Epidermolysis bullosa (EB) refers to a family of rare genodermatoses characterized by an inherited tendency toward recurrent cutaneous and mucosal blistering at sites of mechanical trauma. According to the National Epidermolysis Bullosa Registry, EB affects approximately 12,500 individuals in the United States, with an incidence of 50 new EB cases per 1 million live births annually.¹

Historically, EB has been classified into a variety of subtypes based on clinical findings, and a growing number of eponyms and otherwise distinctive EB variants have been described in the literature. The current classification system, however, which was revised in 2008, divides EB into four major types based on the ultrastructural level of blister formation: EB simplex, junctional EB (JEB), dystrophic EB, and Kindler syndrome.² In general, patients with EB simplex have a milder phenotype, and patients with junctional and dystrophic EB have a more severe phenotype; however, there are particularly severe variants of EB simplex, as well as milder forms of junctional and dystrophic EB. Kindler syndrome is a very rare EB variant characterized by recurrent blistering, photosensitivity, cutaneous atrophy, poikiloderma, and systemic complications due to mucosal blistering.

Depending on the particular genotype, the clinical manifestations of EB may range from minimal blistering of the hands and feet to severe, widespread, mutilating blistering that can involve the epithelial mucosa of other organ systems. Although all patients with EB are at risk for complications such as pain, infection, and scarring, those with more severe variants are also at risk for a multitude of chronic morbidities, including nutritional deficiencies and failure to thrive, severe scarring and contractures, cutaneous squamous cell carcinomas, laryngeal complications, esophageal strictures, and ocular complications that may lead to blindness.^3,4

The care of a patient with EB involves a multidisciplinary approach and must incorporate a variety of lifestyle modifications and specialized skin care to minimize disease severity and complications. Some of the acute and chronic complications associated with EB lead to hospitalization for inpatient management. In addition, hospitalists may be involved with the initial presentation of EB in the neonate or young infant.

Hospital management of a patient with EB requires a comprehensive understanding of the expected clinical features, severity, and complications based on the type of EB present. For example, when caring for a patient with RDEB, it is imperative to know what is generally considered “normal” to see on physical examination. Interpreting clinical information in an appropriate context is essential for providing the highest level of complex care, especially in patients with more severe types of EB. In addition, as a general hospitalist, it is also vital to remember that individuals with EB are also susceptible to other diseases or conditions that may be seen in the general population. It is therefore important to consider all potential etiologies of the patient’s presenting symptoms when formulating a differential diagnosis and to avoid the temptation to explain every sign and symptom as “part of having EB.”

PATHOPHYSIOLOGY

The various subtypes of EB result from mutations in one of over ten known associated genes, all of which encode ultrastructural protein components of the dermal–epidermal junction (Table 67-1). The three most commonly recognized EB types—EB simplex, JEB, and dystrophic EB—involve either intraepidermal, intra-lamina lucida, or sublamina densa blister formation, respectively (Figure 67-1). Kindler syndrome, a rare subtype of EB, involves blister formation involving multiple cleavage planes. Disruption of the integrity of the basement membrane zone or suprabasal cell–cell adhesion desmosomal proteins in affected tissues results in mechanical fragility of the skin and, in some forms of EB, extracutaneous mucosa. Affected patients are predisposed to the development of recurrent blisters, erosions, ulcers, and nonhealing wounds. Inheritance of EB may be either autosomal dominant, as in most forms of EB simplex and in dominant dystrophic EB (DDEB), or autosomal recessive, as in JEB and RDEB.

The hospitalist can most skillfully care for EB patients by understanding the typical presentation and clinical course of each of the different types of EB. For example, recessive dystrophic EB (RDEB) manifests as severe, chronic, progressive cutaneous and extracutaneous blistering that results in significant risk of scarring and associated complications of the skin, eyes, gastrointestinal tract, genitourinary tract, and respiratory tract as well as chronic pain and failure to thrive, among other concerns. In contrast, patients with DDEB typically manifest chronic, recurrent cutaneous blistering that favors the extremities but have minimal associated risk of extracutaneous complications. A thorough understanding of overall disease severity based on EB type and of the acute and chronic complications associated with each type of EB better equips the hospitalist to provide the most appropriate medical care to affected patients and their families.

Skin and mucosal blistering, the cardinal clinical features of EB, may be present at birth, may develop shortly after birth or in early infancy, or may less commonly present later in childhood, adolescence, or young adulthood. It is typically very difficult to reliably predict the type of EB present in a newborn or young infant who develops cutaneous blistering based on clinical examination alone; skin biopsy is generally needed for definitive diagnosis. Onset of cutaneous blistering later in childhood, adolescence, or adulthood is typically seen either with limited forms of EB simplex or with DDEB.

EB simplex is characterized by localized or generalized cutaneous blistering without significant involvement of the mucosal epithelia, although superficial erosions involving the oral cavity may be seen. Due to the superficial, intraepidermal localization of blisters to the basal or suprabasal layers, blisters may rupture quickly and present as erosions. Cutaneous blisters associated with EB simplex usually heal without scarring (Figure 67-2). Milia, though classically associated with dystrophic forms of EB, are also encountered in EB simplex, but with less frequency. Other abnormalities may include dystrophic nails, hypotrichosis, and focal or diffuse keratoderma of the palms and soles. Failure to thrive, constipation, and anemia may be seen in more severely affected patients. Some patients with EB simplex may not present with blistering until later childhood or early adulthood (Figure 67-3). Inheritance is usually autosomal dominant, although rare autosomal recessive subtypes have been reported, including EB simplex with muscular dystrophy. Rare variants of EB simplex include EB simplex with muscular dystrophy and EB simplex with pyloric atresia.

JEB typically presents at birth with generalized blistering, although more localized variants may be seen (Figure 67-4). Inheritance is autosomal recessive and blisters form within the basement membrane zone at the level of the lamina lucida. Patients with JEB are at significant risk for extracutaneous involvement of the ocular, gastrointestinal, genitourinary, and respiratory systems, which may result in blistering and stricture formation. Affected patients are therefore at increased risk for nutritional compromise, failure to thrive, anemia, respiratory complications, infection, and sepsis. Associated findings include atrophic scarring, exuberant granulation tissue, dystrophic or absent nails, milia formation, significant dental enamel hypoplasia with dental caries, and scalp abnormalities. Patients with the more severe subtype, JEB-Herlitz, usually do not survive infancy, whereas those with the non-Herlitz subtype display some clinical improvement with age. JEB with pyloric atresia and laryngo-oculo-cutaneous syndrome are rare, severe variants.

Dystrophic EB involves blister formation below the level of the basement membrane zone within the dermis. Inheritance may be autosomal dominant or autosomal recessive. Dystrophic EB typically presents at birth or during infancy with either localized or generalized blistering. RDEB presents at birth with generalized blistering that results in significant, severe scarring, including progressive scarring of the hands and feet that leads to pseudosyndactyly and flexion contractures (Figure 67-5). Significant systemic involvement of the gastrointestinal, genitourinary, and respiratory tracts, leading to malabsorption, anemia, dysphagia, esophageal strictures, urethral strictures, stridor, tracheolaryngeal stricture, and failure to thrive, among other complications, is the norm. (Table 67-2) Patients with RDEB also have a significant risk of developing squamous cell carcinoma of the skin, corneal ulcerations and scarring, and dental caries. Other complications include cardiomyopathy, glomerulonephritis, chronic renal failure, and osteoporosis. DDEB generally has a milder phenotype, with less significant systemic involvement and a tendency toward reduced blistering with advancing age. Milia formation and dystrophic or absent nails are commonly seen. Systemic complications such as ocular complications, genitourinary complications, and respiratory tract involvement are not generally seen with DDEB. A rare variant of dystrophic EB is bullous dermolysis of the newborn, which presents at birth with generalized blisters. Although atrophic scarring, nail dystrophy, and milia are commonly seen, blistering typically resolves during infancy and systemic complications, other than excessive caries formation, are not seen.

Kindler syndrome is a very rare autosomal recessive disorder that typically presents at birth with generalized blisters. It is characterized by blister formation involving multiple cleavage planes, generalized skin fragility and blistering, cutaneous atrophy, photosensitivity, and poikiloderma. Systemic complications include esophageal strictures, chronic diarrhea and malabsorption, urethral strictures, gingival hyperplasia, and periodontitis. Patients with Kindler syndrome have an increased risk for the development of mucocutaneous squamous cell carcinoma.

Although some subtypes of EB may improve with age, it is generally a chronic disease punctuated by recurrent exacerbations of cutaneous and mucosal blistering and, for patients with junctional and RDEB, both acute and chronic systemic complications. In those with the more severe forms of EB, life expectancy can be significantly reduced as a result of failure to thrive, recurrent infections, laryngeal complications, and sepsis during infancy. Mortality in early adulthood is usually the result of aggressive squamous cell carcinoma. Patients with milder forms of EB may have a normal life expectancy.

The differential diagnosis of blistering disorders in neonates and infants is extensive and includes other inherited diseases characterized by skin blistering or erosions, infectious diseases, and immunobullous disorders (Table 67-2). Common disorders to be considered include herpes simplex virus infection, staphylococcal scalded skin syndrome, bullous impetigo, traumatic blisters, and child abuse. A general approach to the initial evaluation of a neonate or infant with cutaneous and/or mucosal blistering and suspected EB is presented in Algorithm A (Figure 67-6).

Where possible, evaluation of the neonate or infant with cutaneous blistering should be directed by a clinician with expertise in EB given the complexity of diagnosis and prognosis. Proper diagnosis of EB depends on identifying the ultrastructural localization of blister formation in the skin and on excluding other causes of blistering disease.⁴ A skin biopsy for routine histology may help exclude other blistering diseases; however, use of more specific diagnostic testing, in particular immunofluorescence mapping (IFM), has replaced the use of routine histology for the diagnosis and classification of the different types of EB.

Optimal sensitivity of diagnostic testing by IFM for EB requires sampling of a freshly induced blister in the skin. When EB is suspected, a freshly induced blister can be created by using a pencil eraser held against the skin with moderate pressure and rotated several times with a twisting motion, thus creating a shear force that results in separation of the dermal–epidermal junction, and blister formation. The skin biopsy should be performed at the edge of the blister. Where possible, the specimen(s) should be processed for examination under both light microscopy and IFM of the basement membrane zone in order to facilitate the diagnosis of the type of EB present. Historically, use of transmission EM was commonly used in the diagnostic evaluation of EB; however, the technical expertise required to process and interpret EM with regard to EB is available in only a limited number of laboratories. IFM, which uses a panel of antibodies to basement membrane components and allows the ultrastructural level of the blister to be determined precisely, is more readily available, less expensive, and allows for more rapid results than EM; it may also allow for the detection of relative loss of expression of the affected protein. Specific molecular diagnostic DNA mutation analysis is helpful in confirming a diagnosis of EB and correctly identifying the EB type; however, genotype-phenotype correlation is highly variable and the expense of DNA testing is often prohibitive. Therefore the greatest utility of DNA testing at this time is for consideration for prenatal counseling.

The majority of EB patients requiring hospitalized care are those with severe generalized RDEB, and therefore much of the following discussion pertains to this specific EB patient population. Patients with more severe forms of JEB, in particular JEB-Herlitz, may also require hospitalization, and may suffer from similar complications. RDEB is debilitating and progressive, and results in a perpetual inflammatory state. Directly or indirectly, nearly every organ system is affected. The high degree of morbidity leads to frequent need for hospital care, especially in older children, adolescents, and young adults.

Hospitalists should approach patients and families with the understanding that they may have suffered traumatic healthcare encounters in the past due to an unfortunate lack of familiarity with EB on the part of many healthcare providers, which can result in suboptimal care and iatrogenic complication. Patients and caregivers may therefore be nervous or frightened while in the hospital. The astute hospitalist will gain trust and rapport by first acknowledging that the family may know much more about the disease and also by reassuring the patient, especially if a younger child, that providers will not touch him/her without first explaining what to expect. It can be helpful to ask the patient or the caregiver how to touch, move, or manipulate the patient during an examination in order to minimize pain and discomfort. Finally, it is important to realize that the patient and caregivers are experts in managing the day-to-day dressing changes and skin care. Practicing these behaviors, as well as modeling them to other providers, will increase the chance that patients and families are comfortable, and lessen the chance of undesirable, traumatic experiences.

There are no therapies that consistently reduce blister formation in patients with EB. As a chronic, and in some cases multisystem disease, management of patients with EB focuses on the prevention and treatment of skin blistering and infections, pain management, and on careful monitoring for EB-related complications, particularly in patients with JEB and RDEB (see Table 67-3). Although children with EB may be hospitalized for a variety of EB-related complications, they may also be admitted for non-EB indications. The inpatient team should be aware of the myriad complications and issues that may arise with EB patients as well as with general principles of skin and wound care for patients with EB. Additionally, it is important for providers to modify certain hospital interventions such as intravenous catheter placement, intubation, and bladder catheterization in order to prevent iatrogenic damage to the skin or other affected organs.