Diagnosis: Dystrophic epidermolysis bullosa
The patient has the Hallopeau-Siemens variant of dystrophic epidermolysis bullosa (EB). EB comprises a group of rare genetic states that are characterized by extremely fragile skin and recurrent blister formation following minor mechanical friction or trauma.
The three major forms of EB are defined by the depth of blister formation. EB simplex features blisters within the basal keratinocytes of the epidermis. Junctional EB is characterized by blister formation at the level of the basement membrane. Such defects could include structural alterations of laminin 5 and laminin 6 of collagen XVII. Dystrophic EB signifies blister formation below the basement membrane. In addition to skin fragility, dystrophic EB is characterized by mucocutaneous blistering, scarring, and nail dystrophy. This form also features defects of the sublamina densa within the upper dermis. EB affects an estimated 50 of every million babies born; 92% have EB simplex; only 5% fit the designation of dystrophic EB.
Dystrophic EB is caused by a mutation in COL7A1, which is the gene that encodes type VII collagen, the major component of anchoring fibrils. The condition occurs either as an autosomal dominant or as a recessive trait. The dominant form manifests as one of two variants. In the Pasini variant, there is generalized blister formation, atrophic scarring, absence or dystrophy of nails, and milia formation. In addition, patients develop small, firm, white papules on the trunk referred to as albopapuloid lesions. The Cockayne-Touraine variant is differentiated clinically by the absence of albopapuloid lesions.
The recessive dystrophic form of EB, which is the form our patient had, is often referred to as the Hallopeau-Siemens variant. It commonly presents at birth as a severe generalized disorder not only of the skin but also of multiple extracutaneous organs. Characteristic of this variant is the formation of webs (pseudosyndactyly), followed by complete encasement of the hands and feet by a keratinous sac of scar tissue referred to as the “mitten” or “glove” deformity. Patients with recessive dystrophic EB inversa, a variant of Hallopeau-Siemens, have widespread involvement of the oral cavity and esophagus rather than of the distal extremities.
Of note clinically is that all the dystrophic forms of EB are associated with an increased incidence of squamous cell carcinoma (SCC) of the skin. Commonly arising in an area of chronic blistering and scar formation, these tumors tend to be more aggressive than most SCC and have been known to metastasize.
Immunofluorescence antigen mapping and electron microscopy can be helpful to confirm the clinical diagnosis. In this patient’s case, we took biopsy samples for specific immunofluorescence with monoclonal antibody LH7.2 against type VII collagen. Testing showed strong linear staining at the dermal-epidermal junction in control skin but markedly reduced staining of the epidermis in the patient’s skin, confirming our clinical diagnosis.
The diagnosis of EB is often based on clinical findings aided by a positive family history. Problems can arise when evaluating newborns with a blistering disease in the absence of any elicitable family history of EB. A major concern in such a baby would be neonatal and intrauterine herpes simplex. One must also consider injury from childbirth that might not be totally ascribed to inherent mechanical fragility. Other possible diagnoses in a baby with blisters would include incontinentia pigmenti and congenital erythropoietic porphryia.
Note that in newborns, the clinical presentation of all forms of EB is very similar. Most pediatric dermatologists would agree that in the absence of previous definitive characterization of another affected family member, accurate subclassification of any newborn suspected of having EB is almost impossible based on clinical morphology alone. Thus, molecular analysis has proved to be extremely helpful to categorize the skin defect.
Regrettably, there are no specific therapies for dystrophic EB. In terms of preventive measures, patients and their parents must understand the need to make the environment as mechanically atraumatic as possible. Careful protective coverings are needed for those skin areas most frequently traumatized. Adhesive tape and tight-fitting garments will result in blister formation and are to be avoided.
Topical measures include the proper use and application of compresses and dressings. The highest priority is the prevention of de novo blister formation. Clean, sterile, nonadhesive dressings applied to the elbows, knees, shoulders, and other areas exposed to mechanical stimuli will cushion impact. Once blisters develop, careful fluid drainage followed by application of antibiotic ointment and sterile dressings is required. A variety of synthetic dressings are now available.
Initial studies demonstrated the clinical efficacy of phenytoin (Dilantin), a known inhibitor of collagenase synthesis, in cases of recessive dystrophic EB. Early reports indicated reduced numbers of blisters and enhanced healing time. Dosages were similar to those routinely employed for seizures. Although a second study failed to confirm any major statistically significant benefit, some patients exhibit long-term benefit from phenytoin therapy.
Patients with dominant dystrophic EB continue to develop blisters and scarring throughout their lifetime. Although most patients have a normal life span, some die early from metastatic SCC or spread of cutaneous infections. The hope for EB in the future would be corrective gene transfer to normalize the defects in these individuals.
Our patient was in no acute distress, but we opted for a trial with oral phenytoin in addition to her wound care routine. She felt she gained some relief, and we have continued the medication for three years to date.