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FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
KEY FACTS
Feature Description
Gene Involved : APC tumor suppressor gene
Chromosome : Chromosome 5q21
Inheritance : Autosomal Dominant
Penetrance : 100% if untreated
Pathophysiology : Mutation in APC gene → defective β-catenin regulation → uncontrolled cell proliferation → formation of thousands of polyps
Cancer Risk Colorectal cancer by age ~40 unless prophylactic colectomy is done
FAP : PATHOLOGY
Feature Description
Histology : Multiple adenomatous colonic polyps (esp. tubular and villous adenomas)
Sequence Follows the adenoma-carcinoma sequence:
APC mutation (initiation)
KRAS mutation (progression)
p53 mutation (malignancy) |
FAP : CLINICAL FEATURES
Usually asymptomatic initially
Numerous colonic polyps by adolescence
Rectal bleeding, diarrhea, abdominal pain (later)
Colorectal cancer if untreated
Associated features depending on subtype (see below)
FAP: VARIANTS AND SYNDROMES
Syndrome Features
Gardner syndrome : FAP + osteomas, epidermoid cysts, dental abnormalities, desmoid tumors
Turcot syndrome : FAP + CNS tumors, especially
medulloblastoma (APC mutation)
or
glioblastoma (MMR mutation)
Attenuated FAP Fewer polyps (<100), later onset cancer, also APC-related
FAP: GENETICS + MOLECULAR
Gene Function Mutation Consequence
APC Tumor suppressor gene that regulates β-catenin Loss of function → β-catenin accumulates → ↑ transcription of proliferative genes
Two-hit hypothesis First hit: inherited APC mutation
Second hit: somatic mutation → polyp formation
FAP: MEMORIZATION TIPS
“APC is on 5 — Alive or Die”: APC mutation on chromosome 5 → if untreated, 100% chance of death by colon cancer
FAP = Family of Polyps – Think thousands of polyps inherited through family.
Gardner “gardens” tumors outside the colon (osteomas, cysts, etc.)
Turcot = Turban tumor (brain) – Associated with CNS tumors
WNT SIGNALING PATHWAY
State β-Catenin Status Result
No Wnt signal : Degraded by destruction complex (APC, Axin, GSK-3β) No gene transcription
Wnt signal ON : β-catenin stabilized → enters nucleus Activates gene transcription (cell proliferation, survival)
✅ USMLE Pearl:
APC gene is part of the β-catenin destruction complex.
If APC is mutated (e.g., FAP), β-catenin accumulates → ↑ transcription of oncogenes.
APC: adenomatous polyposis coli
CELL ADHESION
Anchors E-cadherin to the actin cytoskeleton
Important for tissue integrity and polarity
✅ Disruption → Loss of contact inhibition (a hallmark of cancer)
Beta catenin
STEP 1 MNEMONICS & TIPS
“B for both”:
β-catenin is used both in signaling and adhesion
“Beta-catenin builds and breaks”
Builds tissue via adhesion
Breaks cell cycle control via overactivation in cancer
“When APC is AWOL, β-catenin is out of control”
APC loss → β-catenin accumulation → uncontrolled proliferation
MISMATCH REPAIR (MMR) MUTATIONS
CLINICAL ASSOCIATION: LYNCH SYNDROME (HNPCC)
Feature Description
Also called Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Mutation: Germline mutation in MMR genes: MLH1, MSH2, MSH6, PMS2
Inheritance: Autosomal dominant
Mechanism: One inherited mutation + second somatic hit (Knudson’s two-hit hypothesis)
Key Cancers
Colorectal cancer (right-sided) – early onset, non-polypoid
** Endometrial cancer (most common extracolonic in women) **
Ovarian, gastric, urothelial, small bowel, pancreatic, brain (esp. glioblastoma)
Skin tumors (sebaceous neoplasms – Muir-Torre variant) |
✅ Mnemonic: “Lynch = MEGO”
M – MSI
E – Endometrial cancer
G – GI (colon, stomach, small bowel)
O – Ovarian cancer
VON HIPPEL–LINDAU (VHL) DISEASE
OVERVIEW
Feature Detail
Inheritance Autosomal Dominant
Gene VHL tumor suppressor gene
Chromosome Chromosome 3p25
Penetrance Nearly 100% by age 65
Key Mechanism Loss of VHL protein → failure to degrade HIF-1α → ↑ angiogenesis and tumor formation
von Hippel Lindau
MOLECULAR PATHOPHYSIOLOGY
Normal Function of VHL Consequence of Mutation
VHL protein tags HIF-1α for ubiquitination and degradation (under normoxia) HIF-1α accumulates → activates transcription of pro-angiogenic genes (VEGF, PDGF, EPO)
✅ Mnemonic:
“VHL = Very High Levels of HIF”
CLINICAL FEATURES (VHL-Associated Tumors)
Organ/System Tumor Type
CNS : Hemangioblastomas (cerebellum, retina, brainstem, spinal cord)
Kidney: Clear cell renal cell carcinoma (ccRCC) — bilateral, early onset
Adrenal gland: Pheochromocytoma (less common than in MEN 2)
Pancreas: Pancreatic cysts, neuroendocrine tumors
Eye : Retinal angiomas/hemangioblastomas – may lead to vision loss
Inner ear Endolymphatic sac tumors – hearing loss, vertigo
✅ VHL = multiple highly vascular tumors
✅ Hemangioblastomas + RCC + Pheo = classic triad tested
HIF-1alpha
CORE CONCEPT
Feature Details
What is HIF-1α? Transcription factor that responds to low oxygen (hypoxia)
Gene name HIF1A
Normal function Induces transcription of pro-angiogenic and glycolytic genes in hypoxic conditions
Key Target Genes
VEGF (vascular endothelial growth factor)
EPO (erythropoietin)
GLUT1, glycolytic enzymes
PDGF, TGF-α |
REGULATION of HIF-1alpha
Oxygen Level What Happens to HIF-1α
Normoxia (normal O₂) Hydroxylated by prolyl hydroxylase, recognized by VHL protein → ubiquitinated → degraded in proteasome
Hypoxia (low O₂) Hydroxylation inhibited → HIF-1α stabilizes → translocates to nucleus → dimerizes with HIF-1β → activates transcription
✅ USMLE Pearl: The VHL tumor suppressor gene negatively regulates HIF-1α under normoxia
HIF-1alpha
PATHOLOGY ASSOCIATIONS
Disease Role of HIF-1α
Von Hippel–Lindau disease (VHL) Mutation in VHL gene → failure to degrade HIF-1α → ↑ VEGF, EPO → hemangioblastomas, RCC, pheochromocytomas
Clear cell Renal Cell Carcinoma (ccRCC) Commonly shows upregulated HIF-1α due to VHL loss (even sporadically)
Tumors in general Many exploit HIF-1α to grow in hypoxic microenvironments
High-altitude adaptation ↑ HIF-1α → ↑ EPO → ↑ RBC production (secondary polycythemia)
✅ Mnemonic: HIF = Helps In Famine (oxygen famine)
BOARD-STYLE CLUES & APPLICATIONS
Young patient with bilateral RCC or hemangioblastomas → think VHL → think HIF-1α dysregulation
Tumors exploiting hypoxia to increase angiogenesis → likely using HIF-1α
High-altitude athlete with ↑ hematocrit → HIF-1α-mediated EPO response
📚 STEP 1 MNEMONICS
“HIF gets High In Fasted (hypoxic) cells”
→ HIF-1α is active during hypoxia, turns on survival pathways
“HIF makes blood and vessels”
→ ↑ EPO, ↑ VEGF
“VHL puts HIF on a leash”
→ If VHL is mutated, HIF-1α is unleashed, driving angiogenesis and tumor growth
Tuberous sclerosis : overview
Feature Detail
Inheritance Autosomal Dominant
Genes TSC1 (hamartin, chromosome 9q34)
TSC2 (tuberin, chromosome 16p13)
Function TSC1 and TSC2 form a complex that inhibits mTOR → suppresses cell growth/proliferation
Mechanism Mutation → mTOR disinhibition → ↑ cell proliferation → hamartoma formation
Penetrance High (variable expressivity)
✅ Mnemonic: “TSC = Too many Soft Cell tumors”
Tuberous sclerosis
NEUROLOGIC FEATURES (VERY HIGH YIELD)
Manifestation Description
Cortical tubers Hamartomas in cortex → seizures, developmental delay
Subependymal nodules Benign growths near ventricles
Subependymal giant cell astrocytoma (SEGA) May obstruct foramen of Monro → hydrocephalus
Infantile spasms Seizures in infants, associated with poor prognosis
Intellectual disability Common, variable severity
✅ USMLE Pearl: TS is a leading cause of childhood seizures + mental retardation
PATHOPHYSIOLOGY
Normal In TSC
TSC1/2 → inhibit mTOR pathway → control cell growth TSC1/2 loss → unchecked mTOR activation → hamartomas in multiple organs
✅ Step 1 Focus: Dysregulated mTOR is central to tumor syndromes like TSC
NEUROLOGIC FEATURES (VERY HIGH YIELD)
Manifestation Description
Cortical tubers Hamartomas in cortex → seizures, developmental delay
Subependymal nodules Benign growths near ventricles
Subependymal giant cell astrocytoma (SEGA) May obstruct foramen of Monro → hydrocephalus
Infantile spasms Seizures in infants, associated with poor prognosis
Intellectual disability Common, variable severity
✅ USMLE Pearl: TS is a leading cause of childhood seizures + mental retardation
DERMATOLOGIC FEATURES (CLASSIC STEP 1 FINDINGS)
Finding Description
Hypomelanotic macules (“ash leaf spots”) Hypopigmented patches, visible with Wood’s lamp
Facial angiofibromas (adenoma sebaceum) Red papules in malar region (butterfly distribution)
Shagreen patch Thick, leathery skin on lower back
Ungual fibromas Flesh-colored tumors near or under fingernails
✅ Mnemonic: “Ash-leaf on the face, shagreen on the base”
BRUTON AGAMMAGLOBULINEMIA (X-LINKED)
CLINICAL PRESENTATION
Age Symptoms
Usually begins after 6 months of age - Recurrent bacterial infections: otitis media, pneumonia, sinusitis
Especially from encapsulated organisms (e.g., Strep pneumo, H. influenzae, Neisseria)
Enteroviral infections (e.g., polio, coxsackie) due to lack of neutralizing antibodies
Giardia lamblia infections (due to ↓ IgA) |
✅ Classic Step 1 Clue: Male infant with recurrent sinopulmonary infections starting after 6 months
STEP 1 RAPID RECALL
✅ X-linked recessive → affects boys
✅ Mutation in BTK → arrested pre-B cell maturation
✅ ↓ B cells, ↓ all immunoglobulins
✅ Recurrent bacterial infections (especially encapsulated organisms)
✅ Onset after 6 months
✅ IVIG therapy
✅ Avoid live vaccines
MAJOR GENETIC TYPES
Type Mutation Inheritance T B NK
X-linked SCID (most common) IL2RG gene (common γ-chain) X-linked recessive ↓ ↓ ↓
Adenosine deaminase (ADA) deficiency ADA gene Autosomal recessive ↓ ↓ ↓
JAK3 deficiency JAK3 gene Autosomal recessive ↓ ↓ ↓
RAG1/RAG2 deficiency Failure of V(D)J recombination Autosomal recessive ↓ ↓ Normal
IL-7R deficiency IL-7 receptor gene Autosomal recessive ↓ Normal Normal
✅ Most forms → T-cell deficiency leads to nonfunctional B cells, even if present
SCID: CLINICAL PRESENTATION
Tight Junctions (Zonula Occludens)
High-Yield Features:
• Function:
• Seal adjacent cells together near the apical surface.
• Prevent paracellular movement of solutes.
• Maintain cell polarity by separating apical and basolateral surfaces.
• Composition:
• Key proteins: Claudins and Occludins (very testable).
• Linked to actin cytoskeleton via ZO-1 protein (Zonula Occludens-1).
• Location:
• Found in epithelial and endothelial cells.
• Especially prominent in intestinal mucosa, blood-brain barrier, and renal tubules.
Clinical Correlates:
• Pathogens targeting tight junctions:
• Clostridium perfringens enterotoxin and Vibrio cholerae disrupt tight junctions → leads to leaky epithelium and watery diarrhea.
• H. pylori targets ZO-1 → disrupts gastric epithelium.
Tips:
• If the question asks about maintaining selective permeability or blood–brain barrier integrity → choose tight junctions.
• Associated diseases: Think paracellular leaks and loss of barrier function.