A 68-year-old Caucasian female presented to the office with acute onset of a solitary, asymptomatic, spontaneous, tense blister of three days’ duration on the lateral aspect of the right great toe.
She is active and plays a lot of tennis. However, there was no history of trauma or friction from footwear prior to the eruption, and she never had anything such as this blister appear. There is no history of photosensitivity and the patient cannot recall any new drug intake in the preceding couple of weeks. The patient had visited a nail salon two days prior for nail care and polish. She remembers that she felt a prick when the nail technician was working on the great toe but thought nothing of it.
The dermatological exam revealed a 3.5 cm x 1.3 cm tense solitary bullae on the fibular aspect of the left hallux. It is a tense, non-tender blister on a non-erythematous base. No erythema is present around the base and there is no pain at the toe. Prior to the formation of the blister, the patient did not have any itching or any redness in the area.
Her history includes insulin-dependent diabetes for 30 years and the recent incorporation of an insulin pump to help manage her diabetes. There is a history of osteoarthritis, back problems, epilepsy, heart disease, hypertension and sinus problems. She notes meticulous foot hygiene and denies any history of calluses, corns or ulcers. Her most recent HbA1c was 6.4 and the fasting blood sugar on the morning of the appointment is 69, which is somewhat low. The rest of the past medical history is noncontributory.
1. What are the characteristics of this condition?
2. What is the most likely diagnosis?
3. What is your differential diagnosis?
4. What was a key to making the diagnosis?
5. What complications can arise from this condition?
1. A 3.5 cm x 1.3 cm tense solitary bullae on the fibular aspect of the left hallux as well as a tense, non-tender blister on a non-erythematous base
2. Bullosis diabeticorum
3. Blister beetle dermatitis, insect bite reaction, friction blisters (mechanical trauma), contact dermatitis, vesicular tinea pedis, dyshidrotic eczema (pompholyx), blistering distal dactylitis, bullous fixed drug reactions, bullous pemphigoid, bullous systematic lupus erythematosus, epidermolysis bullosa acquisita, bullous impetigo and bullous erythema multiforme
4. A biopsy of the involved skin revealing a subepidermal bulla without any inflammatory infiltrate as well as a negative direct immunofluorescence test
5. Secondary infection can occur if the bulla ruptures go untreated.
The physical exam showed that despite a 30-year history of diabetes, there was no loss of protective sensation (Semmes-Weinstein monofilament 5.07) and no loss of vibratory sensation to all five toes and metatarsal heads bilaterally.
The vascular status was normal in that she had palpable pulses of the dorsalis pedis and posterior tibial arteries, and there was no dysvascularity to the toes. The orthopedic exam did reveal a mild hallux abducto valgus deformity of the involved foot and a rectus alignment on the left foot. No hammertoe deformities were present.
A complete set of radiographs did not reveal any pathology to the soft tissues or bone underlying the large bullae. There was no acute fracture, tumor or dislocation present.
A biopsy of the involved skin showed a subepidermal bulla without any inflammatory infiltrate. A direct immunofluorescence test was negative.
Within two weeks, the patient recovered uneventfully with slight residual hyperpigmentation but no scarring. Based on the clinical, histopathological and immunofluorescence pattern, I diagnosed the patient with bullosis diabeticorum.
Bullosis diabeticorum, also known as diabetic bullous dermopathy, bullous disease of diabetes and diabetic bullae, is a rare, distinct, spontaneous, noninflammatory, blistering condition of unknown etiology occurring in patients with diabetes mellitus.1 Clinical history and location raise the index of suspicion.
In most cases, bullosis diabeticorum manifests as an abrupt, spontaneous development of blisters on the lower extremity (toes, feet and shins). This patient did not have a history of antecedent trauma or infection. The blisters have a propensity to be large and often have an asymmetrical shape as I saw with this patient. The blisters are painless and not pruritic.2 Histopathology of the bullae show cleavage at both the intra-epidermal and subepidermal levels. The only serious complication is secondary infection if the bulla ruptures go untreated. Some do recommend de-roofing the blister and treating it with antibiotics, but no studies have occurred because it is such a rare occurrence.
There is no reference in the existing literature about the relationship of the occurrence of diabetic bullae and the degree of metabolic derangement or glycemic control.3 The condition reportedly affects approximately 0.5 percent of patients with diabetes in the U.S. population.4 One study found a higher incidence of bullosis diabeticorum in patients with skin of color. Researchers found that bullosis diabeticorum occurs in 334 out of 1,000 Hispanics, 296 out of 1,000 African-Americans, 243 out of 1,000 Asians and 184 out of 1,000 Caucasians.5
Blister beetle dermatitis. Beetles do not bite or sting, but they do release a vesicating agent called cantharidin (the same agent that doctors use to place on a wart to cause a blistering effect). The beetles exude this blistering fluid if they are pressed or crushed on the skin, but the patient needs to be in contact with the insect. Treatment of these blisters mimics the treatment of other blisters: drainage of the bullae and application of cold, wet compresses and topical antibiotics. Treatment of this blister also requires cleansing with acetone, ether, soap or alcohol to remove the cantharidin.2
Friction blister (mechanical trauma). Low intensity pressure on friction leads to lichenification and hyperpigmentation whereas heavier and persistent friction leads to hyperkeratosis and callus formation. Sudden shearing forces may lead to friction blisters, erosions or ulcers. Mid-epidermal necrosis, heat, sweating and maceration increase the risk of blistering. The use of acrylic or polypropylene socks as well as the newer toe socks with individual space for each toe has lessened the incidence of blisters, particularly in between the toes. One should perform biomechanical evaluation of the foot to assess if there are signs of previous rubbing (callus, hyperpigmentation, thickening of skin). Evaluation of the foot for bunions and hammertoes can help in making the diagnosis.
Contact dermatitis (poison ivy). Bullae and vesicles occur in a linear configuration. It is rare to see a solitary lesion. It is common for patients to have a history of being out in the yard or woods. This is a form of delayed hypersensitivity. The time between the exposure causing the eruption and the onset of symptoms is between one day and two weeks.
Irritant dermatitis. Chemical irritants that can cause the condition include: chlorine, cleansers, detergents and soaps, fabric softeners, glues on artificial nails, perfumes and topical medications. Skin lesions present with severe pruritus at the site of contact with an erythematous, edematous area. Vesicles and bullae may develop, and these are usually linear or grouped.
Vesicular tinea pedis. This causes vesicles between the toes, on the sides and tops of the feet. These may become larger and form blisters. When the lesions burst, they leave scales. Vesicular tinea pedis is usually extremely itchy.
Pompholyx (dyshidrotic eczema). This type of eczema of unknown cause is characterized by a pruritic vesicular eruption on the fingers, palms and soles. A more appropriate term for this vesicular eruption is pompholyx, which means bubble. The clinical course of dyshidrotic eczema can range from self-limited to chronic, severe or debilitating. Dyshidrotic eczema is considered to be a reaction pattern caused by various endogenous conditions and exogenous factors. The hypothesis of sweat gland dysfunction has been in dispute because researchers have not shown that vesicles are associated with sweat ducts. A 2010 case report provided clear histopathologic evidence that sweat glands do not play a role in dyshidrosis.6
Blistering distal dactylitis. This is an acute superficial infection of the anterior fat pad of the digit caused by group A streptococci or Staph aureus. This occurs as a purulent vesicle or bulla on an erythematous base.7
Bullous drug eruptions. Blisters occur as a complication of the administration of drugs, resulting in bullous drug eruptions. The more common drugs are sulfonamides, non-steroidal anti-inflammatory drugs and anti-seizure meds. This manifests with a very inflammatory base.
Bullous pemphigoid. This is most common in subepidermal bullous disease. Bullous pemphigoid is a disease of elderly men. Urticarial lesions precede tense bullous lesions. It is caused by autoantibodies directed against proteins.
Epidermolysis bullosa. This is a family of diseases that shows blistering in response to mild trauma. The condition occurs on both cutaneous surfaces and mucosal tissue. Different epidermolysis bullosa subtypes are based on the cleavage plane of the blister and caused by keratin gene mutations.
Bullous impetigo. This affects infants and children younger than 2 years. It causes painless, fluid-filled blisters that are usually on the trunk, arms and legs. The skin around the blister is usually red and itchy, but not sore. The blisters break and scab over with a yellow-colored crust.
Bullous erythema multiforme. Infections, most commonly the herpes simplex virus, usually trigger this hypersensitivity reaction. Bullous erythema multiforme presents with a skin eruption characterized by a typical target lesion. There may be mucous membrane involvement. It is acute and self-limiting, usually resolving without complications. The upper limbs are more commonly affected than the lower. Palms and soles may be involved. The face, neck and trunk are common sites. Skin lesions are often grouped on elbows and knees. There may be an associated mild itch or burning sensation.
Vesicle and bulla. A vesicle is a fluid-filled cavity or elevation smaller than 0.5 cm and a bulla measures large than 0.5 cm.2 Other authors use the size 1.0 cm as the split between the vesicle and the bullae.5 Vesicles may be discrete, irregularly scattered or grouped as in herpes zoster or linear as in allergic contact dermatitis. Other examples include: poison ivy, early chicken pox, herpes simplex and dyshidrosis.
Bullae are rounded or irregularly shaped blisters containing serous or seropurulent fluid. They are usually unilocular but may be multilocular. The walls of the bulla are flaccid and thin, and subject to spontaneous rupture. Examples include: pemphigus, bullous pemphigoid, poison ivy and second-degree burns.
Hemorrhagic bullae are common in pemphigus, herpes zoster, severe bullous drug eruptions and lichen sclerosus.
The fluid in the cavity exerts equal pressure in all directions to give rise to a spherical shape. On the sole, the vesicles may be non-palpable due to the thicker stratum corneum.
Formation of blisters. Blisters arise from cleavage at various levels of the epidermis (intra-epidermal) or at the dermal-epidermal interface (sub-epidermal). The amount of pressure to collapse the blister may predict whether the blister is intra-epidermal or sub-epidermal. The characteristic of blisters in various dermatoses tends to be uniform and reproducible, which aids in diagnosis.
Proper diagnosis requires a biopsy from the site with histopathologic examination of the blister cavity edge. One also examines the biopsy specimen for deposits of immune reactants, immunoglobulins and complement components.
Pathological evaluation. Blisters look similar from afar. However, their assessment is based on the microscopic analysis. The critical assessments are: blister separation plane, the mechanisms of blister formation, the character of the inflammatory infiltrate, its pattern, and the specific cell types involved.8
Nikolsky’s sign. This is when the intact epidermis shears away from underlying dermis, leaving a moist surface. Slight pressure or rubbing of the blister elicits this sign. Nikolsky’s sign is present in pemphigus vulgaris and is not present in bullous diabeticorum.
Asboe-Hansen sign or indirect Nikolsky sign (bullae spread phenomenon). This is elicited by pressure on an intact bulla, gently forcing the fluid to spread under adjacent unblistered skin.
Dr. Morse is the President of the American Society of Podiatric Dermatology. He is a Fellow of the American College of Foot and Ankle Surgeons, and the American College of Foot and Ankle Orthopedics and Medicine. Dr. Morse is board certified in foot surgery. He is on the Podiatric Residency Educational Committee at the Washington Hospital Center in Washington, D.C.
1. James WD, Berger TG, Elston DM (eds). Andrews’ Diseases Of The Skin, 11th edition. Saunders Elsevier, Philadelphia, 2011, p. 2
2. Wolff K, Goldsmith L, (eds). Fitzpatrick’s Dermatology in General Medicine, seventh edition. McGraw-Hill, New York, 2008, pp.1469-70.
3. Ghosh SK, Bandyopadhyay D, Chatterjee G. Bullosis diabeticorum: a distinctive blistering eruption in diabetes mellitus. Int J Diabetes Dev Ctries. 2009; 29(1):41–42.
4. Jacqueline M, Junkins-Hopkins. Bullous Disease of Diabetes. E-Medicine. Available from: www.emedicine.com/derm/topic62.htm  , accessed on Nov. 6, 2012.
5. Taylor S, Badreshia-Bansai S, et al. Treatments for Skin of Color. Elseiver-Saunders, Edinburgh, 2011, p. 25.
6. Lee WJ, Lee DW, Kim CH, et al. Pompholyx with bile-coloured vesicles in a patient with jaundice: are sweat ducts involved in the development of pompholyx? J Eur Acad Dermatol Venereol. 2010; 24(2):235-6.
7. Hall BJ, Hall JC. Sauer’s Manual of Skin Disease, 10th edition. Lippincott Williams and Wilkins, Philadelphia, 2011, p. 586.
8. Elder DE. Lever’s Histopathology of the Skin, ninth edition. Lippincott Williams, Philadelphia, 2005, pp. 243-244.