eMedicine Specialties > Pediatrics: General Medicine > Dermatology
Epidermolysis Bullosa
Updated: Jul 30, 2009
Introduction
Background
Epidermolysis bullosa (EB) is a rare group of inherited disorders that manifests as blistering or erosion of the skin and, in some cases, the epithelial lining of other organs, in response to little or no apparent trauma.
Categorizations of the types of epidermolysis bullosa were once controversial and often confusing because more than 20 types of epidermolysis bullosa have been described. The following major types of epidermolysis bullosa have been identified:
- Epidermolytic - Epidermolysis bullosa simplex (EBS)
- Lucidolytic - Junctional epidermolysis bullosa (JEB)
- Dermolytic - Dystrophic epidermolysis bullosa (DEB)
These major types were based on the precise ultrastructural level at which the split responsible for blistering occurs.
The 3 main types of epidermolysis bullosa were clinically and histologically delineated by the 1960s.1 In the 1970s, electron microscopy revealed abnormal epidermal keratin filaments in epidermolysis bullosa simplex, disordered dermal anchoring fibrils in dystrophic epidermolysis bullosa, and defective hemidesmosomes in junctional epidermolysis bullosa. Antigens identified with immunohistochemistry in the 1980s2,3 led to discovery of the major epidermolysis bullosa genes in the 1990s.4,5,6
The identified genes include those that encode keratins 5 and 14 in epidermolysis bullosa simplex, collagen VII in dystrophic epidermolysis bullosa, and laminin 5 in Herlitz junctional epidermolysis bullosa. Toward the end of millennium, as the complex structure of desmosomes and hemidesmosomes was unraveled, the genes responsible for the rare subtypes were found, including those that encode α6β4 integrin in epidermolysis bullosa with pyloric atresia, plectin in epidermolysis bullosa with muscular dystrophy, and plakophilin in epidermolysis bullosa with ectodermal dysplasia.
During the past few years, systemic data collection and analysis have been performed on several thousands of patients with epidermolysis bullosa worldwide, and more than 1000 mutations, encompassing more than 10 structural genes, have now been documented. More has been learned about the molecular basis of epidermolysis bullosa, this group of diseases shares clinical or molecular features with several other genodermatoses. The leading authority on epidermolysis bullosa has included Kindler syndrome as the fourth major epidermolysis bullosa type.7
Eponyms associated with different forms of epidermolysis bullosa include the following:
- Dowling-Meara
- Köebner
- Weber-Cockayne
- Kallin
- Mendes de Costa
- Herlitz
- Ogna
- Carmi
- Cockayne-Touraine
- Pasini
- Hallopeau-Siemens
- Shabbir
- Laryngoonychocutaneous (LOC)
- Kindler
Pathophysiology
Cytolysis causes blisters in the epidermis or basement membrane zone of the skin. In epidermolysis bullosa simplex, cytolysis causes blisters in the basal or spinous layers of the epidermis, and keratinocytes often have abnormal density and organization of keratin filaments. In junctional epidermolysis bullosa, the epidermis separates from the basal lamina, forming a blister cavity in the plane of the lamina lucida, where hemidesmosome structure and density are frequently diminished. In dystrophic epidermolysis bullosa, the basal lamina remains attached to the epidermis, but the blister cavity forms beneath the lamina densa of dermoepidermal junction, and anchoring fibrils may appear abnormal, reduced in number, or altogether absent.
Frequency
United States
The exact prevalence of epidermolysis bullosa is unknown. Mild variants have been estimated to occur as frequently as 1 per 50,000 births. The more severe varieties are believed to occur in 1 per 500,000 births annually.
Mortality/Morbidity
Depending on the type of epidermolysis bullosa, disease severity may range from occasional mild blistering of the hands and feet to severe and widespread formation of bullae. These lesions may result in nonhealing erosions, infection, scarring, and joint contracture. Death may occur during infancy or early childhood, due to sepsis, renal failure, upper airway occlusion, or failure to thrive.8,9 Mortality is also related to the abnormalities or anomalies associated with epidermolysis bullosa. The most significant morbidity in adults with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa, is cutaneous squamous cell carcinoma (SCC). By mid adulthood, nearly all individuals with dystrophic epidermolysis bullosa have had one SCC, and nearly 80% die of metastatic SCC.10
Healing of dystrophic epidermolysis bullosa results in dystrophic or scarring change. In epidermolysis bullosa simplex, when blisters cleave in the epidermis, healing occurs without scarring. In junctional epidermolysis bullosa, when blisters cleave below the epidermis but above the basal lamina, blistering leads to mild atrophic changes.
Race
The epidermolysis bullosa simplex Ogna variant has been described in Norwegian individuals.
Sex
Epidermolysis bullosa is an autosomal inherited disorder. The incidence does not differ by sex.
Age
The onset of epidermolysis bullosa simplex is at birth or early infancy. The onset of junctional epidermolysis bullosa is at birth. The onset of dystrophic epidermolysis bullosa is at birth or early childhood. The onset of Kindler syndrome is usually within the first year of life.
Clinical
History
- Important findings in epidermolysis bullosa (EB) include the age of onset; the size, frequency, and location of blisters; and the possible inciting factors (eg, heat, trauma).
- Check for a family history of blistering disease and for the patient's geographic and racial ancestry. Evaluation of any patient with suspected epidermolysis bullosa should include mapping of the family's pedigree. However, an absence of affected family members does not, by itself, establish that the mode of transmission is autosomal recessive because apparently isolated cases can be due to spontaneous mutation or incomplete penetrance of an autosomal dominant trait.
- Review of systems should include a search for mucosal involvement, including oral, nasopharyngeal, ocular, genitourinary, GI, and respiratory symptoms.
Physical
- Perform a complete physical examination with emphasis on inspecting all skin areas and mucosal surfaces. Evaluate the size, location, and character of the blisters and determine the level at which to slit them.
- Examine the patient for involvement of the nails, hair, or teeth.
- Areas prone to blistering due to pressure, trauma, or excessive heating include the fingers, hands, elbows, feet, legs, and diaper area (in infants). See Media files 1-5, Media file 10, Media files 12-13, and Media file 17.
Ruptured bulla and newly erupted bulla of the leg in a newborn with epidermolysis bullosa simplex (EBS).
Dystrophic epidermolysis bullosa (DEB) with multiple blisters and erosions.
Dystrophic epidermolysis bullosa (DEB) with generalized blistering and erosion.
Dystrophic epidermolysis bullosa (DEB) that subsequently healed, with scarring.
Junctional epidermolysis bullosa (JEB). Image shows a newborn with bulla of the finger, the usual site of blistering secondary to trauma.
Dystrophic nails in a neonate with junctional epidermolysis bullosa (EB).
Ruptured bullae on the abdomen in a neonate with junctional epidermolysis bullosa (JEB).
A large bullae on the elbow in a neonate with junctional epidermolysis bullosa (JEB).
Ruptured bulla of the hand in a newborn with epidermolysis bullosa simplex (EBS).
- Congenital localized absence of skin is now known to be a phenotypic pattern that neonates with any major form of epidermolysis bullosa may demonstrate at birth. See Media files 6-7 ,Media file 11, and Media file 14.
Junctional epidermolysis bullosa (JEB) with an associated defect of a congenital absence of the skin.
Junctional epidermolysis bullosa (JEB) with an associated defect of a congenital absence of the skin and an ear anomaly.
Congenital localized absence of skin, nose, in a neonate with junctional epidermolysis bullosa (JEB).
Congenital localized absence of skin on the scrotum in a neonate with junctional epidermolysis bullosa (JEB). Absence of the foreskin was also noted.
Causes
- Genetics
- Most subtypes of epidermolysis bullosa simplex (EBS) are autosomal dominant disorders, rare patients with autosomal recessive have been reported.11
- Junctional epidermolysis bullosa (JEB) is an autosomal recessive disorder.
- Dystrophic epidermolysis bullosa (DEB) is either autosomal dominant or autosomal recessive.
- Kindler syndrome is an autosomal recessive disorder.12
- Types of epidermolysis bullosa and associated characteristics7
Table 1. Ultrastructural Findings of Major Types and Subtypes of Epidermolysis BullosaOpen table in new window
[ CLOSE WINDOW ]Table
Type or Subtype Ultrastructural Site of Skin Findings Other Ultrastructural Findings Epidermolysis bullosa simplex Localized Basal layer Split may spread to suprabasilar layer Dowling-Meara Basal layer in subnuclear cytoplasm Dense, circumscribed clumps of keratin Filaments Muscular dystrophy Predominantly in basal layer, above level of hemidesmosome attachment plaque Reduced integration of keratin filaments with hemidesmosome Autosomal recessive Basal keratinocytes Absent or reduced keratin filaments within basal keratinocytes Superficialis Split usually at interface between granular and cornified cell layers ... Lethal acantholytic Suprabasal cleavage and acantholysis Perinuclear retraction of keratin filaments Plakophillin-1 deficiency Mid epidermal cell-cell separation Diminutive suprabasal desmosomes, perinuclear retraction of keratin filaments Pyloric atresia (PA) Lower basal layer, above level of hemidesmosome plaque Reduced integration of keratin filaments with hemidesmosome Junctional epidermolysis bullosa Herlitz Lamina lucida Markedly reduced or absent hemidesmosome, absent sub-basal dense plate Non-Herlitz Lamina lucida Hemidesmosome may be normal or reduced in size and number Pyloric atresia Lamina lucida Small hemidesmosome plaques often with attenuated sub-basal dense plate Dominant dystrophic epidermolysis bullosa Generalized Sub-lamina densa Normal or decreased numbers of anchoring fibrils Bullous dermolysis of the newborn Sub-lamina densa Electron-dense stellate bodies within basal layer, reduced anchoring fibrils Recessive dystrophic epidermolysis bullosa Severe generalized Sub-lamina densa Absent or rudimentary anchoring fibrils Generalized other Sub-lamina densa Reduced or rudimentary-appearing anchoring fibrils Bullous dermolysis of the newborn Sub-lamina densa Electron-dense stellate bodies within basal layer, reduced anchoring fibrils Type or Subtype Ultrastructural Site of Skin Findings Other Ultrastructural Findings Epidermolysis bullosa simplex Localized Basal layer Split may spread to suprabasilar layer Dowling-Meara Basal layer in subnuclear cytoplasm Dense, circumscribed clumps of keratin Filaments Muscular dystrophy Predominantly in basal layer, above level of hemidesmosome attachment plaque Reduced integration of keratin filaments with hemidesmosome Autosomal recessive Basal keratinocytes Absent or reduced keratin filaments within basal keratinocytes Superficialis Split usually at interface between granular and cornified cell layers ... Lethal acantholytic Suprabasal cleavage and acantholysis Perinuclear retraction of keratin filaments Plakophillin-1 deficiency Mid epidermal cell-cell separation Diminutive suprabasal desmosomes, perinuclear retraction of keratin filaments Pyloric atresia (PA) Lower basal layer, above level of hemidesmosome plaque Reduced integration of keratin filaments with hemidesmosome Junctional epidermolysis bullosa Herlitz Lamina lucida Markedly reduced or absent hemidesmosome, absent sub-basal dense plate Non-Herlitz Lamina lucida Hemidesmosome may be normal or reduced in size and number Pyloric atresia Lamina lucida Small hemidesmosome plaques often with attenuated sub-basal dense plate Dominant dystrophic epidermolysis bullosa Generalized Sub-lamina densa Normal or decreased numbers of anchoring fibrils Bullous dermolysis of the newborn Sub-lamina densa Electron-dense stellate bodies within basal layer, reduced anchoring fibrils Recessive dystrophic epidermolysis bullosa Severe generalized Sub-lamina densa Absent or rudimentary anchoring fibrils Generalized other Sub-lamina densa Reduced or rudimentary-appearing anchoring fibrils Bullous dermolysis of the newborn Sub-lamina densa Electron-dense stellate bodies within basal layer, reduced anchoring fibrils
Table 2. Major Types of Epidermolysis BullosaOpen table in new window
[ CLOSE WINDOW ]Table
level of Skin Cleavage Major Type Known Targeted Protein Intraepidermal (epidermolytic) Epidermolysis bullosa simplex Keratins 4 and 14; plectin; α6β4 integrin; plakophillin-1 desmoplakin Intra-lamina lucida (lamina lucidolytic) Junctional epidermolysis bullosa Laminin-332(laminin 5); type XVII collagen; α6β4 integrin Sub-lamina densa (dermolytic) Dystrophic epidermolysis bullosa Type VII collagen Mixed Kindler syndrome Kindlin-1 Table 3. Mutational Analyses and Inherited Epidermolysis Bullosalevel of Skin Cleavage Major Type Known Targeted Protein Intraepidermal (epidermolytic) Epidermolysis bullosa simplex Keratins 4 and 14; plectin; α6β4 integrin; plakophillin-1 desmoplakin Intra-lamina lucida (lamina lucidolytic) Junctional epidermolysis bullosa Laminin-332(laminin 5); type XVII collagen; α6β4 integrin Sub-lamina densa (dermolytic) Dystrophic epidermolysis bullosa Type VII collagen Mixed Kindler syndrome Kindlin-1 Open table in new window
[ CLOSE WINDOW ]Table
Epidermolysis Bullosa Subtype Target Gene(Protein) Types of Known Mutations Epidermolysis bullosa simplex - Suprabasal PKP1 (plakophilin1) Splice site, deletion, nonsense DSP (desmoplakin) Nonsense, deletion Epidermolysis bullosa simplex - Basal KRT5 (keratin-5) Missense, nonsense, deletion, splice site KRT14 (keratin-14) Missense, nonsense, deletion, insertion, splice site, in-frame deletion/insertion PLEC1 (plectin) Missense, nonsense, deletion, insertion, in-frame deletion/insertion ITGA6, ITGB4 (α6β4 integrin) missense, nonsense, deletion, insertion, splice site Junctional epidermolysis bullosa - Herlitz LAMA3, LAMB3, LAMC2 (laminin-332) Nonsense, deletion, insertion, splice site Junctional epidermolysis bullosa - Other LAMA3, LAMB3, LAMC2 (laminin-332) Missense, nonsense, deletion, insertion, splice site COL17A1 (type XVII collagen) Missense, nonsense, deletion, insertion, splice site ITGA6, ITGB4 (α6β4 integrin) Missense, nonsense, deletion, insertion, splice site Dystrophic epidermolysis bullosa - Dominant COL17A1 (type VII collagen Missense, splice site Dystrophic epidermolysis bullosa - Recessive COL17A1 (type VII collagen Missense, nonsense, deletion, insertion, splice site Kindler syndrome KIND1 (kindling-1) Nonsense, deletion, insertion, splice site Epidermolysis Bullosa Subtype Target Gene(Protein) Types of Known Mutations Epidermolysis bullosa simplex - Suprabasal PKP1 (plakophilin1) Splice site, deletion, nonsense DSP (desmoplakin) Nonsense, deletion Epidermolysis bullosa simplex - Basal KRT5 (keratin-5) Missense, nonsense, deletion, splice site KRT14 (keratin-14) Missense, nonsense, deletion, insertion, splice site, in-frame deletion/insertion PLEC1 (plectin) Missense, nonsense, deletion, insertion, in-frame deletion/insertion ITGA6, ITGB4 (α6β4 integrin) missense, nonsense, deletion, insertion, splice site Junctional epidermolysis bullosa - Herlitz LAMA3, LAMB3, LAMC2 (laminin-332) Nonsense, deletion, insertion, splice site Junctional epidermolysis bullosa - Other LAMA3, LAMB3, LAMC2 (laminin-332) Missense, nonsense, deletion, insertion, splice site COL17A1 (type XVII collagen) Missense, nonsense, deletion, insertion, splice site ITGA6, ITGB4 (α6β4 integrin) Missense, nonsense, deletion, insertion, splice site Dystrophic epidermolysis bullosa - Dominant COL17A1 (type VII collagen Missense, splice site Dystrophic epidermolysis bullosa - Recessive COL17A1 (type VII collagen Missense, nonsense, deletion, insertion, splice site Kindler syndrome KIND1 (kindling-1) Nonsense, deletion, insertion, splice site
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Further Reading
Keywords
epidermolysis bullosa, EB, bullous disorder, blister, blistering, skin erosion, epidermolysis bullosa simplex, EBS, junctional epidermolysis bullosa, JEB, dystrophic epidermolysis bullosa, DEB, Herlitz junctional EB, pyloric atresia, ectodermal dysplasia, Dowling-Meara syndrome, Köbner syndrome, Weber-Cockayne syndrome, Kallin syndrome, Mendes de Costa syndrome, Ogna syndrome, Carmi syndrome, Cockayne-Touraine syndrome, Pasini syndrome, Hallopeau-Siemens syndrome, Shabbir syndrome, Kindler syndrome, muscular dystrophy, failure to thrive, squamous cell carcinoma, SCC, treatment, diagnosis
