📚 Question Bank

The extension of a blister to adjacent unblistered skin when pressure is applied over the top of the bulla is known as the Asboe-Hansen sign.

Option B: Nikolsky sign refers to easy peeling of skin on applying tangential pressure over a bony prominence. It is classically seen in pemphigus vulgaris, pemphigus foliaceus, and staphylococcal scalded skin syndrome.

Option C: Dimple sign refers to the dimpled appearance of a dermatofibroma on squeezing the adjacent skin.

Option D: The traditional bulla spread or Lutz sign involves applying lateral pressure to the blister, which causes the spread of the bulla.

The given image showing linear deposition of IgA at the dermo-epidermal junction is diagnostic for linear IgA disease or chronic bullous disorder of childhood or IgA pemphigoid.

It is the most common immunobullous disease in infants and children. It may occur lt;5 years or at 60-65 years of age. It occurs in genetically susceptible individuals and can be triggered by drugs like vancomycin, penicillin, and NSAIDs. The main target antigen is BP180 or BPAg2.

The classic triad of clinical features is:

• Tense blisters
• Vesicles
• Annular erythema

Onset is abrupt in children with involvement of the perioral and perianal regions. In adults, the extensor areas and trunk are affected. The blisters are arranged in an annular pattern. This is called the crown of jewels or string of pearls appearance, as shown below.

This clinical scenario with tense blisters showing subepidermal separation and neutrophilic infiltration at the basement membrane points towards a diagnosis of IgA pemphigoid or linear IgA disease or chronic bullous disease of childhood. The drug of choice is dapsone. It is bacteriostatic against M. leprae.

It also has an anti-inflammatory action by decreasing the action of neutrophil enzymes. Hence, it is useful in the treatment of IgA pemphigoid, linear IgA disease and chronic bullous disease of childhood.

Direct immunofluorescence microscopy is used in the diagnosis of epidermolysis bullosa acquisita. It is positive due to the presence of antibodies against type VII collagen.

Direct immunofluorescence microscopy is negative in blistering conditions with congenital protein defects:

• Epidermolysis bullosa simplex - K5/K14 defect
• Epidermolysis bullosa junctionale - Laminin defect
• Epidermolysis bullosa dystrophica - Collagen VII defect
• Hailey-Hailey disease - SERCA protein defect (ATP2C1 mutation)
• Darier's Disease- SERCA protein defect (ATP2A2 mutation)

Intraepidermal intercellular deposition of IgA on immunofluorescence is seen in IgA pemphigus.

It is characterized by IgA antibodies against desmosomal components. As in pemphigus vulgaris, the pattern of immunofluorescence is intraepidermal and intercellular.

Direct immunofluorescence staining in various immunobullous conditions is shown in the following table.

Disease

Pemphigus vulgaris Pemphigus foliaceus Bullous pemphigoid Pemphigoid gestationis

Deposit s

IgG and C3

IgG and C3

IgG and C3

IgG and C3

Location

Intraepidermal intercellular Intraepidermal intercellular Subepidermal (at DEJ) Subepidermal (at DEJ)

Pattern

Fish-net/ Reticular Fish-net/ Reticular Linear, n-serrated Linear

Disease Deposit

s

Location Pattern

Epidermolysis bullosa acquisi ta

Linear IgA disease IgA pemphigus

Dermatitis herpetiformis

IgG

IgA IgA IgA

Subepidermal (at DEJ)

Subepidermal (at DEJ) Intraepidermal intercellular Papillary tips

Linear, u-serrated

Linear

Fish-net/ Reticular Granular

Flaccid bullae on the skin and oral erosions suggest a diagnosis of mucocutaneous pemphigus vulgaris.

Oral erosions usually precede skin manifestations. The skin lesions are flaccid blisters with clear fluid on an erythematous base, that rupture to produce painful erosions. These are distributed over the face, scalp, upper chest, back, and neck.

Options B and D: Bullous pemphigoid and epidermolysis bullosa acquisita show subepidermal involvement with tense blisters.

Option C: Pemphigus foliaceus causes superficial blisters with no mucosal involvement.

In pemphigus vulgaris, autoantibodies are directed towards desmoglein 3. Desmoglein 1 and desmocollins can also be involved. Desmoglein 3 is present predominantly in the mucosal epithelium. Thus, antibodies against it lead to severe mucosal blistering. Desmoglein 3 is also involved in pemphigus vegetans.

Patients with pemphigus foliaceus, who have anti-desmoglein 1 antibodies alone, exhibit skin blistering without mucosal involvement.

Epidermolysis bullosa simplex is associated with congenital defects in K5/K14 antigens. Junctional epidermolysis bullosa is associated with congenital defects in laminin.

This clinical picture is suggestive of pemphigus vulgaris. The first-line investigation is Tzanck smear.

It allows us to visualize the histology by collecting material from the floor of a fresh blister that is stained with Giemsa or any Romanowsky stain. Tzanck cells are seen on microscopy.

Direct immunofluorescence microscopy (DIF) is the most accurate test.

Flaccid lesions, mucosal involvement, and the presence of acantholytic cells are suggestive of pemphigus vulgaris.

Option A: There is no mucosal involvement in pemphigus foliaceus.

Option C: Dermatitis herpetiformis presents with multiple small vesicles and no acantholysis. Option D: Bullous pemphigoid presents with tense bullae and no acantholysis.

The given image shows a characteristic fish-net appearance on direct immunofluorescence, which is diagnostic of pemphigus vulgaris.

This pattern is due to intraepidermal intercellular deposition of IgG and C3.

Direct or indirect immunofluorescence cannot be used to differentiate between pemphigus vulgaris and pemphigus foliaceus, as they present similarly.

Options A and C: Bullous pemphigoid, cicatricial pemphigoid, and epidermolysis bullosa acquisita present linear or shoreline pattern is seen in due to IgG and C3 deposits along the

dermo-epidermal junctions, as seen in the following image.

Option D: Dermatitis herpetiformis presents with focal granular deposits of IgA at papillary tips, as seen below.

Direct immunofluorescence test is the most accurate test to diagnose Pemphigus Vulgaris.

Direct Immunofluorescence uses anti-IgG antibodies which detects the anti-desmoglein IgG antibodies deposited on the Desmosomes. These desmosomes are present at cell junctions; this leads to the fishnet pattern.

The given image shows a row of tombstones appearance, which is classically seen in pemphigus vulgaris.

In this condition, there is suprabasal splitting of the epidermis leading to blister formation. The basal layer remains adherent to the basement membrane, and gives the resemblance to the row of the tombstones.

The given clinical scenario is suggestive of pemphigus foliaceus. The blisters are formed due to a split at the subcorneal layer.

Pemphigus foliaceus is a less severe variant of pemphigus vulgaris with antibodies against desmoglein-1. It presents with fewer flaccid bullae and mucosal sparing. It more commonly results in erosions with erythema, scales, and crust. Collarette scales may be present.

Sodium valproate and isoniazid do not cause drug-induced pemphigus. The commonly implicated drugs include:

• Penicillamine (most common)
• ACE inhibitors
• Antibiotics - penicillins, cephalosporins, rifampicin
• Piroxicam
• Glibenclamide
• Phenobarbital
• Aspirin

Drug-induced pemphigus usually occurs after 1 year of taking the drug. It is more common in individuals with other associated autoimmune conditions.

Note: Common drugs (mnemonic - PCR) are penicillamine, captopril, rifampicin.

Paraneoplastic pemphigus (PNP) is most commonly associated seen with non-Hodgkin's lymphoma.

PNP is a fatal autoimmune blistering disease associated with underlying benign or malignant neoplasms. It commonly presents 2-3 years after the development of malignancy, but can sometimes precede it as well. It is associated with multiple antigens including desmoglein, desmoplakin, periplakin.

Other associated diseases include:

• Chronic lymphocytic leukemia
• Waldenstrom's disease
• Castleman disease
• Spindle cell tumor
• Thymoma

This clinical scenario is suggestive of herpes gestationis or pemphigoid gestationis. The initial site of involvement is the periumbilical region.

It is a variant of bullous pemphigoid in pregnancy and is associated with antibodies against BP180. It presents in the II or III trimesters with pruritic, grouped vesicles that later spread to the abdomen, trunk, thighs. It flares in the intrapartum period and tends to resolves spontaneously in the postpartum period. However, it can recur in subsequent pregnancies.

This clinical scenario and image showing linear IgG deposits in a u-serrated pattern on direct immunofluorescence microscopy are suggestive of epidermolysis bullosa acquisita (EBA), in which autoantibodies are formed against collagen VII.

It is an acquired autoimmune disorder, presenting in adults between 44-54 years. It has a chronic, relapsing course. Two main clinical forms can be differentiated:

• Classical mechanobullous - Skin fragility, erosions, blisters, crusts, and scars on traumaprone areas like hands, knuckles, elbows, knees, toes.
• Inflammatory - Resembles other pemphigoid diseases such as bullous pemphigoid. Associated with inflammatory infiltrate in the dermis.

The following image shows erosions and crusting in a patient with EBA.

This clinical scenario and the image showing superficial blisters are suggestive of epidermolysis bullosa simplex, which is an autosomal dominant condition associated with a defect in K5/K14

proteins.

Epidermolysis bullosa congenita is a group of congenital mechanobullous disorders that arise after trauma and are common over the hands, feet, elbows, and knees. There are three forms of this condition.

Type

Epidermolysis bullosa simple x

Junctional epidermolysis bull osa

Epidermolysis bullosa dystro phica

Defective protein K5/K14

Laminin

Collagen VII in anchoring fib rils

Features

Intraepidermalblister with sp lit in basal layerHeals withou t scarring

Dermoepidermaljunction blis ter with split in lamina lucida layerPerioral involvement is frequentMay heal with scarri ng

Subepidermaltense blisters w ith defect in sublamina densa Frequent mucosal involveme ntHeal with scarring

This clinical scenario along with the given image showing pruritic, multiple, grouped papules and vesicles located on extensor aspects is suggestive of dermatitis herpetiformis.

It is associated with gluten-sensitive enteropathy or celiac disease. It is also associated with HLA DQ2/DQ8/B8. Deposition of IgA antitransglutaminase antibodies in the dermal papillae results in subepidermal blisters and vesicles.

This condition is associated with a small increase in the risk of T-cell lymphoma.

The given image showing itchy, grouped vesicles in a patient with celiac disease is suggestive of dermatitis herpetiformis. The drug of choice is dapsone.

The initial treatment of choice for dermatitis herpetiformis is a gluten-free diet.

Dapsone is used when response to dietary modification is inadequate or slow. It is highly effective in such cases and improves symptoms within one week of starting the drug.

Note: Gluten-containing grains such as barley, rye, oats, wheat (BROW) should be avoided in the diet. Rice and maize are tolerated.

Granular deposits of IgA on direct immunofluorescence are suggestive of dermatitis herpetiformis or Duhring's disease. The characteristic microscopic feature is subepidermal blisters

with papillary tip microabscesses containing neutrophils.

It presents as grouped vesicles and papules. These lesions are commonly located over the extensor aspects of knees, elbows, buttocks, back, scalp which are associated with intense pruritus.

Nikolsky's sign is positive in the following conditions:

• Pemphigus vulgaris
• Pemphigus foliaceus
• Staphylococcal scalded skin syndrome

Nikolsky's sign refers to the separation of the normallooking epidermis from the dermis by applying firm tangential sliding pressure, thereby producing an erosion. It is seen in conditions that produce intraepidermal blisters. Hence it is negative in subepidermal bullous conditions like bullous pemphigoid and epidermolysis bullosa acquisita.

Pseudo-Nikolsky's sign refers to epidermal separation as a result of epidermal necrosis, not acantholysis.

It is seen in

• Toxic epidermal necrolysis
• Steven-Johnson syndrome

The given image showing greasy hyperkeratotic papules and the nail changes described point to a diagnosis of Darier’s disease. It occurs due to a mutation of the ATP2A2 gene.

Darier's disease is an autosomal dominant condition that occurs due to dysfunction of

the SERCA2 calcium channel (encoded by ATP2A2 gene), which is essential for desmosomal function. It results in acantholysis and dyskeratosis.

The papules begin over sun-exposed areas and gradually expand to form plaques over the seborrheic areas. The following nail changes, also shown in the image below, are characteristic of Darier's disease:

• Longitudinal erythronychia
• Longitudinal leukonychia
• Distal v-shaped nicks

Note: Hailey-Hailey disease is due to a mutation in ATP2C1 gene, which also encodes the SERCA protein.

Corps ronds are seen in keratosis follicularis or Darier's disease.

It is an autosomal dominant condition that is characterized by keratotic papules over the seborrheic areas. The following histopathology findings are seen:

• Acantholysis - loss of cohesion between keratinocytes
• Dyskeratosis - abnormal premature keratinization in the epidermis
• Lacunae - in suprabasal area
• Corps ronds - rounded dyskeratotic cells with eosinophilic cytoplasm in the epidermis
• Corps grains - small cells with shrunken cytoplasm

Dilapidated brick wall appearance is characteristically seen in Hailey-Hailey disease.

It is an autosomal dominant disorder occurring due to a mutation in the ATP2C1 gene encoding the SERCA calcium channel ATPase. It causes blistering, particularly in the intertriginous areas.

On histology, there is a widespread loss of cohesion between suprabasal keratinocytes leading

to acantholysis, which is incomplete. Hence, separated keratinocytes are still partially connected to each other giving the appearance of a dilapidated or broken brick wall, as shown in the following image.