Skill Checkup: A Student With an Inherited Blistering Condition and Painful Bullae on His Feet

William D. James, MD

Disclosures

April 12, 2021

Dystrophic epidermolysis bullosa is one of a heterogeneous group of bullous disorders called epidermolysis bullosa (EB) that are characterized by blister formation in response to minimal mechanical trauma and extracutaneous findings in some forms of the disease. EB is classified into four primary clinical phenotypes and more than 30 subtypes based on level of skin cleavage (location of blister formation) and the mode of inheritance, severity, and molecular and morphologic variations. The four major types of EB (with the site of blister separation) are epidermolysis bullosa simplex (EBS; intraepidermal cleavage), junctional epidermolysis bullosa (JEB; within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (DEB; sublamina densa, upper dermis), and Kindler epidermolysis bullosa (KEB; basal keratinocytes, lamina lucida, or below the lamina densa). EB involves changes in at least 16 genes. Most EB cases are inherited but some can occur spontaneously. DEB is associated with mutations in the COL7A1 gene coding for type VII collagen, which is the main component of anchoring fibrils. These help stabilize the epidermis and dermis as they extend from the dermal-epidermal basement membrane to the upper layer of the papillary dermis. This patient's history and current presentation match a dominantly inherited, milder, localized subtype of DEB where there are no extracutaneous manifestations of disease. In this localized form of DEB, blistering on the hands and feet and nail dystrophy are the main findings. Milia and atrophic scars can also be seen.

Bullous pemphigoid is an acquired inflammatory, subepidermal, blistering disease with acute or subacute onset and tense blisters. It is often associated with pruritus. In its most common form, generalized tense bullae arise on any part of the skin, with a predilection for the flexural surfaces. In the acral form of disease, bullae appear on the soles, palms, and face. In bullous pemphigoid, IgG antibodies bind to the basement membrane and activate an inflammatory reaction that eventually leads to hemidesmosomal protein degradation and blister formation. Bullous pemphigoid is more common in older individuals. Its childhood disease form is limited in duration. This patient's history and the morphology of his bullae make this diagnosis unlikely.

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal blistering disease of the skin and mucous membranes. EBA is caused by antibodies targeting type VII collagen, the major component of anchoring fibrils that connect the basement membrane to dermal structures. The classic presentation is blisters localized to areas that are prone to injury, such as the hands, feet, knees, elbows, and buttocks. Chronic skin fragility and secondary scarring often result in restriction of mobility in the extensor skin surface. A subtype of disease is characterized by mucosal membrane involvement, with blisters forming in the mouth, nose, eyes, and other mucosal membranes, leading to organ dysfunction (eg, visual loss, dysphagia, and malnutrition). EBA typically occurs in the fourth and fifth decades of life. Although this patient suffers from blistering, EBA is probably not the diagnosis because of the age of onset, likely inheritance of his condition (EBA is autoimmune), and disease course.

Linear IgA dermatosis (LAD) is an autoimmune subepidermal vesiculobullous disease that may be idiopathic or drug-induced and which affects both children and adults. Clinically, LAD is a heterogeneous disease that resembles other blistering diseases, such as bullous pemphigoid. In LAD, linear deposition of IgA at the basement membrane zone leads to complement activation and neutrophil chemotaxis. This in turn results in loss of adhesion at the dermal-epidermal junction and blister formation.

LAD has a bimodal age of onset, pediatric (6 months to 10 years) and adult (older than 60). In children, lesions are typically found in the anogenital area and lower abdomen. The feet, hands, and face — particularly the perioral area — are also involved. In adults, blistering can be seen on the trunk and extensor surface of the limbs. Some patients may experience a prodrome of pruritus. The lesions of LAD appear as clear and/or hemorrhagic round or oval vesicles or bullae on normal, erythematous, or urticarial skin. Erythematous plaques, blanching macules and papules, fixed drug eruption–like dusky patches with central violaceous changes, or targetoid erythema multiforme–like lesions can also occur. Bullae can be found as a single lesion or more typically in cluster formations (jewels and beads signs). These signs and symptoms do not match the patient's presentation despite his blistering.

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