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What has caused a 42-year-old man with high blood pressure and type 2 diabetes to suddenly develop large blisters on his right lower leg? That's the question facing Madeline DeWane, MD, and Daniela Kroshinsky, MD, MPH, both of Harvard Medical School in Boston.

As they reported in , when the patient presented to the emergency department, he explained that the lesions had developed over the past day and a half, with no apparent reason. He noted having a tingling sensation in the affected leg, but no pain or itching. He had not had any injuries or exposure to chemicals or extreme temperatures that might explain the blistering.

His medical history included being diagnosed with diabetes at age 25 and having gastroparesis. His treatment for diabetes included insulin lispro (three times daily) and insulin glargine (20 units nightly).

Physical examination showed normal vital signs and body temperature; his legs and arms were warm, and distal pulses were palpable.

The medical team noted dark macules on both shins and tight, fluid-filled blisters on the front of his right lower leg, the top of his foot, and toes. There was no redness or swelling around the blisters. Examination of the rest of the skin and mucocutaneous tissues revealed no other unusual findings.

Lab tests showed that the patient's blood glucose level was 375 mg/dL (20.81 mmol/L) and hemoglobin A1c level was 9.8%. Findings of a basic metabolic panel and complete blood cell count were unremarkable, except for a hemoglobin level of 10.9 g/dL, indicating mild anemia.

Clinicians diagnosed the patient's dermopathy as bullosis diabeticorum.

The condition was diagnosed based on the spontaneous onset of the blisters on noninflamed skin in an individual with long-standing diabetes. Bullosis diabeticorum, also referred to as diabetic bullae or bullous eruption of diabetes mellitus, is also characterized by hyperpigmented macules and patches that generally develop on the front of the lower legs.

DeWane and Kroshinsky said they considered several differential diagnoses and treatment approaches. In this case, initial treatment for a skin infection would not be correct, "because the lack of surrounding erythema, warmth, tenderness, and serous crusting make infection unlikely."

The possibility of bullous pemphigoid was also unlikely, given that the blister was located on "a single distal extremity," the researchers said. Finally, treatment with prednisone would not be advised due to a potential adverse effect on the patient's hyperglycemia.

The team aspirated the blisters using a sterile needle and covered them with nonstick petrolatum dressing. After wrapping the patient's right foot and leg in gauze, the team placed an elastic bandage on the area to provide gentle compression. The patient was then discharged.

Approximately 12 months later, clinicians followed up with the patient by phone. He reported that his bullae had healed and not reoccurred.

Discussion

The prevalence of the relatively rare condition of bullosis diabeticorum has not been determined. However, as the case authors noted, small retrospective studies have suggested an annual among patients with diabetes from 0.16% to 0.50%; the condition has also been linked with long-standing peripheral neuropathy.

"The pathophysiology of bullosis diabeticorum is unclear and may be multifactorial," although may be a contributor to premature aging of connective tissue, DeWane and Kroshinsky noted.

In addition, they said, diabetes may be associated with an increased risk for cutaneous blisters, with one study suggesting that "the time to development of suction blisters was significantly shorter in patients with insulin-dependent diabetes compared with controls when suction mechanical force was applied to the skin."

Given that bullosis diabeticorum typically occurs on the extremities, trauma has also been implicated as a possible cause, although in most reported cases the blisters developed spontaneously, DeWane and Kroshinsky noted. And while cases reported in the medical literature have generally occurred in individuals with long-standing or poorly controlled diabetes, bullosis diabeticorum can also develop before diabetes has been diagnosed, as well as in patients whose diabetes is .

The condition generally develops suddenly, the authors noted, presenting with one or more tense, painless blisters on otherwise normal-appearing skin. The size of the blisters varies from a few millimeters up to 10 cm or more; the blisters tend to be filled with sterile fluid, which may be clear or tinged with blood.

While most cases of bullosis diabeticorum resolve on their own within 2 to 6 weeks, prior to healing the lesions are associated with a risk of secondary bacterial infection.

The condition has a broad range of differential diagnoses, including "bullous pemphigoid, linear IgA [immunoglobulin A] bullous dermatosis, epidermolysis bullosa aquisita, porphyria cutanea tarda, bullous impetigo, bullous cellulitis, and blisters resulting from edema or friction," DeWane and Kroshinsky said. They cautioned that cases of bullous pemphigoid have recently been in patients after beginning treatment with dipeptidyl peptidase 4 inhibitors such as sitagliptin (Januvia) and saxagliptin (Onglyza), with symptoms improving after the medication was discontinued.

The blisters and lesions that characterize bullosis diabeticorum should be managed with gentle wound care and infection-prevention measures, the case authors said. "Because bullae on the feet and lower legs can limit mobility and may be associated with an increased risk of unintentional rupture, potentially resulting in large areas of denuded skin, a sterile needle can be used to aspirate large bullae."

The authors advised application of nonstick dressings to cover the blister site, and use of gentle compression if needed to prevent fluid from reaccumulating in the blister. While more invasive treatment strategies such as early deroofing and other surgical intervention have been suggested, "there is no evidence supporting these interventions in the absence of infection," DeWane and Kroshinsky said.

They concluded that "patients with bullosis diabeticorum need careful monitoring of their affected skin and should follow up with their primary care clinician or endocrinologist to optimize glycemic control and screen for other complications of diabetes."

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