Chapter 186. Other Bullous Diseases

There are a number of bullous diseases other than pemphigus and bullous pemphigoid that are important to recognize. Porphyria cutanea tarda is a porphyria that has no extracutaneous manifestations (Figures 186-1, 186-2, and 186-3). Dystrophic epidermolysis bullosa belongs to a family of inherited diseases where blister formation can be caused by even minor skin trauma. PLEVA (pityriasis lichenoides et varioliformis acuta) is a minor cutaneous lymphoid dyscrasia that can appear suddenly and persist for weeks to months. Dermatitis herpetiformis is a recurrent eruption that is usually associated with gluten and diet-related enteropathies.

Patient Story

A middle-aged woman presented with tense blisters on the dorsum of her hand (Figure 186-1). One bulla was intact and the others had ruptured, showing erosions. Work-up showed elevated porphyrins in the urine (which fluoresced orange-red under a Wood lamp) and the patient was diagnosed with porphyria cutanea tarda.

Epidemiology

• Porphyria cutanea tarda (PCT) occurs mostly in middle-aged adults (typically 30 to 50 years of age) and is rare in children.
• It is especially likely to occur in women on oral contraceptives and in men on estrogen therapy for prostate cancer.1
• Alcohol, pesticides, and chloroquine have been implicated as chemicals that induce PCT.1
• PCT is equally common in both genders.
• There is an increased incidence of PCT in persons with hepatitis C (Figures 186-2 and 186-3).

Etiology and Pathophysiology

• The porphyrias are a family of illnesses caused by various metabolic derangements in the metabolism of porphyrin, the chemical backbone of hemoglobin. Whereas the other porphyrias (acute intermittent porphyria and variegate porphyria) are associated with well-known systemic manifestations (abdominal pain, peripheral neuropathy, and pulmonary complications), PCT has no extracutaneous manifestations. Photosensitivity is seen (as with variegate porphyria). PCT is associated with a reduction in hepatic uroporphyrin decarboxylase.

Risk Factors

• Hepatitis C.
• Alcohol-induced liver injury.
• Hemochromatosis.2

Diagnosis

Clinical Features

The classic presentation is that of blistering (vesicles and tense bullae) on photosensitive “fragile skin” (similar to epidermolysis bullosa). Scleroderma-like heliotrope suffusion of the eyelids and face may be seen. As the blisters heal, the skin takes on an atrophic appearance. Hypertrichosis (especially on the cheeks and temples) is also common and may be the presenting feature.

Typical Distribution

Classically, the dorsa of the hands are affected (Figures 186-1, 186-2, and 186-3). Facial suffusion (heliotrope) may be seen along with hypertrichosis of the cheeks and temples.

Laboratory Studies

The diagnosis can be confirmed by the orange-red fluorescence of the urine when examined under a Wood lamp. Increased plasma iron may be seen (associated with increased hepatic iron in the Kupffer cells). Diabetes is said to occur in 25% of individuals.

• Twenty-four-hour urine collection for porphyrins—These will be elevated in PCT.
• Skin biopsy may help confirm PCT if the other information is not clear.
• Once the diagnosis is made, secondary causes of PCT should be investigated:
  • Serum for ferritin, iron, and iron-binding capacity to look for hemochromatosis.
  • Order liver function tests and if abnormal order tests for hepatitis B and C.
  • Consider α-fetoprotein and liver ultrasound if considering cirrhosis and/or hepatocellular carcinoma.
  • Order an HIV test if risk factors are present.

Differential Diagnosis

• The acral vesiculobullous lesions may suggest nummular or dyshidrotic eczema. In younger individuals, the acral blistering may suggest epidermolysis bullosa. The lesions may also suggest erythema multiforme bullosum. The heliotrope suffusion may suggest dermatomyositis and the atrophic changes may suggest systemic sclerosis.

Management

• If the onset is associated with alcohol ingestion, estrogen therapy, or exposure to pesticides, reducing exposure is warranted.2
• Phlebotomy of 500 mL of blood weekly until the hemoglobin is decreased to 10 g is associated with biochemical and clinical remission within a year.1
• Low-dose chloroquine can help maintain remissions, whereas high-dose chloroquine can exacerbate the illness.1

Follow-Up

• Periodic clinical follow-up until remission is achieved is necessary along with constant education and reinforcement of the need to avoid precipitants.

Patient Education

• Avoidance of potential precipitants (alcohol, estrogens, pesticides) and avoidance of excess sunlight exposure (to avoid hypersensitivity) are important. Avoidance of trauma and careful wound care is also necessary.

Patient Story

A 34-year-old pregnant woman presents with active blistering in her axilla and past history revealed that she lost her fingernails and toenails (Figure 186-4A) as a young child. She was diagnosed as a child with recessive dystrophic epidermolysis bullosa. None of her children had been affected because her husband was neither affected nor a carrier (Figure 186-4B). A topical steroid ointment helped relieve the pain and calm the blistering in her axilla.

Epidemiology

• Dystrophic epidermolysis bullosa belongs to a family of inherited diseases characterized by skin fragility and blister formation caused by minor skin trauma.3 There are autosomal recessive and autosomal dominant types, the severity of this disease may vary widely. Onset is in childhood and in later years severe dystrophic deformities of hands and feet are characteristic (Figure 186-5). Malignant degeneration is common, especially squamous cell carcinoma, in sun-exposed areas.

Etiology and Pathophysiology

• Dystrophic epidermolysis bullosa has vesiculobullous skin separation occurring at the sub-basal lamina level, as opposed to junctional epidermolysis bullosa, which blisters at the intralamina lucida layer, and epidermolysis bullosa simplex (Figure 186-6), which blisters at the intraepidermal layer.4,5

Diagnosis

Clinical Features

Acral skin fragility and blistering are the hallmark in childhood. Minor trauma can induce severe blistering. As the disease progresses initially, painful and ultimately debilitating dystrophic deformities are typical. Repeated blistering of the hands can lead to fusion of the fingers and the “mitten” deformity (Figure 186-5).

Typical Distribution

The typical distribution is acral (hands and feet), although blistering may extend proximally secondary to trauma.

Laboratory Studies and Biopsy

There are no laboratory tests to confirm the diagnosis. A punch biopsy can provide adequate tissue for the dermatopathologist to differentiate between the different forms of epidermolysis bullosa: simplex, junctional, and dystrophic.

Differential Diagnosis

• Erythema multiforme bullosum may have a similar appearance, but the distribution is less apt to be limited to the distal extremities.
• The appearance of an acral blistering on fragile skin is also characteristic of PCT, but the age of onset of PCT is typically in middle age and not in childhood.
• The first appearance of the condition may be confused, with staphylococcal scalded skin syndrome (see Chapter 116, Impetigo).6

Management

Management is primarily prevention of trauma, careful wound care, and treatment of complicating infections. Other supportive measures such as pain management and nutritional support are often necessary. Screening the skin for squamous cell carcinoma is important in the dystrophic form.4

Follow-Up

Periodic skin examinations should be done to help manage symptoms and screen for malignancy.

Patient Education

Avoid trauma and come in early if there are any signs of infection or malignancy.

Patient Story

A 22-year-old man presented with a varicelliform eruption that he has had for 6 weeks (Figure 186-7). Initially, he was diagnosed with varicella and given a course of acyclovir. Then he was misdiagnosed with scabies and treated with permethrin. A correct diagnosis was made of PLEVA by clinical appearance and confirmed with biopsy. His skin lesions cleared with oral tetracycline.

Epidemiology

• PLEVA or Mucha-Habermann disease and pityriasis lichenoides chronica are maculopapular erythematous eruptions that can occur in crops of vesicles that can become hemorrhagic over a course of weeks to months (Figures 186-7 and 186-8).7
• There is a predilection for males in the second and third decades.
• PLEVA occurs in preschool and preadolescent children as well.8

Etiology and Pathophysiology

• PLEVA has traditionally been classified as a benign papulosquamous disease. However, there is increasing evidence that suggests that PLEVA should be considered a form of cutaneous lymphoid dyscrasia.9 It may even, represent an indolent form of mycosis fungoides (see Chapter 176, Cutaneous T-Cell Lymphoma).

Diagnosis

Clinical Features

PLEVA occurs with crops of maculopapular and papulosquamous lesions that can vesiculate and form hemorrhagic vesicles (Figures 186-7 and 186-8). Although it resembles varicella, new crops of lesions continue to appear over weeks and months. It can be thought of as “chickenpox that lasts for weeks to months.”

Typical Distribution

Lesions typically occur over the anterior trunk and flexural aspects of the proximal extremities. The face is spared.

Laboratory Studies

There are no specific laboratory tests for PLEVA except biopsy.

Biopsy

A punch biopsy is helpful in making the diagnosis. It may be necessary to differentiate PLEVA from lymphomatoid papulosis (see “Differential Diagnosis” below).

Differential Diagnosis

• Varicella—A varicella direct fluorescent antibody test can confirm acute varicella. If no viral testing was done and what appeared to be varicella persists, PLEVA should be considered (Chapter 123, Chickenpox).
• Pityriasis lichenoides chronica is the chronic form of PLEVA and can be distinguished from PLEVA by length of time and biopsy (Figure 186-9). It has a more low-grade clinical course than PLEVA and the lesions appear over a longer course of time.
• Erythema multiforme is a hypersensitivity syndrome in which target lesions are seen. The target lesions have epidermal disruption in the center with vesicles and/or erosions. Look for the target lesions to help differentiate this from PLEVA (see Section 14, Hypersensitivity Syndromes).
• Lymphomatoid papulosis presents in a manner similar to PLEVA with recurrent crops of pruritic papules at different stages of development that appear on the trunk and extremities. Although it has histologic features that suggest lymphoma, lymphomatoid papulosis alone is not fatal. It is important to differentiate this from PLEVA because these patients need to be worked up for coexisting malignancy. These patients tend to be older and a punch biopsy can make the diagnosis.
• Gianotti-Crosti syndrome (papular acrodermatitis of childhood) may resemble PLEVA but the lesions are usually acral in distribution (Figure 186-10).5 The erythematous papules and vesicles are found on the extremities and sometimes on the face. It is a benign syndrome associated with many childhood viruses that may last 2 to 8 weeks.

Management

• UV A1 phototherapy has been deployed with some success.10 Various reports suggest the efficacy of macrolides and tetracyclines, probably more for their antiinflammatory properties than for their antibacterial effects.

Follow-Up

Needed only if the disease does not resolve.

Patient Education

This is usually a temporary disease but if it becomes chronic there are treatments that could help such as oral macrolides or tetracycline.

Patient Story

A young man with a past history of diarrhea and malabsorption carries a past diagnosis of gluten-induced enteropathy. Despite a gluten-free diet he continues to have a pruritic eruption on his shoulders, back, extremities and buttocks. (Figures 186-11 and 186-12). While the most likely diagnosis is dermatitis herpetiformis, a punch biopsy was performed to confirm this before starting the patient on oral dapsone.

Epidemiology

• Dermatitis herpetiformis is a chronic recurrent symmetric vesicular eruption that is usually associated with diet-related enteropathy.11 It most commonly occurs in the 20 to 40 years of age group. Men are affected more often than women.

Etiology and Pathophysiology

• The disease is related to gluten and other diet-related antigens that cause the development of circulating immune complexes and their subsequent deposition in the skin. The term herpetiformis refers to the grouped vesicles that appear on extensor aspects of the extremities and trunk and is not a viral infection or related to the herpes viruses. The disease is characterized by the deposition of immunoglobulin (Ig) A along the tips of the dermal papillae. The majority of patients will also have blunting and flattening of jejunal villi, which leads to diarrhea even to the point of steatorrhea and malabsorption.

Diagnosis

Clinical Features

The clinical eruption is characterized by severe itching, burning, or stinging in the characteristic extensor distribution. Herpetiform vesicles and urticarial plaques may be seen. Because of the intense pruritus, characteristic lesions may be excoriated beyond recognition (Figures 186-11 and 186-12).

Typical Distribution

Classically, the lesions (or excoriations) are seen in the extensor aspects of the extremities, shoulders (Figures 186-11), lower back, and buttocks (Figures 186-12).

Laboratory Studies

If the patient has gluten-induced enteropathy, antigliadin and antiendomysial antibodies may be present. A blood test for antigliadin antibody is a sensitive test for gluten-induced enteropathy.

Biopsy

Diagnosis is confirmed by a punch biopsy. It is best to biopsy new crops of lesions. A standard histologic examination will show eosinophils and microabscesses of neutrophils in the dermal papillae and subepidermal vesicles. Direct immunofluorescence reveals deposits of IgA and complement within the dermal papillae.

Differential Diagnosis

• Scabies may have a similar appearance with pruritus, papules, and vesicles. If the lesions and distribution suggest scabies, it should be ruled out with skin scraping looking for the mite, feces, and eggs. If the scraping is negative, but the clinical appearance suggests scabies, empiric treatment with permethrin should be considered as well. If the lesions persist, consider a punch biopsy to look for dermatitis herpetiformis (Chapter 143, Scabies).
• Nummular and dyshidrotic eczema may also be diagnostic considerations, but response to steroids in eczema may be helpful in differentiation (Chapters 145, Atopic Dermatitis and 147, Hand Eczema).
• The classic differential for PCT is pseudoporphyria (caused by NSAIDs like Naprosyn), epidermolysis bullosa acquisita, and variegate porphyria.

Management

• With a gluten-free diet, 80% of patients will show improvement in the skin lesions (Figure 186-12). The degree of benefit is dependent upon the strictness of the diet.11
• A gluten-free diet may help the enteropathy and decrease the subsequent development of small bowel lymphoma.
• Dapsone at an initial dose of 100 to 200 mg daily with gradual reduction to a 25- to 50-mg maintenance level may be necessary indefinitely.12

Follow-Up

Follow-up is needed to control the disease and monitor nutritional status.

Patient Education

Nutritional counseling is important for all patients with gluten-induced enteropathy. Persons with dermatitis herpetiformis and gluten-induced, enteropathy should not eat wheat and barley but can eat rice, oats and corn.

Patient Resources

• MedlinePlus. Porphyria—http://www.nlm.nih.gov/medlineplus/ency/article/001208.htm.
• Genetics Home Reference. Epidermolysis Bullosa Simplex—http://ghr.nlm.nih.gov/condition=epidermolysisbullosasimplex.
• National Institute of Arthritis and Musculoskeletal and Skin Diseases. Epidermolysis Bullosa—http://www.niams.nih.gov/Health_Info/Epidermolysis_Bullosa/default.asp.
• PubMed Health. Dermatitis Herpetiformis—http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002451/.
• DermNet NZ. Pityriasis Lichenoides—http://dermnetnz.org/scaly/pityriasis-lichenoides.html.

Provider Resources

• Medscape. Porphyria Cutanea Tarda—http://emedicine.medscape.com/article/1103643.
• Medscape. Epidermolysis Bullosa—http://emedicine.medscape.com/article/1062939.
• Medscape. Dermatitis Herpetiformis—http://emedicine.medscape.com/article/1062640.
• Medscape. Pityriasis Lichenoides—http://emedicine.medscape.com/article/1099078.