What is selective neuronal necrosis, and which neurons are most vulnerable?
β Most common pattern of hypoxic-ischemic injury in the neonatal brain. Neurons most vulnerable (in order): hippocampus (CA1 region), cerebral cortex (layers 3, 5, 6), thalamus, brainstem nuclei, Purkinje cells of cerebellum. π Term infants β cortical/deep gray matter injury; Preterm infants β periventricular white matter injury. Mechanism: excitotoxicity via glutamate, oxidative stress, and mitochondrial failure.
What is Alagille syndrome? What gene is involved?
β Autosomal dominant disorder caused by mutations in JAG1 (Jagged1) on chromosome 20p12 (Notch signaling pathway). π ‘Bile duct paucity + butterfly vertebrae + posterior embryotoxon = Alagille.’ Key features: (1) Chronic cholestasis with intrahepatic bile duct paucity, (2) Characteristic facies β triangular face, broad forehead, pointed chin, deep-set eyes, (3) Cardiac defects β peripheral pulmonic stenosis (most common), (4) Butterfly vertebrae, (5) Posterior embryotoxon (eye finding). Labs: elevated conjugated bilirubin, elevated GGT. Prognosis variable β some need liver transplant.
What is McCune-Albright syndrome? What mutation causes it?
β Caused by postzygotic somatic activating mutation in GNAS1 gene (encodes GsΞ± protein β constitutive cAMP activation). NOT inherited β always mosaic. π Classic triad: (1) Polyostotic fibrous dysplasia (bone lesions), (2) CafΓ©-au-lait spots with IRREGULAR (‘coast of Maine’) borders, (3) Precocious puberty (gonadotropin-independent). May also cause hyperthyroidism, Cushing syndrome, GH excess. π ‘Coast of Maine’ cafΓ©-au-lait spots = McCune-Albright vs. ‘coast of California’ (smooth borders) = neurofibromatosis.
What is Neurofibromatosis Type 1 (NF1)? Diagnostic criteria?
β Autosomal dominant. Mutation in NF1 gene on chromosome 17q β loss of neurofibromin (a RAS-GAP tumor suppressor). Diagnosis requires β₯2 of: (1) β₯6 cafΓ©-au-lait macules (β₯5mm prepubertal, β₯15mm postpubertal), (2) β₯2 neurofibromas or 1 plexiform neurofibroma, (3) Axillary or inguinal freckling (Crowe sign), (4) Optic glioma, (5) β₯2 Lisch nodules (iris hamartomas), (6) Distinctive bony lesion (sphenoid dysplasia, tibial pseudarthrosis), (7) First-degree relative with NF1. π CafΓ©-au-lait with SMOOTH borders (‘coast of California’) = NF1. Complications: learning disabilities (most common), malignant peripheral nerve sheath tumors, pheochromocytoma.
What is Neurofibromatosis Type 2 (NF2)?
Autosomal dominant. Mutation in NF2 gene on chromosome 22q β loss of merlin/schwannomin. π Bilateral vestibular schwannomas (acoustic neuromas) = pathognomonic. Also: meningiomas, ependymomas, cataracts (posterior subcapsular). NF2 is much rarer than NF1. Mnemonic: NF2 = chromosome 22 = 2 acoustic neuromas.
What is Tuberous Sclerosis Complex (TSC)? Key neonatal findings?
β Autosomal dominant. Mutations in TSC1 (hamartin, chr 9) or TSC2 (tuberin, chr 16) β mTOR pathway activation. π Neonatal presentation: cardiac rhabdomyomas (most common cardiac tumor in neonates β often detected prenatally, can cause arrhythmias/outflow obstruction, many regress spontaneously). Skin: ash-leaf spots (hypopigmented macules β use Wood lamp), shagreen patches, facial angiofibromas (adenoma sebaceum β appear later). Brain: cortical tubers, subependymal nodules, subependymal giant cell astrocytomas (SEGA). Also: renal angiomyolipomas, lymphangioleiomyomatosis (LAM). π ‘Cardiac rhabdomyoma in a fetus/neonate β think TSC.’
What is Von Hippel-Lindau (VHL) disease?
β Autosomal dominant. Mutation in VHL tumor suppressor gene on chromosome 3p25 β loss of VHL protein β failure to degrade HIF β upregulated VEGF β vascular tumors. Key features: (1) CNS hemangioblastomas (cerebellum most common, also spinal cord, retina), (2) Retinal angiomas/hemangioblastomas, (3) Clear cell renal cell carcinoma (bilateral, multifocal), (4) Pheochromocytoma, (5) Pancreatic neuroendocrine tumors and cysts, (6) Endolymphatic sac tumors. π ‘Hemangioblastomas + renal cell carcinoma = VHL.’ Screening begins in childhood with ophthalmologic exams and biochemical testing.
What is Sturge-Weber syndrome? Key features?
β Sporadic (NOT inherited). Caused by somatic activating mutation in GNAQ gene. π Port-wine stain (nevus flammeus) in V1 distribution (forehead/upper eyelid) + ipsilateral leptomeningeal angiomatosis. NOT a phakomatosis in the traditional sense (no tumor predisposition). Key features: (1) Facial port-wine stain (V1 > V2), (2) Leptomeningeal venous angioma β seizures (often refractory, contralateral), (3) ‘Tram-track’ intracranial calcifications on imaging, (4) Glaucoma (ipsilateral β from episcleral hemangioma), (5) Hemiparesis/hemiplegia contralateral to lesion. π ‘Port-wine stain in V1 + seizures = Sturge-Weber.’ Note: NOT all port-wine stains = Sturge-Weber β risk is highest when V1 distribution bilaterally.
What is classic galactosemia? Enzyme deficiency and presentation?
β Autosomal recessive. Deficiency of galactose-1-phosphate uridylyltransferase (GALT). π Neonate presents days after starting breast milk or lactose-containing formula with: vomiting, jaundice (conjugated), hepatomegaly, E. coli sepsis, cataracts, hypoglycemia, coagulopathy, renal tubular dysfunction. Detected on newborn screen (most states). Galactose-1-phosphate accumulates β toxic. Treatment: lifelong galactose-free diet (soy formula). Even with treatment, long-term complications include: ovarian failure (hypergonadotropic hypogonadism in females), speech/language delays, learning difficulties. π ‘Sick neonate + E. coli sepsis + cataracts + liver failure after starting feeds β think galactosemia.’
What is galactokinase deficiency? How does it differ from classic galactosemia?
Autosomal recessive. Deficiency of galactokinase β galactose cannot be phosphorylated β galactitol accumulates. KEY DIFFERENCE from classic galactosemia: galactokinase deficiency causes CATARACTS ONLY β no liver disease, no intellectual disability, no E. coli sepsis. π ‘Cataracts without systemic illness in a neonate on milk β think galactokinase deficiency.’ Galactitol accumulation in the lens causes osmotic cataracts. Treatment: dietary galactose restriction. Much milder than classic galactosemia.
What are the key urea cycle defects? What is the common presentation?
β All urea cycle defects β hyperammonemia. Enzymes in order: (1) CPS I (carbamyl phosphate synthetase) β mitochondrial, (2) OTC (ornithine transcarbamylase) β mitochondrial, X-LINKED, (3) ASS (argininosuccinate synthetase) β citrullinemia, (4) ASL (argininosuccinate lyase) β argininosuccinic aciduria, (5) Arginase β argininemia. π OTC deficiency is the MOST COMMON urea cycle defect and the only X-LINKED one. Presentation: normal at birth β progressive lethargy, poor feeding, vomiting, tachypnea (respiratory alkalosis initially), then encephalopathy, seizures, coma. Labs: β ELEVATED AMMONIA + respiratory alkalosis (central hyperventilation) + NORMAL anion gap + NO ketoacidosis (distinguishes from organic acidemias). Treatment: stop protein, IV dextrose, nitrogen scavengers (sodium benzoate, sodium phenylbutyrate), arginine supplementation, dialysis if severe.
How do you differentiate proximal vs. distal urea cycle defects using amino acid levels?
β Key differentiating lab: plasma citrulline level. PROXIMAL defects (CPS I, OTC): citrulline is LOW or absent (defect is before citrulline synthesis). To distinguish CPS I from OTC: measure urine orotic acid β elevated in OTC (carbamyl phosphate shunts to pyrimidine pathway), normal/low in CPS I. DISTAL defects: citrulline is ELEVATED. ASS deficiency (citrullinemia): very high citrulline. ASL deficiency (argininosuccinic aciduria): elevated citrulline + elevated argininosuccinic acid in blood/urine. π ‘Hyperammonemia + low citrulline + high urine orotic acid = OTC deficiency.’
Describe the composition of colostrum vs. mature breast milk.
β COLOSTRUM (first 3-5 days): Higher in: protein (especially secretory IgA, lactoferrin, leukocytes), sodium, chloride, fat-soluble vitamins (A, E, K), minerals (zinc), growth factors. Lower in: fat, lactose, total calories. Yellow color from beta-carotene. Rich in immunologic factors β ‘first vaccine.’ MATURE MILK (by ~2 weeks): Higher in: fat, lactose, total calories, water-soluble vitamins. Lower in: protein, sodium. ~20 kcal/oz. π Colostrum = more protein and immunoglobulins; Mature milk = more fat and lactose.
How does foremilk differ from hindmilk?
FOREMILK: milk at the beginning of a feed. Higher in water content, lactose. Lower in fat. More volume. HINDMILK: milk at the end of a feed. β Higher in FAT content (2-3x more fat than foremilk). Higher caloric density. π ‘Hindmilk = high fat.’ Important for weight gain in preterm infants. Exclusively foremilk feeding β poor weight gain, loose stools (lactose overload).
How does preterm breast milk differ from term breast milk?
β PRETERM breast milk (compared to term milk): Higher in: protein, fat, sodium, chloride, IgA, lactoferrin, calories, medium-chain fatty acids. Lower in: lactose, calcium, phosphorus. Preterm milk gradually transitions toward term milk composition over 4-6 weeks. π Preterm milk is naturally higher in protein and fat to support rapid growth, but still requires FORTIFICATION (human milk fortifier) for adequate calcium, phosphorus, protein, and calories for VLBW infants.
When do neonatal primitive reflexes appear and disappear? (Moro, palmar grasp, ATNR, Babinski, rooting, stepping)
β MORO: Present at birth (28-32 wks GA) β disappears by 4-6 months. π Persistence beyond 6 months = concerning for upper motor neuron lesion. PALMAR GRASP: Present at birth (28 wks) β disappears by 3-4 months (must disappear for voluntary grasp to develop). ATNR (asymmetric tonic neck reflex / ‘fencing’): Present at birth β most prominent at 2 months β disappears by 6-7 months. π Obligate ATNR (cannot break out of posture) is ALWAYS abnormal. BABINSKI (plantar response): Upgoing toes NORMAL in infants β becomes downgoing by 12-24 months. ROOTING: Present at birth β disappears by 3-4 months. STEPPING/WALKING: Present at birth β disappears by 2 months β reappears as voluntary walking ~12 months. GALANT (trunk incurvation): Present at birth β disappears by 4-6 months.
How do you use the Hardy-Weinberg equation?
β Hardy-Weinberg equilibrium: pΒ² + 2pq + qΒ² = 1 and p + q = 1. p = frequency of dominant allele; q = frequency of recessive allele. pΒ² = homozygous dominant; 2pq = heterozygous (carriers); qΒ² = homozygous recessive (affected in AR disease). π Board approach: For autosomal recessive disease, you are usually given disease INCIDENCE (= qΒ²). Step 1: qΒ² = incidence β solve for q. Step 2: p = 1 - q. Step 3: Carrier frequency = 2pq. Example: PKU incidence = 1/10,000 β qΒ² = 1/10,000 β q = 1/100 β p β 1 β carrier frequency = 2(1)(1/100) = 1/50. Assumptions: large population, random mating, no selection/mutation/migration.
What is propionic acidemia? Presentation and key labs?
β Autosomal recessive. Deficiency of propionyl-CoA carboxylase. One of the classic organic acidemias. Presentation: typically in first days-weeks of life with poor feeding, vomiting, lethargy, hypotonia β metabolic crisis β coma. π Labs: SEVERE metabolic acidosis with ELEVATED ANION GAP + KETOSIS + HYPERAMMONEMIA (secondary) + pancytopenia (bone marrow suppression). Urine organic acids: elevated 3-hydroxypropionate, methylcitrate, propionylglycine, tiglylglycine. Blood: elevated propionylcarnitine (C3) on acylcarnitine profile. π Distinguishing from urea cycle defects: organic acidemias have KETOSIS + HIGH ANION GAP + acidosis, while urea cycle defects have respiratory ALKALOSIS + normal anion gap + NO ketosis. Long-term complications: cardiomyopathy, pancreatitis, basal ganglia injury. Treatment: restrict isoleucine, valine, methionine, threonine; biotin supplementation; carnitine.
What are the different forms of congenital adrenal hyperplasia (CAH)?
β 21-HYDROXYLASE DEFICIENCY: ~95% of CAH. AR. Cannot convert 17-OHP β 11-deoxycortisol. β17-OHP (screening marker). Salt-wasting (75%) or simple virilizing. Females: ambiguous genitalia. Males: salt-wasting crisis ~1-2 weeks (hyponatremia, hyperkalemia). 11Ξ²-HYDROXYLASE DEFICIENCY: ~5% of CAH. β11-deoxycortisol, βDOC. Virilization + HYPERTENSION (DOC has mineralocorticoid activity) + hypokalemia. π ‘CAH + hypertension = 11Ξ²-hydroxylase deficiency.’ 3Ξ²-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY: Rare. Affects all steroid pathways. Males: undervirilized (ambiguous genitalia). Females: mild virilization (from DHEA). Salt-wasting. 17Ξ±-HYDROXYLASE DEFICIENCY: Rare. βDOC and corticosterone. Hypertension + hypokalemia. Males: undervirilized/female phenotype (cannot make sex steroids). Females: no puberty. LIPOID CAH (StAR mutation): Most severe. Cannot convert cholesterol to pregnenolone. All 46,XY appear female. Adrenal crisis. Large lipid-laden adrenals.
What is ornithine transcarbamylase (OTC) deficiency?
β Most common urea cycle defect. X-LINKED recessive (only X-linked UCD). OTC enzyme (mitochondrial) converts ornithine + carbamyl phosphate β citrulline. Males: severe neonatal hyperammonemia β presents day 2-3 of life with vomiting, lethargy, tachypnea β seizures, coma, cerebral edema. Carrier females: variable β can range from asymptomatic to protein aversion to intermittent hyperammonemia during catabolic stress. π Diagnostic keys: Hyperammonemia + LOW plasma citrulline + ELEVATED urine orotic acid (carbamyl phosphate shunts into pyrimidine synthesis pathway). Plasma glutamine elevated. Treatment: emergency β stop protein, IV glucose, nitrogen scavengers (sodium benzoate, phenylbutyrate), arginine, dialysis. Long-term: protein restriction, nitrogen scavengers, possible liver transplant.
Explain the Fick principle and oxygen consumption in neonates.
β FICK PRINCIPLE: VOβ = CO Γ (CaOβ - CvOβ). VOβ = oxygen consumption; CO = cardiac output; CaOβ = arterial oxygen content; CvOβ = mixed venous oxygen content. Rearranged: CO = VOβ / (CaOβ - CvOβ). π Neonatal oxygen consumption: ~6-8 mL/kg/min (roughly 2x adult on per-kg basis). CaOβ = (1.34 Γ Hgb Γ SaOβ) + (0.003 Γ PaOβ). The dissolved Oβ component (0.003 Γ PaOβ) is negligible. Clinically: if VOβ increases (fever, cold stress, sepsis) and CO cannot compensate β mixed venous Oβ drops β tissue hypoxia. Thermoneutral environment minimizes Oβ consumption. Cold stress increases VOβ significantly via non-shivering thermogenesis (brown fat).
What are the expected functional levels for myelomeningocele at different spinal levels?
β THORACIC LEVEL (T12 and above): No lower extremity function. Wheelchair dependent. High risk of scoliosis, hip dislocation. HIGH LUMBAR (L1-L2): Hip flexion present (iliopsoas). No knee extension. Wheelchair dependent. May use standing frame. LOW LUMBAR (L3-L4): β Knee extension present (quadriceps β L3-L4). Some hip adduction. Household/community ambulation with KAFO braces and crutches. L4: adds tibialis anterior (foot dorsiflexion). MID-SACRAL (L5-S1): L5: foot dorsiflexion and eversion. S1: adds plantar flexion (gastrocnemius), hip extension. Community ambulation with AFOs. LOW SACRAL (S2-S4): Near-normal ambulation. May have bowel/bladder dysfunction. π General rule: the LOWER the lesion, the BETTER the ambulation prognosis. π Most patients with myelomeningocele have associated Chiari II malformation and hydrocephalus. Bowel and bladder dysfunction present in nearly all levels.
What are the components of the Apgar score?
β Assessed at 1 and 5 minutes of life (and every 5 min if <7). 5 components, each scored 0-1-2: (1) APPEARANCE (color): 0 = blue/pale all over, 1 = acrocyanosis (body pink, extremities blue), 2 = completely pink. (2) PULSE (heart rate): 0 = absent, 1 = <100 bpm, 2 = β₯100 bpm. (3) GRIMACE (reflex irritability): 0 = no response, 1 = grimace, 2 = cry/cough/sneeze. (4) ACTIVITY (muscle tone): 0 = limp, 1 = some flexion, 2 = active motion. (5) RESPIRATION: 0 = absent, 1 = slow/irregular/weak cry, 2 = good cry. π The 1-minute Apgar reflects need for immediate intervention. The 5-minute Apgar better correlates with outcome. Apgar score ALONE should NOT be used to diagnose asphyxia. Low Apgar can be caused by prematurity, maternal medications, congenital anomalies. Resuscitation should NOT be delayed to assign Apgar scores.
What is the Sarnat staging system for HIE?
β Sarnat staging classifies neonatal hypoxic-ischemic encephalopathy (HIE) severity. STAGE 1 (MILD): Hyperalert, jittery, uninhibited reflexes, sympathetic overdrive (mydriasis, tachycardia), normal or slightly increased tone, no seizures. Duration <24 hours. Normal outcome expected. STAGE 2 (MODERATE): β Lethargy, hypotonia, decreased spontaneous movements, seizures common, parasympathetic overdrive (miosis, bradycardia), weak reflexes, weak suck. Duration 2-14 days. π Stage 2 = COOLING CANDIDATE (therapeutic hypothermia indicated). Outcome: 20-40% develop significant disabilities. STAGE 3 (SEVERE): Comatose, flaccid, absent reflexes, absent suck/gag, variable pupils (often fixed/dilated), prolonged seizures β may decrease as brain injury worsens, failure of spontaneous respiration. Outcome: high mortality, survivors have severe disability. π ‘Sarnat 2 or 3 + criteria met β cool.’
