for rubella RNA (throat swab, CSF)
- Serology (abnormally high or persistent concentrations of IgM and/or IgG antibodies)
- Viral culture (nasopharynx, blood)
Fetus:
- IgM antibody serology (chorionic villi, amniotic fluid)
- PCR for rubella RNA (chorionic villi, amniotic fluid)
How is congenital rubella infection treated
Intrauterine rubella infection:
- < 16 weeks: Counsel about potential maternal-fetal transmission and the possibility of terminating the pregnancy.
- > 16 weeks: reassurance and symptomatic therapy (e.g., acetaminophen)
Congenital rubella syndrome:
-supportive care (based on individual disease manifestations) and surveillance (including monitoring for late-term complications)
How is congenital rubella infection prevented
Immunization of seronegative women before pregnancy
Nationally notifiable condition
What is the CCC triad of congenital rubella syndrome
Cataracts
Cochlear defects
Cardiac abnormality
How common is congenital CMV infection
~0.5%-1% of live births per year in the US
What is the pathogen that causes congenital CMV infection
Cytomegalovirus
How is congenital CMV infection transmitted
Mother: via CMV-contaminated blood, urine, saliva, and genital secretions:
- Blood transfusions
- Sexual transmission
- Droplet transmission
- Transplant-transmitted infection (e.g., bone marrow, lungs, kidneys)
Fetus: transplacental transmission from an infected mother
Newborn: during birth or postnatal via breastmilk from infected mother
How does congenital CMV infection present
Fetal infection:
- Increased risk of fetal demise
- IUGR
- Oligohydramnios or polyhydramnios, placental abnormalities
Newborn infection:
- Severity
- Subclinical infection (∼ 90%): ∼ 10% go on to develop a late complication (most commonly hearing loss)
- Symptomatic infection at birth (∼ 10%): ∼ 70–80% go on to develop a late complication.
- CNS findings
- Hydrocephalus
- Microcephaly .
- Sensorineural hearing loss (∼ 30%)
- Chorioretinitis (∼ 10%)
- Nonspecific findings (similar to other TORCH infections)
- Petechiae, purpura (blueberry muffin rash)
- Hepatosplenomegaly, jaundice
- Small for gestational age (SGA)
- Seizures, lethargy, poor suck
- Hemolytic anemia, thrombocytopenia
- Pneumonia
- Late complications
- Hearing loss, vision impairment
- Psychomotor retardation, intellectual disability
- Dental abnormalities
How is congential CMV infection diagnosed
Fetus and newborn
- CNS imaging:
- hydrocephalus,
- periventricular calcifications,
- intraventricular hemorrhage
- Ultrasound:
- periventricular calcifications,
- hyperechogenic foci (bowel and liver, ascites)
- hydrops fetalis
Newborn and mother:
- CMV IgM antibodies (blood)
- Viral culture or PCR for CMV DNA (urine, saliva)
Fetus
- Viral culture or PCR for CMV DNA (amniotic fluid)
- CMV IgM antibodies (fetal blood)
What is the differential in suspected congenital CMV infection
Congenital toxoplasmosis:
- Causes chorioretinitis, hydrocephalus, and intracranial calcifications
- Intracranial calcifications in congenital toxoplasmosis typically show ring-enhancement.
How is congenital CMV infection treated
Fetus:
- Severe anemia: intrauterine blood transfusions
- Thrombocytopenia: platelet transfusions
Newborn:
- Supportive therapy of symptoms (e.g., fluid and electrolyte imbalances, anemia, thrombocytopenia, seizures, secondary infections)
- Ganciclovir, valganciclovir, or foscarnet
Mother:
-Valacyclovir is the only therapy approved during pregnancy
How is congenital CMV infection prevented
Frequent hand washing, especially after contact with bodily secretions of small children (e.g., diaper changing)
Avoidance of food sharing with children
Avoidance of kissing small children on the mouth
How common is congenital herpes simplex virus infection
~1:3,000-10,000 live births per year
What pathogen causes congenital herpes simplex virus infection
Mainly HSV-2; in rare cases HSV-1
How is congenital HSV infection transmitted
Mother:
- Primary infection: contact with contaminated oral secretions via small skin lesions
- Reactivation: usually in immunocompromised individuals
Fetus:
-transplacental transmission from an infected mother (rare)
Newborn: perinatal transmission during birth (∼ 30% transmission rate if mother has not yet undergone seroconversion at time of delivery)
How does congential HSV infection present
Intrauterine HSV infection (∼ 5% of cases):
- Fetal demise, preterm birth, very low birth weight
- Microcephaly, hydrocephalus, and other CNS defects
- Microphthalmia and chorioretinitis
- Vesicular skin lesions
Perinatal and postnatal transmission:
- Skin, eye, and mouth disease
- Vesicular skin lesions
- Keratoconjunctivitis leading to cataracts, chorioretinitis
- Vesicular lesions of oropharynx
- CNS disease
- Meningoencephalitis (manifesting with fever, lethargy, irritability, poor feeding, seizures, bulging fontanelle)
- Possibly vesicular skin lesions
- Disseminated disease
- Features similar to those of sepsis, with organ involvement (e.g., liver, CNS, lungs, heart, adrenal glands, kidneys, GI tract)
- Vesicular skin lesions (may not appear until late in disease course)
How is congenital HSV infection diagnosed
Mother: typically a clinical diagnosis
Fetus: The ultrasound may show CNS abnormalities.
Newborn (and mother)
- Standard: viral culture of HSV from skin lesions, conjunctiva, oro/nasopharynx, or rectum
- Alternative: PCR for HSV DNA (CSF, blood)
How is congenital HSV infection treated
Newborn and mother: IV acyclovir or valacyclovir
Additionally in newborns: supportive therapy of fluid/electrolyte imbalances, SIRS, septic shock, seizures, secondary infections, etc.
How is congential HSV infection prevented
Antiviral therapy (acyclovir) beginning at 36 weeks of gestation for individuals with a known history of HSV lesions
Cesarean delivery in women with active genital lesions or prodromal symptoms (e.g., burning pain)
How is neonatal jaundice treated
Phototherapy:
- Primary treatment in those with unconjucated hyperbilirubinaemia
- Procedure:
- Exposure to blue light (non-UV, wavelength: 420–480 nm) → photoisomerization (major mechanism) and photooxidation (minor mechanism) of unconjugated (hydrophobic) bilirubin in skin to water-soluble forms → excretion of water-soluble form in urine and/or bile
- Continued until total bilirubin levels < 15 mg/dL
- Adequate fluid supplementation to prevent dehydration
- Eye protection to prevent retinal damage
- Contraindications:
- Concomitant use of photosensitizing medications
- Congenital erythropoietic porphyria
- Family history of porphyria
Exchange transfusion:
- Most rapid method for lowering serum bilirubin concentrations
- Indications
- Threshold in a 24-hour-old term baby is a total serum bilirubin value > 20 mg/dL
- Inadequate response to phototherapy, or a rapid rise in the total serum bilirubin level (> 1 mg/dL/hour in less than 6 hours)
- Acute bilirubin encephalopathy
- Hemolytic disease, severe anemia
- Procedure
- Use ABO-matched and Rh-negative erythrocyte concentrate.
- Exchange blood in quantities of 5–20 mL via an umbilical venous catheter until total serum bilirubin is < 95thpercentile on nomogram.
- Side effects
- Higher mortality and morbidity from infections
- Acidosis
- Thrombosis
- Hypotension
- Electrolyte imbalances
IV immunoglobulin:
- Indications: used in cases with immunologically mediated conditions, or in the presence of Rh, ABO, or other blood group incompatibilities that cause significant neonatal jaundice
- Dose range for IVIG: 500–1000 mg/kg
What are the potential side effects of phototherapy use in neonatal jaundice
Diarrhea, dehydration
Changes in skin hue (bronzing) and skin rashes
Separation of the neonate from the mother
↑ Risk of AML
Bronze baby syndrome (rare):
- Occurs in infants with elevated direct bilirubin (conjugated bilirubin > 2mg/dL) following phototherapy
- Thought to be caused by abnormal accumulation of bronze-colored pigments (photoisomers of bilirubin) within the skin
- Presents with a reversible grayish-brown discoloration of the skin, urine, and serum
- Usually resolves slowly after cessation of phototherapy without complications
What are potential complications of neonatal jaundice
Acute bilirubin encephalopathy:
- Onset within first days of life
- Lethargy, hypotonia (floppy infant syndrome), poor feeding
- Fever, shrill cry
- Stupor, apnea, seizures
- Possibly fatal if neurotoxicity is severe
Kernicterus (chronic bilirubin encephalopathy):
- Develops over first years of life
- Pathophysiology: deposition of unconjugated bilirubin (liposoluble) in the basal ganglia and/or brain stem nuclei
- Clinical features:
- Cerebral paresis, hearing impairment, vertical gaze palsy
- Movement disorder (athetosis)
- Apparent intellectual and developmental disabilities
- Dental enamel hypoplasia
What is the prognosis of neonatal jaundice
Favorable in most cases
In rare cases, kernicterus may occur, resulting in permanent neurological sequelae.
How is neonatal jaundice prevented
Interruption of enterohepatic circulation with adequate enteral nutrition
Frequent feeds with breast milk
Protein-rich nutrition in the form of breast milk or special formula feeds
In the case of dehydration, protein-rich feeding solutions are preferred over glucose or water.
What is haemolytic disease of the fetus and newborn (HDFN)
A condition characterised by blood group incompatibility between mother and fetus that leads to the destruction of foetal erythrocytes by maternal antibodies
What is the aetiology of HDFN
ABO incompatibility:
- Present in ∼ 20% of all pregnancies
- However, only 5–10% of newborns from these pregnancies are symptomatic.
Rh incompatibility:
-Rare following routine anti-D prophylaxis
Kell blood group system incompatibility:
-Second most common cause of severe HDFN after Rh disease
Risk factors:
- Maternal exposure to fetal blood during pregnancy
- Antenatal procedures (e.g., amniocentesis, cesarean delivery, termination of pregnancy)
- Pregnancy-related complications (e.g., ectopic pregnancy, placental abruption)
- Trauma
What is the pathophysiology HDFN
ABO incompatibility:
- Highest risk: mother with blood group O; newborn with blood group A or B
- Maternal antibodies (anti-A and/or anti-B) against nonself antigens of the ABO system are present even if sensitization has not occurred, so fetal hemolysis may occur during the first pregnancy.
Rh incompatibility:
- In an Rh-negative mother and Rh-positive newborn: maternal exposure to fetal blood (fetomaternal hemorrhage) → production of maternal IgM antibodies against the Rh antigen → over time, seroconversion to Rh-IgG (able to cross the placenta)
- In a subsequent pregnancy with an Rh-positive newborn: rapid production of maternal IgG anti-D antibodies to fetal RhD antigens → Rh-IgG agglutination of fetal RBCs with hemolytic anemia → risk of HDFN with possible hydrops fetalis
What is nonimmune hydrops fetalis
A subgroup of haemolytic diseases of the fetus and newborn not caused by red cell alloimmunisation
How common is nonimmune hydrops fetalis
Incidence: ∼ 1 in 4,000 pregnancies
Accounts for over 90% of all hydrops fetalis cases
What causes nonimmune hydrops fetalis
Congenital heart defects and arrhythmias
Chromosomal aberrations (e.g., Turner syndrome, Down syndrome, trisomy 18)
Severe fetal anemia (e.g., thalassemia, twin-to-twin transfusion syndrome, fetomaternal hemorrhage)
Congenital TORCH infections (especially parvovirus B19 infection)
What is the pathophysiology of nonimmune hydrops fetalis
Severe fetal anemia → hypoxia → ↓ hepatic and renal blood flow → activation of RAAS → ↑ central venous pressure and ↓ lymphatic flow → fetal edema
What are the clinical heatures of HDFN
Prenatal:
-Hydrops fetalis (expected in cases of Rh incompatibility and in nonimmune hydrops fetalis)
Postnatal:
- Neonatal anemia
- Hepatosplenomegaly
- Neonatal jaundice
- Usually present at birth or manifests within the first 24 hours of life
- In Rh incompatibility, unconjugated bilirubin levels may be dangerously high, causing kernicterus.
- Hypoxia
- Prematurity
- Scattered petechiae (rare but associated with poor prognosis)
ABO incompatibility usually has a significantly milder course of disease than Rh incompatibility
Anaemia may conceal cyanosis
How is HDFN diagnosed
The diagnosis of HDFN requires evidence of hemolysis in the presence of fetomaternal blood incompatibility.
Prenatal diagnosis:
Imaging
-Ultrasound: to determine hydrops fetalis
– Fetal pleural or pericardial effusions
– Fetal ascites
– Fetal subcutaneous or nuchal edema
– Placental edema
-Doppler sonography of fetal blood vessels:
– Increased flow rate indicates fetal anemia.
Postnatal diagnosis:
- If the newborn has signs of hemolysis, conduct a Coombs test (either direct or indirect).
- Rh incompatibility: positive
- ABO incompatibility: weak positive or negative
What is a Coombs test
An agglutination test that is used either to detect haemolytic antibodies and/or complement proteins that are already bound to erythrocytes (direct Coombs test) or unbound anti-erythrocyte antibodies in serum (indirect Coombs test).
What is neonatal alloimmune thrombocytopenia
A rare condition in newborns characterised by maternal-fetal platelet incompatibility resulting in fetal thrombocytopenia
The leading cause of severe thrombocytopenia in the newborn
What is the pathophysiology of neonatal alloimmune thrombocytopenia
Formation of maternal antibodies against fetal platelets (most commonly targeting platelet antigen 1a) → maternal IgG cross the placenta and result in the destruction of fetal platelets → fetal and neonatal thrombocytopenia
What are the clinical features of neonatal alloimmune thrombocytopenia
Mild: asymptomatic thrombocytopenia
Moderate: petechia and/or ecchymoses within a few hours after birth
Severe: spontaneous intracranial hemorrhage
How is HDFN treated
Prenatal:
- Intrauterine blood transfusion via the umbilical vein, umbilical artery, peritoneal cavity, or heart (should only be performed in centers with experience in fetal transfusions.)
- Possible IV immunoglobulin (IVIG) in severe cases
Postnatal:
-Anemia: iron supplementation and, if necessary, RBC transfusion.
-Hyperbilirubinemia: phototherapy; if necessary, exchange transfusion with red blood cells
See “Treatment” in neonatal jaundice.
-In severe cases, IV immunoglobulin (IVIG) may be administered.
How is neonatal HDFN prevented
SCREENING:
ABO and Rh typing of the mother
- Rh-positive mothers do not need further screening.
- Rh-negative mothers: screening for anti-D antibodies
- No anti-D antibodies (unsensitized mothers): antibody screening repeated at 28 weeks’ gestation and at delivery.
- Anti-D antibodies manifest with an anti-D antibody titer > 1:8, which indicates maternal sensitization to fetal Rh antigens (sensitized mothers).
- Further monitoring with amniocentesis and imaging is required for evidence of hemolysis.
Fetomaternal hemorrhage in Rh-negative mother
- Conduct a rosette test (initial test of choice).
- This is a qualitative test that assesses whether fetomaternal hemorrhage has occurred.
- The apt test is an alternative to the rosette test, but it only differentiates whether the origin of blood is fetal/newborn or from the mother, e.g., from:
- – Newborn gastrointestinal (stool, vomiting) or pulmonary bleeding
- – Antepartum hemorrhage (e.g., vasa previa)
- If the rosette test is positive, conduct a Kleihauer-Betke test.
- Quantitative testing to evaluate fetomaternal hemorrhage
- The amount of fetal hemoglobin determines the amount of Anti-D immunoglobulin necessary.
- Flow cytometry is an alternative, but its use is limited by equipment and costs.
Fetal Rh genotyping
ANTI-D IMMUNOGLOBULIN:
Anti-D prophylaxis protects newborns in subsequent pregnancies
Only indicated in unsensitised mothers
Anti-D should be adminstered during the 28th week of gestation and within 72 hours following the birth of an Rh-positive baby Anti-D should also be given in any sensitising events: -miscarriage -ectopic pregnancy -termination of pregnancy -bleeding during pregnancy -invasive procedures: -- amniocentesis -- chorionic villus sampling
Dose:
- Standard dose: 300μg (1500 IU) IV/IM
- If whole fetal blood is >30 mL (i.e., fetal RBCs > 15 mL): 300 μg (1500 IU) IM should be given for every 30 mL of fetal blood volume.
What is Vitamin K deficiency bleeding of the newborn (VKDB)
Spontaneous bleeding in a newborn caused by a deficiency of vitamin K dependent coagulation factors.
How common is VKDB
Without prophylaxis it affects ~0.25-1.7% of newborns
What is the aetiology of vitamin K deficiency bleeding
The underlying cause is always a deficiency of vitamin K, which can be due to various factors:
- Exclusive breastfeeding: low vitamin K levels in breast milk (most important in late-onset VKDB)
- Low liver storage capacity
- Poor placental passage of vitamin K
- Vitamin K deficiency in the mother (e.g., because of anticonvulsant therapy; most important in early-onset VKDB; maternal malnutrition)
- Underdeveloped intestinal flora (which produces vitamin K), e.g., due to premature birth
- Chronic diarrhea of the newborn
- Long-term antibiotic treatment in newborns
- Cholestatic diseases (e.g., biliary atresia)
How does VKDB present
Early onset: within 24 hours after birth; intracranial bleeding common
Classic: within 4 weeks after birth; intracranial bleeding rare
Late onset: between 2–8 months after birth; intracranial bleeding common
How is VKDB diagnosed
Coagulation studies:
- ↑ Prothrombin time (PT)
- Normal or ↑ activated partial thromboplastin time (PTT)
- Normal bleeding time
- ↓ Factors II, VII, IX, and X
How is VKDB treated
Transfusions as necessary
Administration of vitamin K
How is VKDB prevented
Newborns can recieve intramuscular vitamin K (0.5-1mg) at birth
What is hyperbilirubinaemia
Characterised by serum bilirubin levels of ≥ 1.1 mg/dL (11mg/L)
What is the epidemiology of Gilbert syndrome
Most common inherited hyperbilirubinemia: The prevalence is 3–7% in the US
♂ > ♀
Age of onset: adolescence
What causes Gilbert syndrome
Mutation in the promoter region of UGT1A1 gene → mild reduction of UDP-glucuronosyltransferase activity → ↓ conjugation of bilirubin → ↑ indirect bilirubin
Alternative: missense mutation in UGT1A1 gene
Impaired hepatic bilirubin uptake
Autocomal recessive or autosomal dominant inheritance pattern
How does Gilbert syndrome present
Asymptomatic or unspecific symptoms such as fatigue and loss of appetite
Transient, usually mild jaundice (varying from mild scleral jaundice to general jaundice)
Triggering factors of transient jaundice:
- Stress (e.g., trauma, illness, exhaustion)
- Fasting periods
- Alcohol consumption
How is Gilbert syndrome diagnosed
Slightly ↑ indirect bilirubin but < 3 mg/dL (higher levels are possible during episodes of increased bilirubin breakdown)
Normal liver function
No evidence of hemolysis
Detection of mutation using PCR
How is Gilbert syndrome treated
No treatment required as this is a benign condition
What is the aetiology of Crigler-Najjar syndrome type I
UDP-glucuronosyltransferase is (almost completely) absent.
Autocomal recessive inheritance
How does Crigler-Najjar syndrome type I present
Excessive, persistent neonatal jaundice
Kernicterus: neurological symptoms (onset during infancy or later in childhood)
How is Crigler-Najjar syndrome type I diagnosed
- ↑ Indirect bilirubin (20–50 mg/dL)
- Normal liver function tests
- No evidence of hemolysis
How is Crigler-Najjar syndrome type I treated
Phototherapy: conversion of unconjugated bilirubin (hydrophobic bilirubin) to more polar, water-soluble form → ↑ excretion via urine and/or bile
Plasmapheresis during acute rises in serum bilirubin levels
Tin protoporphyrin
Calcium carbonate
Liver transplantation is the only curative treatment.
What is the prognosis for Crigler-Najjar syndrome type I
Without treatment, Crigler-Najjar syndrome type I is incompatible with life because it causes kernicterus.
If treated, patients may survive past puberty, but most will eventually develop kernicterus.
What is the aetiology of Crigler-Najjar syndrome type II
Reduced levels of UDP-glucuronosyltransferase
Autosomal recessive or autosomal dominant inheritance pattern
What is the other name for Crigler-Najjar syndrome type II
Arias syndrome
How does Crigler-Najjar syndrome type II present
Often asymptomatic
No neonatal jaundice, although jaundice may occur during the patient’s first year of life
No neurological symptoms
How is Crigler-Najjar syndrome type II diagnosed
↑ Indirect bilirubin (< 20 mg/dL)
Normal liver function tests
No evidence of hemolysis
Responds to phenobarbital → ↓ serum bilirubin levels
How is Crigler-Najjar syndrome type II treated
Patients are less likely to develop kernicterus. Specific treatment may therefore not be required. The following treatment options are, however, available if patients become icteric.
Phenobarbital: leads to induction of UDP-glucuronosyltransferase
Phototherapy (as in type I)
Avoid hormonal contraception and hepatic enzyme inhibitors
What is the prognosis for Crigler-Najjar syndrome type II
Usually favourable
Management of jaundice allows for normal quality of life
What causes Dubin-Johnson syndrome
Defective multidrug resistance-associated protein 2 (MRP2) → impaired excretion of conjugated bilirubin from the hepatocytes into the bile canaliculi
Autosomal recessive inheritance
How does Dubin-Johnson syndrome present
Mild to moderate jaundice
- Onset often occurs during adolescence
- May worsen because of medication (particularly contraceptives) or pregnancy
Splenomegaly may occur in rare cases.
How is Dubin-Johnson syndrome diagnosed
Direct hyperbilirubinemia (direct bilirubin/total bilirubin up to 50%)
Liver biopsy: dark, granular pigmentation (due to accumulation of epinephrine metabolites)
How is Dubin-Johnson syndrome treated
Not required (benign condition)
Be careful when administering a drug that is toxic to hte liver as it may worsen jaundice
Contraindication for oral contraception
What is the aetiology of Rotor syndrome
Defective organic anion transport proteins (OATP) 1B1 and 1B3 in hepatocytes → impaired transport and reduced storage capacity of conjugated bilirubin (direct bilirubin)
Autosomal recessive inheritance
How does Rotor syndrome present
Usually asymptomatic but mild jaundice may occur (milder presentation compared to Dubin-Johnson syndrome)
How is Rotor syndrome diagnosed
Moderate, direct hyperbilirubinemia and mild, indirect hyperbilirubinemia
Normal liver function test
↑ Urinary coproporphyrins I and III (fraction of isomer I < 70% of total)
Liver biopsy: normal, no pigmentation
How is Rotor syndrome treated
Not required
Be careful when administering a drug that is toxic to hte liver as it may worsen jaundice
Contraindication for oral contraception
How can the liver biopsy differences in Rotor vs Dubin-Johnson syndrome be remembered
In Rotor syndrome, the liver appears Regular
In Dubin-johnson syndrome, the liver appears Dark
What are glycogen storage disorders
Hereditary metabolic disorders characterised by defects in the enzymes responsible for glycogenolysis or glycolysis
13 different types have been found
All types cause abnormal accumulation of glycogen due to impaired glycogen metabolism
What is the epidemiology for glycogen storage disorders
Incidence: up to 1:20,000 live births
Age of onset: presentation during infancy or childhood
Sex: ♂ = ♀
Mode of inheritance: mostly autosomal recessive (types I, II, III, and V)
What is the pathophysiology of glycogen storage disorders
Defective enzymes responsible for glycolysis or glycogenolysis → impaired glycogen metabolization → ↑ storage of either normal or abnormal glycogen
Liver, heart, and muscle are the most common sites of glycogen storage and are, therefore, predominantly affected.
What are the clinical features of glycogen storage disorders
Glycogen storage disorders can be classified as muscle and/or liver GSD according to the presenting symptoms.
Muscle involvement:
- Seen in types II, III, IV, V
- Two groups of skeletal muscle symptoms are seen:
- Defects of muscle glycogenolysis and muscle glycolysis:
- – Easy fatiguability, exercise intolerance
- – Cramps
- – Rhabdomyolysis → myoglobinuria (burgundy-colored urine)
- Defects of muscle glycogenesis (type IV) and lysosomal glycogenolysis (type II):
- – progressive weakness of extremities and trunk (proximal myopathy)
- Cardiac involvement
- Seen in several types (e.g., type II, type III)
- Hypertrophic cardiomyopathy and/or conduction defects are most common in type II.
Liver involvement
- Seen in types I, III, IV
- Hypoglycemia (typically fasting hypoglycemia) and ketosis
- Symptoms of hypoglycemia in infancy: seizures, hypotonia, poor feeding, cyanosis, irritability
- Hepatomegaly → distended abdomen
Additional clinical manifestations:
- Growth delay/growth retardation/failure to thrive: types I, II, III, IV
- Anemia: type I
- Hyperlipidemia: types I, III
- Macroglossia: type II
- Lactic acidosis: type I
- Hyperuricemia: type I
How are glycogen storage disorders diagnosed
Initial tests:
- Muscle and/or liver biopsy (depending on the enzyme deficiency): glycogen storage appears as PAS-positive granules .
- Enzyme assays in RBCs, leukocytes, liver tissue, muscle tissue, or fibroblasts (depending on the enzyme deficiency)
Confirmatory test: DNA testing for the gene defects
Additional tests:
- Muscle GSD
- Ischemic forearm test: an important test to evaluate if a patient has a metabolic disorder of muscle function
- – A sphygmomanometer cuff is tied around the arm and inflated to beyond systolic blood pressure. The patient is then asked to repeatedly form a fist. The cuff is then deflated and multiple blood samples are taken to measure serum lactate levels.
- – The normal response to an ischemic exercise test is an increase in the levels of lactate as a result of anaerobic metabolism of glucose.
- – In the case of GSD type III and type V, not enough glucose is produced from glycogen. As a result, lactate levels do not rise.
- ↑ Creatine kinase
- Electroneuromyography: to identify proximal myopathy
- ECG and/or echocardiography: to identify cardiac hypertrophy and conduction blocks
- Liver GSD
- ↑ Serum biotinidase serves as diagnostic biomarkers in type I and type III
- Liver function tests and abdominal ultrasonography: to detect liver cirrhosis and/or hepatic failure
What is the management of glycogen storage disorders
General:
- Most forms of GSD can be managed effectively with dietary therapy (e.g., uncooked corn starch, glucose preparations) with the aim of preventing hypoglycemia and/or muscle symptoms
- Foods rich in fructose and galactose should be avoided in patients with GSD type I
Definitive therapy:
- Enzyme replacement therapy is available for some forms of GSD
- A liver transplant may be required in the case of liver GSD that progress to liver cirrhosis and/or result in poor metabolic control.
- Cardiac involvement
- Severe conduction defects: pacemaker implantation
What is galactosemia
Hereditary defects in enzymes that are responsible for the metabolism of galactose
What is galactose
A component of the disaccharide lactose, which is present in breast milk
How does galactosemia present
Poor feeding Failure to thrive Vomiting, diarrhea Jaundice, hepatomegaly Cataracts Cognitive impairment ↑ Risk of E. coli sepsis (esp. in neonates) Hypoglycemia
How is galactosemia diagnosed
Newborn screening test: ↑ galactose/galactose-1-phosphate in blood
Urine galactose levels: galactosuria
Total serum bilirubin: hyperbilirubinemia
How is galactosemia treated
Complete cessation of lactose-containing feeds and lifelong adherence to galactose-free and lactose-free diet
What is the most common cause of anaphylaxis related emergnecy admissions
Food allergies
WHat is the aetiology of food allergies
Hypersensitivity reaction against select ingredients in food
What are the most common food allergens
Cow's milk Eggs Nuts Peanuts Seafood (shellfish, fish) Soy Wheat Fruits (eg kiwi)
What is the pathophysiology of food allergies
Commonly IgE-mediated: Type I hypersensitivity reaction (immediate onset; within minutes to 2 hours of ingestion)
Mixed IgE/non-IgE-mediated and non-IgE-mediated reactions are also possible (delayed onset; hours to days after ingestion)
What are the typical clinical features of food allergies
Skin (most common): pruritus, urticaria, exanthem, angioedema, atopic dermatitis
Respiratory: rhinitis (often with sneezing), nasal congestion, dyspnea, wheezing, laryngeal edema
Gastrointestinal tract: oral allergy syndrome (oral pruritus, tingling numbness, and swelling of the lips, tongue, palate, and throat) , nausea, vomiting, abdominal pain, diarrhea
Cardiovascular: hypotension, tachycardia, dysrhythmias
CNS: headache
Non-IgE or mixed reactions are typically limited to the ckin and GI tract
Respiratory manifestations can be fatal
How is a food allergy diagnosed
Patient history: determine type of food, time and amount of ingestion, and the type of reaction
Suspected IgE-mediated reaction:
- IgE skin prick test
- RAST (radioallergosorbent test)
- An immunoassay that detects specific compounds using antibodies coupled to radioactive tags.
- Previously used to detect allergen-specific IgE but is no longer widely used.
- IgE serum levels are measured in response to predetermined food allergens.
- Total IgE-antibody serum test
- N-methylhistamine (urine)
If above tests are inconclusive or suspected food is not a common allergen:
- Elimination diet: The suspected allergens are eliminated from the patient diet, while being observed for an improvement in symptoms without the need for medication.
- Oral food challenge: the effect of potential allergens on the mucous membranes is tested (the patient is given different foods that contain potential allergens to chew but not swallow in increasing doses over a fixed period of time). May be implemented after a positive elimination diet.
How does infantile colic present
Otherwise healthy infant with appropriate weight gain
Paroxysmal episodes of loud and high pitched crying that often occur at the same time each day (usually in the late afternoon or evening)
Hypertonia (e.g., clenched fists, stretched legs) during episodes
Infant is not easily consoled
How is infatile colic diagnosed
crying that lasts ≥ 3 hours per day, ≥ 3 days per week, for ≥ 3 weeks in an otherwise healthy infant <3 months old
How is infantile colic treated
Reassurance
Soothing techniques
Trial of various feeding techniques
What are the differentials in suspected food allergy
Infantile colic
Lactose and fructose intolerance
Coeliac disease
How are food allergies treated
Avoid allergens and in case of emergency treat anaphylactic reactions
Oral immunotherapy is a novel approach being studies and not yet widely available
What is the prognosis following a food allergy diagnosis
The majority of children with milk and egg allergies will outgrow them by 5 years of age.
A lot of children with food allergies will develop asthma and allergic rhinitis.
Adult-onset food allergies usually remain for life.
How is anaphylaxis treated
Stabilize the patient (ABCDE approach).
- Airway assessment and management
- Rapid sequence intubation (RSI) for airway compromise
- Oxygen: Provide FiO2 of 100% (e.g., high-flow O2 by nonrebreather mask).
- Aggressive IV fluid resuscitation if hypotension present
- Position the patient supine.
If anaphylaxis is likely, start initial treatment immediately:
- Remove inciting allergen
- Administer adrenalin IM 1:1,000 (1 mg/mL) into the anterolateral thigh
Once stabilized, consider adjunctive therapy with antihistamines, corticosteroids (e.g., methylprednisolone)
Continuous reassessment and subsequent management
What are primitive reflexes
Reflexes that are normally present during infancy and disappear with the development of inhibitory pathways to the subcortical motor areas (usually within the 1st year of life
What is the clinical relevance of primitive reflexes persistence
In children: indicates impaired brain development
In adults: suggests frontal lobe lasions (frontal release signs)
What are the types of primitive reflexes
Moro reflex Rooting reflex Sucking reflex Palmar grasp Plantar grasp Plantar reflex Stepping reflex Galant reflex Asymmetrical tonic neck reflex (ATNR) Glabellar tap sign Landau reflex Snout reflex Parachute reflex
What is the Moro reflex
Holding an infant in the supine position while supporting the head, then allowing the head to suddenly fall back elicits abduction and extension of the infant’s arms and elbows, followed by their flexion.
Age of resolution: 3-6 months
What is the clinical significance of the Moro reflex
Unilateral absence:
- Ipsilateral brachial plexus injury
- Ipsilateral fractured clavicle
Bilateral absence indicates brain injury (e.g., due to birth asphyxia, intracranial hemorrhage) or bilateral brachial plexus injury
What is the rooting reflex
Stroking the cheek elicits turning of the head towards the stimulus and opening of the mouth
Age of resolution: 4 months
What is the sucking reflex
Touching the roof of the mouthe elicits a sucking motion
Age of resolution: 4 months
What is the clinical relevance of the rooting reflex and the sucking reflex
Unilateral absence indicates peripheral nerve injury
Bilateral absence or premature resolution:
- Perinatal asphyxia
- Intracranial hemorrhage
What is the palmar grasp
Stimulation of the palm elicits a grasping motion
Resolves around 3-6 months
What is the clinical relevance of the palmar grasp
Unilateral absence:
- Brachial plexus injury
- Peripheral nerve injury
Bilateral absence of the reflex at birth may indicate cerebral palsy.
What is the plantar grasp
Stimulation of the sole elicits curling of the toes (plantar flexion).
Resolves at 3 months
What is the clinical relevance of the plantar grasp
Bilateral absence: suggestive of cerebral palsy.
What is the plantar reflex
Stroking the sole of the foot from heel to toe elicits dorsiflexion of the foot with concomitant extension of the big toe and fanning of the other toes.
Resolves at 12-24 months
What is the clinical relevance of the plantar reflex
Persistence or reappearance after 24 months indicates an upper motor neuron lesion (Babinski sign).
What is the stepping reflex
Holding the infant upright with feet on the examination table elicits a stepping motion with alternating flexion and extension of the legs.
Resolves at 2 months
What is the clinical relevance of the stepping reflex
Infants born at term step from heel to toe.
Preterm infants tiptoe.
What is the galant reflex
Holding the infant in the prone position and stroking it on one side of the paravertebral region elicits flexion of the lower back and hip towards the stimulus.
Resolves at 2-6 months
What is the clinical relevance of the galant reflex
Persistent galant reflex may be associated with bed wetting
What is the asymmetrical tonic neck reflex
Turning the head to one side elicits extension of the arm and leg on the side the head is facing and flexion of the contralateral arm and leg (fencing posture).
Resolves at 3-4 months
What is the clincial relevance of the aymmetrical tonic neck reflex
The ATNR aids in the development of hand eye coordination
What is the glabellar tap sign
Tapping the glabella elicits blinking
Resolves 4-6 months
What is the glabella
The region of the face above the root of the nose and between the eyebrows.
What is the clinical relevance of the glabellar tap sign
Persistent glabellar tap sign is a frontal release sign called Myerson sign
What is the landau reflex
Placing the infant in a prone position elicits arching of the back and raising of the head
Resolves by 24 months
What is the snout reflex
Tapping or applying light pressure to closed lips elicits puckering
Resolves at 4 months
What is the parachute reflex
Holding the infant in an upright position, followed by sudden lowering towards the examination table elicits extension of the infant’s arms.
This reflex appears at 6–9 months of age and persists
What is the clinical relevance of the parachute reflex
Infants suffering from neonatal encephalopathy may show an asymmetric or absent parachute reflex
How is developmental delay defined
Should be suspected when the child’s age is >25% of the mena age at which a particular milestone is attained or >1.5 standard deviations on a standardised developmetnal screening tests
What is the normal weight for age velocity
Term neonates lose up to 7% of their birth weight in the first few days after delivery and normally regain it within 2 weeks.
Birth weight should double by 4 months, triple by 1 year and quadruple by 2 years of age.
WHat is the normal height/length for age velocity
An infant’s height/length increases by approx. 30% within the first 6 months and by approx. 50% within the first year.
Midparental height (target height):
♀ height = [mother’s height in cm + (father’s height in cm - 13)]/2
♂ height = [father’s height in cm + (mother’s height in cm + 13)]/2
From birth to 6 months: 2.5 cm (1 in) per month
From 6 months to 1 year: 1.3 cm (0.5 in) per month
WHat is the normal wight for height/length
Useful in detecting malnutrition in children <5 years of age
Heigh/length at 1 year of age should be ~50% more than birth height/length
WHat is the clinical relevance of head circumference for age
Used for microcephaly and macrocephaly screening, especially during the first 3 years of life
What is the normal head circumference for age increases
In a healthy infant, head circumference increases by:
- 5 cm during first 3 months.
- 4 cm between 3–6 months.
- 2 cm between 6–9 months.
- 1 cm between 9–12 months.
How is microcephaly defined and when is it observed
A head circumference that is > 2 standard deviations below the mean size for a given age and sex (usually < 3rdpercentile)
Seen in:
- chromosomal trisomies,
- fetal alcohol syndrome,
- congenital TORCH infections,
- cranial anatomic abnormalities,
- neural tube defects
How is microcephaly defined and when is it observed
A head circumference that is ≥ 2 standard deviations above the mean size for a given age and sex (usually ≥ 97thpercentile)
Seen in:
- hydrocephalus,
- neurofibromatosis,
- tuberous sclerosis,
- skeletal dysplasia,
- acromegaly,
- intracranial hemorrhage,
- cerebral metabolic diseases (e.g., Tay-Sachs disease, maple syrup urine disease)
WHat is the rule of fives in developmental growth
Normal growth rates in children can be approximated by multiples of five: birth–1 year (50–75 cm, 25 cm/year), 1–4 years (75–100 cm, 10 cm/year), 4–8 years (100–125 cm, 5 cm/year), 8–12 years (125–150 cm, 5 cm/year).
What is failure to thrive
Inadequate growth of a child for their age
Seen in up to 10% of children in the United States (most <18 months of age)
Anthropometric criteria of FTT:
- Weight-for-age: <5th percentile
- Length-for-age: <5th percentile
- Body mass index-for-age: <5th percentile
- Deceleration of weight velocity that crosses 2 major lines on the growth chart
What is the aetiology of failure to thrive
Nonorganic FTT (∼ 90% of cases):
- No underlying disorder
- Usually associated with:
- Wrong feeding practices
- Wrong preparation of formula feeds
- Child neglect
- Poor socioeconomic status
- Intrauterine growth restriction
- Prematurity and low birth weight
Organic FTT (∼ 10% of cases) is associated with disorders that:
- Prevent nutrient intake
- Cleft palate and/or lip
- Gastroesophageal reflux disease
- Prevent nutrient absorption
- Hypertrophic pyloric stenosis
- Food intolerance
- Celiac disease
- Inflammatory bowel disease
- Inborn errors of metabolism
- Cause excessive calorie loss
- Cystic fibrosis
- Congenital heart defects (CHDs)
- Malignancies
- Other chronic diseases
What are the clinical features of failure to thrive
Developmental delay
Failure to gain weight despite adequate feeds
Recurrent vomiting and diarrhea
Recurrent infections
General signs of malnutrition (e.g., lymphadenopathy, oedema, organomegaly)
How is failure to thrive diagnosed
History of feeding habits (e.g., number and frequency of feeds, food refusal)
Laboratory studies
- Complete blood count and ESR
- Urinalysis
- Hepatic and renal function tests
- Thyroid function tests
- Immunoglobulin levels assessment: to evaluate for underlying immunodeficiencies (e.g., HIV, tuberculosis)
Imaging
- Hand and wrist x-ray
- Echocardiogram
- Upper gastrointestinal series with small bowel follow-through
How is failure to thrive treated
Treatment of the underlying cause
Counseling parents on appropriate child nutrition
Formula supplementation for infants and nutritional supplementation for toddlers
Close follow-up and monitoring of the child’s growth
What is involved in the physical examination of a well child
Charting of growth and recording of developmental milestones
Evaluation of resolution of primitive reflexes
BP measured after 3 y/o
Abdo: palpate for masses (Wilms tumor, neuroblastoma)
Heart: New murmurs, rate/rhythm disturbances
Spine: Assess for scoliosis once able to stand
Evaluate for developmetnal dysplasia of the hip in neonates and tibial torsion, femoral torsion, and metatarsus adductus in the first 2-4 years of life
Genital: For testicular descen and congenital hydrocele in all male infants; imperforate hymen in all female infants; and inguinal hernias in all infants; pubescent genital development (Tanner stages)
How is visual devlopment and acuity screened for
Ocular motility and visual acuity assessment
Photoscreening: Paaediatric vision test used to detect errors of refraction, screen for amblyogenic risk factors and test visual acuity in preverbal or non-cooperative children
Physiological red reflex evaluation (in newborns): absence or leukocoria should prompt further investigation
Strabismus and amblyopis screening: Strabismus is a normal finding in children <3months old
How is hearing loss screened for in children
Recommended in newborns and then at ages 4,5,6,8, and 10; or if there are >1 risk factor for hearing loss which include:
- FH of childhood hearing loss
- TORCH infections
- History of meningitis/ head trauma
- Recurrent or persistent otitis media
- Neonatal ICU stay for >5 days
- Behavioural abnormalities
Screening tests included:
- Electric response audiometry
- Tympanometry
- Otoacoustic emission
Undetected hearing loss in children:
- Can cause speech, language or social delay
- May be mistake for neurodevelopmental disorder, especially communication disorders
What is expected by 2 months old
Raises head and chest when prone
Follows objects past midline
Coos
Smiles back (social smile) Recognises parents
What is expected by 4 months old
Holds head straight
Roles over front to back
Props self up on wrists in prone position
Holds and shakes rattle
Laughs
Makes constant sounds
Localises sounds
What is expected by 6 months old
Sits without support
Rolls over back to the front
Grabs and transfers objects from one hand to the other
Raking grasp
Babbles
Develops stranger anxiety (6-9months)
Develops object permanence (6-9months)
What is expect by 9 months old
Crawls
Stands when holding on to something
Pincer grasp (9-12months)
Says mama or dada
Orients to name
Imitates actions
Has separation anxiety
What is expected by 12 months old
Starts to walk
Can throw objects
Points at objects
Knows 1-5 words
Follows commands
What is expected by 18 months old
Starts to run
Learns to walk backwards with help
Stacks up 4 blocks
Uses spoon and cup
Knows 10-50 words
Play pretend
What is expected by 2 years old
Walks up and downstairs, stepping with both feet on each step
Kicks ball
Jumps
Stacks up to 6 blocks (number of blocks = years x 3)
Draws a line
Knows >50 words
Uses sentences of up to 2 words
Engages in parallel play (2-3 years)
Moves away and comes back to parent
Follows 2 step commands
Removes clothes
WHat is expected by 3 years old
Alternates feet when walking up and down the stairs
Pedals a tricycle
Stacks up to 9 blocks
Copies a circle
Mostly intelligible speech
Knows >300 words and understnads >1000 words
Uses sentences of up to 3 words
Understands gender difference
Brushes teeth and grooms self
Has bladder and bowel control (however, bed wetting until 5 years of age is considered normal)
Plays away from parents
What is expected by 4 years old
Hops on one foot
Catches and throws ball overhand
Copies a square
Tells complex stories
Can identify some colours and numbers
Plays cooperatively
May have imaginary friends
What is expected by 5 years old
Skips
Copies a triangle
Can tie shoelaces
Can write some letters
Speak fluently
Counts 10 or more things
Uses sentences of up to 5 words
Learns how to read
Understands directions (left and right)
Plays dress up
What is the definition of short stature
Children: height of > 2 SDs below the mean for children of the same age, sex, and similar genetic background
Adults: height of ≤ 4 ft 10 in (147 cm) for women and ≤ 5 ft 1 in (155 cm) for men
What is proportionate short stature
Limbs proportionate to trunk
Seen in most cases of familial short stature
What is disproportionate short stature
Limbs disproportionately short compared to trunk
Seen in most cases of skeletal dysplasia
What is growth failure
Growth rate below the rate considered appropriate for sex and age
What are the causes of short stature
Short stature can have a variety of genetic, systemic, and psychosocial causes.
Genetic causes include:
- Familial short stature
- Constitutional growth delay
- Laron syndrome
- Turner syndrome
Systemic causes include:
- Congenital hypothyroidism
- GH deficiencies
- Glucocorticoid excess
Psychosocial causes include:
- Maternal substance use (e.g., alcohol)
- Psychosocial short stature
- Psychiatric conditions (e.g., anorexia nervosa)
How is short stature investigated and diagnosed
Patient history:
-Physical examination findings
-Growth rate
-Family history of short stature
-Midparental height (estimated adult height of a child calculated on the basis of parental height), calculated via the following formula:
♀ = [mother’s height in cm + (father’s height in cm - 13)]/2
♂ = [father’s height in cm + (mother’s height in cm + 13)]/2
Laboratory tests:
- FBC, differential blood count, ESR
- Thyroid function tests (Hypothyroidism)
- Renal function tests and urinalysis (in case of CKD and associated renal osteodystrophy)
- Screening for GH deficiency (Hypopituitarism)
- Hormone profile (LH, FSH, estrogen/testosterone) for puberty status assessment
- Karyotyping
Imaging tests
- X-ray: used to determine an individual’s bone age and height by comparing their x-ray images of the left hand and wrist to those displayed in the standard bone development atlas
- Cranial MRI: in suspicion of hypothalamic or pituitary tumors
How is short stature treated
Management depends on the underlying cause:
- Reassurance that low height is a normal variant (e.g., familial short stature) that does not require treatment
- Discontinuation of growth-inhibiting medication (e.g., glucocorticoids)
- Sex hormone substitution in children with delayed puberty and growth
- GH supplementation (e.g., somatropin) in cases of GH deficiency, idiopathic short stature, and Turner syndrome
- In case of primary severe IGF-1 deficiency: mecasermin (recombinant insulin-like growth factor)
- Treatment of underlying conditions
What is tall stature
A height of more than 2 standard deviations above the population mean or exceeding the 97th percentile on the normal growth curve for age and sex
Most tall children do not have a pathological cause
How is growth evaluated
History:
- Assess milestones (exclude developmental delay)
- Determine midparental height
Physical examination
- Accurate serial measurements of individual body areas
- Proportional vs disproportional growth (e.g., disproportionately long extremities usually indicate Marfan syndrome)
- Length or height
- Growth velocity
- Exclude the following:
- Secondary sexual characteristics
- Neurological lesions
- Dysmorphisms
Further diagnostic measures (if a pathological cause is suspected)
- Bone age
- Karyotyping
- Endocrine laboratory tests (depends on which pathology is suspected e.g., insulin-like growth factor for excess growth hormone, or TSH and T4 hormone for hyperthyroidism)
What is gigantism
A rare disorder characterised by abnormal linear growth during childhood due to growth hormone excess while the epiphyseal growth plates are still open
What is the pathophysiology of gigantism
Most common: ↑ growth hormone (GH) secretion from the anterior pituitary (i.e., adenoma ) → ↑ IGF-1 synthesis → ↑ cell growth and proliferation
↑ GHRH secretion from the hypothalamus (i.e., tumors)
↑ Production of IGF-binding protein → ↑ half-life of IGF-1
What are the risk factors for gignatism
Associated with an ↑ incidence of pituitary tumors
Multiple endocrine neoplasia type 1 (MEN 1)
McCune-Albright syndrome
Carney complex
Neurofibromatosis
Tuberous sclerosis
What are the clinical features of gigantism
Tall stature
↑ Growth of distal limbs (i.e., hands, feet, fingers, toes)
Tumor mass symptoms: headaches, visual changes , features of hypopituitarism
Progressive macroencephaly
Coarse facial features, frontal bossing, prognathism
Obesity
How is gigantism diagnosed
↑ Serum IGF-1
↑ GH after oral glucose tolerance test confirms pituitary gigantism.
After a biochemical diagnosis is established:
- MRI: pituitary mass
- CT if MRI is negative: exclude other GH-secreting tumors (e.g., pancreas, adrenal glands, ovarian, bronchial)
How is gigantism treated
Transsphenoidal surgery: pituitary adenoma excision
Medical therapy
- Somatostatin analogs (e.g., octreotide )
- GH receptor antagonists (e.g., pegvisomant)
What are the potential complications of gigantism
Carpal tunnel syndrome
Cardiovascular disease
- Heart failure (the most common cause of death)
- Hypertension
Osteoarthritis
Endocrine disorders (i.e., hypogonadism, diabetes, hyperprolactinemia)
Benign tumors (i.e., uterine leiomyomas, prostatic hypertrophy, colonic polyps)
What are the endocrine disorders that result in tall stature
Gigantism
Precocious puberty
Hyperthyroidism
What is Beckwith-Wiedemann syndrome
Congenital disorder of growth with a predisposition to tumour development
What is the epidemiology of Beckwith-Wiedemann syndrome
∼ 1/15,000 newborns in the US
Increased risk of Wilms tumor, hepatoblastoma, neuroblastoma, adrenal tumors
What is the aetiology of Beckwith-Wiedemann syndrome
WT2 gene mutation on chromosome 11 (~80% of cases)
What are the clinical features of Beckwith-Wiedemann syndrome
Macrosomia, omphalocele (i.e., exomphalos)
Macroglossia, organ enlargement (heart, liver, kidney, etc.)
Hemihypertrophy (hemihyperplasia): One side or a part of one side of the body is larger than the other.
Features of neonatal hypoglycemia: irritability, intellectual disability
Genitourinary abnormalities
Facies: midface hypoplasia, infraorbital and earlobe creases
Cleft palate (rare)
How is Beckwith-Wiedemann syndrome diagnosed
↓ Blood glucose, ↑ serum insulin, IGF-2 (hypoglycemia)
Screening options for embryonal tumors:
- Abdominal ultrasound every 3 months until 8 years of age
- Alpha-fetoprotein levels every 3 months until 4 years of age
How is Beckwith-Wiedemann syndrome treated
Frequent feedings to maintain sufficient blood glucose levels
Resection of embryonal tumors
What is sotos syndrome
Cerebral gigantism
What is the epidemiology of sotos syndrome
1/10,000–14,000 newborns
What is the aetiology of sotos syndrome
Autosomal dominant mutation in the NSD1 gene on chromosome 5
What are the symptoms of sotos syndrome
Tall stature
Macrocephalus
Facies
- High forehead
- Elongated face
- Hypertelorism
- Pointed chin
- Receding hairline
Psychomotor retardation
Hypotonia
Delays in achieving milestones (e.g., walking, talking, clumsiness)
How is sotos syndrome diagnosed
Clinically
DNA studies (5q35 microdeletions and partial NSD1 deletions in 10–15% of cases)
Prenatal diagnosis possible
How is sotos syndrome treated
Only symptomatic treatment is possible
Multiprofessional approach
What is the course of sotos syndrome
Normal growth rate from 3–5 years of age (only moderately increased adult height)
Permanent cognitive-developmental impairments are common.
What are the gentic disorder causes of tall stature
Sotos syndrome Marfan syndrome Homocystinuria Fragile X syndrome Neurofibromatosis type 1 Klinefelter syndrome (47, XXY) Weaver syndrome
What is puberty
A phase of development between childhood and complete, functional maturation of the reproductive glands and external genitalia (adulthood)
What are the phases of pubertal changes
The age of pubertal onset may vary, but the order of changes that occur in each person is consistent.
Adrenarche: activation of adrenal androgen production (axillary and pubic hair, body odor, and acne)
Gonadarche: activation of reproductive glands by the pituitary hormones FSH and LH
Thelarche: onset of breast development
Pubarche: onset of pubic hair growth
Menarche: onset of menstrual bleeding:
- Anovulatory cycle: The menstrual cycle may be irregular in adolescents during the first few months/years after menarche.
- Immaturity of the hypothalamic-pituitary-gonadal axis → irregular secretion of gonadotropins → short luteal phase, and lack of progesterone → endometrium remains in the proliferative phase → irregular menses and heavy menstrual bleeding
- Does not require treatment because menses become regular as hypothalamic-pituitary-gonadal axis matures
What is the physiology of puberty
Unknown initial trigger → ↑ activators and/or ↓ inhibitors of GnRH secretion → pulsatile GnRH secretion→ ↑ FSH and ↑ LH secreted by the anterior pituitary gland → stimulation of the Leydig cells and Sertoli cells in the testicles, and the theca and granulosa cells in the ovary.
The hypothalamic-pituitary-gonadal axis is tightly regulated by a negative feedback mechanism.
Testosterone inhibits further GnRH secretion from the hypothalamus.
FSH-stimulated Sertoli cells also secrete inhibin, which further inhibits FSH secretion from the pituitary.
What influences puberty
General health (nutritional state, bodyweight) Genetics Social environment (e.g., family stress)
What is normal pubery for girls
Normal age of onset: 8–13 years (average 11 years)
Normal order of changes: adrenarche → gonadarche → thelarche (age of onset 8–11 years) → growth spurt (age of onset 11.5–16.5 years) → pubarche (mean age of onset 12 years) → menarche (age of onset 10–16 years, mean age: 13 years)
The first sign of puberty is breast development
What is normal puberty for boys
Normal age of onset: 9–14 years (average 13 years)
Normal order of changes: adrenarche → gonadarche (age of onset 9–14 years) → pubarche (mean age of onset 13.5 years)→ growth spurt (mean age of onset 13.5 years)→ androgenic hair growth
The first visible sign of puberty in males is testicular enlargement
What is precocious puberty
The appearance of secondary sexual characteristics before the age of 8y in girls and 9y in boys
What is the epidemiology of precocious puberty
Incidence: 1:5,000 to 1:10,000 children
Ten times more common in girls than boys.
How is precocious puberty classified
Central precocious puberty (gonadotropin-dependent precocious puberty, true precocious puberty)
Peripheral precocious puberty (gonadotropin-independent precocious puberty, peripheral pseudopuberty, peripheral precocity)
Isosexual precocious puberty: premature development of secondary sexual characteristics appropriate for gender (can be complete or incomplete)
Heterosexual precocious puberty: masculinization of girls or feminization of boys
Benign pubertal variants
- Precocious thelarche
- Idiopathic premature pubarche
- Premature adrenarche
- Precocious menarche
Obesity-related precocious sexual development
What is central precocious puberty
Precocious puberty with elevated GnRH levels
What causes central precocious puberty
Idiopathic (most common cause)
CNS lesions
- Intracranial tumors (e.g., hamartoma, glioma, craniopharyngioma)
- Trauma
- Infections (e.g., encephalitis, meningitis)
- Hydrocephalus
Obesity-related precocious sexual development
Systemic conditions: tuberous sclerosis, neurofibromatosis
Radiation
What is the pathophysiology of central precocious puberty
Early activation of the hypothalamo-hypophyseal axis → abnormally early initiation of pubertal changes → early development of secondary sexual characteristics
What are the clinical features of central precocious puberty
Premature sexual development typically follows the normal pattern of puberty, except that it is early.
Symmetric development of secondary sexual characteristics or, occasionally, as isolated premature thelarche, adrenarche, or menarche.
Increased growth velocity: Children 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).
How is central precocious puberty diagnosed
Laboratory tests:
- Serum LH and FSH: increased
- GnRH stimulation test (gold standard): evaluates the reactivity of the hypothalamic-pituitary-axis to GnRH stimulation
- Indications: suspicion of precocious puberty or delayed puberty
- Method: base LH and FSH values → administer GnRH → blood is drawn after a certain time for reevaluation of LH and FSH levels
- Gonadotropin (LH and FSH) levels increase after intravenous administration of GnRH.
- Serum testosterone/estradiol: increased
Imaging:
-X-ray of the left hand and wrist: allows comparison between skeletal maturation and chronological age
– Assess and confirm accelerated bone growth.
Bone age is within 1 year of a child’s age: Puberty likely has not started.
– 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: when ↑ LH is confirmed
– Perform in girls ≤ 6 years of age, all boys, and children with neurologic symptoms.
– Rule out intracranial causative pathology.
How is central precocious puberty treated
GnRH agonist (e.g., leuprolide, buserelin, goserelin): to prevent premature fusion of growth plates
Close monitoring of therapy
Follow-up is recommended every 4–6 months to assess progression.
Manage underlying cause.
What is peripheral precocious puberty
Precocious puberty without elevated GnRH levels (due to ↑ peripheral synthesis of or exogenous exposure to sex hormones)
What is the aetiology of peripheral precocious puberty
↑ Androgen production
- Congenital adrenal hyperplasia
- Virilizing ovarian and adrenocortical tumors (e.g., Sertoli-Leydig cell tumor, Leydig-cell tumor)
↑ Estrogen production
- McCune-Albright syndrome
- HCG-secreting germ cell tumors (e.g., dysgerminomas)
↑ β-hCG production
- Dysgerminoma
- Malignant embryonal cell carcinoma
- Choriocarcinoma
Primary hypothyroidism
Exogenous steroid use
Obesity-related precocious sexual development
What are the clinical features of peripheral precocious puberty
May not follow the normal developmental pattern (signs of estrogen or androgen excess)
May exhibit possible features of an underlying condition (e.g., cafe-au-lait spots in McCune-Albright syndrome, testicular mass in Leydig-cell tumor)
How is peripheral precocious puberty diagnosed
Laboratory tests:
- Serum basal FSH and LH: decreased
- GnRH stimulation test
- No increase in LH levels after GnRH administration.
- Precocious pseudopuberty is associated with low basal LH levels (prepubertal values).
- Serum testosterone/estradiol levels: increased (depending on the tumor)
- TSH, T3 hormone: suspicion of hypothyroidism
- Serum DHEA-S and 17-hydroxyprogesterone: in cases of hyperandrogenism
- Corticotropin stimulation test: suspicion of congenital adrenal hyperplasia or an adrenal tumor
Imaging:
- X-ray of left wrist and hand: accelerated bone growth
- Ultrasound of the ovaries, testicles, and abdomen (cases of increased ovarian and/or uterine volume than expected for age, diagnostic uncertainty)
How is peripheral precocious puberty treated
Precocious puberty caused by excessive hormonal production from a tumor in the body: surgical removal
Precocious puberty caused by Congenital Adrenal Hyperplasia: cortisol replacement
Ovarian cysts: no intervention is necessary (spontaneous resolution is common)
What is obesity related precocious sexual devleopment
Obesity is associated with early pubertal development, mainly due to obesity-related insulin resistance. This resistance leads to increased insulin and leptin levels.
What is the pathophysiology of obesity related precocious sexual development
Central mechanism: Obesity causes increased secretion of leptin, which leads to increased GnRH pulsatility → ↑ production of gonadotropins and sex hormones → early development of secondary sexual characteristics and early gonadarche.
Peripheral mechanism: Obesity causes insulin resistance and compensatory hyperinsulinemia → premature adrenarche, thelarche, and pubarche.
- Adrenals and ovaries: ↑ androgens
- Liver: ↓ SHBG
- Adipocytes: ↑ aromatase → ↑ bioavailability of sex steroids
What is McCune-Albright syndrome
A genetic syndrome caused by a G-protein activating mutation and subsequent continupus stimulation of endocrine functions
What is the epidemiology of McCune-Albright syndrome
Accounts for 5% of cases of precocious puberty (more common in females)
Affects 1 in 100,000 to 1 in 1,000,000 individuals in the general population
Peak incidence: early childhood
What is the aetiology of McCune-Albright syndrome
Mosaic mutation in the GNAS1 gene on chromosome 20 (autosomal recessive inheritance)
Some cells have a normal version of the GNAS1 gene, while other cells have the mutated version.
Embryos only survive if mosaicism occurs.
If the mutation occurs before fertilization, it affects all cells so is incompatible with life.
What is the pathophysiology of McCune-Albright syndrome
Activating mutation in GNAS gene → impaired Gs-protein signaling → constitutively activated adenylate cyclase → excess production of cAMP
What are the clinical features of McCune-Albright syndrome
Unilateral café-au-lait spots with unilateral, ragged edges
Polyostotic fibrous dysplasia
Endocrinopathies:
- Peripheral precocious puberty (most common)
- Cushing syndrome
- Acromegaly
- Hyperthyroidism
How is McCune-Albright syndrome diagnosed
Clinical features
Laboratory tests:
- Increased hormone levels (e.g., estradiol, testosterone, cortisol, thyroid hormone, growth hormone, prolactin, somatomedin C)
- Increased alkaline phosphatase
- Molecular testing: GNAS1 analysis
Imaging:
- X-rays of long bones: well-defined, lobulated lesions with a thin cortex and a radiolucent, ground-glass appearance
- CT/MRI: identify fibrodysplastic lesions
- Bone scan: determine the extent of bone disease
How is McCune-Albright syndrome treated
Symptomatic: treat underlying endocrinopathies
Estrogen synthesis inhibitors
- Ketoconazole
- Testolactone: an aromatase inhibitor that prevents the conversion of androstenedione to estrone and testosterone to estrogen
Selective estrogen receptor modulators (e.g., tamoxifen)
What are the differentials for McCune-Albright syndrome
Neurofibromatosis type 1
Fibrous dysplasia
What is the prognosis for McCune-Albright syndrome
The condition is lethal when the mutation affects all cells (i.e., occurs before fertilization), but survivable in patients affected by mosaicism.
What are the 3 Ps of McCune-Albright syndrome
Polyostotic fibrous dysplasia
Pigmentation (cafe au lait spots)
Precocious puberty
What is delayed onset of puberty
Absent or incomplete development of secondary sex characteristics by the age of 14 years in boys or 13 years in girls
What is the aetiology of delayed onset of puberty
Physiological causes: constitutional growth delay
Pathologic causes:
- Hypergonadotropic hypogonadism
- Primary gonadal insufficiency (e.g., Klinefelter syndrome, Turner syndrome, androgen insensitivity syndrome)
- Secondary gonadal insufficiency (e.g., chemotherapy, pelvic irradiation, infections, trauma/surgery, autoimmune disease)
- Hypogonadotropic hypogonadism (e.g., CNS lesions, Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, Prader-Willi syndrome, Gaucher disease)
- Malnutrition (e.g., anorexia nervosa)
- Chronic diseases (e.g., inflammatory bowel disease, hypothyroidism, cystic fibrosis)
What are the clinical features of delayed onset of puberty
Clinical features: depend on the underlying condition
Physical examination
- Tanner staging (testes ≤ 3 ml, absent breast buds, pubic/axillary hair or menarche)
- Assessment of height (short stature)
- Assessment of weight
- Neurological exam (anosmia)
How is delayed onset of puberty diagnosed
Medical history (e.g., positive family history of delayed onset of puberty, tanner staging, BMI)
Routine tests:
- Serum LH, FSH, and testosterone/estradiol
- Low or normal with low testosterone/estradiol: constitutional growth delay, isolated GnRH deficiency, functional hypogonadotropic hypogonadism (e.g., medical illness, malnutrition), or hypothalamic-pituitary disorders (e.g., malformations, hemochromatosis, injury, tumors)
- Elevated: primary hypogonadism
- X-ray of the left hand and wrist
- First imaging study
- Shows delayed bone age (less than the individual’s chronological age)
Additional tests: based on suspected etiology
- Serum prolactin level (elevated in prolactinoma)
- IGF-1 levels (exclude growth hormone deficiency)
- TSH and T4 hormone: evaluate amenorrhea and hypothyroidism
- Karyotype (Turner syndrome in girls, Klinefelter syndrome in boys)
- Complete blood and biochemical tests (e.g., FBC, ESR, LFT, U and Es, creatinine): suspected systemic disorder in children
- Antiendomysial antibody: screen for celiac disease in patients with signs of malabsorption
- Abdominal ultrasound (streak ovaries in Turner syndrome, testicular mass)
- Head MRI: suspected prolactinoma (e.g., headaches, bitemporal hemianopia)
How is delayed onset of puberty treated
Constitutional growth delay:
- expectant management
- No treatment is needed as catch-up growth eventually occurs and the individual reaches a normal adult height.
- Serial growth measurements at frequent intervals (∼ every 6 months)
- Reassuring the child and parents is sufficient.
Other pathologies:
Treatment of the underlying disease
Hormonal therapy
-Testosterone: used in boys to achieve secondary sex characteristics (e.g., virilization, growth spurt)
– Boys with constitutional growth delay usually respond well after one or two courses of testosterone therapy.
– If little or no response is seen, isolated GnRH deficiency should be suspected in boys over the age of 18 years.
-Estradiol: used in girls with primary gonadal insufficiency (e.g., Turner syndrome)
– Initially: low-dose estradiol that is gradually increased
– After 2 years: Add cyclic progestin therapy to induce menstruation.
What is Bruton agammaglobulinaemia
AKA X linked agammaglobulinaemia
X-linked recessive disease that causes a complete deficiency of mature B lymphocytes
What is the epidemiology of Bruton agammaglobulinaemia
Occurs mainly in boys
What is the aetiology of Bruton agammaglobulinaemia
Defect of Bruton tyrosine kinase expressed in B cells leading to a complete deficiency of mature B cell
What are the clinical features of Bruton agammaglobulinaemia
Symptoms develop between 3 and 6 months of age when maternal IgG levels in fetal serum start to decrease.
Hypoplasia of lymphoid tissue (e.g., tonsils, lymph nodes)
Recurrent, severe, pyogenic infections (e.g., pneumonia, otitis media), especially with encapsulated bacteria (S. pneumoniae, N. meningitidis, and H. influenzae)
Hepatitis virus and enterovirus (e.g., Coxsackie virus) infections
How is Bruton agammaglobulinaemia diagnosed
Flow cytometry:
- Absent or low levels of B cells (marked by CD19, CD20, and CD21)
- Normal or high T cells
Low immunoglobulins of all classes
Absent lymphoid tissue, i.e., no germinal centers and primary follicles
How is Bruton agammaglobulinaemia treated
IV immunoglobulins
Prophylactic antibiotics
Live vaccines are contraindicated in patients with Bruton agammaglobinaemia
How can Bruton agammaglobulinaemia be remembered
Brutal defects in a B cell make little Boys feel unwell
What is selective IgA deficiency (SIgAD)
Most common primary immunodeficiency that is characterized by a near or total absence of serum and secretory IgA
What is the epidemiology of selective IgA deficiency
~1:220 to 1:1000
Unknown aetiology
What are the clinical features of selective IgA deficiency
Often asymptomatic
May manifest with sinusitis or respiratory infections (S. pneumoniae, H. influenzae)
Chronic diarrhea, partially due to elevated susceptibility to parasitic infection (e.g. by Giardia lamblia)
Associated with autoimmune diseases (e.g., gluten-sensitive enteropathy, inflammatory bowel disease, immune thrombocytopenia) and atopy
Anaphylactic reaction to products containing IgA (e.g., intravenous immunoglobulin)
How is selective IgA deficiency diagnosed
Decreased serum IgA levels (< 7 mg/dL)
Normal IgG and IgM levels
False-positive pregnancy tests
How is selective IgA deficiency treated
Treatment of infections
Prophylactic antibiotics
Intravenous infusion of IgA is not recommended because of the risk of anaphylactic reactions (caused by the production of anti-IgA antibodies).
To prevent transfusion reactions, IgA-deficient patients must be given washed blood products without IgA or obtain blood from an IgA-deficient donor
What are the Six As of selective IgA deficiency
Asymptomatic Airway infections Anaphylaxis to IgA containing products Autoimmune diseases Atopy
What is common variable immunodeficiency (CVID)
Primary immunodeficiency with low serum levels of all immunoglobulins despite phenotypically normal B cells
What is the epidemiology of CVID
F=M
Onset: later than other B-cell defects (typically at 20-40 y/o)
What is the aetiology of CVID
Most cases are sporadic with no known family hisotry
What is the pathophysiology of CVID
B cells are phenotypically normal but are unable to differentiate into Ig-producing cells, resulting in low immunoglubulins of all classes
What are the clinical features of CVID
Recurrent pyogenic respiratory infections, e.g., sinopulmonary infections (in rare cases, enteroviral meningitis)
Associated with a high risk of lymphoma, gastric cancer, bronchiectasis, and autoimmune disorders (e.g., rheumatoid arthritis, autoimmune hemolytic anemia, immune thrombocytopenia, vitiligo)
How is CVID diagnosed
Quantitative immunoglobulin levels: low levels of IgG, IgA, and IgM
Decreased number of plasma cells
Flow cytometry shows subsets of normal B and T cells
Poor response to immunizations
How is CVID treated
Treatment of infections
Prophylactic antibiotics
IV immunoglobulins
What is neuroblastoma
A malignant embryonal neuroendocrine neoplasm of the sympathetic nervous system that originates from neural crest cells, potentially secretes catecholamines and is usually found in the adrenal glands or sympathetic ganglia
what is the epidemiology of neuroblastoma
Most common malignancy of the adrenal medulla in infants and third most common childhood cancer overall following leukaemia and brain tumours
Mean age of diagnosis is 1-2 y/o
The majority of children have progressed to advanced stage disease by the time of diagnosis
What is the aetiology of neuroblastoma
Cause: unclear
Genetic associations:
- chromosomal abnormalities, especially deletions (found in ∼ 50% of neuroblastomas)
- Deletions of 1p, 11q, and 14q chromosomosomal regions
- Amplification and overexpression of oncogene MYCN (N-myc)
Risk factors:
- Maternal: gestational diabetes, opiates, folate deficiency
- Congenital syndromes: Turner syndrome, neurofibromatosis, Hirschsprung’s disease, Beckwith-Wiedemann syndrome
- Familial
What are the clinical features of neuroblastoma
General:
- Failure to thrive or weight loss
- Fever
- Nausea, vomiting, loss of appetite
- Hypertension
Localised symptoms:
- Abdomen (>60% of cases):
- Palpable, firm, irregular abdominal mass that may cross the midline (in contrast to Wilms tumor, which is smooth and usually does not cross the midline)
- Abdominal distension and pain
- Hepatomegaly
- Constipation
- Chest (~20% of cases):
- Spinal cord compression → back pain, weakness, numbness, ataxia, loss of bowel or bladder control
- Scoliosis
- Dyspnea, cough
- Inspiratory stridor
- Neck:
- Horner syndrome
- Symptoms due to spinal cord compressions
Mets locations:
- Orbit of the eye:
- periorbital ecchymoses (raccoon eyes)
- Proptosis
- Bones:
- Bone pain
- Anaemia (bone marrow suppression)
- Skin:
- Subcutaneous nodules
Paraneoplastic syndromes:
- Chronic diarrhea → electrolyte imbalances
- Opsoclonus-myoclonus-ataxia: a paraneoplastic syndrome of unclear etiology characterized by rapid and multi-directional eye movements, rhythmic jerks of the limbs, and ataxia (dancing eyes dancing feet syndrome)
- Possibly hypertension, tachycardia, palpitations, sweating, flushing (hypertension is more commonly seen in pheochromocytoma)
What are the stages of neuroblastoma
International Neuroblastoma Staging System
- Localized tumor
Complete gross excision with or without microscopic residuals
Negative ipsilateral lymph nodes
2A.
Localized tumor
Incomplete gross excision
Negative ipsilateral lymph nodes
2B.
Localized tumor
Complete or incomplete gross excision
Positive ipsilateral lymph nodes
3.
Unresectable unilateral tumor that crosses the midline with or without lymph node involvement
Any tumor with positive contralateral lymph nodes
Midline tumor with bilateral tumor or lymph node involvement
4.
Any tumor with dissemination to distant lymph nodes or other organs (e.g., bone, liver, skin), with the exception of Stage 4S disease
4S.
Localized primary tumor with dissemination to skin, liver, or bone marrow, occurring in infants < 12 months
How is neuoblastoma diagnosed
Laboratory tests:
Urine
- ↑ Catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in 24-hour urine
- Urinalysis
Blood
- ↑ Catecholamine metabolites (HVA/VMA)
- ↑ Lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE)
- FBC with differential
- Serum chemistry profile
- Liver and kidney function tests
Other procedures:
Imaging:
- To identify the primary site
- Abdominal ultrasound
- CT or MRI (depending on the presumable site of the lesion)
Scintigraphy:
- MIBG scan: Uptake scan of metaiodobenzylguanidine (MIBG) combined with a radioactive iodine tracer.
- In MIBG non-avid tumors: technetium bone scan and plain radiographs
Biopsy:
- Image-guided needle aspiration of the tumor or biopsy at the time of surgical tumor resection
- Evaluation for MYCN gene amplification
- Evaluation for DNA ploidy
- Bilateral bone marrow biopsy of iliac crests
What is the pathology of neuroblastoma
Homer Wright rosettes: Halo-like clusters of neuroblast cells surrounding a central pale area containing neuropil (associated with tumors of neuronal origin such as neuroblastoma, medulloblastoma, primitive neuroectodermal tumors, and pineoblastoma)
Small round blue cells with hyperchromatic nuclei
Bombesin and NSE positive
What are the differentials in suspected neuroblastoma
Wilms tumor Pheochromocytoma Lymphoma Sarcomas Osteomyelitis or transient synovitis
How is neuroblastoma treated
Neuroblastoma patients are treated based on their risk category (low, intermediate, or high), which is based on the stage of their neuroblastoma (extent of disease), age at diagnosis, and the presence/absence of MYCN amplification.
Low risk: generally children with early-stage disease (Stages 1–2) and no MYCN amplification
- Observe
- Preoperative chemo
- Surgery
Intermediate risk: generally children with intermediate and late-stage disease (Stages 3–4) and no MYCN amplification
- Preoperative chemo
- Surgery
- Post op chemo
- Radiation
High risk: generally children with late-stage disease and/or MYCN amplification
- Pre op chemo
- Surgery
- Post op chemo
- Radiation
- GD2 antibody, dinutuximab, GM-CSF, IL-2 and cis-retinoic acid
- MIBG therapy post op
Stage 4S (an exception): disseminated disease in infants (< 12 months)
- Better prognosis than other stage 4 neuroblastoma and spontaneous regression is very common
- Children with Stage 4S belong to the low-risk or intermediate-risk groups unless they have a MYCN amplification, in which case they are high-risk patients
What pre op chemotherapy may be used in neuroblastoma
Doxorubicin
Cyclophosphamide
Etoposide
Platinum drug
What determines prognosis in neuroblastoma
Prognosis depends on the risk group.
Important factors include:
-Age
-Children with MYCN amplification are classified as high risk
-Histopathology, disease dissemination and biochemical markers
What is Wilms tumor
Nephroblastoma
Most common renal malignancy in children
What is the epidemiology of Wilms tumor
Peak incidence between 2 and 5 years
Most common malignant neoplasm of the kidney in children
What is the aetiology of Wilms tumor
The exact aetiology of Wilms tumor remains unknown, but it is associated with several genetic mutations and syndromes.
Genetic predisposition:
- Gene mutations have been found in children both with and without genetic syndromes who have Wilms tumor.
- Associated with loss of function mutations of tumor supressor genes on chromosome 11
- The WT1 (Wilms tumor 1) gene is the most important Wilms tumor gene (mutated in ∼ 10–20% of cases).
- WT2 (Wilms tumor 2) gene
Associated syndromes:
- WAGR syndrome: Deletion of the 11p13 band leads to the deletion of the WT1 gene and other genes, such as PAX6
- Wilms tumor
- Aniridia
- Genitourinary anomalies
- – Pseudohermaphroditism, undescended testes in males (due to gonadal dysgenesis)
- – Early-onset nephrotic syndrome
- Range of intellectual disability
- Denys-Drash syndrome: point mutation in WT1 gene, which encodes a zinc finger transcription factor
- Wilms tumor
- Pseudohermaphroditism, undescended testes in males (due to gonadal dysgenesis)
- Early-onset nephrotic syndrome caused by diffuse mesangial sclerosis
- Beckwith-Wiedemann syndrome: mutations of the WT2 gene
What is WAGR syndrome
Wilms tumor, Aniridia, Genitourinary anomalies and Range of intellectual disability
