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Epidermolysis Bullosa Clinical Presentation

  • Author: M Peter Marinkovich, MD; Chief Editor: William D James, MD  more...
 
Updated: Jan 08, 2014
 

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 epidermolysis bullosa 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, which is demonstrated in the image below.

Recessively inherited dystrophic epidermolysis bul Recessively inherited dystrophic epidermolysis bullosa, oral cavity blistering and scarring
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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.

Epidermolysis bullosa simplex

Epidermolysis bullosa simplex 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 epidermolysis bullosa simplex subtypes include Koebner, Dowling-Meara, and Weber-Cockayne forms. An epidermolysis bullosa simplex variant associated with mottled pigmentation has been described in several families.

Mild epidermolysis bullosa simplex

Weber-Cockayne subtype is the most common form of epidermolysis bullosa simplex. 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. The Weber-Cockayne subtype is shown in the image below.

Epidermolysis bullosa simplex, Weber-Cockayne subt Epidermolysis bullosa simplex, Weber-Cockayne subtype. This mild bullous disease is characterized by localized blistering at sites of trauma such as the feet.

Severe epidermolysis bullosa simplex

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 epidermolysis bullosa simplex. Dowling-Meara epidermolysis bullosa simplex involves more oral mucosa and manifests with grouped herpetiform blisters (hence the term epidermolysis bullosa simplex herpetiformis).The Koebner subtype is shown in the images below.

Epidermolysis bullosa simplex, Koebner subtype. Pa Epidermolysis bullosa simplex, Koebner subtype. Palmoplantar blistering and hyperkeratosis are noted.
Epidermolysis bullosa simplex, Koebner subtype. Cl Epidermolysis bullosa simplex, Koebner subtype. Close-up image shows hyperkeratotic papules and plaques on the palm.

Hemidesmosomal epidermolysis bullosa

Hemidesmosomal epidermolysis bullosa describes blistering at the lowest aspect of the basal keratinocyte layer at the level of the attachment structures that fasten the basal epidermis to the basement membrane, termed hemidesmosomes. This subtype 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. It should be noted that the most recent classification consensus conference on epidermolysis bullosa separates epidermolysis bullosa with muscular dystrophy into the simplex category, while placing epidermolysis bullosa with pyloric atresia into the junctional category.

Epidermolysis bullosa 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. This disorder can sometimes be associated with pyloric atresia. Some patients can present with dental abnormalities.

Epidermolysis bullosa 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.

Junctional epidermolysis bullosa

Junctional epidermolysis bullosas is a collection of diseases characterized by intralamina lucida blistering. Primary subtypes include a lethal subtype termed Herlitz or junctional epidermolysis bullosa letalis, a nonlethal subtype termed junctional epidermolysis bullosa mitis, and a generalized benign type termed generalized atrophic benign epidermolysis bullosa.

Lethal junctional epidermolysis bullosa

The Herlitz or letalis form of junctional epidermolysis bullosa 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. Patients with lethal forms of junctional epidermolysis bullosa 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 junctional epidermolysis bullosa 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. The Herlitz subtype is shown in the image below.

Junctional epidermolysis bullosa, Herlitz subtype. Junctional epidermolysis bullosa, Herlitz subtype. This severe disease is characterized by generalized intralamina lucida blistering at birth, significant internal involvement, and a poor prognosis.

Nonlethal junctional epidermolysis bullosa

Patients with junctional epidermolysis bullosa manifesting generalized blistering who survive infancy and clinically improve with age have junctional epidermolysis bullosa 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 junctional epidermolysis bullosa mitis can present with blistering localized to the intertriginous regions.

Generalized atrophic benign epidermolysis bullosa

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 generalized atrophic benign epidermolysis bullosa have the potential to bear children and have a typical life expectancy. It should be noted that generalized atrophic benign epidermolysis bullosa is lumped together with nonlethal junctional epidermolysis bullosa in the newest epidermolysis bullosa classification consensus; however, it is clear that these 2 diseases are quite distinct clinically.

Dystrophic epidermolysis bullosa

This 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 dystrophic epidermolysis bullosa

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 dystrophic epidermolysis bullosa variants.

Recessively inherited epidermolysis bullosa

This group of diseases ranges from mild to severe in presentation.

A localized form, termed recessively inherited epidermolysis bullosa mitis, often involves acral areas and nails but shows little mucosal involvement. This subtype also demonstrates clinical manifestations similar to the dominantly inherited forms of dystrophic epidermolysis bullosa.

Severe recessively inherited epidermolysis bullosa, as described by Hallopeau-Siemens, usually shows generalized blistering at birth and subsequent extensive dystrophic scarring that is most prominent on the acral surfaces. This can produce pseudosyndactyly (mitten-hand deformity) of the hands and feet. Flexion contractures of the extremities are increasingly common with age. Nails and teeth also are affected. Involvement of internal mucosa can result in esophageal strictures and webs, urethral and anal stenosis, phimosis, and corneal scarring. Malabsorption commonly results in a mixed anemia resulting from a lack of iron absorption, and overall malnutrition may cause failure to thrive (see Diet). Patients with severe recessively inherited epidermolysis bullosa who survive to childhood are at significant risk of developing aggressive SCC in areas of chronic erosions. Pseudosyndactyly is shown in the image below.

Recessively inherited dystrophic epidermolysis bul Recessively inherited dystrophic epidermolysis bullosa pseudosyndactyly (mitten-hand deformity) of the hands and feet

Ectodermal dysplasia-skin fragility syndrome is a rare disorder characterized by skin erosions, skin fragility and peeling beginning at birth or infancy that may be accompanied by alopecia, palmoplantar keratoderma, painful fissures, and nail dystrophy. Failure to thrive, cheilitis, hypohidrosis, and pruritus are other potential complications. The underlying molecular defect has been shown to be loss of function of the desmosomal protein plakophillin 1. Plakophillin is expressed mainly in suprabasilar keratinocytes and outer root sheath cells. Microscopic findings in this disease usually show intraepidermal acantholysis, located in the areas where plakophillin 1 is normally expressed. The molecular defect involves loss of function mutations in the PKP1 gene coding for plakophillin 1.[7]

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Causes

Many stratified squamous epithelial tissues, such as the skin and oral mucosa, contain a complex BMZ. The BMZ is composed of many specialized components that combine to form anchoring complexes. At the superior aspect of the BMZ, keratin-containing intermediate filaments of the basal cell cytoskeleton insert on basal cell plasma membrane condensations termed hemidesmosomes. Anchoring filaments extend from the basal cell plasma membrane into the extracellular environment and span the lamina lucida, connecting hemidesmosomes with the lamina densa. At the most inferior aspect of the BMZ, type VII collagen-containing anchoring fibrils extend from the lamina densa into the papillary dermis, connecting the lamina densa to anchoring plaques, trapping interstitial collagen fibrils. Thus, the cutaneous BMZ connects the extensive basal cell cytoskeletal network with the abundant network of interstitial collagen fibrils in the dermis.

Keratin filaments

Keratins 5 and 14 combine to form intermediate filaments in basal keratinocytes. Keratins contain a central alpha-helical rod with several nonhelical interruptions, as well as nonhelical carboxyterminal and aminoterminal regions. The regions of highest conservation between the keratins are located on the ends of the keratin rod in the helix boundary motifs. Keratin intermediate filaments insert upon electron-dense structures termed hemidesmosomes.

Hemidesmosomes

These structures contain intracellular proteins, including plectin and BP230. Plectin (HD1) is a 500-kd protein that binds intermediate filaments. BP230, also termed BPAG1, is a 230-kd protein that has homology to both desmoplakin and plectin. BP230, like plectin, functions in the connection between hemidesmosomes and intermediate filaments. Hemidesmosomes also contain the intracellular portions of the transmembrane proteins collagen XVII (BP180) and alpha-6-beta-4 integrin. The beta-4 integrin subunit performs a central role in hemidesmosome formation and contains an especially large cytoplasmic domain, which interacts with other proteins of the hemidesmosomal plaque. Collagen XVII is a transmembrane collagenous protein that interacts with alpha-4 integrin and BP230 intracellularly and with laminin 5 extracellularly.

Anchoring filaments

These structures contain the extracellular portions of collagen XVII (BP180) and alpha-6-beta-4 integrin. In addition, anchoring filaments contain the molecules laminin 5 and laminin 6. Similar to all members of the family of laminin proteins, laminin 5 is a large heterotrimeric molecule, containing alpha-3, beta-3, and gamma-2 chains. Laminin 5 forms a disulfide-bonded attachment to laminin 6, the other known anchoring filament laminin, which contains alpha-3, beta-1, and gamma-1 chains. Laminin 5 also forms a strong association with type VII collagen, which serves to connect anchoring filaments with anchoring fibrils.

Anchoring fibrils

Type VII collagen is the primary component of anchoring fibrils. Type VII collagen contains a large N-terminal globular domain (NC-1), which interacts with laminin 5 in the lamina densa; a long collagenous domain; and a smaller C-terminal globular domain (NC-2), which is cleaved proteolytically during anchoring fibril formation. Type VII collagen chains form a triple helix; then, 2 molecules join together in an antiparallel fashion. Next, anchoring fibrils are formed by lateral associations of antiparallel dimers. Anchoring fibrils wind around the dermal interstitial collagen fibrils and reinsert back upon the lamina densa, attaching the BMZ to the underlying dermis.

Molecular pathology of epidermolysis bullosa simplex

Most cases of epidermolysis bullosa simplex are associated with mutations of the genes coding for keratins 5 and 14. The level of skin separation is at the mid basal cell associated with variable intermediate filament clumping.

Most epidermolysis bullosa simplex keratin gene mutations are inherited dominantly and interfere with keratin filament assembly. A smaller subset of patients with recessively inherited disease of varying severity exists.

Mutations coding for the most conserved regions of keratins 5 and 14 (helix boundary domains) produce the most severe forms of epidermolysis bullosa simplex. Of the severe forms, the Dowling-Meara subtype exhibits intermediate filament clumping. Conversely, milder forms of the disease, such as the Weber-Cockayne subtype, are associated with mutations at the less conserved regions of keratin 5 and keratin 14 genes.

In patients with epidermolysis bullosa simplex, the mutations that code for the amino terminus of keratin 5 are associated with mottled pigmentation. A small group of patients with recessively inherited epidermolysis bullosa simplex has been shown to have associated muscular dystrophy caused by mutations of the gene coding for HD1/plectin.

Recently, 2 rare variants of superficial epidermolysis bullosa simplex subtypes have been described, termed lethal acantholytic epidermolysis bullosa simplex (caused by BPAG!/BP230 gene mutations) and ectodermal dysplasia skin fragility syndrome (caused by plakophillin gene mutations). The former is characterized by complete alopecia, severe nail involvement, oral and respiratory tract involvement, and superficial sheetlike separations of the skin. The latter is characterized by generalized erosions, palmoplantar keratoderma, painful fissures, and some nail dystrophy and hair loss.

Molecular pathology of junctional epidermolysis bullosa

Junctional epidermolysis bullosa has a highly variable molecular etiology and represents a collection of different diseases. These diseases all cause blistering in the lamina lucida and variable hemidesmosomal abnormalities. Mutations in genes coding for laminin 5 subunits (alpha-3 chain, laminin beta-3 chain, laminin gamma-2 chain), collagen XVII (BP180), a6 integrin, and b4 integrin have been demonstrated.

More than one half of junctional epidermolysis bullosa cases are caused by 1 of 2 recurrent nonsense mutations in the LAMB3 gene, which is helpful for mutation analysis and prenatal testing.

Herlitz (letalis) junctional epidermolysis bullosa is characterized by null mutations of laminin-5 genes, resulting in a lack of laminin-5 expression in the tissues of patients.

Missense mutations of laminin-5 genes that result in expression of presumably dysfunctional laminin 5 can result in a milder phenotype, such as generalized atrophic benign epidermolysis bullosa. Generalized atrophic benign epidermolysis bullosa also can be caused by mutations of the gene coding for collagen XVII (BP180).

Mutations of the genes coding for beta-4 and alpha-6 integrin also have been associated with junctional epidermolysis bullosa. In this group of diseases, separation of the skin occurs at the level of the hemidesmosome region. The resultant molecular defects contribute to the clinical manifestation of pyloric atresia.

Molecular pathology of dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa thus far has been associated in all cases with mutations of the gene coding for type VII collagen (COL7A1). Anchoring fibrils are affected in patients with dystrophic epidermolysis bullosa, and the degree of involvement ranges from subtle changes to complete absence.

In all patients, a sublamina lucida plane of blister cleavage is present. In some patients, defects of type VII collagen secretion are present.

In the recessive forms, COL7A1 mutations usually cause premature termination codons, resulting in an absence of type VII collagen in tissue. COL7A1 mutations, which do not cause premature termination codons, usually produce less severe disease. For example, mutations that produce glycine substitutions of the triple helical region can interfere with triple helical assembly of the type VII collagen molecule. These types of mutations, which exert a dominant-negative type of effect, are present in many patients with milder dominant forms of this disease.

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Contributor Information and Disclosures
Author

M Peter Marinkovich, MD Associate Professor, Department of Dermatology and Program in Epithelial Biology, Stanford University Medical Center; Dermatology Service, VA Palo Alto Health Care System

M Peter Marinkovich, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Van Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Jean Paul Ortonne, MD Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Jean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Ngoc Pham, MD, to the development and writing of this article.

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Epidermolysis bullosa simplex, Weber-Cockayne subtype. This mild bullous disease is characterized by localized blistering at sites of trauma such as the feet.
Epidermolysis bullosa simplex, Koebner subtype. Palmoplantar blistering and hyperkeratosis are noted.
Epidermolysis bullosa simplex, Koebner subtype. Close-up image shows hyperkeratotic papules and plaques on the palm.
Junctional epidermolysis bullosa, Herlitz subtype. This severe disease is characterized by generalized intralamina lucida blistering at birth, significant internal involvement, and a poor prognosis.
Dominantly inherited dystrophic epidermolysis bullosa. The blistering in this disease often is localized and is characterized by scarring and milia in healed blister sites.
Dominantly inherited dystrophic epidermolysis bullosa. This subtype, similar to other dystrophic and junctional epidermolysis bullosa subtypes, can result in nail dystrophy and loss.
Recessively inherited dystrophic epidermolysis bullosa pseudosyndactyly (mitten-hand deformity) of the hands and feet
Recessively inherited dystrophic epidermolysis bullosa, oral cavity blistering and scarring
Recessively inherited dystrophic epidermolysis bullosa, squamous cell carcinoma
Diagram illustrating the organization of the dermal epidermal basement membrane and level of disruption in epidermolysis bullosa subtypes
 
 
 
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