IMMUNE BULLOUS DERMATOSIS OF CHILDHOOD

CASE PRESENTATION

Johan Jams- a 7 years old Indian boy- was admitted to the pediatric inpatient ward on 03/03/12 for a 5 days history of vesiculobullous non itchy eruption, initially on the elbows that progressed to involve the upper and lower limbs, the axilla and groin, the eyelids and the lips.

Initially in a private clinic he was prescribed zithromax and topical bactroban.

Lesions were getting more extensive and parents revised the Dermatology clinic in Farwaniya Hospital. He was diagnosed as shingles??

CASE PRESENTATION

Later the parents revised the Infectious Disease Hospital and he was referred back to Farwaniya Hospital as Steven Jhonson Syndrome case.

Dermatologists requested a skin biopsy which revealed a linear pattern of deposition of IgA together with C3 at the BMZ consistent with the diagnosis of Chronic Bullous Disease Of Childhood (CBDC).

NORMAL SKIN, with labels

Vesicles and bullae are accumulations of fluid within or under the epidermis.

Subepidermal blisters Occur between the dermis and the epidermis. Their roofs are relatively thick and so they tend to be

tense and intact. They may contain blood.

Intra-epidermal blisters appear within the spinosum or granulosum cell

layer of the epidermis So have thin roofs and rupture easily Leave an oozing denuded surface.

Subcorneal blisters Form just beneath the stratum corneum at the

outermost edge of the epidermis Have even thinner roofs Tendency to break is more marked

BLISTERING DISORDERS IN INFANCY AND CHILDREN

Epidermolysis Bullosa Herpes Simplex and

Zoster Epidermolytic

Hyperkeratosis Incontinentia Pigmenti Mastocytosis Bullous Impetigo Staphylococcal

Scalded Skin Syndrome

Erythema Multiforme

Toxic Epidermal Necrolysis

Scabies Suction blisters Immunobullous

Disorders Pemphigus Bullous pemphigoid Dermatitis

herpetiformis Epidermolysis Bullosa

Acquisita Linear IgA dermatoses

AUTOIMMUNE BULLOUS DISORDERS

Pemphigus Bullous Pemphigoid (BP) Dermatitis Herpetiformis (DH) Epidermolysis Bullosa Acquisita (EBA) Linear IgA Dermatoses (Chronic Bullous Disease

Of Childhood –CBDC)

Clinically they may be indistinguishable in children

Immunobullous diseases in childhood are uncommon but should be considered if the

blistering condition has been persistent for longer than a month, particularly if unresponsive to antibiotic therapy.

Diagnosis is made by correlating the histologic

findings with the direct immunofluorescence (DIF).

Blisters may appear flaccid, tense or may present as erosions

IMMUNE - MEDIATED INTRAEPIDERMAL BULLOUS DISEASES PEMPHIGUS VARIANTS

IMMUNE - MEDIATED INTRAEPIDERMAL BULLOUS DISEASES PEMPHIGUS VARIANTS

PEMPHIGUS VULGARIS

Autoimmune blistering disease of the skin and

mucous membranes with intraepidermal blisters.

Very rare in childhood.

Painful fragile blisters occur in lower epidermis, just above the basal layer, anywhere on the body, arising on normal or erythematous skin.

Nikolsky sign is positive. o Mucous membrane lesions (particularly in the mouth) occur in 50-70% and may be the sole

sign for an average of 5 months before skin lesions develop.

Erosions may involve the pharynx or the larynx, causing hoarseness.

Neonatal PV occurs when maternal IgG crosses the placenta, and remits when maternal

antibodies decrease (~6–12 months).

OTHER PEMPHIGUS VARIANTSOTHER PEMPHIGUS VARIANTS

Pemphigus foliaceus Endemic pemphigus (Fogo selvagem [in

Brazil]) Paraneoplastic pemphigus (PNP) [Seen

with lymphoma & leukemia] Drug-induced pemphigus (caused by

penicillamine or captopril) Pemphigus erythematosus (Senear-Usher

syndrome [SUS]– Hybrid between PV & SLE)

Pemphigus foliaceus Endemic pemphigus (Fogo selvagem [in

Brazil]) Paraneoplastic pemphigus (PNP) [Seen

with lymphoma & leukemia] Drug-induced pemphigus (caused by

penicillamine or captopril) Pemphigus erythematosus (Senear-Usher

syndrome [SUS]– Hybrid between PV & SLE)

Pathogenesis

IgG autoantibodies are directed against desmosomes (cell adhesion proteins) in epidermis.

Acantholysis (loss of cell-to-cell adhesion) in areas of deposition of IgG.

Diagnosis

DIF is positive for IgG and C3 along keratinocyte surfaces.

Histology: Suprabasilar acantholysis in PV / NP and

Granular cell layer acantholysis in PF, and pemphigus erythematosus .

TREATMENT

Prednisone 1–2 mg/kg per day. Steroid-sparing agents: cyclophosphamide,

azathioprine, cyclosporine, methotrexate, or gold

High-potency topical steroids might be helpful for localized disease

Intravenous immunoglobulins (IVIG) may be a

promising therapy.

Prognosis Prognosis without treatment is poor. Infection

is often the cause of death.

IMMUNE-MEDIATED SUBEPIDERMAL BULLOUS DERMATOSES

IMMUNE-MEDIATED SUBEPIDERMAL BULLOUS DERMATOSES

Bullous PemphigoidEpidermolysis Bullosa

AcquisitaIgA Mediated Disorders

1.DERMATITIS HERPETIFORMIS2.LINEAR IgA DISEASE

Bullous PemphigoidEpidermolysis Bullosa

AcquisitaIgA Mediated Disorders

1.DERMATITIS HERPETIFORMIS2.LINEAR IgA DISEASE

BULLOUS PEMPHIGOID

Large, tense blisters arising on normal or erythematous skin.

Mucous membrane involvement in 10–35%. Sites of predilection: lower abdomen, inner

thighs, flexor forearms or generalized. Bullae may have clear or hemorrhagic fluid. Nikolsky sign is negative. Early lesions tend to look urticarial and are

quite pruritic. Very rare in childhood.

Pathogenesis

BP antigens are proteins in hemidesmosomes (cell-to-matrix adhesion proteins) in BMZ. IgG can activate complement, causing leukocyte adherence to the BM, and subsequently leading to dermal–epidermal separation.

Diagnosis DIF: linear pattern of IgG and C3 at BMZ. Indirect immunoflourescence: 70–80% of patients will have circulating IgG which binds to stratified squamous epithelium.

GENERALIZED DISCRETE AND CONFLUENT ANNULAR EDEMATOUS RED PLAQUES WITH CRUSTED PAPULES AND VESICLES AT THE PERIPHERY IN A 6-YEAR OLD GIRLSHE WAS TREATED FOR PRESUMED LINEAR IGA BULLOUS DISEASE OF CHILDHOOD WITH ORAL DAPSONE WITHOUT IMPROVEMENT. THE BIOPSY SHOWED A SUBEPIDERMAL VESICLE, AND DIRECT IMMUNOFLUORESCENCE REVEALED C3 AND IMMUNOGLOBULIN G ALONG THE BASEMENT MEMBRANE ZONE TYPICAL OF BULLOUS PEMPHIGOID.

Histology subepidermal blister without necrosis.

Treatment Prednisone 1–2 mg/kg per day. Steroid-sparing agents: cyclophosphamide,

azathioprine, cyclosporine, methotrexate, or gold

Localized BP can be treated with high-potency topical steroids

Prognosis BP may be self-limited and can last several

months to many years.

Very rare in childhood

Clinical features: monomorphic

Blisters: flaccid,ruptures easily

Content of blisters: fluid filled.

Oral lesion :are common

Nikolsky’s sign:Positive

Acantholytic cells are seen

Very rare in childhood

Polymorphic

Tense ,firm

Mostly hemmorhagic

o Less commono Negative

o No acantolytic cells.

pemphigus pemphigoid

EPIDERMOLYSIS BULLOSA ACQUISITA Epidemiology

Few isolated cases of children seen Pathophysiology

Autoimmune Subepidermal Blistering condition Signs

Trauma prone areas more commonly affected Tense Blisters and Erosions over extensor

surfaces Knuckles Dorsal hands Elbows Knees Ankles

Mucosal involvement Oral, nasal, and esophageal mucosa Conjunctival mucosa

THE FAMILY OF IGA-MEDIATED BULLOUS DERMATOSIS

THE FAMILY OF IGA-MEDIATED BULLOUS DERMATOSIS

Dermatititis herpetiformis

Linear IgA Disease(Bullous Disease of

Childhood)

Dermatititis herpetiformis

Linear IgA Disease(Bullous Disease of

Childhood)

DERMATITIS HERPETIFORMIS Most common immunobullous disease in

children

Characterized by intensely pruritic chronic papules and vesicles located symmetrically over extensor surfaces, scalp hairline and posterior nuchal area.

Primary lesions: erythematous papules,urticarial plaques or vesicles, but crusted lesions are frequently the only lesions seen. Large bullae infrequent.

Mucous membrane involvement uncommon.

Onset is usually in adolescence or later.

Most have GI abnormality similar to celiac disease (villous atrophy of the small intestine) but are asymptomatic.

Lesions can be exacerbated by gluten or oral iodides

Sometimes associated with GI lymphomas, or autoimmune disease (e.g.thyroid disease, diabetes, SLE, Sjögren syndrome, or vitiligo).

Pathogenesis

IgA deposits are complexes of immunoglobulins and GI-derived antigens which react with an unidentified skin antigen.

IgA activates complement, causing chemotaxis of neutrophils which release enzymes causing

blistering.

Diagnosis

o Histology: dermal papillary collections of neutrophils with subepidermal blisters within lamina lucida of BMZ.

o DIF shows granular IgA and C3 deposits.

o Circulating Antireticulin antibodies of IgA and IgG classes can be detected in the majority of patients.

o Circulating IgA autoantibodies to endomysium, tissue transglutaminase (tTG) and gliadin are

also detected.

Treatment

Dapsone 2mg/kg per day. Gluten-free diet may be effective.

Prognosis Lifelong disorder, persisting indefinitely with varying severity.

CHRONIC BULLOUS DISEASE OF CHILDHOOD (LINEAR IGA DERMATOSIS) Background Linear immunoglobulin A (IgA) dermatosis

(LAD) is an autoimmune subepidermal vesiculobullous disease that may be idiopathic or drug-induced. Children and adults are affected, with disease of the former historically referred to as chronic bullous dermatosis of childhood (CBDC). It is the second most common immunobullous disease in childhood.

The clinical presentation is heterogeneous and appears similar to other blistering diseases, such as bullous pemphigoid and dermatitis herpetiformis.

Pathophysiology

Caused by linear deposition of IgA to a 97-kDa

antigen in lamina lucida of BMZ.

Antibody deposition leads to complement activation and neutrophil chemotaxis, which eventuates in loss of adhesion at the dermal-epidermal junction and in blister formation.

Associations 1. Drugs: vancomycin, lithium, diclofenac 2. Lymphoid and nonlymphoid

malignancies

Diagnosis

Usually overlooked initially, because of its confusion with bullous impetigo.

Histology: Subepidermal bulla with neutrophils along

the BMZ, often in papillary tips.

DIF: IgA in a homogeneous linear pattern along

BMZ; occasional IgG and C3.

Three patterns of IgA deposition (found on electron microscopy): in lamina lucida

(similar to BP); at or below lamina densa (similar

to epidermolysis bullosa acquisita).

Low titer IgA serum autoantibodies can sometimes be detected.

Epidermal Basement Membrane Zone Antigens in Bullous Diseases

Mortality/Morbidity

The mean duration is 3.9 years, ranging from 2.1-7.9 years. Remission has been reported to occur in 64% of children, in most cases within 2 years.

The disease tends to wax and wane in severity. Drug-induced cases typically resolve quickly once the causative agent is withdrawn. Cutaneous lesions usually heal without scarring, while mucous membranes lesions heal with scarring.

Ocular linear IgA dermatosis may lead to blindness. Nose, pharynx, larynx, oesophagus and rectum can be involved.

Sex The female-to-male ratio is 1.6:1.

Age Disease in children commences at ages

ranging from 6 months to 10 years, with a mean of 3.3-4.5 years.

History Some patients note a prolonged period of

prodromal itching before lesions appear. Patients with ocular manifestations may

complain of pain, or discharge. Rash latency in vancomycin-induced cases of

linear IgA dermatosis ranges from 1-13 days after first dose .

Physical

The classic primary lesions of linear IgA dermatosis are clear and/or hemorrhagic vesicles or bullae on normal, erythematous, or urticarial skin.

Cutaneous manifestations may also include erythematous plaques, blanching macules and papules, or targetoid erythema multiforme–like lesions.

The diagnosis is not dependent on the presence of vesicles and/or bullae and a morbilliform variant has been described.

Bullae may be discrete or arranged in a herpetiform pattern, often described as the cluster of jewels sign. Alternatively, vesicles and bullae may be seen at the edge of annular lesions, the appearance of which has been described as the string of beads sign.

Lesions in children are typically localized to the lower abdomen and anogenital areas with frequent involvement of the perineum. Other sites of involvement include the feet, the hands, and the face, particularly the perioral area

Physical

Oral lesions include vesicles, ulcerations, erosions, desquamative gingivitis, or erosive cheilitis, and they may precede skin lesions.

children and adults frequently complain of ocular symptoms, such as burning, or discharge.

Ophthalmologic findings even in the absence of ocular complaints may include subconjunctival fibrosis , symblepharon formation, and cicatricial entropion .

Bullous lesions on the genital area in a child with linear IgA dermatosis

cluster of jewels

ANNULAR LESIONS DEMONSTRATING THE STRING OF BEADS SIGN.

Treatment

Dapsone 2mg/kg per day Prednisone 1–2 mg/kg per day Most cases respond to combination of

prednisone and dapsone Topical antibiotics and nonstick gauze

covering if lesions are oozing or crusted Other drugs: colchicine, sulfapyridine

Prognosis

Usually lasts several years and then remits. Occasionally, persists into puberty.

DIFFERENTIAL DIAGNOSIS

• Bullous impetigo • Pemphigus • Bullous pemphigoid • Epidermolysis bullosa • Erythema multiforme • Bullous systemic lupus

erythematosus

EPIDERMOLYSIS BULLOSA EB is a group of genetic diseases where mild

trauma induces blister formation, presenting usually in the neonatal period.

EB is divided into scarring (dystrophic) and nonscarring (simplex and junctional) types.

Non scarring types demonstrate an intra epidermal separation (EB simplex) or a separation at the dermal–epidermal junction (junctional EB).

Scarring types: subepidermal blisters are found in dystrophic EB.