Short Notes for 3rd Year Dermatology PG Theory Examination

a) Mixed Connective Tissue Disease (MCTD)

Definition & Concept

• Overlap syndrome (where each disease meets full diagnostic criteria)
• Undifferentiated connective tissue disease (UCTD) (only ~4% of UCTD progresses to MCTD)

Epidemiology

• Female > Male (strong female predominance)
• Any age; peak incidence in the 2nd–4th decade

Pathogenesis

• High-titre anti-U1 RNP antibodies (anti-ribonucleoprotein) are the serologic hallmark
• ANA shows a speckled (particulate) pattern on immunofluorescence, reflecting nuclear RNP antibody activity
• Particulate epidermal nuclear IgG deposition on direct immunofluorescence (DIF) of skin is a distinctive finding
• Anti-TS1-RNA antibodies define a subpopulation with predominant lupus-like features
• Absence of anti-Sm antibodies helps distinguish MCTD from SLE

Clinical Features

• Raynaud phenomenon with digital pitting/ulcers
• Puffy, sausage-shaped fingers
• Sclerodactyly (in SSc-like overlap)
• Malar rash, photosensitivity (in SLE-like overlap)
• Mechanic's hands, Gottron's papules (in myositis-like overlap)
• Livedo reticularis

• Pulmonary: Pulmonary arterial hypertension (PAH), pulmonary fibrosis — major causes of mortality
• Renal: Less severe than SLE; responds to steroids
• CNS: Trigeminal neuropathy, aseptic meningitis
• Cardiovascular events
• Thrombotic thrombocytopenic purpura (TTP)

Investigations

Diagnostic Criteria (Sharp/Alarcon-Segovia)

1. High-titre anti-U1 RNP antibodies
2. At least 3 of the 5 clinical features: Raynaud phenomenon, swollen hands/fingers, synovitis, myositis, acrosclerosis/esophageal dysmotility
3. Absence of anti-Sm antibodies

Treatment

• Acute inflammation (arthritis, myositis): Prednisone 1 mg/kg/day
• LE features respond best to therapy; SSc features respond least
• Hydroxychloroquine for SLE-like manifestations
• Steroid-sparing agents early (azathioprine, methotrexate)
• Bisphosphonates for osteoporosis prophylaxis (long-term steroids)
• Rituximab for life-threatening, refractory complications (response rate ~80% in thrombocytopenia)
• PAH: Endothelin receptor antagonists, PDE5 inhibitors
• ILD: Mycophenolate mofetil, cyclophosphamide

Prognosis

• Generally better than systemic sclerosis due to lower incidence of renal disease
• Higher mortality risk: younger age of onset, PAH, Raynaud phenomenon, livedo reticularis
• Main causes of death: PAH, pulmonary fibrosis, cardiovascular events, renal disease, TTP, infection

b) Necrobiosis Lipoidica Diabeticorum (NLD)

Definition

• First described by Oppenheim (1929) as "dermatitis atrophicans diabetica"
• Renamed necrobiosis lipoidica diabeticorum by Urbach in 1932
• Term shortened to NL after first non-diabetic case (Goldsmith, 1935)

Epidemiology

• F : M = 3:1 to 8:1
• Mean age of onset: ~30–34 years overall; ~22 years in insulin-dependent (Type 1) diabetics; ~49 years in Type 2 diabetics
• Prevalence in diabetics: 0.3% to 3%
• In 15% of cases, NL precedes diabetes by an average of 2 years
• Only 0.3–3% of diabetics develop NL; control of diabetes does not influence course
• Thyroid dysfunction: found in 15–25% of patients with NL
• Association with celiac disease in diabetic patients

Pathogenesis

1. Microangiopathy — diabetic microangiopathic vascular changes → collagen degeneration → granulomatous response
2. Immune complex vasculitis — immunoreactants in vessel walls of lesional and uninvolved skin
3. Primary collagen disease — decreased collagen synthesis by fibroblasts from NL lesions; loss of cross-striations on EM; collagen concentration reduced
4. Venous hypertension — relevant when lesions favour lower extremities
5. Elevated plasma fibronectin, factor VIII-related antigen, α2-macroglobulin detected
6. Platelet aggregation abnormalities and reduced fibrinolysis contribute to microthrombus formation

Clinical Features

• Small, sharply bordered red-brown papules ± slight scale; do not blanch on diascopy

• Well-circumscribed, firm, depressed, yellow-brown atrophic plaques with a smooth, "glazed porcelain" surface
• Peripheral violaceous or pink-red raised indurated rim
• Central yellow atrophic area with prominent telangiectasias and ectatic veins
• Usually bilateral, multiple

• Classic: Anterior shins (pretibial) — most common
• Less common: ankles, calves, thighs, feet
• Rare: forearms, face, scalp, palms, soles, trunk

• Ulceration in 13–35% of cases (usually post-trauma; Koebner phenomenon)
• Decreased sensation (pinprick, fine touch), hypohidrosis, partial alopecia within plaques
• Squamous cell carcinoma arising in chronic ulcers (rare but important)
• Anesthesia of plaques

• Early: comma-shaped vessels
• Advanced: irregular arborizing vessels
• Whitish areas = degenerated collagen
• Yellow-orange patches = granulomatous inflammation

Histopathology

• Palisaded granulomatous dermatitis involving the full thickness of the reticular dermis, often extending into subcutaneous fat septa
• "Layered" or tiered arrangement — horizontal tiers of palisaded granulomas alternating with degenerated (necrobiotic) collagen
• Histiocytes (often multinucleated), lymphocytes, plasma cells
• Plasma cells in perivascular infiltrate — distinctive feature
• No mucin increase (differentiates from granuloma annulare)
• Epidermis: thinned with loss of rete ridge pattern (atrophic)
• Vascular changes: endothelial swelling, fibrosis, hyalinization → vessel wall thickening, endarteritis obliterans
• Extracellular lipid deposition demonstrable with adipophilin staining (or oil red O on frozen sections)
• Punch biopsy appears rectangular rather than tapered due to firm dermis

Differential Diagnosis

• Granuloma annulare (most important)
• Necrobiotic xanthogranuloma (NXG)
• Sarcoidosis / Angio-lupoid sarcoidosis
• Diabetic dermopathy
• Lipodermatosclerosis
• Morphea / Lichen sclerosus
• Granulomatous infections (leprosy, dimorphic fungi, tertiary syphilis)

Investigations

• Fasting blood glucose / HbA1c — screen for diabetes
• OGTT — if diabetes not yet diagnosed
• Thyroid function tests (15–25% have thyroid dysfunction)
• Skin biopsy — for histopathological confirmation
• Direct immunofluorescence — immunoreactants in vessel walls

Treatment

• Superpotent topical corticosteroids ± occlusion (for early lesions)
• Intralesional triamcinolone into the active inflammatory border (NOT the yellow atrophic centre — risk of ulceration)
• Topical tacrolimus 0.1% ointment (calcineurin inhibitor; effective in uncontrolled series)

• Antimalarials (hydroxychloroquine)
• Pentoxifylline (improves microcirculation)
• Aspirin + dipyridamole (variable results; RCTs showed no significant benefit)
• Niacinamide
• Methotrexate
• Mycophenolate mofetil
• Doxycycline, colchicine, thalidomide
• TNF-α inhibitors (infliximab, adalimumab — case reports)
• JAK inhibitors — emerging promising option
• Short course systemic corticosteroids (benefit in series of 6 patients)
• Cyclosporine (severe ulcerations)

• Topical PUVA — improvement in ~50% in prospective uncontrolled studies
• UVA1 phototherapy; pulsed-dye laser; fractional CO₂ laser; photodynamic therapy

• Avoid trauma; local wound care
• Topical GM-CSF or bovine collagen for ulcerations
• Tretinoin gel 0.025% BID for atrophy

• Excision to deep fascia/periosteum + split-thickness skin grafting

Prognosis

• Clinical course often indolent; spontaneous remission in <20% (one study: 17% after 8–12 years)
• Plaques tend to stabilize; formation of new lesions tapers off
• Glycaemic control does not clearly influence outcome
• Main concerns: ulceration, cosmesis, rare SCC transformation

Exam Tip: For a 10-mark short note, aim to cover: definition/history → epidemiology → pathogenesis → clinical features → investigations/histopathology → DD → treatment → prognosis. Both topics above follow this structure. For MCTD, emphasize anti-U1 RNP antibodies and the pentad of features. For NLD, the key distinguishing points are the palisaded granulomatous histology with no mucin, the layered/tiered collagen necrobiosis, plasma cells, and the diabetes association.

Short Notes for 3rd Year Dermatology PG Theory Examination

a) Hidradenitis Suppurativa (HS)

Definition & Synonyms

Epidemiology

• Prevalence: ~0.1% in the USA
• Female : Male = 3:1
• Peak onset: third decade of life (18–29 years)
• Disproportionately affects women, African Americans, and young adults
• Post-pubertal onset; pediatric cases are uncommon (hormonal workup essential)
• Risk factors: obesity, smoking, mechanical friction, family history (AD inheritance in some)

Pathogenesis

1. Terminal follicle hyperkeratosis → plugging of follicular infundibulum
2. Follicular epithelium ruptures → release of keratin, sebum, bacteria, and hairs into the dermis
3. Intense inflammatory response → tender nodules → abscess → sinus tract formation → scarring
4. Secondary bacterial infection with S. aureus, Streptococcus pyogenes, gram-negative organisms

• IL-12/IL-23 pathway dysregulation
• TNF-α overexpression
• Innate and adaptive immune involvement
• Sebaceous gland atrophy precedes pilosebaceous unit inflammation

• Autosomal dominant inheritance in some families
• Mutations in gamma-secretase genes: NCSTN, PSENEN, PSEN1 identified
• Mutation-positive patients: severe, extensive disease; onset before age 13

• Metabolic syndrome, obesity, type 2 diabetes, dyslipidemia, hypertension
• Inflammatory bowel disease (Crohn's > UC)
• Polycystic ovarian syndrome (PCOS)
• Inflammatory joint disorders / spondyloarthropathy
• Anxiety and depression

Clinical Features

• Most common: axillae (bilateral)
• Women: inguinal, submammary areas
• Men: buttock, perianal, perineal, atypical areas (retroauricular, trunk)

1. Tender, firm red nodules → become fluctuant and painful
2. Rupture and suppuration → foul-smelling discharge
3. Sinus tract formation — burrowing horizontally under the skin, extending several centimetres
4. Honeycombed fistulous tracts with chronic infection
5. Dense fibrotic scarring → restricted movement (in severe cases)
6. Ropelike fibrotic bands across affected areas

Staging (Hurley Classification)

• Mild ≤3 | Moderate 4–10 | Severe ≥11

Histopathology

• Keratin-filled sinus tract within dermis extending into subcutaneous fat
• Surrounded by marked fibrosis and mixed inflammatory infiltrate
• Granuloma formation in chronic disease
• Lymphocytic, neutrophilic, plasma cell infiltrate
• Destruction of sebaceous glands and pilosebaceous units

Differential Diagnosis

• Common furuncle / carbuncle (typically unilateral)
• Bartholin abscess
• Scrofuloderma (cutaneous TB)
• Actinomycosis
• Granuloma inguinale
• Lymphogranuloma venereum
• Pilonidal sinus
• Crohn's disease perianal fistulae

Complications

• Squamous cell carcinoma (after average 19 years of active disease) — most feared
• Pyoderma gangrenosum (PG) — median 19 years after onset; rapidly expanding painful ulcer
• Urethral, vesical, rectal fistulae
• Lymphedema (penis and groin)
• Anaemia, hypoproteinaemia
• Amyloidosis
• Interstitial keratitis
• PASH syndrome (PG + Acne + Suppurative Hidradenitis)
• PASS syndrome (PG + Acne + Suppurative Hidradenitis + Spondyloarthropathy)

Treatment

• Weight reduction, smoking cessation
• Loose-fitting soft fabrics, antiseptic washes (chlorhexidine, benzoyl peroxide)
• Psychological support; pain management
• Laser hair reduction (in unaffected skin)
• Avoid incision and drainage (high recurrence)

• Intralesional triamcinolone (5–10 mg/mL) into active lesions
• Topical clindamycin, resorcinol, dapsone
• Oral antibiotics: tetracyclines (doxycycline, minocycline); clindamycin + rifampin 300 mg BD (most studied combination)
• Hormonal: spironolactone, OCPs (anti-androgenic), finasteride (men), metformin
• Oral zinc (adjuvant)
• Oral retinoids if concurrent cystic acne
• Surgical deroofing, limited local excision

• Above + biologics:
  • Adalimumab — FDA-approved (only biologic with regulatory approval for HS); 160 mg Day 1, then 80 mg Day 15, then 40 mg weekly
  • Infliximab
  • Ustekinumab (IL-12/23 inhibitor)
  • IL-17 inhibitors (secukinumab, bimekizumab)
  • IL-23 inhibitors
  • Anakinra (IL-1 receptor antagonist)
• Apremilast, cyclosporine, colchicine + minocycline
• Nd:YAG laser, CO₂ laser ablation

• IV ertapenem (bridge therapy)
• Wide surgical excision of entire involved area
• Wound closure: split-thickness skin grafting, secondary intention healing, regional flaps
• CO₂ laser excision
• Recurrence rate: up to 50% even after complete excision

b) Tuberous Sclerosis Complex (TSC)

Definition

Genetics & Pathogenesis

• Autosomal dominant with variable expressivity and penetrance
• Prevalence: 1 in 5,800 to 1 in 15,000 births
• Up to 50% of cases arise from spontaneous mutations
• Two tumour suppressor genes:

• Hamartin and tuberin form a physical complex → inhibits mTOR (mammalian target of rapamycin) signalling
• Loss-of-function mutations → unregulated mTOR activation → unchecked cell proliferation → hamartoma formation
• TSC2 mutations more common and associated with more severe phenotype
• TSC2 is adjacent to PKD1 — contiguous deletions cause features of both TSC and ADPKD
• Hamartomas show loss of heterozygosity of the remaining normal allele

Cutaneous Features

• Present in 85% of patients
• Congenital, oval, leaf-shaped white macules (1–12 cm)
• Best seen under Wood's lamp
• ≥3 macules >5 mm required for diagnostic criterion
• May also appear as confetti macules (multiple tiny white spots) or linear form
• Focal poliosis (tufts of white hair) may accompany

• Present in >90% of patients older than 4 years
• 1–3 mm, yellowish-red, translucent, discrete, waxy papules
• Distributed symmetrically over cheeks, nose, nasolabial folds, forehead ("butterfly distribution")
• Appear after age 4; persist and increase in number indefinitely
• Histology: vascular fibrous tissue (angiofibroma)

• Previously called "fibrous forehead plaque"
• Located on head (not limited to forehead)
• Histologically identical to angiofibroma
• Marker for more serious intracranial involvement

• Present in ~50% of patients
• Small, digitate, protruding, asymptomatic periungual and subungual fibromas
• Appear at puberty
• Nail changes: longitudinal grooves, long leukonychia, short red streaks

• Connective tissue naevus
• Skin-coloured to slightly pink, cobblestone-textured plaque on lower back/lumbosacral region
• Present in ~30–50%

Systemic Features

• Cortical tubers: potato-like hamartomas in cerebral cortex → seizures, intellectual disability; may progress to gliomas
• Seizures: 80–90% have seizures or EEG abnormalities; infantile spasms (West syndrome) common
• Subependymal nodules ("candle drippings") — calcified lesions in ventricular walls
• Subependymal giant cell astrocytoma (SEGA) — may cause obstructive hydrocephalus
• Mental deficiency: present in 40–60%; variable severity

• Angiomyolipomas — most common renal finding; bilateral, multiple; benign but may bleed; surgical removal if >4 cm
• Renal cysts (~20–30%)
• Increased risk of renal cell carcinoma
• CKD → end-stage renal failure (rare but serious)

• Cardiac rhabdomyomas (43%) — most common cardiac tumour in infants; highly specific for TSC; often regress after birth; detectable prenatally on fetal echo

• Pulmonary lymphangioleiomyomatosis (LAM) — mainly in women in 3rd–4th decade
• Diffuse proliferation of smooth muscle cells + cystic degeneration
• Progressive respiratory failure or spontaneous pneumothorax

• Retinal phakomas (hamartomas) — in ~50%
• Pigmentary changes, nystagmus, angioid streaks, retinal achromic patch

• Bone cysts, sclerotic lesions in ~50%

• ≥5 dental enamel pits in permanent teeth — diagnostic marker

Diagnostic Criteria (2012 International TSC Consensus)

1. ≥3 hypomelanotic macules (≥5 mm)
2. ≥3 angiofibromas OR fibrous cephalic plaque
3. ≥2 periungual fibromas (Koenen tumours)
4. Shagreen patch
5. Retinal hamartoma
6. Cortical dysplasia (tubers)
7. Subependymal nodules
8. Subependymal giant cell astrocytoma (SEGA)
9. Cardiac rhabdomyoma
10. Lymphangioleiomyomatosis (LAM)
11. Renal angiomyolipoma (≥2)

1. Confetti-like macules
2. ≥3 dental enamel pits
3. ≥2 intraoral fibromas
4. Retinal achromic patch
5. Multiple renal cysts
6. Non-renal hamartomas

Investigations

Treatment

• Angiofibromas: topical rapamycin 0.1–1% — first-line non-invasive (lesions recur on stopping → maintenance needed)
• Shaving, dermabrasion, laser ablation (CO₂ or pulsed-dye laser) for cosmesis
• Koenen tumours: surgical excision

• Everolimus — FDA/EMA approved for:
  • Subependymal giant cell astrocytoma (SEGA)
  • Renal angiomyolipoma
  • Pulmonary LAM
  • Facial angiofibromas (oral and topical routes)
  • Epilepsy
• Sirolimus (rapamycin) — effective for multiple manifestations
• mTOR inhibitors are now first-line treatment for many TSC manifestations
• Avoid cranial irradiation for astrocytomas (risk of subsequent glioblastoma)

• Antiepileptic drugs (vigabatrin for infantile spasms — first-line)
• Everolimus for refractory epilepsy
• Neurosurgical resection for refractory focal epilepsy

• Angiomyolipoma >4 cm: prophylactic surgical removal; everolimus can reduce size
• Regular imaging to screen for RCC

• Regular skin, ophthalmologic, neurological, renal, cardiac, pulmonary follow-up
• Genetic counselling for family members

Prognosis

• Highly variable due to extreme phenotypic variability
• Main determinants: severity of neurological involvement (epilepsy, intellectual disability), renal disease, and pulmonary LAM
• Early mTOR inhibitor therapy has significantly improved outcomes

Exam Tips:

• For HS: Remember the follicular occlusion tetrad, Hurley staging (I/II/III), and that adalimumab is the only FDA-approved biologic. I&D is discouraged. SCC is the feared long-term complication.
• For TSC: The mnemonic HAMARTOMAS covers the key features. Remember Bourneville (first describer), TSC1 = hamartin, TSC2 = tuberin, mTOR pathway, and that mTOR inhibitors (everolimus/rapamycin) are now first-line treatment. Rhabdomyomas are the most specific early finding (cardiac, seen prenatally).