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Skin Disorders - Comprehensive Clinical Notes

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Part 1: Fundamentals - Approach to Skin Lesions

Primary Lesion Terminology (Harrison's, Chap. 59)

Secondary Lesion Terminology

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Part 2: Inflammatory Skin Disorders

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2.1 Eczema / Atopic Dermatitis (AD)

• The word "eczema" derives from Greek ekzein - "to boil forth." It is a reaction pattern, not a single disease.
• Hallmark histology: spongiosis (intercellular edema of epidermis) with dermal perivascular lymphoid infiltrate and exocytosis.
• In acute eczema: marked spongiosis, minimal acanthosis; subacute: spongiosis + acanthosis + hyperkeratosis; chronic: minimal spongiosis, compact hyperkeratosis, irregular acanthosis, thickened papillary dermal collagen.
• Eosinophils in the infiltrate suggest allergic cause; neutrophils suggest secondary infection.

• Chronic, inflammatory - defined by pruritus and a relapsing-remitting course.
• Associated with the "atopic march": AD → food allergies → asthma → allergic rhinoconjunctivitis (→ eosinophilic esophagitis).
• Key genetic defect: filaggrin (FLG) mutation - impairs the stratum corneum barrier, allowing allergen penetration.
• Immunology: increased IgE synthesis, elevated serum IgE, impaired delayed-type hypersensitivity.

• 50% present in year 1 of life; 80% by age 5.
• 80% of patients ultimately co-express allergic rhinitis or asthma.
• Infantile: weeping inflammatory patches/crusted plaques on face, neck, extensor surfaces.
• Childhood/adolescent: flexural dermatitis - antecubital and popliteal fossae (classic).
• Adults: localized disease - lichen simplex chronicus or hand eczema.
• Cutaneous stigmata: perioral pallor, Dennie-Morgan folds (extra skin fold below lower eyelid), increased palmar skin markings, increased susceptibility to Staphylococcus aureus infections.
• Pruritus is a dominant feature in ALL age groups; worsened by dry skin.
• About 40% of childhood AD persists into adult life.

1. Pruritus and scratching
2. Course marked by exacerbations and remissions
3. Lesions typical of eczematous dermatitis
4. Personal or family history of atopy
5. Clinical course >6 weeks
6. Lichenification of skin
7. Presence of dry skin

• Avoid drying/irritating agents; maintain adequate skin hydration.
• Topical corticosteroids - first-line for flares (potency matched to site).
• Topical calcineurin inhibitors (tacrolimus, pimecrolimus) - steroid-sparing, safe for face/folds.
• Dupilumab (anti-IL-4Ra biologic) - FDA-approved for moderate-to-severe AD; highly effective.
• Systemic: cyclosporine, methotrexate, azathioprine for severe refractory cases.
• Antibiotics if secondary S. aureus infection (mupirocin topically or oral antibiotics for widespread infection).

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2.2 Psoriasis

• Chronic immune-mediated inflammatory disorder. T-cell driven: activated T cells elaborate cytokines (TNF-alpha, IL-17, IL-23) responsible for keratinocyte hyperproliferation.
• Normal epidermal turnover: 28 days; in psoriasis: 3-4 days (7-10x faster).
• Genetic predisposition: HLA-Cw6 strongly associated (especially with guttate psoriasis).

• Auspitz sign: removal of scale produces pinpoint bleeding (dilated capillaries).
• Koebner phenomenon: new lesions appear at sites of trauma.
• Nail changes: pitting, oil spots (salmon patches), onycholysis, subungual hyperkeratosis (present in 50% of patients).
• Psoriatic arthritis: affects ~30% of patients; seronegative (RF negative); can be destructive.

• Topical glucocorticoids (medium-high potency) - tachyphylaxis and skin atrophy with prolonged use.
• Calcipotriène (vitamin D analogue) - first-line alternative.
• Tazarotene (topical retinoid).

• Narrowband UVB - most commonly used.
• PUVA (psoralens + UVA) - highly effective but increases risk of skin cancer.
• Important: UV therapy is contraindicated with concurrent cyclosporine use.

Key point: Oral glucocorticoids are contraindicated in psoriasis - can trigger rebound pustular or erythrodermic psoriasis on withdrawal.

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2.3 Acne Vulgaris

1. Follicular hyperkeratinization (abnormal desquamation → comedone formation)
2. Increased sebaceous gland activity (androgenic stimulation)
3. Cutibacterium acnes (formerly Propionibacterium acnes) proliferation
4. Inflammatory response to C. acnes antigens and lipase products

• Comedones: Non-inflammatory - open (blackhead - oxidized melanin) or closed (whitehead)
• Inflammatory lesions: Papules, pustules
• Nodules/cysts: Deep, large - risk of scarring; can cause profound psychological impact

• Friction/trauma (helmets, chin straps)
• Comedogenic cosmetics/hair products
• Glucocorticoids (topical or systemic)
• Progestin-only contraceptives, lithium, isoniazid, androgens, halogens, phenytoin, phenobarbital
• Polycystic ovarian syndrome (PCOS)

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2.4 Rosacea

• Chronic facial disorder of blood vessels and pilosebaceous units.
• Four subtypes: Erythematotelangiectatic, Papulopustular, Phymatous (rhinophyma), Ocular.
• Triggers: sun, heat, alcohol, spicy food, exercise, emotional stress, certain skincare products.
• Distribution: central face - nose, cheeks, forehead, chin.
• Unlike acne: no comedones; facial flushing often precedes other changes.

• Topical metronidazole or azelaic acid for erythema/papulopustules.
• Topical brimonidine or oxymetazoline for persistent erythema/flushing (alpha agonists).
• Oral doxycycline (subantimicrobial dose 40 mg/day) for moderate-severe.
• Laser/IPL therapy for telangiectasias and persistent erythema.
• Oral isotretinoin for phymatous rosacea (rhinophyma).

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Part 3: Infectious Skin Disorders

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3.1 Bacterial Infections

• Most common superficial bacterial skin infection in children.
• Staphylococcus aureus (most common) or Group A Streptococcus.
• Non-bullous (70%): honey-colored crusts, often perioral/nasal.
• Bullous (30%): S. aureus phage group II - exfoliatin toxin cleaves desmoglein-1 → flaccid bullae.
• Treatment: topical mupirocin or retapamulin for localized; oral cephalexin or amoxicillin-clavulanate for widespread; consider MRSA coverage (clindamycin, TMP-SMX) if resistant.

• Deep dermis + subcutaneous fat inflammation.
• Typically Group A Strep or S. aureus.
• Presents: warm, tender, erythematous, swollen, non-elevated skin (unlike erysipelas).
• Erysipelas: superficial, involves lymphatics - sharply demarcated, raised border (compared to cellulitis's diffuse blending). Often involves face or lower limbs; usually Group A Strep.
• Treatment: Penicillin/amoxicillin for strep; dicloxacillin/cephalexin for staph; vancomycin/daptomycin for MRSA.

• Life-threatening deep soft tissue infection - rapidly spreading necrosis of fascia.
• Type 1 (polymicrobial - mixed aerobes + anaerobes): diabetics, immunocompromised.
• Type 2 (Group A Strep monomicrobial): healthy adults - associated with toxic shock.
• "Dishwater" fluid at fascial planes; severe pain then paradoxical anesthesia (nerve destruction).
• Treatment: Urgent surgical debridement + broad-spectrum antibiotics (piperacillin-tazobactam ± clindamycin to suppress toxin production + vancomycin for MRSA coverage).

• Exfoliatin toxins A and B cleave desmoglein-1 in superficial epidermis → generalized blistering.
• Primarily affects neonates and young children (lack protective antibodies; renal immaturity).
• Nikolsky sign positive (light lateral pressure separates epidermis).
• Adults: rare; seen in renal failure (toxin accumulation) or immunocompromised.
• Treatment: IV antistaphylococcal antibiotics; supportive care.

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3.2 Viral Infections

• HSV-1: orolabial ("cold sores"); increasingly causes genital herpes.
• HSV-2: genital herpes predominantly.
• Primary: grouped vesicles on erythematous base - ulcerate, crust, heal in 2-4 weeks.
• Recurrences: shorter, milder; prodrome of tingling/burning; triggered by UV, stress, fever, immunosuppression.
• Tzanck smear: multinucleated giant cells (does not distinguish HSV from VZV).
• PCR is the gold standard for diagnosis.
• Treatment: acyclovir, valacyclovir, famciclovir.

• Reactivation of latent VZV in dorsal root ganglion.
• Prodrome: dermatomal pain/burning → unilateral dermatomal vesicular rash (does NOT cross midline).
• Ramsay Hunt syndrome: VZV reactivation in geniculate ganglion → ipsilateral facial palsy + ear vesicles + hearing loss.
• Complication: postherpetic neuralgia (PHN) - pain persisting >3 months after rash; risk increases with age.
• Treatment: start antivirals within 72 hours (valacyclovir 1 g TID x7 days); corticosteroids debated for acute pain; gabapentin/pregabalin/TCAs/SNRIs for PHN.
• Prevention: Shingrix (recombinant zoster vaccine, RZV) - 2-dose series, ~97% efficacy at preventing shingles, recommended age 50+.

• Poxvirus; umbilicated pearly papules; spreads by skin contact.
• Self-limited in immunocompetent; extensive in HIV/immunocompromised.
• Treatment: curettage, cryotherapy, cantharidin, or watchful waiting.

• Warts (verrucae): common (hands), plantar, flat (verruca plana), condylomata acuminata (anogenital).
• High-risk types (16, 18): cervical, anogenital, oropharyngeal malignancies.
• Treatment: destructive (cryotherapy, laser), chemical (salicylic acid, podophyllin, trichloroacetic acid), immunomodulatory (imiquimod).

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3.3 Fungal Infections

• Superficial fungi infecting keratinized tissue (skin, hair, nails).
• Genera: Trichophyton, Microsporum, Epidermophyton.

• Diagnosis: KOH preparation (hyphae); Wood's lamp (M. canis fluoresces blue-green).
• Treatment: topical azoles for limited disease; oral terbinafine (dermatophytes) or itraconazole/fluconazole for nail/extensive disease.

• Candida albicans most common.
• Sites: oral (thrush - white plaques, easily scraped), esophageal, vulvovaginal, intertriginous (moist, erythematous plaques with satellite pustules).
• Risk factors: antibiotics, immunosuppression, diabetes, corticosteroids, pregnancy.
• Treatment: topical nystatin or azoles for superficial; systemic fluconazole for refractory/invasive.

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Part 4: Autoimmune & Blistering Skin Disorders

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4.1 Bullous Pemphigoid (BP)

• Autoimmune - IgG autoantibodies against hemidesmosomal proteins BP180 (type XVII collagen) and BP230 at the dermal-epidermal junction (DEJ).
• Results in subepidermal blister formation (blister roof contains full-thickness epidermis).
• C3 complement deposition at DEJ.

• Most common autoimmune blistering disorder.
• Age: typically elderly (>70 years).
• Prodrome: pruritic urticarial plaques for weeks-months before blistering.
• Tense bullae (unlike pemphigus - which are flaccid) on an erythematous/urticarial base.
• Distribution: flexural areas (inner thighs, axillae), abdomen; mucous membrane involvement rare or mild.
• Nikolsky sign: negative (blister roof is strong - full epidermis).

• Skin biopsy: subepidermal split + eosinophilic infiltrate.
• Direct immunofluorescence (DIF): linear IgG and C3 at DEJ (gold standard).
• Indirect IF: circulating anti-BMZ antibodies.
• ELISA for anti-BP180/BP230 antibodies - correlates with disease severity.

• Remission occurs; median treatment period ~2 years with 50% remission at 3 years.
• 1-year mortality: 19-40% (Europe), lower in US (6-19%) - reflects age and comorbidity of affected population.
• Poor prognostic factors: old age, poor general health, neurologic disease, extensive disease, high anti-BP180 titers.

• Potent topical corticosteroids (clobetasol) - evidence supports efficacy comparable to systemic, with less toxicity in older patients.
• Oral prednisone (0.5-1 mg/kg/day).
• Steroid-sparing agents: doxycycline + niacinamide, azathioprine, mycophenolate mofetil, methotrexate.

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4.2 Pemphigus Vulgaris (PV)

• IgG autoantibodies against desmoglein-3 (and in mucocutaneous disease, desmoglein-1) - desmosomal proteins essential for keratinocyte-keratinocyte adhesion.
• Results in intraepidermal acantholysis (loss of cell-cell adhesion) → flaccid blister formation just above the basal layer ("suprabasal split").

• Any age (peak 40-60); higher prevalence in Jewish and Mediterranean populations.
• Flaccid bullae that rupture easily, leaving painful erosions.
• Nikolsky sign: positive (lateral pressure on normal skin causes superficial sheet of epidermis to slide off).
• Mucosal involvement prominent (oral erosions often precede skin blistering by months).
• Unlike BP: lesions preferentially on non-flexural areas; no pruritic prodrome.

• Skin biopsy: suprabasal acantholysis with "tombstone" row of basal cells.
• DIF: intercellular IgG and C3 in a "fish-net" (net-like) pattern in epidermis.
• ELISA: anti-Dsg3 (mucosal PV) and anti-Dsg1 (mucocutaneous PV) antibodies.

• Oral prednisone (1-1.5 mg/kg/day) - mainstay.
• Rituximab (anti-CD20) - now recommended early; superior to high-dose steroids alone in several trials.
• Steroid-sparing: azathioprine, mycophenolate mofetil, cyclophosphamide.
• Dapsone for mucosal disease.

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Key Differences: BP vs PV

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4.3 Dermatitis Herpetiformis (DH)

• IgA-mediated - associated with celiac disease (gluten-sensitive enteropathy).
• Extremely pruritic, grouped vesicles on extensor surfaces (elbows, knees, buttocks, shoulders).
• DIF: granular IgA deposits in dermal papillae (pathognomonic).
• Treatment: gluten-free diet (first-line and addresses both DH and GI pathology); dapsone for rapid symptom control.

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4.4 Lupus Erythematosus (Cutaneous Manifestations)

• Erythematous plaques with adherent scale, follicular plugging, and scarring alopecia.
• Distribution: face, scalp, ears.
• Can be isolated skin disease (~80%) or marker of SLE.
• Areas of previous inflammation: hypopigmented center with rim of hyperpigmentation.
• Histology: vacuolar interface change, follicular plugging, mucin deposition.

• Malar (butterfly) rash: erythema over cheeks/nose, spares nasolabial folds; photosensitive.
• Lupus hairs: short broken hairs at frontal scalp - sign of disease flare.
• Photosensitivity, discoid lesions, oral ulcers, alopecia.
• Subacute cutaneous LE (SCLE): anti-Ro/SSA antibodies; annular or psoriasiform lesions.

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Part 5: Skin Tumors

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5.1 Basal Cell Carcinoma (BCC)

• Most common human malignancy - >2 million cases/year in the US (Fitzpatrick's).
• Risk factors: UV exposure, fair skin, immunosuppression, radiation, arsenic exposure, Gorlin syndrome (nevoid BCC syndrome - PTCH1 gene mutation).

• BCC almost never metastasizes but causes significant local destruction ("locally aggressive").
• High-risk "H-zone" of face: nose, eyelids, eyebrows, temples, lips, ear, periauricular skin.
• Mohs micrographic surgery: gold standard for high-risk locations; 5-year cure rate 99.4% (primary), 92.4% (recurrent) - superior to standard excision (3-4x lower recurrence rate).
• Vismodegib and sonidegib (hedgehog pathway inhibitors) for locally advanced or metastatic BCC.

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5.2 Squamous Cell Carcinoma (SCC)

• Second most common skin cancer; unlike BCC, SCC can metastasize (risk 2-5% overall; higher on lip/ear).
• Risk factors: UV (cumulative dose more important than BCC), immunosuppression (organ transplant patients have 250x higher SCC risk), HPV (anogenital/mucosal SCC), scarring/chronic wounds (Marjolin's ulcer), arsenic, radiation, chemical carcinogens.

• Rough, scaly, erythematous papule on sun-exposed skin.
• Risk of progression to SCC: ~1-5% per lesion per decade.
• Treatment: cryotherapy, 5-fluorouracil cream (field therapy), imiquimod, PDT.

• Irregular, firm papule/nodule or ulcerated plaque on sun-damaged skin.
• Lips, ears, scalp, dorsal hands common sites.
• Well-differentiated (keratoacanthoma-like) to poorly differentiated.

• Excision with clear margins for most.
• Mohs surgery: periocular/nasal/ear lesions, large lesions, poorly differentiated histology.
• Adjuvant radiation for perineural invasion, positive margins.
• Cemiplimab or pembrolizumab (anti-PD-1 checkpoint inhibitors) for locally advanced/metastatic SCC.

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5.3 Melanoma

• Rising incidence worldwide - highest in Australia/NZ (35/100,000/year), then North America (21.8/100,000/year), then Europe.
• Mean age of diagnosis: 63 years; 15% diagnosed below age 45.
• Most common site: back in men; lower extremities/trunk in women.
• Risk factors: sunburns/heavy UV exposure, blue/green eyes, blonde/red hair, fair complexion, >100 typical nevi, atypical nevi, personal/family history of melanoma, CDKN2A (p16) mutation.

• <1 mm: excellent prognosis (5-year survival >95%)
• 1-4 mm: intermediate

• 4 mm: poor prognosis

• Ulceration and mitotic rate also affect T staging (AJCC).

• BRAF V600E mutation: present in ~50% of cutaneous melanomas.
• BRAF inhibitors: vemurafenib, dabrafenib (often combined with MEK inhibitors: trametinib, cobimetinib).
• NRAS mutation: ~20%; no approved targeted therapy.
• KIT mutations: acral/mucosal melanomas - imatinib.

• Anti-CTLA-4: ipilimumab.
• Anti-PD-1: pembrolizumab, nivolumab.
• Combination ipilimumab + nivolumab: higher response rates in metastatic melanoma; median overall survival ~2 years in stage IV with chance of long-term control.

• Indicated for Breslow thickness ≥1 mm (or 0.8-1 mm with ulceration or high mitotic rate).
• Positive SLNB → completion lymphadenectomy or observation + adjuvant therapy.

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5.4 Kaposi Sarcoma (KS)

• Vascular neoplasm caused by HHV-8 (KSHV).
• Types: Classic (elderly men, Mediterranean/Eastern European), Endemic (African), Iatrogenic (transplant recipients), Epidemic (AIDS-associated).
• Violaceous/red-purple plaques and nodules on skin, mucosa, and viscera.
• HIV-associated KS: CD4 count typically <200.
• Treatment: local (radiation, cryotherapy, intralesional vinblastine) or systemic (pegylated liposomal doxorubicin, paclitaxel for extensive disease); HAART in HIV patients often leads to regression.

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Part 6: Other Important Skin Disorders

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6.1 Urticaria & Angioedema

• Urticaria ("hives"): transient, intensely pruritic wheals (edematous plaques) lasting <24 hours at any single site; caused by mast cell degranulation → histamine release.
• Angioedema: deeper dermis/subcutaneous/submucosal edema; can involve lips, tongue, larynx (life-threatening).
• Acute (<6 weeks): often IgE-mediated (foods, drugs, insect stings); infections; physical.
• Chronic (>6 weeks): 80-90% idiopathic (chronic spontaneous urticaria = CSU); evaluate thyroid autoimmunity, H. pylori, hepatitis.
• Hereditary angioedema (HAE): C1-esterase inhibitor deficiency; bradykinin-mediated; no urticaria; no response to antihistamines or epinephrine.
• Treatment: nonsedating H1 antihistamines; systemic steroids for acute severe; omalizumab (anti-IgE) for chronic refractory; epinephrine for anaphylaxis/laryngeal edema.

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6.2 Alopecia

• Permanent destruction of follicles.
• Causes: discoid lupus, lichen planopilaris, central centrifugal cicatricial alopecia, folliculitis decalvans.
• Key feature: inflammatory process at periphery + fibrosis at center; once scarring occurs, hair loss is irreversible.

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6.3 Drug Reactions

SJS/TEN (Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis):

• Nikolsky sign positive over blistered areas.
• SCORTEN score predicts mortality in TEN.
• Management: immediate drug withdrawal, ICU/burn unit, cyclosporine or IVIg (controversial), wound care, nutritional support, ophthalmology.

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6.4 Figurate/Annular Erythemas (Systemic Disease Markers)

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Quick Reference Summary Table

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