Bullous Dermatoses in Childhood: Part I - SKINmed. 2007;6:73–78

Célia Kalil, MD; Zatti Fachinello, MD; Stela Cignachi, MD; Marcia Ramos-e-Silva, MD, PhD

A classification of bullous dermatoses in childhood is presented, according to the histologic location of the bulla and the heritability of the disease, combined with the most recent laboratory examinations used in dermatologic practice. For a better understanding of the proposed classification, the authors also present a review of this group of diseases, which vary greatly within the group. In this first part of the classification and review, the group of bullous dermatoses with nonhereditary characteristics and intraepidermal cleavage is described.

Establishing a classification system for any condition presents challenges; however, dermatologists need guidelines to evaluate skin diseases correctly, to judge their severity, and to choose appropriate medication. Due to the difficulties in identifying bullous dermatoses in childhood, we propose herein a classification that considers the histologic findings and the origin and heritability of these diseases, taking into account the findings of laboratory examinations, in an attempt to facilitate the study and understanding of these conditions.

Bullous dermatoses in childhood can be classified as diseases of hereditary or nonhereditary origin, and each of these classes, in turn, can be divided according to the epidermal level of the formation of the bulla or vesicle, that is, whether the lesion is intraepidermal or subepidermal. Thus, there are 4 main categories. Raised circumscribed lesions with diameters up to 5 mm and containing serous, hemorrhagic, or purulent fluid are termed vesicles, and the same type of lesions but with diameters larger than 5 mm are termed bullae. 1 The proposed classification ( Table ) is based on the heritability and on the location of the cleavage for the formation of the bulla. Each type is described below, with reference to its placement in this classification.

Table. Classification of Bullous Dermatoses in Childhood

Nonhereditary Bullous Dermatoses With Intraepidermal Cleavage

Contact Eczema

Contact eczema is characterized clinically by the presence of pruriginous papules or erythematous plaques at the location of the contact areas. Lesions may be covered by numerous tense and small vesicles. Allergic contact dermatitis constitutes at least 20% of all childhood dermatitis diseases and, in 77% of cases, it is associated with atopy. 2, 3

Diagnosis is made by patch test. 2, 4 There are multitudinous factors, in addition to the sensitizing agent, that modify the development of allergic contact dermatitis, among which are age, sex, contact with irritants, and atopic constitution. 5, 6 Thus, contact eczema should be further divided into allergic and irritant contact dermatitis. In allergic contact dermatitis histopathology, there is perivascular dermatitis in the dermis and spongiosis in the epidermis; in the lesion caused by the primary irritant, there is necrosis of the epidermis and infiltration with polymorphonuclear leukocytes. 7 The allergens that most frequently produce positive patch tests are nickel sulfate, cobalt chloride, potassium dichromate, a fragrance mix, thiomersal, mercury, neomycin sulfate, and para-tertiary butyl phenol formaldehyde resin. 5, 6

Dermatophytosis

Dermatophytoses are more frequent in adults than in children, and tinea capitis is the most common form of mycotic infection. 8 Clinically, in dermatophytosis, small vesicles and pustules appear on the erythematous and desquamative papules. The location is asymmetrical, and the vesicular lesions are more common on the palms and soles. The direct mycologic examination of the scale or the roof of the vesicle establishes the diagnosis, confirmed by direct mycologic examination with culture. 7

Scabies

In childhood, scabies can cause small vesicles on top of an erythematous base ( Figure 1 ) with the characteristic location in folds. The lesions are pruriginous and symmetrical. In small children scabies may affect only the palms and soles. 7

“The proposed classification is based on heredity and location of the cleavage for bulla formation.”

Figure 1. Scabies. Courtesy of Tania Cestari.

Prurigo Strophulus

The vesicles are on top of an erythematous base and become hemorrhagic. They are located mainly in exposed areas. Histopathology is unspecific; there is intercellular and intracellular edema and occasionally spongiotic vesicles with infiltrated perivascular inflammation in the beginning with neutrophils. 7

Viral Infections

Viral infections are characterized by vesicles with a depression or central umbilication and by presence of the Tzanck cells. The bullous lesions may be caused by DNA or RNA viruses.

DNA Virus

Human Herpes Virus and Varicella-Zoster Virus

Herpes simplex virus vesicles are grouped in bunches on an erythematous base. The primary infection with herpes simplex virus type 1 in children is usually asymptomatic; however, in 25% to 30% of the cases, it manifests as herpetic gingivostomatitis. 9, 10

Studies of recurrent herpes simplex labialis have shown that treatment with topical or oral acyclovir is largely ineffective. 10 Prophylactic oral acyclovir, on the other hand, reduced the frequency of outbreaks by 50% to 78% when used in doses from 400 to 1000 mg/d. 11 The virus enters the nerve endings underlying the primary infection and travels to the dorsal root ganglia, where it remains dormant. Reactivation prompts the virus to travel back down the efferent nerve to any of its branches, causing recurrences in the same nerve distribution, but sometimes at different sites from the primary infection. 10

Varicella presents as umbilicated vesicles and papules in several evolutionary stages, in other words, it is polymorphic ( Figure 2 ). Eruption begins on the trunk, face, and scalp and extends centripetally. Encephalitis and pneumonia can occur in immunodepressed patients. 7 Varicella is a highly contagious disease attacking over 90% of children before the age of 10 years. 10

In herpes zoster, the vesicles appear 1 or 2 days after the beginning of symptoms. They are small, tense, filled with a clear fluid, and may be located on an erythematous base. In some cases they can form great bullae. The dermatomal distribution of the lesion is characteristic. 7 Half of the cases affect thoracic dermatomes. It is rarely seen in children, in whom the presence of prodromes is uncommon. 10

Figure2. Varicella.

Poxvirus

Vaccinia begins with an umbilicated vesicle that soon turns into a pustule with erythema and hardening around the location ( Figure 3 ). The erythema reaches its climax in 10 days. In 21 days the crust comes off, leaving a characteristic punctiform scar. 12

Variola begins with fever, indisposition, and headache. Exanthema appears in a period that varies from 2 to 4 days and develops in a sequence of macules, papules, vesicles, pustules, and finally crusts. All lesions are always in the same evolutionary stage. Variola was eradicated in 1980 by mass vaccination. 12

Cowpox is characterized by papules or papules that quickly change into vesicles and progress into umbilicated pustules, which can become hemorrhagic and even ulcerating. 9

Monkey pox occasionally infects humans and is similar to variola, but of less intensity. 12

In orf virus infection, the lesions vary from 1 to 4 papules in the hands, progressing in 6 recognized evolutionary stages: maculopapular, circular, nodular, regenerative, papillomatous, and regressive. Vesicle nodules are painful, firm, slightly tense, reddish violet, and can measure between 1 and 2 cm in diameter. 7

Milker nodules or virus of bovine papular stomatitis, when affecting humans, is clinically identical to orf. 12

Figure3. Vaccinia.

RNA Virus

Herpangina is caused by the coxsackie A (1–6, 8, 10, 16, 22) virus. The vesicles are characterized by their large number (>20), diameter (1 to 2 mm and with red halo) and location (soft palate, uvula, tonsils, anterior and posterior pillars, and posterior wall of the pharynx). They break up quickly and leave shallow ulcers covered with a gray-white exudate. Healing occurs after a week. 7

Hand-foot-mouth disease is caused by the coxsackie A 16 virus, presenting as nonumbilicated vesicles, painful, small, pearled, varying in numbers from 5 to 50, and located on the palms and soles and in the mouth, each one with a red halo, oval rather than round. 7

Exanthema by echovirus rarely produces vesicles. 7

Vesicular stomatitis is caused by a rhabdo-virus. The vesicles are located in the buccal mucous membrane, in the gums and pharynx posterior wall, appearing after prodromes of fever, myalgia, and nauseas. 7

Miliaria

This is the common cause of widespread vesicles in children and babies and the lesions usually appear in the first week of life. 13 A recent study of pustular eruptions in neonates reports that miliaria pustulosa is the most commonly seen noninfectious disease, 14 while others reported it to be rare in neonates. 15 Favorable factors for it are heat, humidity, hyperthermia and occlusive therapies. 7 Miliaria can be classified in four clinical groups according to the level of occlusion of the eccrine duct 16 : crystallina (sudamina), rubra (prickly heat), pustulosa (a variant of miliaria rubra), and profunda. Miliaria crystallina is the most superficial, with clear, asymptomatic, small vesicles located on the trunk. Miliaria rubra forms monomorphic papulovesicles with more burning than itching. 17 In miliaria rubra and miliaria pustulosa the intraepidermal duct obstruction is intermediate, with extravasation of sweat into the lower epidermis, while in miliaria profunda the obstruction occurs at the dermoepidermal junction. 16

Bullous Impetigo

A large superficial bulla of clear content is seen in the initial stage of the disease and, usually, there is no erythema around it. The bulla lasts 2 to 3 days and ruptures, forming typical circinate lesions with desquamation and central erythema. It is caused mainly by the coagulase-positive Staphylococcus aureus. 18 Contagious impetigo is caused by Streptococcus or Staphylococcus species, or both, beginning with a small erythematous macule that quickly develops into a pustule that bursts, leaving crusts with a characteristic honeycomb color. 19

Staphylococcal Scalded Skin Syndrome

Staphylococcal scalded skin syndrome occurs in children and newborns, being rare in adults. It is caused by Staphylococcus aureus (group II, phagotype 71). It is characterized by the presence of flaccid bullae involving large skin areas, usually around the mouth, in the genitalia, axilla, groin area, and neck. The lesions burst easily, leaving a moistened erythematous base of scalded appearance. The disease is caused by toxins and in involved skin gives a positive Nikolsky sign. 18 Histopathologically there is cleavage in the upper Malpighian and in the granular layer without inflammatory infiltrate. Treatment is with systemic and topical antibiotics. The use of systemic steroids remains controversial. 7, 18, 20

Pemphigus

Pemphigus is rare in children. The 2 most common clinical forms are pemphigus vulgaris and pemphigus foliaceous. 21 Acantholysis is the characteristic etiopathogeny. 22 Treatment is with steroids, while salts of gold may be used in cases of serious corticoid side effects. Some authors believe that the use of immunosuppressors is not indicated in children, 22, 23 but others have shown safety in individual treatment 21, 24 with a mortality rate below 10% with adjuvant therapy with immunosuppressive drugs. 25, 26 The risks and benefits of all drugs used for treatment must be considered, and long-term follow-up is needed. 21

Pemphigus Vulgaris

This is the most common form of pemphigus (70% of cases) and is relatively rare in children. 27, 28 The main antigens are desmoglein 3 (130 kd) and desmoglein 1 (160 kd). 27, 29 In 80% of cases reported in children, the disease begins with erosions in the mucous membrane, and cutaneous lesions appear only later. 28 It presents with flaccid bullae located in normal-appearing skin, or on an erythematous plaque. The bulla frequently is not noticed because its roof bursts easily by trauma, resulting in large erosions. 7 The Nikolsky sign is positive. 29 Histopathologically, intraepidermal suprabasal bullae, acantholysis, and perivascular inflammatory infiltrate are observed. 23, 29 Direct immunofluorescence demonstrates IgG and C3 intercellular deposit in the epidermis, and the indirect immunofluorescence shows circulating IgG antibodies. 23,28,29 Probably the cases of neonatal pemphigus vulgaris are the result of transplacental transmission of maternal antibodies. The relation of the amount of maternal antibodies to fetal mortality is unknown. 30

Pemphigus Foliaceous

This is a mild form of pemphigus in which autoantibodies against desmoglein 1 induce the formation of superficial bullae. 23 It is characterized by flaccid bullae on an erythematous base and desquamation and crusts on the scalp. It does not affect mucous membranes and it may become erythrodermic. The Nikolsky sign is positive. 22, 23 It affects boys and girls equally. 29 Pemphigus foliaceous responds well to treatment, and spontaneous remission may occur. 7, 22 Some authors suggest initial treatment with topical steroids. 31 Histopathologic examination reveals a subcorneal bulla with acantholytic cells and neutrophilic and eosinophilic dermal infiltrate. 29 Direct and indirect immunofluorescence is similar to that of pemphigus vulgaris, but IgG is found in more superficial areas of the epidermis, and the titers of circulating antibodies are usually higher. 22, 23

Erythematous Pemphigus

This is a localized pemphigus foliaceous. The patient presents with bullous, erythematous, crusty, and hyperkeratotic lesions on nose, ears, and malar areas, which can also affect the scalp, thorax, and extremities. 29 It affects only girls and has a long course with periods of exacerbation. 32 Its histopathology is similar to that of pemphigus foliaceous.

Paraneoplastic Pemphigus

Paraneoplastic pemphigus is an autoimmune mucocutaneous disease associated with lymphoproliferative neoplasias of B cells that has been reported in children and adolescents. A 1995 report found 14 cases to date in children. 33 It is often a presenting sign of occult Castleman’s disease. 34 Histopathologic findings include interface and lichenoid dermatitis with variable intraepidermal acantholysis. Indirect immunofluorescence is positive in all cases for IgG. Pulmonary complications are responsible for the high mortality. 35

Syphilis

In syphilitic pemphigus ( Figure 4 ), the newborn can present erythematous brownish papules and diffuse flaccid bullae over the entire body, especially on the palms and soles. Rhinorrhea, oral lesions, widespread lymphadenopathy and bone pain may be associated. The diagnosis is confirmed by the demonstration of IgM antibodies for Treponema pallidum in the baby. 7

Figure4. Syphilis.

Transient Neonatal Pustular Melanosis

Transient neonatal pustular melanosis is characterized by vesicopustules with variable diameter measuring between 0.15 and 1 cm. It is more frequent in the black race and term neonates. There are no systemic symptoms and the vesicopustules usually disappear within a period of 24 to 72 hours. The histopathology is characterized by the presence of intracorneal or subcorneal pustules with a prevalence of neutrophils. 36 Transient neonatal pustular melanosis is an easily identifiable entity and awareness of this dermatosis will avoid treatment for neonatal septicemia or unnecessary antibiotic therapy. The main differential diagnosis includes erythema toxicum, staphylococcal impetigo, and herpes simplex. 37

Congenital Candidiasis

Congenital cutaneous candidiasis is a rare disorder and is characterized by generalized macules, papules, and pustules. 38 Vesicles and bullae may occur, and there is relative sparing of the perineum and mouth. Desquamation usually occurs within 1 to 2 weeks of onset. Congenital cutaneous candidiasis is generally a benign condition, but it may be associated with disseminated infection, especially in premature infants. 39 Patients with congenital or acquired defects in cell-mediated immunity (T cells, particularly CD 4 ) are susceptible to mucocutaneous forms. 40

Part II of this article will discuss the remaining 3 categories of bullous dermatoses in childhood: nonhereditary with subepidermal cleavage, and hereditary with intraepidermal or subepidermal cleavage.

References