Bullous Dermatoses in Childhood: Part II - SKINmed. 2007;6:128-134

From the Sector of Dermatology, Santa Casa de Misericordia de Porto Alegre, Universidade Federal do Rio Grande do Sul; Hospital Escola Materno-Infantil Presidente Vargas, Porto Alegre, Brazil; Universidade Luterana do Brasil de Canoas, Canoas, Brazil; and Sector of Dermatology and Post-Graduation Course, School of Medicine and HUCFF-UFRJ, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

In part I of this review, 1 a new classification of bullous dermatoses in childhood was described, namely those with nonhereditary characteristics and intraepidermal cleavage. In this second part, the remaining groups, nonhereditary with subepidermal cleavage and hereditary with intraepidermal and subepidermal cleavage, are presented.

Nonhereditary Bullous Dermatoses With Subepidermal Cleavage

1. Herpetiform Dermatitis of the Childhood or Duhring Disease

This cutaneous-intestinal syndrome with papulovesicular eruption of marked location promotes intense itching and burning. Its course has a long and favorable response to sulfone and a gluten-free diet. 2, 3 Clinical, histologic, and immunologic findings are identical in the juvenile and adult forms of herpetiform dermatitis, except for a female propensity in childhood. 4, 5 The skin is erythematous and edematous, with papulovesicles, crusts, and sometimes bullae. The lesions have a herpetiform distribution and are usually symmetric. 4 Intense itching and burning are present, and residual hyperpigmentation may remain ( Figure 1 ). 2 The biopsy results show neutrophil accumulation and few eosinophils with formation of papillar microabscesses. More advanced lesions demonstrate subepidermal bulla. 6 Immunofluorescence is very important for the diagnosis because the results are positive in almost all cases. 7 Biopsy location is also important, and noninvolved skin should be examined. 6 In direct immunofluorescence, deposits of granular IgA are observed in papillar dermis, and some cases show C3, IgM, and IgG deposits. 5, 6 Two types of antibodies are known in herpetiform dermatitis associated with the enteropathy: (1) IgA class antireticulin antibody, which is present in 59% of the cases of herpetiform dermatitis and in almost all of the cases of celiac disease in childhood and (2) antigliadin antibody, especially of the IgG class, which is found in other skin and intestinal diseases. 2, 8

Figure1. Herpetiform dermatitis.

A new antibody of the IgA class against the endomyosin of the flat muscle of the gastrointestinal tract (IgA-EmA) seems to be a sensitive (80%) and specific (100%) marker of the gluten-sensitive enteropathy in herpetiform dermatitis and celiac disease. 7 The skin lesions are clearly linked to gluten-sensitive enteropathy. 5 Sulfone or sulphapyridine should be given; adverse reactions are not frequent with those drugs. A gluten-free diet is recommended. 2, 4, 6

2. Bullous Pemphigoid

Bullous pemphigoid is an autoimmune disease that is rare in children. The bullae are usually large and tense and located in groups on an erythematous base or urticated plaques; they prevail in the flexures of arms and legs, axilla, groins, and lower abdominal area. 4, 9, 10 Mucous lesions occur more commonly in the bullous pemphigoid of childhood, with involvement of the hands and feet more frequent in children younger than 1 year. 9

Biopsy specimens should be obtained from recent bullae and include nonaffected skin. The bulla is subepidermic, having as a floor the dermal papillae and as a roof the epidermis. Infiltrate is composed of neutrophils and eosinophils. 11

Direct immunofluorescence reveals linear deposit of IgG and complement, and with other immunoglobulins (IgA, IgM, and IgE), both in the skin without lesion as in area close to the erythematous lesion. In indirect immunofluorescence, the level of antibodies does not usually reflect the dynamics of the disease. 11

As in adults, the use of corticoids are part of the treatment. Dapsone is reported in a few cases and in combination with prednisone. 9

3. Linear IgA Bullous Dermatosis and Chronic Bullous Dermatosis of Childhood

Linear IgA bullous dermatosis refers to those bullous diseases that do not fulfill the criteria for herpetiform dermatitis or bullous pemphigoid and that present a linear IgA deposit in the basal membrane. 2 Chronic bullous dermatosis of childhood often begins in preschoolers between 4 and 5 years, and the bulla is predominantly monomorphic and tense, with clear or hemorrhagic fluid in an annular or arciform configuration on normal or erythematous skin. 12 Erythematourticated plaques with polycyclic borders are common. Mucous membranes are affected in 60% to 80% of the cases, and itching is inconstant. 4, 12–14 Lesions are similar to those of bullous pemphigoid. The course is chronic, with spontaneous remission and periods of exacerbation, 2, 4 and the disease varies in duration from 3 to 6 years, with possible recurrence. 15 Subepidermic bullae with neutrophilic inflammatory infiltrate in superficial dermis (papillary microabscesses) are the histologic characteristic of the 2 diseases. Mononuclear cells and eosinophils can be present. 12 Biopsy findings of several parts of the body show a histology similar to both herpetiform dermatitis and bullous pemphigoid, which are indistinguishable without immunofluorescence. 2, 12, 14 Direct immunofluorescence demonstrates deposits of linear IgA in the area of the basal membrane in noninvolved skin around the lesions and in the bullae, as well as C3 and IgM in some patients. 2, 14 With indirect immunofluorescence, there are circulating IgA antibodies in more than 80% of children and in only 30% of adults. 12, 14 There are reports of linear IgA bullous dermatosis induced by drugs, mainly endovenous vancomycin. 12 The treatment can begin with sulfone or sulphapyridine. In case it is ineffective, prednisone can be added. 16 The use of colchicine was described as an alternate therapy to dapsone. 16, 17

“Much confusion exists because of similarity of clinical lesions and varied nomenclature of these diseases.”

4. Gestational Herpes of the Newborn

The lesions do not require an exact diagnosis because they are transient, and the condition of the newborn is good. 2, 15 Herpes gestation is associated with pregnancy, puerperium, and hormonal alterations. It occurs especially in second pregnancies, occasionally persists after childbirth, and is often recurrent in subsequent gestations. 18, 19 Vesicles, bullae, erythema, and edema appear on the mother’s skin, suggesting multiform erythema. The itching is variable and sometimes intense. Tense and big bullae located on the skin of normal aspect and large confluent erythematous and edematous lesions on the abdomen are characteristic. 15 In the newborn, the clinical picture is similar to that of the mother, occurring in 5% to 10% of the cases. 11 The course is mild, and regression is spontaneous after a few weeks or months. In the histopathologic examination, the subepidermic bullae, both of the mother and of the newborn, can contain eosinophils. There is pronounced edema of dermal papillae, and dermal perivascular infiltrate is light. 4, 11

Direct immunofluorescence shows linear deposit of C3 in the area of the basal membrane in the edematous, erythematous lesion or on the skin around the mother’s and the newborn’s bullae. Linear IgG deposits can occur in 25% of the cases. Indirect immunofluorescence reveals the so-called gestational herpes factor. 18, 19

The etiopathogeny is unknown. 11, 19 For the newborn, topical treatment to prevent secondary infection in case of blisters may be worthwhile. 2, 11

5. Urticaria Pigmentosa

Urticaria pigmentosa is the most frequently observed form of mastocytosis. In 70% of cases, it disappears at the age of 10. It begins in the first years of life, with small, numerous, and widespread yellowish brown stains ( Figure 2 ). Darier’s sign is positive, and vesicles and bullae can appear on lesions. 20 The diffuse form of cutaneous mastocytosis is almost exclusive to children and can persist into adult life. The appearance of diffuse bullae in the neonatal period can be the first indication of diffuse mastocytosis. 21

Figure2. Urticaria pigmentosa. Photo courtesy of Tania Cestari.

6. Adverse Reactions to Drugs

6.1 Erythema Multiforme

Erythema multiforme is uncommon and characterized clinically by erythematous papules at the beginning that develop into ring lesions with a crust or central bullae. They are often located on the upper extremities. Oral lesions can occur in half of the cases. Treatment is symptomatic, and the lesions tend to regress in 2 weeks. 22

Stevens-Johnson syndrome is more common than erythema multiforme in children. The infections caused by Mycoplasma are the main predisposing factor. It begins with infection prodromes of the upper respiratory tract and abrupt appearance of bullous inflammatory lesions, with prevalence in the oral mucous membrane, lips, and conjunctiva. Treatment requires hospitalization and involves care similar to that required for a major burn. Although the use of oral steroids is controversial, it can be beneficial, and antibiotics are indicated in cases of infection caused by Mycoplasma pneumoniae. 22, 23

6.2 Toxic Epidermal Necrolysis

In children, toxic epidermal necrolysis is characterized by the presence of bullous erythematous areas that evolve to necrosis and loss of epidermis. The Nikolsky sign is positive and the histopathology displays intense necrosis of the epidermis with subepidermic detachment. The inflammatory infiltrate is composed by cytotoxic T lymphocytes. The mortality rate associated with toxic epidermal necrolysis is high. 24

6.3 Fixed Drug Eruption

The most common agents associated with adverse reactions in children are antibiotics reflecting the fact that they are the most common category of drugs prescribed for this age group. Stevens-Johnson syndrome is associated with drug exposure in 15% to 65% of pediatric cases. Drugs most commonly associated with adverse reactions include anticonvulsants, antibiotics, and nonsteroidal anti-inflammatory agents (Table). 25

Table.Vesicobullous Adverse Reactions to Drugs

7. Dermatoses Caused by Photosensitivity

7.1 Phytophotodermatitis

This eruption occurs approximately 1 day after contact with plants and/or vegetation and fruits and after exposure to sunlight. It begins with erythematous macules of uncommon shapes that can progress into hyperpigmented lesions and sometimes formation of bullae. Phytophotodermatitis is self-limited. 26

7.2 Hydroa Aestivale

The primary lesion associated with hydroa aestivale is a papulovesicle in areas exposed to sunlight. Lesions vary from 1 mm to 1 cm and are tense and pruriginous with clear content. They last for a few days and have a brownish black crust; they do not leave scars. The condition generally affects girls in the first decade of life. Treatment is unsatisfactory. 4

7.3 Hydroa Vacciniforme

Hydroa vacciniforme is a rare disease that mainly affects boys. The primary lesion is a pustular vesicle with a similar location to that of hydroa aestivale; when it disappears it may leave a varioliform scar. The course is characterized by periods of multiple recurrences, and regression begins spontaneously at 30 years. Treatment is also unsatisfactory. 4

8. Bullae Caused by Suction

Bullae caused by suction occur during pregnancy as a result of vigorous suction of the fetus. They begin inside the uterus, are flaccid, and range in diameter from 0.5 cm to 2 cm. Bullae are located on the radial surface of the forearms, fists, and hands, especially on thumbs and the index fingers. They are unilateral or bilateral and symmetric. Resolution is spontaneous. 27

Hereditary With Intraepidermal Cleavage

1. Benign Familial Pemphigus, or Hailey-Hailey Disease

Hailey-Hailey disease is a dominant autosomal genodermatosis with variable penetrance that begins at the end of adolescence or the beginning of adult life; it is rare in the first decade of life. 11 The content quickly becomes unclear, and the vesicle breaks up and leaves an eroded area covered with crusts. The lesion tends to a central cure. 4, 28

In the histopathology, there are acantholytic grooves and bullae above the basal layer. The basal cells partially detach, leaving an aspect of a tumbling wall of bricks. Immunofluorescence is negative. 28

The course of the condition is chronic, with periods of exacerbation and remission, 15 and there is no effective treatment to correct the basic defect. Topical and systemic antibiotics, such as tetracycline, and topical and systemic steroids can be used with some result. 28

2. Incontinentia Pigmenti

Also called Bloch-Sulzberger syndrome, incontinentia pigmenti is more common in women and is often fatal in most affected men. It begins with cutaneous lesions present at birth or in the first 2 weeks of life. It has 4 evolutionary stages: (1) vesicobullous, (2) verrucous, (3) pigmentary, and (4) atrophic. The vesicles are tense, appear on top of the erythematous skin (distributed lineally), and can coalesce. They present on the trunk in lateral aspects and in areas around the breasts and extremities in approximately 64% of cases. In histopathology, there is an intraepidermal vesicle, with accumulation of eosinophils, and perivascular infiltrate also rich in eosinophils. 29

3. Epidermolysis Bullosa

Epidermolysis bullosa encompasses a group of genetic diseases of unknown etiology, characterized by the formation of spontaneous or traumatic bullae. 4, 15, 30 It can be subdivided into 3 major groups that are more clearly defined by electronic microscopy and immunohistochemical studies. 30, 31 The severity of the disease depends much more on the depth of the cutaneous cleavage than on the extension and number of lesions. A precise diagnosis is important to determine the correct genetic counseling. 32

3.1 Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most frequent form of epidermolysis bullosa and usually begins in childhood, with good prognosis. It presents with several clinical forms:

Hereditary Bullous Dermatoses With Subepidermic Cleavage

1. Junctional Epidermolysis Bullosa (Atrophic)

This is a recessive autosomal disease that is often fatal. The bullae are present at birth on skin and mucous membranes. Nails are often absent or there is paronychia. Presence of a hoarse cry or aphonia is indicative of pharyngeal lesion. The bulla is located in the basal cells of the plasmatic membrane and basal membrane (lucid lamina). It encompasses clinical forms that range from fatal, as in the Herlitz variant, to benign, as in the atrophic generalized form. 31, 32

2. Dystrophic Epidermolysis Bullosa

Dystrophic epidermolysis bullosa is the cicatricial form that affects both sexes. It has a lifetime disease course, with 2 forms:

3. Erythropoietic or Congenital Porphyria

This condition is rare and has a recessive autosomal inheritance. It appears in patients with a family history and affects children, who rarely reach adult age. The disease acts by decrease of the uroporphyrinogen III-cosynthase. Patients present with bullae; ulcerations; scars in areas exposed to sun-light; mutilating deformities of the hands, ears, face, and nose; cicatricial alopecia; hemolytic anemia; splenomegaly; and red teeth and urine observed by Wood’s lamp. The diagnosis can be made by clinical or laboratory examination, based on an increase in uroporphyrins and coproporphyrins I in urine and coproporphyrins I in feces. The his-topathologic examination shows subepidermic cleavage with thickening of the collagen strips and discreet inflammatory infiltrate. In such cases, prophylaxis, photo protection, and beta carotene (from 120 to 180 mg/d) are possible measures. 13, 35

4. Erythropoietic Protoporphyria

Erythropoietic protoporphyria is a dominant autosomal disease. It is rare, familial, and produced by the deficiency of the enzyme ferrochelatase in the erythrocytes and fibroblasts of the skin. Patients present with photosensitivity, rare bullae, and scars. The clinical picture; increase in protoporphyrins in feces, red blood cells, and plasma; normality of porphyrins in urine (protoporphyrins are not soluble in water); and the fluorescence test of erythrocyte saline suspension confirm the diagnosis. Subepidermic vesicles and accumulation of amorphous homogeneous eosinophilic material around the vessels of the papillar dermis (positive result of periodic acid-Schiff test) can be observed in the histopathology. 13, 35

5. Epidermolysis Bullosa Acquisita

Clinical features in epidermolysis bullosa acquisita are heterogeneous; classical epidermolysis bullosa acquisita resembles the inherited forms of dystrophic epidermolysis bullosa, with major skin fragility and a distribution of lesions over trauma-exposed sites. 36 Epidermolysis bullosa acquisita patients show clinical features resembling bullous pemphigoid, including widespread blisters often on an inflammatory base. 37, 38 The usual laboratory tests for primary blistering disorders, such as direct and indirect immunofluorescence, immunoelectron microscopy, and others, are necessary to confirm diagnosis. 39 Treatment is difficult; the classic form is the most resistant. The other forms may better respond to the usual immunosuppressive/anti-inflammatory regimens. 39

Conclusions

This new classification associating bullous dermatoses in childhood to the presence or absence of hereditary factors and histologic location of the bulla or vesicle and emphasizing the use of other supplementary examinations, such as electronic microscopy and direct and indirect immunofluorescence, aims to explain the great number of dermatologic diseases that belong to that group of pathologies, their variants, and differential diagnoses. An appropriate classification for their understanding, as proposed in this work, can provide clear guidance and help in the diagnosis and prognosis of that group of dermatologic diseases.

References