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MD Pathology Exam: High-Yield Topics

Genetic Diseases & Pediatric Diseases (Robbins)

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PART 1: GENETIC DISEASES

Tier 1 - Most Frequently Examined (Almost Certain to Appear)

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1. Cystic Fibrosis (CF)

• Gene: CFTR on chromosome 7q - encodes chloride channel
• Mutation: deltaF508 (deletion of phenylalanine) - most common; results in misfolded protein that is retained in ER
• Pathophysiology: defective Cl- secretion + increased Na+ reabsorption → thick, viscid mucus
• Morphology:
  • Lungs: chronic airway obstruction, bronchiectasis, lung abscess, colonization with Pseudomonas aeruginosa and Burkholderia cepacia
  • Pancreas: ductal obstruction → pancreatic insufficiency, malabsorption, secondary diabetes mellitus
  • Liver: biliary cirrhosis (minority of patients)
  • Gut: meconium ileus (10-15% of newborns with CF)
  • Male reproductive: absence of vas deferens → infertility
• Sweat test: elevated Cl- (>60 mEq/L)
• Inheritance: autosomal recessive

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2. Familial Hypercholesterolemia (FH)

• Defect in LDL receptor gene (chromosome 19)
• Heterozygotes: TC ~300 mg/dL; premature atherosclerosis in 30s-40s
• Homozygotes: TC >700 mg/dL; MI before age 20; xanthomas, xanthelasmas, corneal arcus
• 5 classes of LDL receptor mutations (synthesis, transport, binding, clustering, recycling defects)
• Inheritance: autosomal dominant (incomplete dominance)

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3. Marfan Syndrome

• Defect: FBN1 gene (chromosome 15) → fibrillin-1 deficiency → microfibril scaffolding disrupted
• Also: loss of TGF-beta sequestration → excessive TGF-beta signaling
• Morphology:
  • Skeletal: tall stature, long limbs (dolichostenomelia), arachnodactyly, scoliosis, pectus excavatum
  • Cardiovascular: cystic medial necrosis of aorta → aortic dissection (main cause of death), aortic regurgitation, MVP
  • Ocular: ectopia lentis (upward lens dislocation, bilateral)
• Inheritance: autosomal dominant

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4. Lysosomal Storage Diseases

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5. Phenylketonuria (PKU)

• Deficiency of phenylalanine hydroxylase (PAH) - chromosome 12q
• Accumulation of phenylalanine → phenylpyruvic acid (toxic to CNS)
• Features: intellectual disability, fair skin/hair/eyes (reduced melanin), eczema, "mousy odor" urine
• Maternal PKU: untreated maternal PKU → cardiac defects, microcephaly, mental retardation in fetus (even if fetus is heterozygous)
• Treatment: phenylalanine-restricted diet + large neutral amino acids
• Inheritance: autosomal recessive

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6. Glycogen Storage Diseases

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7. Cytogenetic Disorders

• Most common chromosomal disorder (1:700 live births)
• Karyotype: 95% nondisjunction trisomy; 4% translocation (Robertsonian); 1% mosaic
• Risk increases with maternal age (meiosis I nondisjunction in oocyte)
• Features: flat face, epicanthal folds, simian crease, small stature, hypotonia, moderate ID
• Associations: AV canal/VSD (40%), ALL (10-20x risk), Alzheimer disease (early onset, ALL patients develop plaques by 40), duodenal atresia, Hirschsprung disease
• Screening: low AFP, low estriol, high beta-hCG, high inhibin A (quad screen)

• Most common sex chromosome aneuploidy in males (1:1000)
• Hypogonadism, small testes, azoospermia, gynecomastia, tall stature
• Elevated FSH/LH, low testosterone
• Barr body present (inactive X)
• Risk of male breast cancer, mediastinal germ cell tumors

• Most common cause of primary amenorrhea
• Short stature, shield chest, webbed neck, low posterior hairline, widely spaced nipples
• Coarctation of aorta (most common cardiac defect), bicuspid aortic valve
• Streak gonads → primary amenorrhea, infertility, no Barr body
• Lymphedema of hands/feet at birth (cystic hygroma in utero)
• Most common cause: 45,X + mosaic (45,X/46,XX) - milder phenotype

• CATCH-22: Cardiac defects, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia
• T-cell immunodeficiency (thymus absent/hypoplastic)

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8. Single-Gene Disorders with Atypical Patterns

• Most common cause of inherited intellectual disability
• Trinucleotide repeat expansion: CGG repeat in FMR1 gene (X-linked)
• Normal: <55 repeats; Premutation: 55-200 repeats; Full mutation: >200 repeats
• Features: large ears, large jaw (macrognathia), macro-orchidism, ID (moderate-severe)
• Sherman paradox: increasing severity with each generation (anticipation)
• Premutation females: premature ovarian failure; Premutation males: FXTAS (tremor/ataxia in elderly)

• Prader-Willi Syndrome: Deletion of paternal 15q11-13 OR maternal UPD (both 15s from mother) → short stature, hypotonia, hyperphagia/obesity, hypogonadism, mild ID
• Angelman Syndrome: Deletion of maternal 15q11-13 OR paternal UPD → "happy puppet" - severe ID, no speech, seizures, ataxic gait, inappropriate laughter

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9. Ehlers-Danlos Syndromes

• Defects in collagen synthesis or structure
• Hyperextensible skin, hypermobile joints, fragile vessels
• Kyphoscoliotic type: Lysyl hydroxylase deficiency (enzyme defect)
• Classical type: COL5A1/2 mutations

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10. Molecular Diagnosis

• PCR, FISH, microarray CGH, next-generation sequencing (NGS)
• Liquid biopsy: circulating tumor DNA/cells
• NIPT (non-invasive prenatal testing): cell-free fetal DNA in maternal blood

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PART 2: PEDIATRIC DISEASES

Tier 1 - Most Frequently Examined

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1. Congenital Anomalies

• Critical periods: Organogenesis (3-8 weeks) is most vulnerable
• Deformation vs. malformation vs. disruption vs. sequence: know the differences
• Neural tube defects: folic acid deficiency, elevated maternal AFP (open NTD)

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2. Neonatal Respiratory Distress Syndrome (NRDS / Hyaline Membrane Disease)

• Cause: Surfactant deficiency (type II pneumocyte immaturity)
• Risk factors: Prematurity (<34 weeks), maternal diabetes (fetal hyperinsulinism delays surfactant), male sex, C-section (no labor stress cortisol)
• Pathogenesis: low surfactant → atelectasis → hyaline membrane formation (fibrin + necrotic pneumocytes)
• Morphology: diffuse atelectasis, eosinophilic hyaline membranes lining alveolar ducts, type II cell hyperplasia (repair)
• Complications: intraventricular hemorrhage, PDA, retinopathy of prematurity, bronchopulmonary dysplasia (BPD)
• Treatment: antenatal glucocorticoids (stimulate surfactant), exogenous surfactant

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3. Sudden Infant Death Syndrome (SIDS)

• Definition: sudden, unexpected death in infant <1 year, unexplained after autopsy
• Peak age: 2-4 months
• Risk factors: prone sleeping, co-sleeping, soft bedding, maternal smoking, prematurity, male sex
• Proposed mechanisms: brainstem serotonin signaling defect (arousal response failure), prolonged QT
• Morphology (subtle, non-specific): petechiae on pleural/pericardial surfaces, pulmonary edema, brainstem gliosis
• Prevention: "Back to Sleep" campaign

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4. Tumors of Infancy and Childhood

• Origin: neural crest cells of adrenal medulla and sympathetic ganglia
• Most common in children <5 years
• Location: adrenal medulla (most common), retroperitoneal, posterior mediastinum
• Features: abdominal mass, catecholamine excess (sweating, hypertension, tachycardia), VMA/HVA elevated in urine
• Homer Wright pseudorosettes (histology)
• Spontaneous regression in infants (<1 yr) - Stage 4S
• Genetics: MYCN amplification = poor prognosis; deletion 1p; 17q gain
• Trk A expression = favorable; Trk B + BDNF = unfavorable (autocrine survival)

• Most common renal tumor in children (peak: 3-4 years)
• Triphasic histology: blastema + stroma + epithelium (tubules)
• Genetics: WT1 (chromosome 11p13), LOH at 11p15 (WT2 locus), CTNNB1
• Associations: WAGR syndrome (Wilms + Aniridia + GU anomalies + mental Retardation), Denys-Drash syndrome, Beckwith-Wiedemann syndrome
• Favorable histology (anaplasia = unfavorable)
• Good prognosis overall (>90% cure with surgery + chemo)

• Most common intraocular tumor of childhood
• Rb gene (13q14) - tumor suppressor, two-hit hypothesis
• Leukocoria (white pupillary reflex) - classic presentation
• Hereditary (bilateral, AD) vs. sporadic (unilateral)

• Most common tumor of infancy
• Capillary hemangioma: grows rapidly in first year, involutes spontaneously
• Associations: PHACES syndrome (posterior fossa, hemangioma, arterial anomalies, cardiac, eye, sternal)

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5. Fetal Hydrops

• Abnormal fluid accumulation: skin edema, ascites, pleural effusion, pericardial effusion
• Immune hydrops: Rh incompatibility (anti-D) → fetal hemolytic anemia → cardiac failure → hydrops (less common now with Rhogam)
• Nonimmune hydrops (more common today): cardiovascular malformations (most common cause), chromosomal (Turner 45,X - cystic hygroma), lysosomal storage diseases, twin-to-twin transfusion

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6. Prematurity and Fetal Growth Restriction

• Prematurity: <37 weeks - surfactant deficiency, IVH, NEC, retinopathy, BPD
• Fetal Growth Restriction (FGR): SGA (<10th percentile)
  • Symmetric FGR: early insult (chromosomal, TORCH infections, teratogens) - poor prognosis
  • Asymmetric FGR: late insult (uteroplacental insufficiency, HTN) - better prognosis (brain sparing)

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7. Necrotizing Enterocolitis (NEC)

• Most common GI emergency in neonates
• Risk factors: prematurity, formula feeding, sepsis
• Pathology: coagulative necrosis of bowel wall, pneumatosis intestinalis (gas in bowel wall on X-ray)
• Complication: bowel perforation, peritonitis, septic shock

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EXAM STRATEGY SUMMARY

Most likely long question (10 marks each):

1. Cystic Fibrosis - pathogenesis + morphology
2. Down Syndrome - genetics + features + complications
3. Lysosomal Storage Diseases - classify with examples
4. Neuroblastoma - pathology + molecular features
5. Neonatal RDS - pathogenesis + morphology

Most likely short notes (5 marks each):

1. Fragile X Syndrome
2. Marfan Syndrome
3. Wilms Tumor
4. SIDS
5. Turner/Klinefelter Syndrome
6. Gaucher disease
7. Tay-Sachs vs. Niemann-Pick
8. Prader-Willi vs. Angelman Syndrome
9. Phenylketonuria
10. Fetal Hydrops

Guaranteed 1-2 mark MCQs:

• Enzyme defects in LSDs (table above)
• Chromosomal numbers in trisomies
• Teratogens and their effects
• Tumor genetics (MYCN, WT1, Rb)
• Sweat chloride cutoff in CF

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