Syndactyly

Epidermolysis bullosa (EB) comprises a group of inherited disorders that are characterized by cutaneous blisters and mucosal erosions, usually resulting from minor trauma and evolving into chronic wounds.1 Genetic defects lead to abnormal protein formation. These abnormal proteins cause skin fragility, blistering, and ulceration. The term epidermolysis bullosa was first used to describe this disorder by Koebner in 1886.1 The incidence of EB ranges from 1:50,000 for the autosomal dominant forms to 1:300,000 for the autosomal recessive forms.2

Classifications of EB

Epidermolysis bullosa is classified broadly according to the cleavage plane of the blister, then further subdivided by genetic mode of transmission and clinical appearance.3

Epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is the autosomal dominant inherited form (Table 1), in which the genetically defective proteins and, therefore, the cleavage plane, are in the epidermis (Figure 1).2,4 Typically, the mucosa, nails, and teeth are not affected; however, mucosa and nails arc affected in certain EBS subtypes, such as EBS with muscular dystrophy (EBS-MD) and Dowling-Meara (EBS-DM). Patients with EBS-MD can experience milia (small, white papules caused by epidermis trapped within the dermis) and scarring, as well as dental, laryngeal, and urethral involvement. Patients with EBS-DM may also have milia, nail loss, and hyperkeratosis of the palms and soles. In other EBS subtypes, blistering can be generalized, as in the Koebner variant, or localized acrally, as in the Weber-Cockayne variant.

Junctional EB

Junctional EB (JEB) occurs in the junction between the epidermis and dermis, in the basement membrane (Table 2). JEB can be inherited as autosomal recessive traits, which may ultimately prove fatal.2,4 The genetically defective proteins and the cleavage plane in most variants are located in the dermalepidermal junction; specifically, the basal lamina at the level of the lamina lucida (Figures 2 and 3).

Scarring occurs in most variants, such as JEB with pyloric atrcsia (JEB-FA), cicatricial JEB (CJEB), and generalized atrophie benign EB (GABEB). Patients with JEB lethalis (JEBL), however, do not experience scarring despite the severe generalized blistering that characterizes this variant. Interestingly, JEBL spares the hands. Patients with JEBL may present with perioral/perinasal hypertrophic granulation tissue; dysplastic teeth; and involvement of the larynx, bronchi, gastrointestinal tract, gallbladder, cornea, and vagina. JEB-PA consists of extensive mucocutaneous blistering and erosions, in addition to gastric outlet obstruction and urinary tract scarring. GABEB involves enamel defects, loss of nails, and multiple cutaneous squamous cell carcinomas. Finally, patients with CJEB can have syndactyly, with contractures and stenosis of the anterior nares.

Dystrophie EB

Patients inherit dys trophic RB (DEB) by both autosomal dominant and recessive traits, in which genetically defective proteins and, therefore, tissue separation occur within the dermis at the level of the anchoring fibrils (Table 3).2,4 DEB is caused by abnormal production of type VII collagen.

DEB is characterized by extensive mucocutaneous involvement with resultant scarring and milia formation. Dominant DEB (DDEB) has pronounced extensor surface involvement, angular contractures, dysphagia, nail dystrophy, partial alopecia of scalp and body, and clawlike deformities of the hands (Figure 4). The recessive DEB of Hallopeau-Siemens (RDEB-HS) presents in 3 forms-generalized, localized, and inverse-and tends to be more severe than the dominant form. RDEB-HS is characterized by esophageal strictures, dental complications, and a mittenlike deformity of the hands. Systemic amyloidosis and cutaneous squamous cell carcinomas arc also associated with RDEB-HS.

Pathogenesis

The majority of patients with EBS have keratin-5 and keratin-14 defects, which are expressed by basal keratinocytes.3,4 These defects disrupt the intricate network of intermediate filaments of the basal keratinocytes and cause a lack of epidermal cohesion. EBS-MD is an exception. Its defect is in the plectin protein found within skin and muscles. The exact chromosomal loci have not been determined; however, a relationship has been discovered with chromosomes 1 and 8. A biochemical defect in galactosylhydroxylsyl glucosyltransferase, an enxyme catalyzing the glucosylation of galactosylhydroxysyl residues during collagen synthesis, has been found in some families with EBS.2,5

Laminin-5 is involved in the cohesion of the anchoring fibrils of the basement membrane,3,4 which helps anchor the basement membrane and epidermis. Most patients with JEB have defects in laminin-5. EB lethalis is caused by mutations in the LAMA3, LAMB3, and LAMC2 genes, which code for laminin-5. LAMB3 has been localized to chromosome 1. JEB-PA has a defect in the [alpha]-6-[beta]-4 integrin complex, which is expressed on epithelial surfaces. GABEB has a defect in the COL17A1 gene encoding type XVII collagen, a transmembrane component of hemidesmosomes. One patient has been discovered with a biochemical defect that increases collagenase activity.2,5

Mutations in COL7A1, the gene encoding collagen type VII, have been discovered in patients with DEB.3,4 Type VII collagen is a major component of dermal anchor fibrils. The COL7A1 gene has been located on chromosome 3 through genetic linkage studies with restriction fragment length polymorphism. The anchoring fibrils may be absent, abnormal, or decreased in amount, depending on the variant of DEB. Increased synthesis of collagenase has also been linked to recessive DEB (RDEB) and increased synthesis and glycosaminoglycan (GAG) accumulation have been linked to DDEB.2,5 GAG accumulation is thought to alter collagen fibril deposition, impairing the structural integrity of the skin.

Diagnosis

History and physical examination are important in EB diagnosis.1 A skin biopsy can rule out other potential causes of blister and erosion formation. Although simple skin biopsy for hematoxylin and eosin staining may be helpful in determining the cleavage plane, the changes are often too subtle to be detected. A biopsy for indirect imimmofluorescence (IIF) can help determine the level of tissue separation; however, electron microscopy of the tissue is the gold standard for diagnosis. Unfortunately, electron microscopy is expensive and has a waiting period for results. IIF can determine the level of blistering and lead to EB diagnosis. Mapping the proteins in the skin and determining where the cleavage is located may help in diagnosis.

Other laboratory tests may help determine those conditions associated with certain EB variants.2 Patients with JEBL can have anemia; therefore, complete blood counts and iron studies should be ordered. High levels of carcinoembryonic antigen have been found in patients with JEBL and RDEB. These levels correlate with disease severity.

Recently, fetoscopy performed at 18 to 20 weeks has achieved prenatal diagnosis for all major EB forms.6 Chorionic villi sampling and amniocentesis during the first trimester of pregnancy have been successful in diagnosing JEB and RDEB.6

Treatment

Wound care, nutritional support, infection control, prevention of trauma, blood transfusion and iron supplements for anemia, and blister therapy arc essential treatments for patients with EB.1,2,7,8 Because the skin is fragile, children should be protected from trauma during normal daily activities, play, and even wound care to inhibit the progression of blistering. To prevent trauma during dressing changes, dressings should be soaked, never pulled off when the skin is dry.6 The patient's skin should be gently patted dry with a soft, nonabrasive towel or dried with a hair dryer set on low heat. Nonadherent, soft gauze dressings should be secured with tape; however, the tape should never touch the skin.

Topical antibiotics should be used on all wounds to prevent infection and alternated every 2 to 3 months. If a wound becomes infected, oral or intravenous antibiotics might be indicated and should be chosen based on bacterial cultures. When blisters appear, fluid should be withdrawn with a sterile syringe with needle, relieving pressure and subsequent trauma.

Patients with EB have an increased metabolic rate and demand, an increased loss of muscle mass and nitrogen, and hypoalbuminemia due to loss of skin integrity.7,8 This protein malnutrition can lead to profound immune dysfunction and susceptibility to infection. Care must be exercised when considering whether to augment protein/nutrient intake with a nasogastric tube because of mucosal fragility. If tube placement is necessary copious lubrication is required. Gastrostomy tubes are sometimes used. Vitamin and iron supplements can be liquefied in a blender to prevent any inadvertent trauma from swallowing the large tablets.2 Extensive and continuous use of iron tablets, however, can worsen the constipation common in patients with EB.6 Intravenous iron dextran is a viable alternative.

Topical therapy with steroids and glutaraldehyde creams have been of benefit to certain patients,2 aiding in rapid healing of the blisters.

Successful systemic therapies include vitamin E, steroids, phcnytoin, and chloroquine.2 Vitamin E reduces collagenase activity, decreasing blister formation; however, there are only a few reports in the literature. Steroids also decrease blister formation, but relapse is inevitable when the steroids are tapered. Long-term steroid use can have significant complications in patients susceptible to infections with poor wound healing abilities. Phenytoin decreases collagenase activity; however, its use has been controversial. Caldwell-Brown et al9 completed a randomized, double-blind, placebo-controlled, crossover trial involving phenytoin for patients with EB. Phenytoin did not reduce blistering or erosions and appears to be ineffective in EB treatment. The mechanism of action of chloroquine is unknown and, although reports are limited, it has shown success.

Surgical intervention should be considered in certain circumstances. Esophageal strictures can be treated with colonie interposition more safely than with balloon dilation.1,2 The mitten deformity common in certain EB variants represents a great therapeutic challenge.1,2,10 The process involves degloving and separating the digits, followed by incision of interphalangeal joints to release the contractures. Split- or full-thickness skin grafts can speed wound healing. After several days, splints are placed to prevent future contractures, and the patient may begin occupational therapy to enhance mobility.

A bilayered cellular matrix (BCM)11 (OrCel, Composite Cultured Skin; Ortec International, Inc, New York, NY) was approved by the Food and Drug Administration (FDA) in 2001 for wound treatment after surgical release of mitten hand deformities.12 In a randomized controlled trial, 12 patients with JEB or DEB demonstrated reduced need for autograft harvesting with the use of the BCM.12

Apligraf (Graftskin) (Organogencsis, Inc, Canton, MA),13-15 a bilayered, tissue engineered, living skin equivalent (LSE) cultured from human neonatal foreskin keratinocytes and fibroblasts, has successfully treated several different wound types. However, Apligraf is FDA approved only for treatment of venous and diabetic ulcers. The LSE is morphologically similar to real skin, but is devoid of Langerhans' cells (making it immunologically inert), vessels, and appendages. The LSE acts as a physical wound covering, stimulates rapid healing through cytokine delivery, and decreases pain without significant adverse effects. Falabella et al14 reported successful use of Apligraf in 1 neonate with EBS-DM; most treated areas healed without any new blister formation. Falabella et al13 then used Apligraf to treat 15 additional patients with EB. Apligraf successfully reduced pain and rapidly healed the wounds of these patients. This rapid wound healing can prevent infection, which might otherwise lead to sepsis and death.

Current investigation into gene replacement therapy1,4 has not been successful to date, despite almost 200 clinical trials. However, there is much hope for the future.

References

1. Haber RM, Hanna W, Ramsay CA, Boxall LB. Hereditary epidermolysis bullosa. J Am Acad Dermatol 1985;13:252-78.

2. Marinkovich MP. Update on inherited bullous dermatoses. Dermatol Clin 1999;17:473-85.

3. Fine JD, Eady RA, Bauer EA, et al. Revised classification system for inherited epidermolysis bullosa: report of the second International Consensus Meeting on Diagnosis and Classification of Epidermaolysis Bullosa. J Am Acad Dermatol 2000;42:1051-66.

4. Uitto J, Christiano AM. Inherited epidermolysis bullosa. Clinical features, molecular genetics, and pathoetiologic mechanisms. Dermatol Clin 1993;11:549-63.

5. Thiers BH. The mechanobullous diseases: hereditary epidermolysis bullosa and epidermolysis bullosa acquisita. J Am Acad Dermatol 1981;5:745-8.

6. Lin AN. Management of patients with epidermolysis bullosa. Dermatol Clin 1996;14:381-7.

7. Gruskay DM. Nutritional management in the child with epidermolysis bullosa. Arch Dermatol 1988;124: 760-1.

8. Gamelli RL. Nutritional problems of the acute and chronic burn patient. Arch Dermatol 1988;124:756-9.

9. Caldwell-Brown D, Stern RS, Lin AN, Carter DM. Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa. N Engl J Med 1992;327:196-7.

10. Greider JL, Flatt AE. Surgical restoration of the hand in epidermolysis bullosa. Arch Dermatol 1988;124:765-7.

11. Martin LK, Kirsner RS. Use of a meshed bilayered cellular matrix to treat a venous ulcer. Adv Skin Wound Care 2002;15:260-4.

12. Silberklang M. Mechanisms of wound healing: studies with the bilayered cellular matrix, OrCel (manufacturer's information). New York, NY: Ortec International Inc; 2002.

13. Falabella AF, Valencia IC, Eaglstein WH, Schachner LA. Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds. Arch Dermatol 2000;136:1225-30.

14. Falabella AF, Schachner LA, Valencia IC, Eaglstein WH. The use of tissue-engineered skin (Apligraf) to treat a newborn with epidermolysis bullosa. Arch Dermatol 1999;135:1219-22.

15. Fine JD. Skin bioequivalents and their role in the treatment of inherited epidermolysis ullosa. Arch Dermatol 2000;136:1259-60.

Jennifer T. Trent, MD, and Robert S. Kirsner, MD

Jennifer T. Trent, MD, is Resident, Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, FL. Robert S. Kirsner, MD, is Associate Professor, Department of Dermatology and Cutaneous Surgery and Department of Epidemiology and Public Health, University of Miami School of Medicine, Miami, FL, and Chief of Dermatology, Veterans Administration Medical Center, Miami, FL.

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