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DEEP VEIN THROMBOSIS (DVT) - Comprehensive Notes

Source: Harrison's 22E (2025) + Major Textbooks + ASH 2020 / ACCP 2022 Guidelines

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1. DEFINITION & OVERVIEW

• DVT = thrombosis (clot formation) within the deep venous system, most commonly the lower extremities
• DVT and pulmonary embolism (PE) are together termed venous thromboembolism (VTE)
• Estimated incidence: 1-2 per 1000 persons/year in the US
• 300,000-600,000 new VTE cases/year in the US; 60,000-80,000 deaths/year
• Up to 30% of patients die within 30 days; 1 in 5 suffer sudden death as the first manifestation
• Leg DVT is ~10 times more common than upper extremity DVT
• Patients present with DVT symptoms about twice as frequently as with PE symptoms

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2. ANATOMY & CLASSIFICATION

Lower Extremity DVT

• Distal (calf) DVT: Below the popliteal vein (posterior tibial, peroneal, anterior tibial, muscular veins)
• Proximal DVT: Involves popliteal vein and above (popliteal, femoral, common femoral, iliac veins)
  • More likely to embolize to lungs
• DVT usually begins in the calf and propagates proximally to popliteal → femoral → iliac veins

Classification by Location

Upper Extremity DVT

• Increasingly common due to:
  • Central venous catheters (CVC), PICC lines, pacemakers, ICDs
  • Chemotherapy access devices
  • Effort thrombosis (Paget-Schroetter syndrome) in athletes
• Risk increases with larger catheter diameter and more lumens
• COVID-19 associated with catheter-based upper extremity DVT
• Complications: PE, SVC syndrome, loss of vascular access, central venous stenosis

Special Forms

• Phlegmasia cerulea dolens: Most severe DVT; diffuse edema of entire limb; limb-threatening
• May-Thurner syndrome: Right proximal iliac artery compresses left proximal iliac vein → recurrent left thigh edema, especially in young women → predisposes to DVT

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3. PATHOPHYSIOLOGY - VIRCHOW'S TRIAD

Coagulation Cascade (Harrison's Ch. 122)

• Vascular injury → tissue factor exposure → TF binds Factor VII → activates downstream
• TF-FVIIa complex → activates FX (via FIX-FVIIIa pathway) → FXa + FVa → prothrombin → thrombin
• Thrombin → converts fibrinogen → insoluble fibrin + activates FXIII → cross-linked stable clot
• Antithrombotic regulators: antithrombin, TFPI, heparin cofactor II, protein C/protein S
• Additional contributors: procoagulant microparticles, inflammatory cells, microvesicles, fibrin structure

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4. RISK FACTORS

Acquired Risk Factors

• Surgery (highest risk): neurosurgery, major abdominal/pelvic surgery, orthopedic (hip/knee replacement)
• Cancer: ~4-fold increased VTE risk; annual risk on chemotherapy ~11% (6x general population)
  • Especially: lung, pancreatic, GI, breast, ovarian, GU cancers; lymphomas; brain tumors
  • Trousseau's syndrome = migratory thrombophlebitis + visceral carcinoma (especially pancreatic)
• Immobilization: prolonged bed rest, paralysis, plaster cast, long-distance travel (>4-6 hrs)
• Prior VTE: strongest predictor of recurrence
• Pregnancy and postpartum period
• Oral contraceptives / hormone replacement therapy (estrogen-containing)
• Obesity (BMI >30)
• Increasing age
• Infections: community- or hospital-acquired
• Inflammatory conditions: IBD, rheumatologic diseases
• Renal disease, heart failure
• Central venous catheters
• COVID-19

Inherited Thrombophilias (Genetic Risk Factors)

• 5-8% of US population has a known genetic predisposition to venous thrombosis
• Factor V Leiden mutation (most common): resistance to activated protein C - autosomal dominant
• Prothrombin G20210A mutation: elevated prothrombin levels
• Protein C deficiency
• Protein S deficiency
• Antithrombin deficiency (most severe thrombophilia)
• Hyperhomocysteinemia (MTHFR mutation)
• Elevated Factor VIII, IX, XI levels

Independent Predictors of Recurrence

• Increasing age
• Obesity
• Malignancy
• Acute extremity paresis

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5. CLINICAL FEATURES

Symptoms

• Unilateral leg pain (especially calf)
• Leg swelling - unilateral, progressive
• Skin erythema and warmth over affected area
• Symptoms may be acute to subacute in onset

Signs

• Calf tenderness on palpation along deep vein distribution
• Pitting edema of the affected limb
• Unilateral calf swelling >3 cm compared to opposite leg
• Erythema and warmth
• Collateral superficial non-varicose veins (visible)
• Homan's sign (calf pain on dorsiflexion of foot) - historically taught but insensitive and non-specific; NOT recommended for diagnosis

Clinical Pearls (Harrison's 22E)

• Not all leg pain is DVT: sudden severe calf pain → ruptured Baker's cyst
• Fever + chills → more likely cellulitis than DVT
• Mild cases: only mild palpation discomfort in lower calf
• Massive DVT: marked thigh swelling, tenderness, erythema
• If diffusely edematous leg → DVT unlikely (except phlegmasia cerulea dolens)
• Upper extremity DVT: asymmetry in supraclavicular fossa or upper arm circumference

Superficial Venous Thrombosis (SVT)

• Erythema, tenderness, palpable "cord" along superficial vein
• Most common: lower extremity (varicose veins), upper extremity (IV catheters)
• Urschel's sign: superficial veins visible in chest wall
• Risk: extension to deep venous system

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6. DIAGNOSIS

Step 1: Pre-test Clinical Probability - Wells DVT Score

• ≤0: Low probability (DVT can be effectively ruled out with negative D-dimer)
• 1-2: Moderate probability
• ≥3: High probability (proceed to imaging)

Step 2: D-Dimer

• High sensitivity, low specificity (many causes of elevated D-dimer)
• Standard threshold: 500 ng/mL (or 500 mcg/L FEU)
• Age-adjusted D-dimer (for PE evaluation, not DVT): Age × 10 ng/mL for patients >50 years
  • Note: Age-adjusted D-dimer does NOT apply to suspected acute DVT
• Negative D-dimer + low/moderate pre-test probability = DVT ruled out (no imaging needed)
• Causes of false positive D-dimer: cancer, pregnancy, infection, post-surgical, age, liver disease, heart failure
• D-dimer is not reliably predictive in cancer patients (baseline elevation common)

Step 3: Imaging

Duplex Compression Ultrasonography (CUS) - PRIMARY TEST

• Gold standard non-invasive test for DVT
• Primary criterion: loss of vein compressibility (non-compressible segment)
  • Normal vein collapses with gentle pressure → creates "wink" appearance
  • DVT: vein remains open/distended under pressure
• Additional features: direct thrombus visualization, altered Doppler flow dynamics
  • Loss of respiratory variation = obstruction at/proximal to measurement site
  • Loss of flow augmentation with calf compression = distal obstruction
• Sensitivity: 96.5% for symptomatic proximal DVT; 71.2% for distal (calf) DVT
• Specificity: ~94%
• Technically poor views: consider CT or MRI venography

CT Venography (CTV)

• Role: evaluation of pelvic veins, assessing for extrinsic compression, when US non-diagnostic
• Challenge: appropriate contrast timing

MR Venography (MRV)

• Superior for pelvic/IVC evaluation, no contrast issue
• Limited in patients with metallic implants

Contrast (Catheter) Phlebography/Venography

• Gold standard (invasive) - largely replaced by CUS
• Used when interventional procedure planned (thrombolysis, stenting)
• Definitive: direct visualization of intraluminal filling defect
• Allows intraluminal pressure measurements, IVUS

Integrated Diagnostic Algorithm (Harrison's 22E)

Suspected DVT
      ↓
Clinical Pre-test Probability (Wells Score)
      ↓                          ↓
 Low/Moderate                   High
      ↓                          ↓
  D-Dimer                   Compression Ultrasound
  Negative → DVT excluded    Non-compressible → DVT confirmed
  Positive → CUS             Compressible → D-dimer / repeat CUS in 7 days

Differential Diagnosis of DVT

• Ruptured Baker's cyst
• Muscle strain/injury (especially gastrocnemius tear)
• Cellulitis (fever + chills suggest this)
• Acute postthrombotic syndrome/venous insufficiency
• Lymphedema
• Hematoma
• Superficial venous thrombosis
• Popliteal artery aneurysm

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7. THROMBOPHILIA WORKUP

• DVT in unusual sites (portal, hepatic, mesenteric, cerebral veins)
• DVT in young patients (<45 years) without provoking factor
• Recurrent unprovoked VTE
• Strong family history
• DVT during pregnancy or OCP use

• Factor V Leiden mutation (PCR)
• Prothrombin G20210A mutation (PCR)
• Protein C activity
• Protein S antigen/activity (free and total)
• Antithrombin activity
• Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin Ab, anti-β2-glycoprotein I Ab
• Homocysteine level
• Factor VIII level

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8. TREATMENT

Phase Classification (ASH 2020 Guidelines)

1. Initial management: First 5-21 days
2. Primary treatment: First 3-6 months
3. Secondary prevention: Beyond 3-6 months

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8A. Anticoagulation - Drug Options

DOACs (Direct Oral Anticoagulants) - FIRST-LINE (ASH & ACCP 2022)

• Rivaroxaban and Apixaban: Can be initiated orally without initial parenteral therapy ("DOAC-only" regimens)
• DOACs vs. warfarin: Lower risk of recurrent VTE, lower major bleeding, no routine monitoring required

Low Molecular Weight Heparin (LMWH)

• Enoxaparin: 1 mg/kg SC q12h OR 1.5 mg/kg SC OD (therapeutic)
• More effective than UFH for DVT prophylaxis in high-risk patients (orthopedic surgery)
• Lower incidence of HIT than UFH
• Preferred in pregnancy (does not cross placenta), cancer patients (historically)
• Limited in severe renal dysfunction (CrCl <30 mL/min) - use anti-Xa monitoring
• Cancer-associated DVT: LMWH was traditional standard; DOACs (edoxaban, rivaroxaban) now found non-inferior in select cancer patients (avoid in GI/GU cancer due to bleeding risk)

Unfractionated Heparin (UFH)

• IV: 80 units/kg bolus (or 5000 units), then 18 units/kg/hr infusion
• Target PTT: 60-80 seconds (corresponds to anti-Xa level 0.3-0.7 units/mL)
• Adjust every 6 hours based on PTT
• Must reach therapeutic levels within 24 hours (delays increase recurrent VTE risk)
• Role: ICU patients, renal failure, when rapid reversal needed (protamine)
• Risk: HIT (heparin-induced thrombocytopenia)

Vitamin K Antagonist (VKA) - Warfarin

• Target INR: 2.0-3.0 (2.5 target)
• Requires bridging with heparin/LMWH for at least 5 days AND until INR therapeutic for 24h
• Warfarin is teratogenic → contraindicated in pregnancy
• Drug and food interactions; requires regular INR monitoring
• Transient hypercoagulable state on initiation (protein C & S fall before other VK-dependent factors)

Fondaparinux

• Factor Xa inhibitor (indirect, parenteral)
• Alternative to LMWH; once-daily SC injection
• Renally cleared; avoid if CrCl <30 mL/min

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8B. Duration of Anticoagulation (ASH 2020 + ACCP)

• Apixaban 2.5 mg BID (AMPLIFY-EXT trial): reduces recurrent VTE vs. placebo, lower bleeding than full dose
• Rivaroxaban 10 mg OD (EINSTEIN-CHOICE trial): superior to aspirin for secondary prevention

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8C. Isolated Calf (Distal) DVT

• ASH 2020 suggests anticoagulation for patients with symptomatic isolated distal DVT
• Randomized trial: 6 weeks anticoagulation did NOT reduce adverse outcomes vs. no treatment in low-risk patients with isolated calf DVT (3% vs 5%, p=0.54), but DID cause bleeding (4% vs 0%)
• Meta-analysis: anticoagulation → 50% reduction in recurrent VTE (RR 0.50; 95% CI 0.31-0.79) without increasing major bleeding
• 2025 meta-analysis (PMID 40400471): supports anticoagulation for isolated distal DVT in symptomatic patients
• Alternative: serial ultrasound at 5-7 days to detect proximal extension; anticoagulate only if extension occurs

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8D. Advanced/Interventional Therapy

Catheter-Directed Thrombolysis (CDT)

• Indications: Extensive proximal (iliofemoral) DVT with high clot burden, phlegmasia, limb-threatening ischemia, young patients with good functional status
• ASH 2020: Suggests CDT over systemic thrombolysis for extensive DVT (if thrombolysis appropriate)
• Agents: tPA (alteplase), urokinase
• Goal: reduce clot burden, prevent post-thrombotic syndrome (PTS)
• ATTRACT trial: CDT did NOT prevent PTS at 24 months vs. anticoagulation alone; did reduce severe PTS

Inferior Vena Cava (IVC) Filter

• Indications:
  • Acute DVT/PE + absolute contraindication to anticoagulation
  • Recurrent PE despite adequate anticoagulation
• ASH 2020 + ACCP: Suggest against routine IVC filter placement; anticoagulation alone preferred when feasible
• Retrievable filters: Preferred; must be removed when anticoagulation resumed
• Complications: filter thrombosis, IVC occlusion, penetration, migration

Surgical Thrombectomy

• Rarely performed; reserved for cases of massive phlegmasia cerulea dolens with arterial compromise

Pharmacomechanical CDT (PCDT)

• Combines CDT with mechanical thrombus disruption/aspiration
• May accelerate thrombus clearance

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8E. Ancillary Measures

• Compression stockings: For symptom relief and edema management
  • Historically used for prevention of PTS; SOX trial showed graduated elastic stockings did NOT prevent PTS vs. placebo
  • ASH 2020: Suggests against routine use of compression stockings for PTS prevention after DVT
• Early ambulation: Encouraged (does not increase PE risk; may reduce symptoms)
• Leg elevation: During acute phase
• Avoid prolonged immobility

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9. COMPLICATIONS

Pulmonary Embolism (PE)

• Most feared acute complication
• Occurs in ~30% of untreated proximal DVT
• Massive PE: systemic hypotension, >50% pulmonary vascular obstruction, cardiogenic shock
• Small PE: pleuritic chest pain (peripheral, near pleural innervation = pulmonary infarction)

Post-Thrombotic Syndrome (PTS)

• Chronic venous insufficiency after DVT
• Incidence: 20-50% after proximal DVT (within 2 years)
• Features: chronic leg pain, swelling, heaviness, skin changes (lipodermatosclerosis), venous ulcers (Villalta scale)
• Mechanism: valvular incompetence + venous obstruction → ambulatory venous hypertension
• Prevention: effective anticoagulation, possibly compression stockings (benefit disputed)
• Treatment: graduated compression, wound care for ulcers, venoactive drugs (diosmin), endovascular intervention for obstructive lesions

Recurrent VTE

• Rate: ~30% over 10 years after a first episode
• Higher in: unprovoked VTE, cancer, antiphospholipid syndrome, thrombophilia

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• Occurs in 2-4% of patients after PE
• Results from persistent pulmonary arterial obstruction + secondary small-vessel arteriopathy
• Features: progressive dyspnea, functional limitation, RV failure
• Treatment: pulmonary thromboendarterectomy (most effective), riociguat, balloon pulmonary angioplasty

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10. DVT IN SPECIAL POPULATIONS

Cancer-Associated DVT

• LMWH traditionally preferred (showed superiority over warfarin)
• DOACs (edoxaban, rivaroxaban): non-inferior to LMWH for most cancers
• Avoid edoxaban/rivaroxaban in GI or GU malignancies (higher luminal bleeding risk) - use LMWH
• ASH 2021 Cancer VTE guidelines: DOAC or LMWH both acceptable depending on bleeding risk
• Duration: Indefinite (as long as cancer active)
• Elevated D-dimer not reliably predictive in cancer (baseline elevation); venous US or venography preferred

Pregnancy-Associated DVT

• LMWH = treatment of choice throughout pregnancy (does not cross placenta; safe)
• Warfarin: teratogenic (especially 6-12 weeks) - contraindicated in 1st trimester
• DOACs: not recommended in pregnancy (insufficient safety data)
• Duration: Continue LMWH through labor/delivery + ≥6 weeks postpartum (minimum 3-6 months total)
• Heparin-associated osteoporosis risk with long-term LMWH

HIT (Heparin-Induced Thrombocytopenia)

• Immune-mediated: IgG antibodies to heparin-PF4 complex
• Paradoxically pro-thrombotic (both arterial and venous)
• Onset: 5-14 days after heparin initiation
• Diagnosis: 4T score + anti-PF4/heparin antibodies + SRA (serotonin release assay)
• Management: stop ALL heparin immediately; switch to argatroban (direct thrombin inhibitor) or fondaparinux; avoid warfarin until platelets recover
• LMWH has lower HIT incidence than UFH

ICU Patients

• High DVT risk due to immobility
• Prophylaxis: subcutaneous UFH or LMWH + sequential compression devices (SCDs)
• LMWH more effective than UFH for DVT prophylaxis in high-risk patients
• Renal dysfunction limits LMWH use → consider UFH with monitoring

Upper Extremity DVT

• Complications: PE (risk similar to leg DVT), SVC syndrome, loss of vascular access, central venous stenosis
• Treatment: anticoagulation × 3 months (same principles as lower extremity)
• Consider CDT for Paget-Schroetter syndrome (effort thrombosis) in young, active patients
• If catheter-related: catheter removal if no longer needed + anticoagulation
• If catheter must remain: anticoagulate with catheter in place

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11. DVT PROPHYLAXIS

Risk Stratification (Caprini Score commonly used)

• Low risk: Early ambulation sufficient
• Moderate risk: Mechanical (SCDs) or pharmacologic prophylaxis
• High risk: Pharmacologic prophylaxis preferred (LMWH or UFH)

Pharmacologic Options

Mechanical Methods

• Sequential compression devices (SCDs) / intermittent pneumatic compression (IPC)
• Graduated compression stockings (GCS): 15-30 mmHg

Long-Distance Travel (>4-6 hours)

• Without risk factors: Ambulation, hydration, calf exercises; no pharmacologic prophylaxis
• With risk factors (prior VTE, recent surgery, cancer, pregnancy): ASH suggests GCS or prophylactic LMWH; aspirin if those not feasible
• ACCP recommends GCS for high-risk travelers on flights >6 hours

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12. GUIDELINE SUMMARY TABLE

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13. KEY CLINICAL FACTS TO REMEMBER

1. Wells Score is the validated pre-test probability tool for DVT; score ≤0 = low probability
2. Compression ultrasonography is the primary diagnostic test; non-compressibility = DVT
3. D-dimer: Highly sensitive but non-specific; negative value in low-risk patient rules out DVT
4. DOACs are first-line anticoagulants for most DVT patients (ASH 2020, ACCP 2022)
5. Rivaroxaban and apixaban do NOT require initial parenteral therapy ("oral-only" approach)
6. Dabigatran and edoxaban require 5-10 days of LMWH/UFH first
7. LMWH preferred in pregnancy (warfarin is teratogenic; DOACs not recommended)
8. 3 months anticoagulation for provoked DVT; indefinite for recurrent/unprovoked/cancer-associated
9. May-Thurner syndrome: Right iliac artery compresses left iliac vein → recurrent left leg DVT in young women
10. Phlegmasia cerulea dolens: Most severe DVT - entire limb swollen, potential limb loss
11. HIT: Stop all heparin immediately; switch to argatroban or fondaparinux (NOT warfarin initially)
12. CTEPH occurs in 2-4% after PE; treat with pulmonary endarterectomy ± riociguat
13. IVC filter: Only when absolute contraindication to anticoagulation; prefer retrievable type
14. Age-adjusted D-dimer applies to suspected PE, NOT suspected DVT
15. Trousseau syndrome = migratory thrombophlebitis + occult cancer (especially pancreatic)

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• Harrison's Principles of Internal Medicine 22nd Edition (2025), Chapters 122, 290, and 74 (Oncologic complications)
• Fuster & Hurst's The Heart, 15th Edition, Chapter 56
• Sabiston Textbook of Surgery, Chapter on Venous Thromboembolism
• Braunwald's Heart Disease, Chapter 87
• ASH 2020 VTE Guidelines: Treatment of DVT and PE
• ACCP/CHEST 2022 Antithrombotic Therapy for VTE

DVT - Quick Summary

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What is it?

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Pathophysiology

• Hypercoagulability (cancer, thrombophilia, OCP, pregnancy)
• Stasis (immobility, heart failure, long travel)
• Endothelial injury (surgery, catheters, trauma)

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Risk Factors

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Clinical Features

• Unilateral leg pain, swelling, erythema, warmth
• Homan's sign - historically taught; NOT reliable
• Massive DVT: entire limb swollen (phlegmasia cerulea dolens = limb-threatening)
• May-Thurner: right iliac artery compresses left iliac vein → recurrent left leg DVT in young women

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Diagnosis - 3 Steps

• ≤0 = Low | 1-2 = Moderate | ≥3 = High

• Negative + low/moderate probability = DVT excluded (no imaging needed)
• Positive = proceed to ultrasound
• Not reliable in cancer patients

• Non-compressible vein = DVT confirmed
• Sensitivity: 96.5% proximal, 71.2% distal DVT

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Treatment

Drug of Choice

Duration

Special Situations

• Pregnancy: LMWH only (warfarin = teratogenic; DOACs = not recommended)
• Cancer: LMWH or DOAC (avoid DOAC in GI/GU cancer - bleeding risk)
• HIT: Stop ALL heparin → switch to argatroban/fondaparinux
• IVC filter: Only if absolute contraindication to anticoagulation

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Complications

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Top 5 Exam Points

1. Wells Score stratifies pre-test probability; score ≤0 + negative D-dimer = DVT excluded
2. DOACs are first-line; rivaroxaban/apixaban need no initial heparin
3. Provoked = 3 months; unprovoked = indefinite consideration
4. LMWH in pregnancy; never warfarin (teratogenic), never DOACs
5. Non-compressible vein on US = DVT confirmed

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NEUROFIBROMATOSIS - Comprehensive Notes

Source: Harrison's 22E (2025) + Goldman-Cecil + Fitzpatrick's + Latest Guidelines

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1. OVERVIEW & CLASSIFICATION

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2. NEUROFIBROMATOSIS TYPE 1 (NF1)

2A. Genetics & Molecular Pathology

• Gene: NF1 on chromosome 17q11.2 - one of the largest human genes
• 60 exons spanning >350 kb of genomic DNA
• Protein: Neurofibromin - a GTPase-activating protein (GAP)
  • Normally converts p21-Ras-GTP (active) → p21-Ras-GDP (inactive)
  • Acts as a tumor suppressor by downregulating the Ras/MAPK/MEK signaling pathway
  • Mutations in NF1 impair this downregulation → uncontrolled cell proliferation
• Mutations are diverse, scattered throughout exons - no consistent genotype-phenotype correlation
• Exception: complete NF1 gene deletion → early-onset multiple neurofibromas, developmental delay, facial dysmorphism
• Derived from neural crest cells: Schwann cells, melanocytes, and related cells most affected

2B. Clinical Features

Cutaneous/Dermatologic

• Café-au-lait macules (CALMs)
  • Most frequent early manifestation; present in virtually all NF1 patients
  • Well-defined, uniformly pigmented, light-to-dark brown macules
  • Size threshold: >5 mm in prepubertal individuals; >15 mm in postpubertal individuals
  • NF1-associated CALMs contain significantly increased numbers of melanocytes (vs. isolated CALMs)
  • Appear in infancy; nearly all patients have them by age 5 years
• Axillary/inguinal freckling (Crowe's sign)
  • Smaller café-au-lait spots in skin folds (axilla, groin, inframammary, neck)
  • Pathognomonic for NF1 (rarely occurs in other conditions)
  • Also contain increased epidermal melanocytes (distinguishes from ordinary freckles)
• Cutaneous neurofibromas
  • Benign peripheral nerve sheath tumors; arise within skin
  • Soft, flesh-colored, sessile or pedunculated papules/nodules
  • Begin appearing in late childhood/adolescence; increase with age and pregnancy
  • Not present at birth; progressively increase in number throughout life
  • May become numerous (hundreds to thousands in severe cases)
• Subcutaneous neurofibromas
  • Firm, palpable nodules along peripheral nerves; may be painful
  • Can be disfiguring
• Plexiform neurofibromas (PNF)
  • Involve multiple nerve fascicles; described as "bag of worms" on palpation
  • Often large; may involve deep tissues and organs
  • Present at birth (congenital) or appear in early childhood
  • Can cause disfigurement, pain, and functional impairment
  • Risk of malignant transformation to MPNST (malignant peripheral nerve sheath tumor): 8-13% lifetime risk
  • Overlying skin often hyperpigmented and hypertrichotic

Ophthalmologic

• Lisch nodules (iris hamartomas)
  • Dome-shaped, melanocytic hamartomas on the iris surface
  • Asymptomatic; detected by slit-lamp examination
  • Found in >90% of adults with NF1 but rare in unaffected individuals
  • Pathognomonic for NF1; increase with age
  • NOT found in NF2
• Optic pathway gliomas (OPG)
  • Most common CNS tumor in NF1; occur in ~15% of patients
  • Usually low-grade pilocytic astrocytomas (WHO Grade I)
  • Most occur in first decade of life (peak age 3-5 years)
  • Most are asymptomatic and discovered incidentally on screening MRI
  • Symptomatic: visual loss, proptosis, precocious puberty (if hypothalamic extension)
  • May spontaneously stabilize or regress

Neurologic

• Spinal neurofibromas: multiple, along spinal nerve roots
• Learning disabilities: ~50% of NF1 patients; most common cognitive complication
• ADHD/attention deficit disorder: common
• Macrocephaly: common
• Epilepsy/seizures: increased risk
• Cognitive impairment: variable; rarely severe
• T2 hyperintensities on MRI: "unidentified bright objects" (UBOs) in basal ganglia, brainstem, cerebellum; significance unclear, may correlate with cognitive issues
• Intracranial gliomas: beyond optic pathway; brainstem gliomas, striatothalamic gliomas

Skeletal

• Scoliosis: dystrophic or non-dystrophic; common
• Short stature: frequent (even without GH deficiency)
• Macrocephaly: head circumference above 97th percentile
• Tibial pseudarthrosis/dysplasia: anterolateral bowing of the tibia; pathognomonic skeletal finding; may progress to fracture and nonunion
• Sphenoid bone dysplasia: characteristic skull base abnormality; may cause pulsating exophthalmos
• Vertebral scalloping, rib penciling

Vascular

• Renal artery stenosis: leading to hypertension in children with NF1
• Intracranial arterial stenoses/moyamoya pattern
• Cerebrovascular disease: increased stroke risk
• Vascular lesions are distinct from atherosclerosis

Endocrine

• Pheochromocytoma: ~1% of NF1 patients (3% per Goldman-Cecil)
  • Usually solitary benign adrenal tumor
  • 90% within adrenal medulla, 10% extra-adrenal (para-aortic)
  • Presentation similar to sporadic pheochromocytoma
• Carcinoid tumors: ~1%; often periampullary or ileal
  • Hepatic metastases → carcinoid syndrome (flushing, diarrhea, bronchoconstriction, tricuspid valve disease)
• Precocious puberty: associated with optic glioma extending to hypothalamus → early GnRH activation
• Growth hormone deficiency: reported in some NF1 patients

Gastrointestinal

• GI neurofibromas: throughout GI tract; may cause obstruction, bleeding
• GIST (gastrointestinal stromal tumors): increased frequency in NF1; usually small intestinal, often multiple
• Carcinoid tumors: periampullary region most common

Malignancies (Lifetime Risk ~60%)

• MPNST (Malignant Peripheral Nerve Sheath Tumors): most important malignancy
  • Risk: 8-15% lifetime; highest malignancy risk in NF1
  • Arise from plexiform neurofibromas
  • Age 20-50 years typical presentation
  • Poor prognosis: 5-year survival ~20-50%
• CNS gliomas: optic pathway, brainstem, high-grade gliomas
• Leukemia: especially juvenile myelomonocytic leukemia (JMML) in children
• Rhabdomyosarcoma: in young children
• Breast cancer: increased risk in women <50 years (2-4x general population)
• Overall: 3-15% additional lifetime cancer risk vs. general population

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2C. NIH Diagnostic Criteria for NF1

1. ≥6 café-au-lait macules: >5 mm (prepubertal) OR >15 mm (postpubertal)
2. ≥2 neurofibromas of any type OR ≥1 plexiform neurofibroma
3. Axillary or inguinal freckling (Crowe's sign)
4. Optic nerve/pathway glioma
5. ≥2 Lisch nodules (iris hamartomas on slit-lamp examination)
6. Sphenoid bone dysplasia OR tibial dysplasia/pseudarthrosis
7. First-degree relative with NF1 (diagnosed by above criteria)

• Heterozygous pathogenic NF1 variant identified by molecular testing (genetic diagnosis)
• Choroidal freckling/choroidal abnormalities on MRI
• Spinal neurofibromas as a qualifying criterion in appropriate context

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3. NEUROFIBROMATOSIS TYPE 2 (NF2)

3A. Genetics & Molecular Pathology

• Gene: NF2 on chromosome 22q11-q12
• Protein: Merlin (also called schwannomin) - a membrane-cytoskeletal linking protein
• Merlin is a tumor suppressor that downregulates cellular growth
• Mutations of NF2 → loss of merlin → uncontrolled proliferation of Schwann cells, meningeal cells
• Diverse mutations; truncating mutations tend to produce more severe disease
• Mosaic NF2 (somatic mosaicism) can present with milder or unilateral disease

3B. Clinical Features

• Bilateral vestibular schwannomas (acoustic neuromas): HALLMARK
  • Benign tumors of cranial nerve VIII (vestibulocochlear nerve)
  • Tumors often begin unilaterally and become bilateral
  • ~60% of patients present with hearing loss, tinnitus, or loss of balance
  • Age of presentation: usually young adulthood (mean ~20s)
  • Younger age of onset = greater ultimate disease severity
  • Children more likely to present with non-CN VIII tumors
• Meningiomas: multiple; intracranial, intraspinal, optic nerve sheath
• Spinal schwannomas: dorsal roots of spinal cord, peripheral nerves, cranial nerves
• Ependymomas and gliomas of CNS (less frequent)
• Juvenile posterior subcapsular cataracts (60-80% of patients) - early marker
• Retinal hamartomas and combined hamartomas of retina and RPE
• Optic nerve sheath meningiomas (especially in children)
• Cutaneous lesions:
  • Café-au-lait spots: present but rarely >6; NO intertriginous freckling
  • Cutaneous schwannomas: plaques with slightly raised, faint violaceous hue, sometimes with hair - characteristic of NF2
  • Occasional cutaneous neurofibromas (indistinguishable from NF1)
• Morbidity: HIGH - patients frequently become paralyzed and deaf
• NO endocrine abnormalities (endocrine tumors are NF1-specific)

3C. Diagnostic Criteria for NF2 (Fitzpatrick's / Manchester Criteria)

1. Bilateral vestibular schwannomas (on CT or MRI)
2. First-degree relative with NF2 + unilateral vestibular schwannoma OR any 2 of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lens opacities
3. Unilateral vestibular schwannoma + any 2 of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lens opacities
4. Multiple meningiomas + unilateral vestibular schwannoma OR any 2 of: schwannoma, glioma, neurofibroma, cataract

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4. COMPARISON TABLE: NF1 vs NF2

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5. OTHER NF SPECTRUM DISORDERS

Schwannomatosis (NF Type 3)

• Third distinct type; NOT allelic to NF1 or NF2
• Gene: SMARCB1 (chromosome 22q11) or LZTR1 mutations
• Features: multiple schwannomas WITHOUT bilateral CN VIII tumors; chronic pain; no neurofibromas or café-au-lait macules
• Sporadic or familial; adult onset typical
• No risk of MPNST

Mosaic/Segmental NF1

• Postconceptional somatic NF1 mutation → mosaicism
• Manifestations (CALMs, neurofibromas, freckling) limited to one body segment
• Risk for NF1 complications in affected area
• Gonadal mosaicism possible: affected children with apparently unaffected parent
• Often misdiagnosed as full NF1

NF1-Noonan Syndrome

• Patients meet NF1 criteria but also have Noonan syndrome features (short stature, pulmonic stenosis, webbed neck, hypertelorism)
• Caused by NF1 mutation with Noonan-like phenotype

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6. SURVEILLANCE / MONITORING GUIDELINES

NF1 Surveillance Schedule

NF2 Surveillance

• Annual MRI brain + spine from diagnosis
• Audiology testing (baseline and annual)
• Ophthalmology (slit lamp for cataracts, visual fields)
• Genetic counseling
• Early family screening (MRI at ~age 10)

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7. TREATMENT

7A. NF1 - General Principles

• No curative treatment exists for NF1 itself
• Many patients with mild disease require only surveillance and symptomatic management
• Genetic counseling recommended for all patients and families
• Treatment directed at specific complications

7B. Plexiform Neurofibromas - MEK Inhibitors (LANDMARK THERAPY)

Selumetinib (Koselugo) - MEK1/2 Inhibitor

• FDA approved 2020: Pediatric patients ≥2 years with NF1 and symptomatic inoperable PN
• FDA approved November 2025: EXPANDED to adult patients (≥18 years) with NF1 and symptomatic inoperable PN (based on KOMET trial)
• FDA approved September 2025: Expanded to pediatric patients ≥1 year (granule formulation - SPRINKLE trial)
• Dose: 25 mg/m² orally twice daily in 28-day cycles
• Mechanism: Inhibits MEK1/2 → blocks RAS-MAPK pathway → reduces tumor proliferation
• Efficacy: Reduces tumor volume in ~70% of pediatric patients; sustained responses
• Side effects (key warnings): Cardiomyopathy, ocular toxicity (retinopathy), GI toxicity (nausea, diarrhea, vomiting), skin toxicity (acneiform rash, paronychia), elevated CPK, embryo-fetal toxicity; capsule formulation → elevated vitamin E + bleeding risk
• Also shows promise in: low-grade astrocytoma, spinal neurofibromas, cognitive dysfunction

Mirdametinib (Gomekli) - Highly Selective MEK Inhibitor (NEW 2025)

• FDA approved February 2025: Adult and pediatric patients ≥2 years with NF1 and symptomatic PN not amenable to complete resection (ReNeu trial - Phase IIb)
• Dose: 2 mg/m² orally twice daily for first 21 days of each 28-day cycle
• Efficacy: ORR ~45-47% in adults; responses deepen over time
• Second MEK inhibitor option for NF1-PN; provides option for patients who failed or cannot tolerate selumetinib
• Key point: Two MEK inhibitors now FDA-approved for NF1 plexiform neurofibromas

7C. Optic Pathway Gliomas (OPG)

• Asymptomatic OPG: usually observe with regular ophthalmologic monitoring
• Symptomatic OPG (visual decline, progression): chemotherapy
  • First-line: Carboplatin + vincristine OR cisplatin + temozolomide
  • Selumetinib: showing promise for NF1-associated OPG and low-grade astrocytoma
• Radiation NOT recommended (risk of secondary malignancies, cerebrovascular injury, and cognitive decline in NF1 patients)
• MEK inhibitors are now being evaluated as first-line therapy for OPG

7D. Surgical Management

• Surgical excision: effective for subcutaneous, intraspinal, intracranial lesions when technically feasible
• Plexiform neurofibromas: surgical debulking possible but complete resection rarely achievable; high recurrence rate; MEK inhibitors preferred for inoperable lesions
• Spinal neurofibromas: surgical decompression if causing cord compression
• Scoliosis: orthopedic management; bracing or spinal fusion if progressive
• Tibial pseudarthrosis: orthopedic management (challenging; high nonunion rate)
• Pheochromocytoma: surgical resection after appropriate alpha-blockade (as for sporadic tumors)

7E. Other Pharmacologic Approaches

• Epilepsy: standard antiepileptics
• ADHD: standard management (methylphenidate, etc.)
• Short stature + GH deficiency: GH replacement if confirmed deficient (note: GH use requires caution given tumor risk)
• Pain management for painful neurofibromas

7F. NF2 Treatment

Vestibular Schwannomas

• Surgery: mainstay; but hearing preservation is challenging even with early intervention
  • Options: total resection (sacrifices hearing), hearing preservation surgery, stereotactic radiosurgery (Gamma Knife)
  • Timing and approach depend on tumor size, hearing status, and patient age
• Stereotactic radiosurgery (SRS/Gamma Knife):
  • For small to medium tumors; slows growth
  • May ultimately cause hearing loss
• Bevacizumab (Avastin): anti-VEGF monoclonal antibody
  • 5 mg/kg IV every 2 weeks
  • Can improve hearing in some patients with vestibular schwannomas
  • Used for patients where surgery/radiation not suitable
  • Role remains uncertain; not uniformly effective
• Annual MRI monitoring for known schwannomas

Other NF2 Tumors

• Meningiomas: surgical resection when symptomatic or growing; SRS an option
• Spinal schwannomas/ependymomas: surgical decompression when causing symptoms
• Cataracts: surgical extraction when visually significant

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8. MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST)

• Most serious complication of NF1
• ~8-15% lifetime risk in NF1; >50-fold increased risk vs. general population
• Most arise from transformation of plexiform neurofibromas
• Typical age: 20-50 years
• Histologically: spindle cell sarcoma with fascicular growth pattern
• Markers of malignant transformation in a plexiform NF:
  • Rapid growth
  • New or worsening pain (especially nocturnal)
  • Hardening of a previously soft mass
  • Neurologic deficit in distribution of affected nerve
• Diagnosis: MRI (heterogeneous signal, perilesional edema, invasion); FDG-PET (high SUV); biopsy confirms
• Treatment: Wide surgical excision (primary); adjuvant radiation; chemotherapy (limited efficacy)
• Prognosis: Poor - 5-year survival ~20-50%; NF1-associated MPNST has worse prognosis than sporadic MPNST

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9. KEY FACTS FOR EXAMS

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10. PATHOLOGY MNEMONICS

• C - Café-au-lait macules (≥6)
• A - Axillary/inguinal freckling
• F - Fibrous neurofibromas (≥2 or 1 plexiform)
• E - Eye: Lisch nodules (≥2)
• PLUS: Optic glioma, Sphenoid dysplasia, Family history

• M - Multiple meningiomas
• I - Intracranial schwannomas
• S - Subcutaneous masses (schwannomas)
• M - Mixed tumors (gliomas, ependymomas)
• E - Eighth nerve tumors (bilateral vestibular schwannomas = hallmark)

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• Harrison's Principles of Internal Medicine 22nd Edition (2025), Chapter 400 (Endocrine Tumors - NF section) and Chapter 74
• Goldman-Cecil Medicine, Chapter 385 (Neurocutaneous Syndromes)
• Fitzpatrick's Dermatology, Chapter 135 (NF1 and NF2)
• Adams & Victor's Principles of Neurology, 12th Edition, Chapter on Phakomatoses
• FDA approval: Mirdametinib (Gomekli) Feb 11, 2025
• FDA approval: Selumetinib expanded to adults Nov 2025 - KOMET trial
• 2021 International Consensus Revised NF1 Diagnostic Criteria

Neurofibromatosis - Quick Summary

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Two Distinct Disorders

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NF1 - Clinical Features

• ≥6 café-au-lait macules (>5mm pre-pubertal; >15mm post-pubertal)
• Axillary/inguinal freckling - pathognomonic
• Cutaneous + subcutaneous neurofibromas
• Plexiform neurofibromas (congenital; "bag of worms")

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NF1 Diagnostic Criteria (NIH 1987, Revised 2021)

1. ≥6 café-au-lait macules (size threshold above)
2. ≥2 neurofibromas OR ≥1 plexiform neurofibroma
3. Axillary/inguinal freckling
4. Optic pathway glioma
5. ≥2 Lisch nodules
6. Sphenoid dysplasia OR tibial dysplasia
7. First-degree relative with NF1
8. (2021 update) Pathogenic NF1 variant on genetic testing

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NF2 - Clinical Features

• Bilateral CN VIII schwannomas → hearing loss, tinnitus, vertigo (onset young adulthood)
• Multiple meningiomas (intracranial + spinal)
• Spinal + cranial nerve schwannomas
• Posterior subcapsular cataracts (60-80%) - early marker
• NO Lisch nodules, NO axillary freckling, NO endocrine tumors
• Café-au-lait spots present but rarely >6
• Very high morbidity: deafness + paralysis common

NF2 Diagnostic Criteria

• Bilateral vestibular schwannomas on MRI OR
• FDR with NF2 + unilateral schwannoma OR 2 of (meningioma, schwannoma, glioma, cataract) OR
• Unilateral vestibular schwannoma + 2 of above features

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Treatment

NF1 - Plexiform Neurofibromas (MEK Inhibitors - KEY)

• Both are MEK1/2 inhibitors - block RAS-MAPK pathway
• Used for symptomatic, inoperable plexiform neurofibromas
• ORR ~45-70%; tumor shrinkage; not curative

NF1 - Other

• Optic glioma: Carboplatin + vincristine; selumetinib (emerging); NO radiation
• Surgery: For accessible subcutaneous/intraspinal/intracranial lesions
• MPNST: Wide resection ± radiation; poor prognosis
• Pheochromocytoma: Alpha-blockade then surgery

NF2

• Vestibular schwannomas: Surgery (hearing preservation challenging), stereotactic radiosurgery
• Bevacizumab 5 mg/kg IV q2 weeks - may improve hearing; role uncertain
• Meningiomas/spinal tumors: Surgery when symptomatic

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Surveillance (NF1)

• Annual: BP, skin, ophthalmology (until age 8), scoliosis, developmental assessment
• Annual whole-body MRI (adults) for MPNST surveillance
• Breast MRI from age 30 in women with NF1
• Genetic counseling for all

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5 Key Exam Points

1. NF1 = chr 17, neurofibromin (RAS-GAP); NF2 = chr 22, merlin
2. Axillary freckling + Lisch nodules = pathognomonic for NF1 (not NF2)
3. Selumetinib and mirdametinib (both MEK inhibitors) FDA-approved for NF1 plexiform neurofibromas
4. No radiation for NF1 optic gliomas (risk of secondary malignancy + vascular injury)
5. MPNST = most dangerous NF1 complication; rapid growth + new pain in a plexiform NF = red flag