Epidermolysis bullosa (EB) is a group of inherited bullous disorders characterized by blister formation in response to mechanical trauma. Historically, EB subtypes have been classified according to skin morphology. Recent discoveries of the molecular basis of EB have resulted in the development of new diagnostic tools, including prenatal and preimplantation testing. Based on a better understanding of the basement membrane zone (BMZ) and the genes responsible for its components, new treatments (eg, gene or protein therapy) may provide solutions to the skin fragility found in patients with EB.
Pathophysiology: EB is classified into 3 major categories, including (1) EB simplex (EBS; intraepidermal skin separation), (2) junctional EB (JEB; skin separation in lamina lucida or central BMZ), and (3) dystrophic EB (DEB; sublamina densa BMZ separation; see Images 5-6). Researchers recently have proposed a new category termed hemidesmosomal EB (HEB), which produces blistering at the hemidesmosomal level in the most superior aspect of the BMZ. EBS usually is associated with little or no extracutaneous involvement, while the more severe hemidesmosomal, junctional, and dystrophic forms of EB may produce significant multiorgan system involvement.
Significant progress has been achieved in finding specific molecular therapies for EB, including protein and gene therapy. Type VII collagen and laminin-5 gene therapy have been proven effective through in vivo models. Type VII collagen protein therapy has similarly been shown to be effective in an in vivo model. Currently, these therapies are being extensively studied at the preclinical stage, in animal models.
Frequency:
In the US: Assuming that mild cases of EBS are reported only 10% of the time, the affected population in the United States is approximately 12,500 persons. According to a National Epidermolysis Bullosa Registry report, 50 EB cases occur per 1 million live births. Of these cases, approximately 92% are EBS, 5% are DEB, 1% are JEB, and 2% are unclassified. Patients with HEB probably constitute much less than 1% of total EB cases.
Internationally: According to the National Epidermolysis Bullosa Registry, the number of EB cases in Norway is 54.0 cases per million live births, in Japan is 7.8 cases per million live births, and in Croatia is 9.6 cases per million live births.
Mortality/Morbidity: Infancy is an especially difficult time for EB patients. Generalized blistering caused by any subtype may be complicated by infection, sepsis, and death. Severe forms of EB increase the mortality risk during infancy. Patients with the Herlitz or letalis form of JEB have the highest risk during infancy with an estimated mortality rate of 87% during the first year of life. In patients with EB that survive childhood, the most common cause of death is metastatic squamous cell carcinoma (SCC) (see Image 9). This skin cancer occurs specifically in patients with recessively inherited EB (RDEB) who most commonly are aged 15-35 years. In contrast, dominantly inherited EBS and DEB and milder forms of JEB may not affect a patient's life expectancy adversely.
Age: Onset of EB is at birth or shortly after. The exception occurs in mild cases of EBS, which may remain undetected until adulthood or occasionally remain undiagnosed.
History: Important general points include age of onset; size, frequency, and location of blisters; possible inciting factors; prior diagnostic attempts; prior therapies; and extent of pain or pruritus.
Review of systems information that can be associated with different EB subtypes includes alteration of growth or development and evidence of mucosal involvement, including oral, nasopharyngeal, ocular, genitourinary, GI, or respiratory symptoms. A family history of blistering disease is an important finding to identify (see Image 8).
Physical: Perform a complete physical examination with an emphasis on inspection of all skin, as well as conjunctival, oral, and genital mucosae. Evaluate the size, location, and character of blisters. Attempt to assess the general level at which lesions split. Usually, superficial blisters manifest as crusted erosions, intraepidermal blisters are flaccid and may expand under pressure, and intralamina lucida blisters are tense and heal with atrophy but no scarring. Sublamina densa blisters heal with scarring and milia formation. Assess for involvement of nails, hair, or teeth.
EBS is a collection of keratin disorders characterized by intraepidermal blistering with relatively mild internal involvement. Lesions typically heal without scarring. Most commonly, these diseases are dominantly inherited, but recessively inherited cases have been reported. The more severe EBS subtypes include Koebner, Dowling-Meara, and Weber-Cockayne forms. An EBS variant associated with mottled pigmentation has been described in several families.
Mild EBS: Weber-Cockayne subtype is the most common form of EBS (see Image 1). Blisters usually are precipitated by a clearly identified traumatic event. They can be mild to severe and most frequently occur on the palms and soles. Hyperhidrosis can accompany this disorder.
Severe EBS: Usually, a generalized onset of blisters occurs at or shortly after birth. Hands, feet, and extremities are the most common sites of involvement. Palmoplantar hyperkeratosis and erosions are common, especially in Koebner EBS (see Images 2-3). Dowling-Meara EBS involves more oral mucosa and manifests with grouped herpetiform blisters (hence the term EBS herpetiformis).
HEB includes 2 rare diseases. The first arises from a disorder of the protein plectin (HD1) and is associated with muscular dystrophy. The second arises from a defect of the a6b4 integrin receptor and is associated with pyloric atresia. Each disease shows intraepidermal blistering at the most basal aspect of the lower cell layer.
EB with muscular dystrophy: This condition is characterized initially by variable blistering activity, followed by onset of muscular dystrophy later in life. The degree of blistering activity does not correlate necessarily with the degree of muscular dystrophy. Some patients can present with dental abnormalities.
EB with pyloric atresia: This condition always is associated with pyloric atresia at birth and usually is accompanied by severe generalized blistering. In most patients, prognosis is poor despite correction of the pyloric atresia because the internal involvement is extensive. While this subtype typically is fatal during infancy, some patients with a milder case of the disease have survived into childhood.
JEB is a collection of diseases characterized by intralamina lucida blistering. Primary subtypes include a lethal subtype termed Herlitz or JEB letalis, a nonlethal subtype termed JEB mitis, and a generalized benign type termed generalized atrophic benign EB (GABEB).
Lethal JEB: The Herlitz or letalis form of JEB is characterized by generalized blistering at birth and arises from an absence or a severe defect in expression of the anchoring filament glycoprotein laminin 5 (see Image 4). Patients with lethal forms of JEB show characteristic periorificial erosions around the mouth, eyes, and nares, often accompanied by significant hypertrophic granulation tissue. Multisystemic involvement of the corneal, conjunctival, tracheobronchial, oral, pharyngeal, esophageal, rectal, and genitourinary mucosae is present. Internal complications of the disease include a hoarse cry, cough, and other respiratory difficulties. Patients with Herlitz JEB are at increased risk for death from sepsis or other complications secondary to the profound epithelial disadhesion, and usually, they do not survive past infancy.
Nonlethal JEB: Patients with JEB manifesting generalized blistering who survive infancy and clinically improve with age have JEB mitis. Usually, these patients do not present with the same type of hoarse cry or other significant respiratory symptoms as do patients with the Herlitz form. Instead, scalp, nail, and tooth abnormalities increasingly may become apparent. Periorificial erosions and hypertrophic granulation tissue can be present. Mucous membranes often are affected by erosions, resulting in strictures. Some patients with JEB mitis can present with blistering localized to the intertriginous regions.
GABEB: This is a relatively mild subtype characterized by generalized cutaneous blistering and presenting at birth. Blistering activity is worsened by increased ambient temperature, and blisters heal with a distinctive atrophic appearance. Extracutaneous involvement is rare, with the exception of teeth. Hypoplastic enamel formation results in significant tooth decay. Nail dystrophies and alopecia are other common clinical manifestations. Individuals with GABEB have the potential to bear children and have a typical life expectancy.
DEB is a group of diseases caused by defects of anchoring fibrils. Blisters heal followed by dystrophic scarring. Formation of milia (1- to 4-mm white papules) results as a consequence of damage to hair follicles.
Dominantly inherited DEB: The onset of disease usually is at birth or during infancy, with generalized blistering as a common presentation. With increasing age, an evolution to localized blistering is present. A common variant described by Cockayne-Touraine has an acral distribution and minimal oral or tooth involvement. Another variant described by Pasini features more extensive blistering, scarlike papules on the trunk (termed albopapuloid lesions), and involvement of the oral mucosa and teeth. Dystrophic or absent nails are common in both of these dominantly inherited DEB variants.
RDEB: This group of diseases ranges from mild to severe in presentation.
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