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PITYRIASIS RUBRA PILARIS (PRP)

3rd Year Dermatology PG Theory Examination — 5 Marks

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DEFINITION

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AETIOLOGY & PATHOGENESIS

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CLASSIFICATION — GRIFFITHS (1980), Modified

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CLINICAL FEATURES

1. Scaliness and erythema of scalp → spreads to face, neck
2. Predilection for sides of neck, extensor surfaces (especially dorsum of proximal phalanges — "knuckle pads")
3. Papules coalesce into red-orange scaling plaques
4. Progresses to erythroderma over 2–3 months

• Islands of sparing (nappes claires) — sharply demarcated areas of normal skin within erythroderma (hallmark sign)
• Waxy, diffuse, yellowish palmoplantar keratoderma — extends up the sides of the soles ("sandal distribution")

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HISTOPATHOLOGY

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DIAGNOSIS

• Psoriasis (most important) — PRP has no nail pitting, no Auspitz sign; islands of sparing; checkerboard parakeratosis on histology
• Ichthyosis, seborrhoeic dermatitis, erythroderma of other causes

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TREATMENT

Topical

• Emollients (mainstay of symptomatic relief)
• Keratolytics: salicylic acid, urea
• Topical corticosteroids, calcineurin inhibitors, vitamin D analogues

Systemic (first-line)

Second-line / Refractory

• Biologics: TNF-α inhibitors (infliximab, etanercept, adalimumab); ustekinumab (anti-IL-12/23); anti-IL-17 agents
• Cyclosporine (5 mg/kg/day)
• Azathioprine (100–150 mg/day)
• Apremilast (PDE4 inhibitor)
• Fumaric acid esters

Phototherapy

• PUVA (psoralen + UVA) / Narrowband UVB — adjunctive role; used with caution as some PRP can worsen with UVB

HIV-associated (Type VI)

• Antiretroviral therapy (ART) — may lead to clearance

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PROGNOSIS

• Type I (classic adult): spontaneous remission in ~80% within 3 years
• Type III (classic juvenile): remission within 1–2 years
• Type II and V: chronic, lasting >20 years; may require long-term retinoids
• Type IV: unpredictable; may resolve in late teens

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Key exam points to remember:

1. Follicular papules + islands of sparing + waxy PPK = classic triad
2. Checkerboard pattern of parakeratosis on histology is pathognomonic
3. Nails never pitted → key distinction from psoriasis
4. CARD14 mutations → familial/Type V PRP
5. Acitretin is first-line systemic treatment

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SCLERODERMA (SYSTEMIC SCLEROSIS)

3rd Year Dermatology PG Theory Examination — 10 Marks

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DEFINITION

1. Vasculopathy (obliterative microangiopathy)
2. Immune dysregulation (autoimmunity, inflammation)
3. Progressive fibrosis of the skin and internal organs

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EPIDEMIOLOGY

• Female : Male ratio = 3:1 to 14:1
• Age of onset: 30–50 years
• SSc has the highest case-specific mortality of any autoimmune rheumatic disease
• Incidence: 0.6–16 per million; Prevalence: 2–233 per million
• Blacks develop disease younger and with greater severity than whites

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CLASSIFICATION

A. Based on Extent of Skin Involvement (LeRoy, 1988)

B. Other Subsets

• SSc sine scleroderma — vascular + immunologic features without skin sclerosis (1.5%)
• Early/undifferentiated SSc — Raynaud's + autoantibodies, not yet fulfilling ACR criteria
• Overlap syndromes — mixed connective tissue disease (MCTD), SSc–myositis, SSc–lupus

C. Localised Scleroderma (Morphoea) — skin only, no systemic involvement

• Plaque, linear, generalised, pansclerotic subtypes

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PATHOGENESIS

GENETIC PREDISPOSITION + ENVIRONMENTAL TRIGGERS
               ↓
        VASCULAR INJURY
               ↓
     IMMUNE DYSREGULATION
               ↓
     FIBROBLAST ACTIVATION
               ↓
     PROGRESSIVE FIBROSIS

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1. GENETIC SUSCEPTIBILITY

• HLA associations: HLA-DRB1, DQB1, DPB1 alleles linked to SSc and specific autoantibody profiles
• Non-HLA genes: STAT4, IRF5, CD247 (T cell signalling), BANK1, BLK (B cell activation)
• CARD14 mutations in familial cases (also seen in PRP)
• ~6.5% of cases are familial
• Concordance in identical twins is only ~5%, emphasising the role of environmental triggers

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2. VASCULOPATHY — The Initiating Event

Mechanism:

• Endothelial cell (EC) injury → triggered by auto-antibodies, reactive oxygen species (ROS), granzyme B from cytotoxic T cells, and viral antigens (CMV molecular mimicry)
• Injured EC → loss of normal vasoregulatory function → imbalance between:
  • Vasoconstrictors (↑ endothelin-1, ↑ thromboxane A₂)
  • Vasodilators (↓ nitric oxide, ↓ prostacyclin)
• Platelet activation → release of TGF-β, PDGF, serotonin → smooth muscle proliferation
• Intimal proliferation and adventitial fibrosis → luminal narrowing → ischaemia

Vascular consequences:

Impaired angiogenesis:

• Despite ischaemia, paradoxically defective neovascularisation occurs — VEGF is elevated but its receptor (VEGFR-2) is dysfunctional
• Circulating endothelial progenitor cells (EPCs) are reduced and dysfunctional

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3. IMMUNE DYSREGULATION — The Amplifying Event

Innate Immunity:

• Type I interferons (IFN-α, IFN-β) are elevated — "interferon signature" seen in SSc
• Toll-like receptors (TLR3, TLR7, TLR8, TLR9) activated by endogenous nucleic acids released from damaged cells → NF-κB activation → pro-inflammatory cytokines (IL-1, IL-6, TNF-α)
• Mast cells — increased in SSc skin; release histamine, TGF-β, chymase → fibroblast activation
• Macrophages — M2 polarisation (alternatively activated) → IL-4, IL-13, TGF-β → pro-fibrotic

Adaptive Immunity:

• CD4⁺ T helper cells (Th2 skewing) predominate in lesional skin
• Th2 cytokines (IL-4, IL-13) → directly stimulate fibroblast collagen synthesis
• Th17 cells → IL-17 → synergises with TGF-β in fibrosis
• Regulatory T cells (Tregs) → reduced/dysfunctional → loss of immune tolerance
• CD8⁺ T cells (cytotoxic) → injure endothelial cells via perforin/granzyme B

• Autoantibodies — hallmark of SSc (almost mutually exclusive):

• Autoantibodies against PDGFR (platelet-derived growth factor receptor) → directly stimulate fibroblast ROS production and collagen synthesis
• B cells also act as antigen-presenting cells perpetuating T cell activation

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4. FIBROBLAST ACTIVATION AND FIBROSIS — The End-Effector

Key pro-fibrotic mediators:

TGF-β Signalling (Central Pathway):

TGF-β binds TGF-βRI/II receptors
        ↓
SMAD2/3 phosphorylation → SMAD4 complex
        ↓
Nuclear translocation → Transcription of COL1A1, COL3A1, ACTA2, CTGF
        ↓
↑ Collagen I & III, fibronectin, TIMP-1
        ↓
↓ Matrix metalloproteinases (MMP-1, MMP-3)
        ↓
NET FIBROSIS (dermis, lungs, kidneys, GI, heart)

Myofibroblast transformation:

• Normal fibroblasts → activated myofibroblasts (α-smooth muscle actin positive, α-SMA⁺)
• Myofibroblasts are autonomous — continue producing ECM even without external TGF-β stimulation
• Epigenetic modifications (DNA methylation, histone modification) lock fibroblasts in a pro-fibrotic state

Epithelial-Mesenchymal Transition (EMT):

• Epithelial cells (e.g., alveolar epithelium) transition to mesenchymal/myofibroblast phenotype under TGF-β → contributes to lung fibrosis

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INTEGRATED PATHOGENESIS — SUMMARY DIAGRAM

GENETIC SUSCEPTIBILITY (HLA, STAT4, IRF5)
            +
ENVIRONMENTAL TRIGGER (silica, virus, oxidants)
            ↓
    ┌───────────────────┐
    │  VASCULAR INJURY  │ ← EC apoptosis, ROS, anti-EC antibodies
    │  (earliest event) │
    └────────┬──────────┘
             ↓
    Platelet activation → TGF-β, PDGF release
    Raynaud's, digital ulcers, PAH, renal crisis
             ↓
    ┌──────────────────────┐
    │  IMMUNE ACTIVATION   │ ← T cells (Th2/Th17), B cells, macrophages (M2)
    │  Autoantibodies       │   IFN signature, IL-4, IL-13, IL-17
    │  (ACA, anti-Scl-70)  │
    └──────────┬───────────┘
               ↓
    ┌──────────────────────────┐
    │  FIBROBLAST ACTIVATION   │ ← TGF-β (SMAD pathway), PDGF, CTGF, ET-1
    │  Myofibroblast           │
    │  transformation (α-SMA⁺) │
    └──────────┬───────────────┘
               ↓
    ┌──────────────────────────┐
    │  PROGRESSIVE FIBROSIS    │
    │  Skin, lungs, GI,        │
    │  kidneys, heart          │
    └──────────────────────────┘

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HISTOPATHOLOGY

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CLINICAL FEATURES (Brief Overview)

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DIAGNOSIS

• Skin thickening of fingers extending proximal to MCP joints (score 9 — sufficient alone)
• Sclerodactyly, fingertip pitting scars/digital ulcers
• Abnormal nailfold capillaroscopy
• PAH and/or ILD
• Raynaud's phenomenon
• SSc-specific autoantibodies (ACA, anti-Scl-70, anti-RNA Pol III)
• Total score ≥9 = definite SSc

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TREATMENT PRINCIPLES

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PROGNOSIS

• dcSSc: 10-year survival ~60–70%; main causes of death = PAH, lung fibrosis, renal crisis
• lcSSc: better prognosis; main late complication = isolated PAH
• Scleroderma renal crisis: >90% mortality before ACE inhibitors; now manageable if treated early

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Key exam points to remember:

1. SSc pathogenesis = Vasculopathy → Immune dysregulation → Fibrosis (in sequence)
2. TGF-β / SMAD pathway is the central driver of fibrosis
3. Earliest event = endothelial injury → Raynaud's
4. Anti-Scl-70 → dcSSc + ILD; Anticentromere → lcSSc/CREST + PAH; Anti-RNA Pol III → renal crisis
5. ACE inhibitors are life-saving in scleroderma renal crisis
6. SSc has highest mortality of all autoimmune rheumatic diseases

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SCLERODERMA (SYSTEMIC SCLEROSIS)

3rd Year Dermatology PG Theory Examination — 10 Marks

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DEFINITION

1. Vasculopathy (obliterative microangiopathy)
2. Immune dysregulation (autoimmunity + inflammation)
3. Progressive fibrosis of the skin and internal organs

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EPIDEMIOLOGY

• F : M ratio = 3:1 to 14:1
• Age of onset: 30–50 years
• Blacks develop disease younger and with greater severity
• SSc carries the highest case-specific mortality of any autoimmune rheumatic disease

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CLASSIFICATION

A. Based on Extent of Skin Involvement (LeRoy, 1988)

B. Other Subsets

• SSc sine scleroderma — vascular + immunological features, no skin sclerosis (~1.5%)
• Early/undifferentiated SSc — Raynaud's + autoantibodies, not yet fulfilling ACR criteria
• Overlap syndromes — SSc + myositis, SSc + SLE, MCTD

C. Localised Scleroderma (Morphoea)

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PATHOGENESIS

GENETIC PREDISPOSITION + ENVIRONMENTAL TRIGGERS
                 ↓
         VASCULAR INJURY  (initiating event)
                 ↓
      IMMUNE DYSREGULATION  (amplifying event)
                 ↓
      FIBROBLAST ACTIVATION  (end-effector)
                 ↓
       PROGRESSIVE FIBROSIS (skin, lungs, GI, kidneys, heart)

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1. GENETIC SUSCEPTIBILITY

• HLA associations: HLA-DRB1, DQB1, DPB1 alleles — linked to specific autoantibody profiles
• Non-HLA genes: STAT4, IRF5 (interferon pathway), CD247 (T cell signalling), BANK1, BLK (B cell activation)
• ~6.5% of cases are familial
• Twin concordance is only ~5% → environmental triggers are essential

• Silica dust — underground coal/gold miners have 190× increased risk of SSc
• Polyvinyl chloride, organic solvents, bleomycin (dose-dependent, reversible)
• Viral triggers — CMV molecular mimicry (anti-UL83 antibodies cross-react with anti-topoisomerase I)

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2. VASCULOPATHY — The Initiating Event

Mechanism of endothelial injury:

• Anti-endothelial cell antibodies (AECA) → complement activation → EC apoptosis
• Reactive oxygen species (ROS) from activated neutrophils and ischaemia-reperfusion
• CD8⁺ cytotoxic T cells → perforin/granzyme B → EC lysis
• CMV-derived antigens → molecular mimicry → autoimmune EC attack

Consequences of EC injury:

Clinical vascular manifestations:

• Raynaud's phenomenon — episodic vasospasm of digital arteries (earliest sign)
• Digital ulcers / gangrene — obliterative endarteritis
• PAH — intimal hyperplasia + medial hypertrophy of pulmonary arterioles
• Scleroderma renal crisis (SRC) — hyperplastic arteriolosclerosis → RAAS activation → malignant hypertension
• Nailfold capillaroscopy — giant loops, avascular areas, haemorrhages (diagnostic tool)

Impaired angiogenesis (paradox):

• Despite ischaemia, VEGF is elevated but its receptor VEGFR-2 is dysfunctional
• Circulating endothelial progenitor cells (EPCs) are reduced and functionally impaired
• → Net result: inadequate vessel repair → progressive vascular obliteration

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3. IMMUNE DYSREGULATION — The Amplifying Event

Innate Immunity:

• Type I interferons (IFN-α, IFN-β) — elevated; "interferon signature" present in SSc blood
• TLR3, TLR7, TLR8, TLR9 activated by endogenous nucleic acids from damaged cells → NF-κB → IL-1, IL-6, TNF-α
• Mast cells — increased in SSc lesional skin; release TGF-β, chymase, histamine → fibroblast activation
• Macrophages — M2 (alternatively activated) polarisation → IL-4, IL-13, TGF-β → pro-fibrotic milieu

Adaptive Immunity — T cells:

• Th2 skewing in lesional skin — IL-4, IL-13 → directly stimulate collagen synthesis by fibroblasts
• Th17 cells — IL-17 → synergises with TGF-β to drive fibrosis
• Tregs (regulatory T cells) — reduced and dysfunctional → loss of peripheral tolerance
• CD8⁺ cytotoxic T cells — injure endothelium via perforin/granzyme B

Adaptive Immunity — B cells and Autoantibodies:

These autoantibodies are almost mutually exclusive in any one patient and serve as prognostic markers.

• Anti-PDGFR antibodies → directly stimulate fibroblast ROS production and collagen synthesis
• B cells also function as antigen-presenting cells → perpetuate T cell autoimmunity

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4. FIBROBLAST ACTIVATION AND FIBROSIS — The End-Effector

Key pro-fibrotic mediators:

TGF-β / SMAD Signalling Pathway (Central):

TGF-β  →  TGF-βR I/II (serine-threonine kinase)
                    ↓
          SMAD2/3 phosphorylation
                    ↓
          SMAD2/3 + SMAD4 complex (nuclear translocation)
                    ↓
     Transcription of:
     • COL1A1, COL3A1 (Collagen I & III)
     • ACTA2 (α-smooth muscle actin)
     • CTGF, fibronectin, TIMP-1
                    ↓
     ↓ MMP-1, MMP-3 (collagen-degrading enzymes)
                    ↓
         NET DERMAL AND VISCERAL FIBROSIS

Myofibroblast Transformation:

• Normal dermal fibroblasts → activated myofibroblasts (α-SMA⁺, contractile)
• Myofibroblasts produce vast amounts of collagen, fibronectin, and CTGF
• They become autonomous — continue ECM synthesis even without external TGF-β (due to autocrine loops)
• Epigenetic locking: DNA methylation of anti-fibrotic genes (FLI1, PPAR-γ); histone modifications → constitutive pro-fibrotic gene expression

Epithelial-Mesenchymal Transition (EMT):

• Under TGF-β, alveolar/tubular epithelial cells transition to myofibroblast phenotype
• Contributes to pulmonary fibrosis and renal interstitial fibrosis

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INTEGRATED PATHOGENESIS SUMMARY

GENETIC SUSCEPTIBILITY (HLA, STAT4, IRF5)
             +
ENVIRONMENTAL TRIGGER (silica, CMV, oxidants)
             ↓
  ┌─────────────────────────┐
  │    VASCULAR INJURY      │ ← AECA, ROS, CD8⁺ T cells
  │  (EC apoptosis/damage)  │
  └──────────┬──────────────┘
             │
   Platelet activation: TGF-β, PDGF, serotonin
   Imbalance: ↑ET-1, ↑TXA₂ vs ↓NO, ↓Prostacyclin
   → Raynaud's, digital ulcers, PAH, SRC
             ↓
  ┌─────────────────────────────────┐
  │     IMMUNE DYSREGULATION        │
  │  Th2/Th17, M2 macrophages,      │
  │  Mast cells, Type I IFN         │
  │  Autoantibodies (ACA, Scl-70,   │
  │  RNA Pol III)                   │
  └──────────────┬──────────────────┘
                 │ TGF-β, IL-4, IL-13, PDGF, CTGF, ET-1
                 ↓
  ┌─────────────────────────────────┐
  │    FIBROBLAST ACTIVATION        │
  │  TGF-β/SMAD pathway             │
  │  Myofibroblast transformation   │
  │  Epigenetic locking             │
  └──────────────┬──────────────────┘
                 ↓
  ┌─────────────────────────────────┐
  │     PROGRESSIVE FIBROSIS        │
  │  Skin → Lungs → GI → Kidney     │
  │  → Heart                        │
  └─────────────────────────────────┘

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HISTOPATHOLOGY

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CLINICAL FEATURES — OVERVIEW

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DIAGNOSIS

• Skin thickening proximal to MCPJs — score 9 (sufficient alone)
• Sclerodactyly, fingertip pitting scars/digital ulcers
• Abnormal nailfold capillaroscopy
• PAH / ILD
• Raynaud's phenomenon
• SSc-specific autoantibodies (ACA, anti-Scl-70, anti-RNA Pol III)

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TREATMENT PRINCIPLES

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Key exam points — must-know:

1. Pathogenesis triad: Vasculopathy → Immune dysregulation → Fibrosis (sequential and interdependent)
2. TGF-β / SMAD pathway is the central driver of fibrosis — know it step-by-step
3. Earliest clinical event = Raynaud's phenomenon (endothelial injury)
4. Anti-Scl-70 → dcSSc + ILD | Anticentromere → lcSSc/CREST + PAH | Anti-RNA Pol III → Renal crisis
5. ACE inhibitors in renal crisis reduced mortality from >90% to manageable levels
6. SSc has highest mortality of all autoimmune rheumatic diseases
7. Myofibroblast transformation + epigenetic locking = why fibrosis is irreversible once established

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A) MALIGNANT MELANOMA

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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EPIDEMIOLOGY

• Incidence rising in light-skinned populations worldwide
• Peak incidence: 4th–5th decade
• Rare in dark-skinned races; acral and mucosal types more common in Asians and Africans
• Children rarely affected; poor prognosis when they are

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RISK FACTORS

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CLINICAL TYPES (Clinicopathologic Classification)

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ABCDE CRITERIA (Screening Tool)

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HISTOPATHOLOGY

• Asymmetry and lack of maturation with depth
• Buckshot (pagetoid) scatter of melanocytes in epidermis
• Irregular junctional nests at rete ridges and suprapapillary plates
• Absent "maturation" (nests fail to become smaller in deeper dermis)
• Dermal mitoses, lymphoid infiltrate, satellite metastases

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STAGING

Clark's Level (depth of invasion):

Breslow Thickness (most important prognostic factor):

• ≤1.0 mm → thin (low risk)
• 1.01–2.0 mm → intermediate
• 2.01–4.0 mm → thick

• 4.0 mm → very thick (high risk)

AJCC TNM Staging:

• T = tumour thickness + ulceration + mitotic rate
• N = nodal involvement (SLN biopsy)
• M = distant metastases (M1c = visceral; worst prognosis)

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INVESTIGATIONS

• Dermoscopy — most useful non-invasive tool
• Excision biopsy — complete removal with 1–3 mm margin (saucerisation technique)
• Sentinel lymph node biopsy (SLNB) — for tumours >1 mm or with ulceration
• Imaging: PET-CT, CT chest/abdomen/pelvis for staging
• Mutation testing: BRAF V600E, KIT, NRAS (guides targeted therapy)
• LDH — elevated in metastatic disease (poor prognostic marker)

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TREATMENT

Surgery (Primary Treatment):

Adjuvant Therapy (Stage III–IV):

Radiation: For lentigo maligna (inoperable), brain metastases, palliative

Isolated Limb Perfusion: Melphalan for unresectable in-transit metastases

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PROGNOSIS

• 5-year survival: Stage I = 97%; Stage II = 68%; Stage III = 63%; Stage IV = 23%
• Ulceration, high mitotic rate, nodal involvement = poor prognostic factors
• Pregnancy does not worsen survival but increases recurrence

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C) DERMATOLOGICAL EMERGENCIES

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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CLASSIFICATION

I. Severe Cutaneous Adverse Drug Reactions (SCARs)

1. Stevens-Johnson Syndrome (SJS)
2. Toxic Epidermal Necrolysis (TEN)
3. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS/DiHS)
4. Acute Generalised Exanthematous Pustulosis (AGEP)

II. Blistering/Exfoliative Emergencies

1. Staphylococcal Scalded Skin Syndrome (SSSS)
2. Pemphigus vulgaris (severe/crisis)
3. Erythroderma / Exfoliative Dermatitis

III. Vascular/Infectious Emergencies

1. Necrotising Fasciitis
2. Meningococcaemia / Purpura Fulminans
3. Toxic Shock Syndrome (TSS)

IV. Miscellaneous

1. Angioedema / Anaphylaxis
2. Calciphylaxis

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KEY CONDITIONS IN DETAIL

1. Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis

• SJS: <10% body surface area (BSA) detachment
• SJS-TEN overlap: 10–30% BSA
• TEN: >30% BSA detachment

• Drug-specific CD8⁺ T cell activation → keratinocyte apoptosis via FasL, perforin/granzyme B, TNF-α, and granulysin (principal mediator)
• HLA associations: HLA-B5701 (abacavir), HLA-B1502 (carbamazepine in Asians)

• Prodrome: fever, malaise, photophobia, painful skin
• Skin: erythema → bullae → sheet-like epidermal detachment; Nikolsky sign positive
• Mucosal involvement: oral, ocular, genital mucosae (distinguishes from SSSS)
• Target-like lesions; atypical targets (flat, 2 zones, no central blister)
• Positive "Asboe-Hansen" sign (lateral pressure extends bulla)

1. Stop offending drug immediately
2. Admit to ICU/burns unit
3. Fluid and electrolyte replacement (Parkland-like formula)
4. Nutritional support (NG tube)
5. Wound care: non-adherent dressings (petroleum-impregnated gauze)
6. Ophthalmology consult (eye drops, lysis of synechiae)
7. Specific treatments:

• IVIG (0.5–1 g/kg/day × 3 days) — most used
• Cyclosporine (3–5 mg/kg/day) — recent evidence supports
• Systemic corticosteroids — controversial; avoid in established TEN
• Etanercept (25–50 mg) — emerging evidence

1. Avoid NSAIDs (antipyretics: paracetamol only)
2. Treat secondary infections (no prophylactic antibiotics)

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2. DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

• Onset: 2–8 weeks after drug initiation (long latency — key distinguisher)
• Morbilliform/erythrodermic rash + facial oedema (characteristic)
• Eosinophilia, atypical lymphocytosis
• Systemic: hepatitis (most common), pneumonitis, myocarditis, nephritis, thyroiditis
• RegiSCAR score used for diagnosis

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3. Erythroderma / Exfoliative Dermatitis

• Psoriasis (most common in adults)
• Seborrhoeic dermatitis
• Malignancy (Sézary syndrome, lymphoma)
• Eczema/atopic dermatitis
• Drugs

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4. Necrotising Fasciitis

• Type I (polymicrobial): Fournier's gangrene (perineum/genitalia)
• Type II (Group A Streptococcus): "flesh-eating bacteria"

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5. Meningococcaemia / Purpura Fulminans

• Non-blanching petechiae/purpura ± haemorrhagic bullae in context of fever/sepsis
• Disseminated Intravascular Coagulation (DIC) → purpura fulminans
• Management: Immediate parenteral benzylpenicillin/ceftriaxone before hospital transfer; ICU; FFP; heparin controversial

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KEY EXAM TABLE — Drug Reactions Comparison

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D) KAPOSI SARCOMA

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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AETIOLOGY / PATHOGENESIS

1. HHV-8 infects endothelial cells and B lymphocytes
2. Viral oncoproteins (v-cyclin, v-FLIP, LANA) subvert cell cycle control, inhibit apoptosis
3. VEGF and inflammatory cytokines (IL-6, bFGF, oncostatin M) drive angiogenesis and spindle cell proliferation
4. Immunosuppression (HIV, iatrogenic) allows unrestricted HHV-8 replication
5. HHV-8 also activates NF-κB pathway → anti-apoptotic signalling

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TYPES OF KAPOSI SARCOMA

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CLINICAL FEATURES

• AIDS-KS: Face (nose, periorbital), oral mucosa (hard palate — pathognomonic), extremities, trunk; follows Langer's lines
• Classic KS: Lower extremities bilaterally
• Any organ may be involved: lungs (haemoptysis), GI tract (bleeding), lymph nodes

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AIDS CLINICAL TRIALS GROUP (ACTG) STAGING

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HISTOPATHOLOGY

1. Patch stage: Irregular vascular spaces lined by bland endothelium; plasma cells and RBC extravasation
2. Plaque stage: Spindle cells between vascular spaces; haemosiderin deposits; hyaline globules (PAS+)
3. Nodular stage: Dense fascicles of spindle cells (tumour cells); slit-like vascular spaces; mitoses; haemosiderin

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DIAGNOSIS

• Clinical + biopsy (tissue confirmation strongly recommended)
• LANA immunostaining for HHV-8 confirmation
• CD4 count and HIV viral load (AIDS-KS)
• CT chest/abdomen/pelvis for staging
• Endoscopy if GI involvement suspected
• Chest X-ray / bronchoscopy if pulmonary KS suspected

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TREATMENT

AIDS-Related KS:

Systemic Chemotherapy:

• Liposomal doxorubicin (Doxil/Caelyx) — first-line; superior response rate and safety
• Paclitaxel — second-line
• Bleomycin + vincristine — resource-limited settings

Local Therapies (adjunctive):

• Radiotherapy — excellent response; palliation of large lesions, lymphoedema
• Intralesional vinblastine — cosmetically accessible lesions
• Topical alitretinoin gel (9-cis-retinoic acid) — cutaneous KS
• Cryotherapy — small superficial lesions
• Imiquimod — topical immunomodulator

Classic KS:

• Localised: Radiotherapy, surgical excision, cryotherapy, laser
• Extensive: Low-dose systemic chemotherapy (vinblastine, bleomycin)
• Reducing immunosuppression (transplant-associated KS)

Experimental/Targeted:

• Pomalidomide (immunomodulatory)
• Imatinib (KIT inhibitor)
• Anti-VEGF agents

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PROGNOSIS

• AIDS-KS: dramatically improved with ART; CD4 recovery is the most important prognostic factor
• Classic KS: indolent; rarely fatal from KS itself
• Lymphadenopathic African KS in children: aggressive; high mortality
• Poor prognostic factors: visceral involvement, CD4 <100, B symptoms

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E) KLIPPEL-TRENAUNAY-WEBER SYNDROME

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

1. Capillary malformation (nevus flammeus / port wine stain)
2. Venous and/or lymphatic malformations (varicosities)
3. Soft tissue and bony hypertrophy of the affected limb

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AETIOLOGY AND PATHOGENESIS

• Sporadic (non-hereditary) in most cases; rarely familial
• Somatic mosaic mutations in PIK3CA (PI3K-AKT-mTOR pathway) — most identified in recent years
• Leads to dysregulated vascular and mesenchymal proliferation during embryogenesis
• Results in failure of normal regression of embryonic lateral vein of the leg (persistent lateral embryonic vein — "marginal vein of Servelle")
• The deep venous system may be hypoplastic or absent (important surgical consideration)

---

CLINICAL FEATURES

Triad:

• Most common and earliest presenting sign
• Geometric, unilateral, violaceous patch — "geographic" pattern
• Typically involving one limb (lower limb in 95% of cases)
• Does not regress spontaneously; darkens with age

• Lateral varicosities from birth or appearing in childhood
• Persistent lateral embryonic vein (marginal vein) — pathognomonic finding
• Deep venous system may be hypoplastic → contraindication to surgery on superficial veins
• Lymphatic malformations → lymphoedema
• Venous thromboembolism (VTE) in up to 22%
• Venous ulcers, thrombophlebitis

• Affected limb is larger and longer than normal
• Results from increased blood flow and growth factor stimulation
• Leads to limb length discrepancy and gait abnormalities
• Can affect digits (macrodactyly), causing functional impairment

Additional Features:

• Hypertrichosis over affected limb
• Lymphoedema
• Recurrent cellulitis
• Altered sweating
• Pain, intermittent claudication
• Intradural spinal cord AVMs (at same segmental level) — rare but serious
• Haematuria (genitourinary involvement)
• GI bleeding (visceral haemangiomas — portal hypertension)
• Coagulopathy (Kasabach-Merritt phenomenon in extensive lesions)

Parkes-Weber Syndrome (additional features):

• AV fistula present → warm, pulsatile limb
• High-output cardiac failure risk
• More aggressive hypertrophy

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INVESTIGATIONS

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DIFFERENTIAL DIAGNOSIS

• Sturge-Weber Syndrome — port wine stain on face (V1 dermatome) + leptomeningeal angioma; no limb hypertrophy
• Proteus Syndrome — progressive asymmetric overgrowth; epidermal naevi; cerebriform connective tissue naevus
• CLOVES Syndrome — PIK3CA mosaic; lipomatous overgrowth + vascular malformations
• Maffucci Syndrome — haemangiomas + enchondromatosis

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MANAGEMENT

Multidisciplinary Team: Dermatology + Vascular Surgery + Orthopaedics + Radiology + Haematology

Conservative Measures:

• Compression stockings (life-long)
• Avoid prolonged standing
• Physiotherapy

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PROGNOSIS

• Chronic, progressive condition — no cure
• QoL significantly impacted by limb discrepancy and venous complications
• VTE and pulmonary embolism are major causes of mortality
• Regular follow-up for orthopaedic, haematological, and renal complications is mandatory

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F) BENIGN ADNEXAL TUMOURS

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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CLASSIFICATION

I. FOLLICULAR (Hair Follicle) Origin

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II. SEBACEOUS GLAND Origin

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III. ECCRINE (Sweat Gland) Origin

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IV. APOCRINE GLAND Origin

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HISTOPATHOLOGICAL PATTERNS (Key for Exams)

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IMPORTANT SYNDROME ASSOCIATIONS

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TREATMENT

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G) LEUKOPLAKIA

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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EPIDEMIOLOGY

• Prevalence: 0.2–4.9% globally
• Male predominance (M:F = 2–3:1)
• Most common in: South and Southeast Asia (tobacco + betel nut use)
• Malignant transformation rate: 0.7–2.9% per year (overall ~5–17%)

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AETIOLOGY / RISK FACTORS

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CLASSIFICATION

A. WHO Classification (Pindborg, 1997 / updated):

B. Based on Size:

• L1: <2 cm; L2: 2–4 cm; L3: >4 cm (size correlates with malignant risk)

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SITES AND MALIGNANT POTENTIAL

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CLINICAL FEATURES

• Homogeneous leukoplakia: Smooth, uniformly white, flat or slightly raised plaque; well-defined borders; often asymptomatic; usually buccal mucosa or alveolar ridge
• Non-homogeneous: Irregular, may have red components; more likely to be dysplastic
• May present on: buccal mucosa (most common), gingiva, tongue (lateral border and ventral surface = high risk)
• Oral hairy leukoplakia (OHL): White, corrugated "hairy" patches on lateral border of tongue; non-removable; caused by EBV replication; marker of HIV immunosuppression (not truly pre-malignant)

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HISTOPATHOLOGY

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MALIGNANT POTENTIAL — HIGH-RISK INDICATORS

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DIAGNOSIS

1. Clinical examination + history
2. Toluidine blue staining — screens for dysplasia (stains DNA in dividing cells; high sensitivity, moderate specificity)
3. Biopsy (incisional, from most suspicious area) — mandatory for all leukoplakias
4. VELscope / Autofluorescence — identifies dysplastic areas
5. Smear for Candida (PAS stain)
6. HPV testing (emerging)

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DIFFERENTIAL DIAGNOSIS

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MANAGEMENT

I. Eliminate Risk Factors:

• Stop tobacco, alcohol, betel nut — most important step
• Remove local irritants (dentures, sharp cusps)
• Treat Candida (fluconazole)

II. Observation (with regular follow-up):

• Homogeneous leukoplakia without dysplasia; <2 cm; easily accessible
• 3–6 monthly reviews; re-biopsy if changes

III. Treatment of Dysplastic/High-risk Lesions:

IV. Medical/Chemoprevention:

V. Transformation to SCC:

• Surgical resection with clear margins ± neck dissection
• Radiotherapy, chemotherapy per oncology protocol

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PROGNOSIS AND FOLLOW-UP

• All patients need life-long surveillance (6–12 monthly)
• Recurrence after treatment: up to 30% for surgical excision; higher for laser/cryotherapy
• PVL has very high recurrence and transformation rate

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H) STAPHYLOCOCCAL SCALDED SKIN SYNDROME (SSSS)

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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EPIDEMIOLOGY

• Primarily affects neonates and children under 5 years
• Rare in adults (predisposing factors: renal failure, immunosuppression, HIV)
• In adults, renal clearance of toxin is normally rapid — absence of renal function → toxin accumulates
• Causative organism: Group 2 S. aureus, phage types 71 or 55 (most common)
• MSSA is more common than MRSA in SSSS

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AETIOLOGY AND PATHOGENESIS

1. S. aureus colonises/infects a remote site (nose, pharynx, ear, conjunctiva, umbilicus in neonates, urinary tract)
2. Produces exfoliative toxins A and B (ET-A, ET-B) — serine proteases
3. Toxins are absorbed systemically and travel to the skin
4. ET-A and ET-B specifically cleave Desmoglein 1 (Dsg-1) — the same target as pemphigus foliaceus autoantibodies
5. Dsg-1 is the predominant adhesion molecule in the superficial epidermis (granular layer)
6. Cleavage of Dsg-1 → split in the granular layer (subcorneal) → superficial blister
7. Dsg-3 (predominant in mucosae and deep epidermis) is not cleaved → mucous membranes spared

• Lack of protective antibodies against ET
• Immature renal clearance → higher circulating toxin levels
• Smaller surface area:volume ratio

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CLINICAL FEATURES

Stages:

• Fever, irritability, skin tenderness
• Diffuse erythema with perioral, periorbital, and intertriginous accentuation (neck, groin, axillae)
• Skin described as resembling a "sunburn"; painful to touch

• Nikolsky sign positive — lateral pressure on erythematous skin → epidermal sliding/slipping
• Blisters form at sites of pressure (where ECG leads are attached/removed; where infant is picked up)
• Large, flaccid bullae → rupture → leave denuded, glistening, "scalded" skin
• Exfoliation in large sheets → begins perioral and spreads centrally

• Widespread peeling with moist, red, denuded areas
• Crusting and desquamation in 3–5 days
• Re-epithelialisation within 1–2 weeks (lesions are very superficial)

Key Distinguishing Features:

• Mucous membranes SPARED (unlike SJS/TEN)
• Palms and soles spared
• Skin is sterile (unlike bullous impetigo — S. aureus not in lesion, only at remote source)
• Patient appears in pain, irritable

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COMPARISON: SSSS vs TEN vs BULLOUS IMPETIGO

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HISTOPATHOLOGY

• Split in the granular layer (subcorneal) — cleavage plane is just below stratum corneum
• Full-thickness epidermal necrosis is absent (cf. TEN)
• Superficial acantholysis; no significant inflammation

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DIAGNOSIS

1. Cultures from remote focus (nares, throat, conjunctivae, perianal area, umbilicus, blood, urine)
2. Skin biopsy / frozen section of blister roof — shows subcorneal split
3. FBC: leukocytosis
4. Urea, creatinine: assess renal function
5. Blood culture: if bacteraemia/septicaemia suspected

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MANAGEMENT

Antibiotics (Definitive Treatment):

Note: Clindamycin resistance is increasing — always use culture-guided therapy.

Supportive Care:

Monitoring:

• Fluid balance (denuded skin = insensible losses similar to burns)
• Watch for secondary infection
• In adults with renal failure: dialysis may be needed (to clear circulating toxin)

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PROGNOSIS

• In children: Excellent — rapid healing within 1–2 weeks; no scarring
• In adults (especially with renal failure/immunosuppression): Mortality up to 60% without treatment
• No post-inflammatory scarring as split is superficial (cf. TEN — scarring and sequelae)

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I) CLASSIFY ICHTHYOSIS; ETIOPATHOGENESIS AND CLINICAL FEATURES OF CONGENITAL ICHTHYOSIS

3rd Year Dermatology PG Theory — 10 Marks

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DEFINITION

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CLASSIFICATION

I. INHERITED ICHTHYOSES

II. ACQUIRED ICHTHYOSIS

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ETIOPATHOGENESIS OF CONGENITAL ICHTHYOSIS

Normal Epidermal Barrier:

• Keratinocytes proliferate in the basal layer → differentiate → cornify → desquamate
• The stratum corneum (SC) = "brick and mortar" structure: corneocytes (bricks) + lipid lamellae (mortar)
• Controlled desquamation by serine proteases (kallikreins) and their inhibitors (LEKTI/SPINK5)

Pathogenetic Mechanisms:

1. Defective Cornified Envelope / Structural Protein Defects

• Filaggrin (from profilaggrin) aggregates keratin intermediate filaments and forms the cornified cell envelope
• Loss-of-function mutations → absent/reduced filaggrin → inadequate corneocyte integrity → xerosis and scaling
• Also disrupts natural moisturising factor (NMF) production (filaggrin breakdown products) → impaired barrier → ↑ TEWL
• Semidominant: heterozygotes = mild IV + atopy risk; homozygotes = severe IV
• Associated with atopic dermatitis (50% of IV patients have atopy)

2. Defective Lipid Metabolism/Transport

• STS enzyme cleaves cholesterol sulphate in SC
• Deficiency → accumulation of cholesterol sulphate → inhibits serine proteases → impaired desquamation
• Scaling is due to retention hyperkeratosis (scale retained, not shed)

• ABCA12 is a lipid transporter in lamellar granules (Odland bodies)
• Deficiency → failure to deliver lipid lamellae into intercellular space of SC → severely defective barrier
• Most severe mutation: Harlequin ichthyosis (complete loss of ABCA12)

• These enzymes process polyunsaturated fatty acids for epidermal ceramide synthesis
• Deficiency → defective ceramide production → abnormal lipid lamellae → impaired barrier → scaling

3. Defective Transglutaminase — Cross-linking Defect

• Transglutaminase-1 cross-links proteins of the cornified cell envelope
• Deficiency → structurally defective corneocytes → abnormal cohesion → scaling
• Bathing suit ichthyosis: temperature-sensitive TGM1 mutations — reduced activity at higher temperatures (trunk) → limited distribution

4. Defective Keratin Filaments — Cytoskeletal Defect

• KRT1 and KRT10 are the main keratins of suprabasal keratinocytes
• Mutations → keratin tonofilament collapse → cytolysis → blistering
• Blister healing → abnormal hyperkeratosis (thickened epidermis as repair response)
• Histology: epidermolytic hyperkeratosis — suprabasal cytolysis with shell of condensed keratin

5. Defective Protease Inhibition — Netherton Syndrome

• SPINK5 encodes LEKTI (Lympho-Epithelial Kazal-type related Inhibitor) — inhibitor of skin kallikreins
• Loss of LEKTI → uninhibited kallikrein 5/7 activity → excessive desquamation + impaired barrier
• Also activates PAR-2 → Th2 inflammation → atopy (eczema, high IgE, food allergies)
• Results in ichthyosis linearis circumflexa (ILC) — polycyclic, serpiginous migrating plaques

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CLINICAL FEATURES OF CONGENITAL ICHTHYOSIS (ARCI)

A. COLLODION BABY — Common Presenting Phenotype of ARCI

• Restricted mouth opening (feeding difficulty) and chest movement (respiratory compromise)
• Ectropion (eversion of eyelids) and eclabium (eversion of lips)
• Fissuring at flexures (neck, elbows, knees)
• Limbs rigid, fingers taped together; ears filled with keratin
• Management: Humidified incubator; emollients (liquid paraffin); NG tube feeding; eye care (lubricating drops)

• Lamellar ichthyosis (~30%)
• CIE (~30%)
• Self-healing collodion baby (SHCB) — rare; resolves completely
• Normal skin (~10%)
• Other ichthyoses

B. LAMELLAR ICHTHYOSIS (LI)

• Presents at birth as collodion baby
• After membrane shedding: large, plate-like, dark, centrally adherent scales with raised borders
• Scales largest over lower extremities ("dry riverbed" appearance)
• Erythema variable (may be mild or absent)
• Ectropion (eversion of lower eyelids — important complication; risk of corneal damage)
• Eclabium (eversion of lips)
• Scarring alopecia at scalp periphery (scales entrap and break hairs)
• Hypohidrosis (scales block eccrine ducts) → heat intolerance; serious risk of hyperthermia
• Palmoplantar keratoderma (variable — minimal hyperlinearity to severe)
• Nails: thickened, ridged
• Mucous membranes and lips usually spared
• Dermatophyte infections of skin and nails are common

C. CONGENITAL ICHTHYOSIFORM ERYTHRODERMA (CIE)

• Also presents as collodion baby
• After membrane shedding: persistent erythroderma with fine, white, generalised scale
• Lower legs: larger, darker scales
• Less ectropion, eclabium, alopecia than LI (classic CIE)
• Variable sweating impairment → heat intolerance
• Mucous membranes usually spared; nails may be ridged

D. HARLEQUIN ICHTHYOSIS — Most Severe ARCI

• Neonate born with thick, armour-like plates of stratum corneum separated by deep red fissures
• Geometric pattern of fissures (resembling harlequin costume)
• Rudimentary/absent ears (sealed with keratin)
• Profound ectropion and eclabium
• Tapered fingertips; hyperconvex nails
• Restricted chest movement → respiratory failure
• Feeding impossible (mouth restricted)
• Historically uniformly fatal before 1980
• Now: survival possible with early intensive care + oral retinoids (acitretin)
• Survivors have persistent, severe erythroderma resembling CIE

E. EPIDERMOLYTIC ICHTHYOSIS (EI) — ADCI

• At birth: generalised blistering + erythroderma; resembles SSSS or EBS
• Bullae heal, leaving hyperkeratosis
• With age: blistering decreases; severe verrucous hyperkeratosis develops (especially flexures — neck, axillae, groin)
• Offensive odour (bacterial colonisation of hyperkeratotic skin)
• Palmar-plantar keratoderma (if KRT1 involved)
• Histology: Epidermolytic hyperkeratosis — suprabasal vacuolisation, keratin clumping, granular layer changes

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INVESTIGATION

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TREATMENT

General Measures:

• Emollients (cornerstone of all ichthyoses): urea 5–10%, lactic acid, glycerine; apply multiple times daily
• Keratolytics: Urea 10–20%, salicylic acid 2–6%, lactic acid 5–12% (not in neonates — systemic absorption)
• Bathing: Long daily soaks → mechanical removal of scales; add salt (NaCl) or oil
• Humidified environment (especially HI neonates)
• Temperature control: Air conditioning; avoid exercise in heat (hypohidrosis)
• Treat secondary infections (Candida, dermatophytes, S. aureus)

Systemic Treatment:

Targeted / Emerging:

• Thymosin β4 (experimental in HI)
• Gene therapy — under investigation for TGM1-related LI
• Enzyme replacement — STS for XLRI (experimental)

Ophthalmology:

• Regular review for ectropion management (lubricating drops, tarsorrhaphy)

Genetic Counselling:

• All families should receive counselling
• Prenatal diagnosis via molecular testing available for known family mutations

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Key exam points across all topics:

• Melanoma: Breslow thickness = single most important prognostic factor; acral → KIT; BRAF in SSM → targeted therapy
• Dermatological emergencies: SCORTEN for SJS/TEN; granulysin = key mediator of TEN
• Kaposi sarcoma: HHV-8; LANA IHC; liposomal doxorubicin first-line systemic
• KTS: PIK3CA mutations; persistent marginal vein; check deep veins before surgery; sirolimus for vascular malformations
• Adnexal tumours: Muir-Torre (sebaceous + colorectal Ca); Cowden (trichilemmoma + breast Ca); BHD (fibrofolliculoma + renal Ca)
• Leukoplakia: Dsg-1 cleavage → mucosae spared in SSSS (Dsg-3 predominates there)
• SSSS: Dsg-1 cleavage by ETs; subcorneal split; mucosae spared; sterile lesions; children; flucloxacillin
• Ichthyosis: Collodion baby is a presenting phenotype, not a diagnosis; TGM1 = LI; ABCA12 = Harlequin; FLG = ichthyosis vulgaris; acitretin is the mainstay systemic treatment