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Epidermolysis Bullosa Simplex

, PhD and , MD.

Author Information
, PhD
GeneDx, Inc
Gaithersburg, Maryland
, MD
Department of Dermatology
University of Colorado School of Medicine
Aurora, Colorado

Initial Posting: ; Last Update: September 1, 2011.


Clinical characteristics.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in nonscarring blisters caused by little or no trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 12 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are the focus of this GeneReview:

  • EBS, localized (EBS-loc; previously known as Weber-Cockayne type)
  • EBS, Dowling-Meara type (EBS-DM)
  • EBS, other generalized (EBS, gen-nonDM; previously known as Koebner type)
  • EBS-with mottled pigmentation (EBS-MP)

The phenotypes for these subtypes range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant.

In EBS, gen-non DM, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-DM.

In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-DM; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.

In EBS-DM, onset is usually at birth; severity varies greatly, both within and among families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. EBS-DM appears to improve with warmth in some individuals. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-DM may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.


EBS-loc can almost always be diagnosed clinically. Diagnosis of generalized forms of EBS requires a skin biopsy obtained from the leading edge of a fresh blister; diagnosis is based on immunohistochemistry using appropriate fluorescent antibodies or transmission electron microscopic examination that reveals splitting within or just above the basal cell layer of the skin. . The four most common forms of EBS are caused by mutation of either KRT5 or KRT14. Molecular genetic testing of KRT5 and KRT14 detects pathogenic variants in approximately 75% of individuals with biopsy-diagnosed EBS-loc, EBS-DM, and EBS-gen-nonDM, and 90%-95% of pathogenic variants in those with EBS-MP.


Treatment of manifestations: Supportive care to protect the skin from blistering; use of dressings that will not further damage the skin and will promote healing. Lance and drain new blisters. Dressings involve three layers: a primary nonadherent contact layer, a secondary layer providing stability and adding padding, and a tertiary layer with elastic properties.

Prevention of primary manifestations: Aluminum chloride (20%) applied to palms and soles can reduce blister formation in some individuals. Cyproheptadine (Periactin®), tetracycline, or botulimun toxin can reduce blistering in some individuals with EBS. Keratolytics and softening agents for palmar plantar hyperkeratosis may prevent tissue thickening and cracking.

Prevention of secondary complications: Watch for wound infection; treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful. Appropriate footwear and physical therapy may preserve ambulation in children who have difficulty walking because of blistering and hyperkeratosis.

Surveillance: For infection and proper wound healing.

Agents/circumstances to avoid: Excessive heat may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin.

Genetic counseling.

EBS caused by pathogenic variants in KRT5 or KRT14 is usually inherited in an autosomal dominant manner, but in rare families, especially those with consanguinity, it can be inherited in an autosomal recessive manner. For autosomal dominant EBS:

  • Affected individuals may have inherited the mutated gene from an affected parent or have the disorder as the result of a de novo pathogenic variant.
  • The chance that an affected person will pass the pathogenic variant to each child is 50%.
  • Prenatal testing is possible for pregnancies at increased risk if the pathogenic variant has been identified in an affected family member.


Clinical Diagnosis

The diagnosis of epidermolysis bullosa simplex (EBS) is suspected in individuals with fragility of the skin manifested by blistering with little or no trauma. The blisters typically heal without scarring. Although examination of a skin biopsy is often required to establish the diagnosis, it may not be necessary in some individuals, especially those with a known family history or characteristic phenotype (i.e., blisters on the palms and soles only).


Skin biopsy. Immunofluorescence antigenic mapping is the sine qua non for the diagnosis of EBS because of its rapid turnaround time and high sensitivity and specificity [Yiasemides et al 2006].

Transmission electron microscopic examination may also be used to identify keratin intermediate filament clumping and further delineate the classification of EBS Dowling-Meara (EBS-DM) [Bergman et al 2007].

To insure the most accurate diagnosis, the leading edge of a fresh blister induced by mechanical friction should be biopsied. The healing in older blisters may obscure the diagnostic morphology.

  • In all cases of EBS, splitting is observed within or just above the basal cell layer of the skin.
  • In EBS-DM, the keratin intermediate filaments (also called tonofilaments) are clumped, a finding that serves as a distinguishing feature [Bergman et al 2007].

    In most cases of EBS, diagnosis using immunofluorescent microscopy is made by mapping the blister. Antibodies to keratin 5 or keratin 14 and other dermal-epidermal junction antigens (typically laminin 332 and type VII collagen) show localization of stained epitopes to the blister floor.

Note: Routine histology (light microscopy) suggests the diagnosis of EB but is an inadequate and unacceptable test for accurately diagnosing the EB type and subtype.

Molecular Genetic Testing

Gene. The two genes in which mutation is currently known to cause the most common forms of EBS are KRT5 and KRT14.

Evidence for further locus heterogeneity. Because only approximately 75% of individuals with biopsy-proven EBS have identifiable pathogenic variants in KRT5 or KRT14, it is possible that variants in another as-yet unidentified gene are also causative [Yasukawa et al 2006, Rugg et al 2007, Bolling et al 2011]. Note: One individual with EBS caused by pathogenic variants in DST, encoding dystonin, has been reported [Groves et al 2010].

Clinical testing

  • Sequence analysis

    Sequence analysis is performed first in KRT5 and KRT14 regions in which a high percentage of pathogenic variants are known to occur; it may be targeted on the basis of the individual's clinical presentation.

    Sequence analysis of the remaining KRT5 and KRT14 exons may be performed if a pathogenic variant is not identified in the initially tested gene regions.

    Pathogenic variant detection rate in individuals with biopsy-diagnosed EBS is 75% [Yasukawa et al 2006, Rugg et al 2007].

Table 1.

Summary of Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex

Gene 1Test MethodEBS SubtypeVariants Detected 2Variant Detection Frequency 3, 4
KRT5 and KRT14Sequence analysis 5EBS-locKRT5 and KRT14 sequence variants75% 6
EBS-MPKRT5 p.Pro25Leu90%-95% 7, 8, 9
KRT14 p.Met119Thr2%-5% 10

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


In individuals with biopsy-diagnosed EBS


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Horiguchi et al [2005] describe a second variant associated with EBS-MP.


Harel et al [2006] describe a KRT14 variant associated with EBS-MP.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • A biopsy of an induced blister is required (especially in newborns) to determine the type of EB and thus should be performed as soon as possible after initial evaluation in order to facilitate genetic testing and to determine recurrence risk.
  • Once a skin biopsy confirms the diagnosis of EBS, genetic testing for the common hot spot regions in KRT5 (exons 1, 5, and 7) and KRT14 (exons 1, 4, and 6) may be undertaken. If no pathogenic variants are found in these regions, sequencing of the remaining exons may be necessary.

Carrier testing for at-risk relatives (in rare families with autosomal recessive inheritance) requires prior identification of the pathogenic variants in the family. Since autosomal recessive EBS-causing variants may be found in any portion of KRT5 and KRT14, full gene sequencing of the affected relative is often required to identify the pathogenic variant.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant(s) in the family.

Clinical Characteristics

Clinical Description

The most common forms of epidermolysis bullosa simplex (EBS) are subdivided into clinical phenotypes — EBS, localized (EBS-loc) (previously known as EBS, Weber-Cockayne type); EBS, generalized (EBS-gen-nonDM) (previously known as EBS, Koebner type); EBS Dowling-Meara (EBS-DM); and EBS-with mottled pigmentation (EBS-MP) — based primarily on dermatologic and histopathologic findings. Although it is now recognized that these phenotypes are part of a continuum with overlapping features, it is reasonable to continue to think of EBS in terms of the phenotypes in order to provide affected individuals with information about the expected clinical course. The clinical features of these disorders are summarized in Table 2.

Table 2.

Diagnostic Clinical Features of the Four Most Common Subtypes of EBS

EBS SubtypeLocalizedGeneralized, non-Dowling-MearaMottled PigmentationDowling-Meara
Age of OnsetInfancy, usually by 12-18 monthsBirth/infancyBirth/infancyBirth
BlistersDistributionUsually limited to hands, feet; can occur at sites of repeated trauma (e.g., belt line)GeneralizedGeneralizedGeneralized
Grouped (herpetiform)NoNoSometimesYes
Hyperkeratosis of palms and soles (keratoderma)OccasionallyOccasionallyCommon, focalCommon, progressive
Nail involvementOccasionallyOccasionallyOccasionallyCommon
Hyper/ HypopigmentationNoCan occurAlwaysCommon

EBS, localized (EBS-loc). Blisters begin in infancy and can present at birth, although the severity is usually mild. The first episodes may occur on the knees and shins with crawling or on the feet at approximately age 12-18 months, after walking is firmly established. Some affected individuals do not manifest the disease until adolescence or early adult life; the classic story is that of the army recruit with EBS-loc who blisters severely after the first enforced march.

Although blisters are usually confined to the hands and feet, they can occur anywhere given adequate trauma; for example, blisters can develop on the buttocks after horseback riding and around the waist after wearing a tight belt. The palms and soles are usually more involved than the backs of the hands and the tops of the feet. Symptoms are worse in warm weather and worsen with sweating. Hyperkeratosis of the palms and soles can develop in later childhood and adult life. Occasionally, a large blister in a nail bed may result in shedding of the nail.

EBS, other generalized (EBS-gen-nonDM). Blisters may be present at birth or develop within the first few months of life. EBS-gen-nonDM is distinguished from EBS-loc by its more widespread involvement and from EBS-DM by absence of clumped keratin intermediate filaments in basal keratinocytes on electron microscopy. In general, EBS-gen-nonDM is milder than EBS-DM, but clinical overlap is high. Similarly, mild EBS-gen-nonDM can be indistinguishable from EBS-loc. Branches of one large pedigree were reported separately as EBS-Koebner (now called EBS-gen-nonDM) and EBS-Weber Cockayne (now EBS-loc), reflecting the heterogeneity in severity even within families. As all these disorders are allelic, this overlap should not be surprising.

EBS with mottled pigmentation (EBS-MP). Skin fragility in EBS-MP is evident at birth and is clinically indistinguishable from generalized forms of EBS. Small hyperpigmented macules begin to appear in early childhood, progress over time, and coalesce to a reticulate pattern. Hypopigmented macules may be interspersed. These changes tend to develop on the trunk (particularly in large skin folds such as the neck, groin, and axillae) and then on the extremities. The pigmentation does not occur in areas of blistering (a factor distinguishing it from post-inflammatory hyperpigmentation and hypopigmentation) and often disappears in adult life. Focal palmar and plantar hyperkeratoses may occur.

EBS, Dowling-Meara type (EBS-DM). Onset is usually at birth and severity varies greatly both within and between families. Blistering can be severe enough to result in neonatal or infant death. Widespread and severe blistering and/or multiple grouped clumps of small blisters (whose resemblance to the blisters of herpetic infection gave the disorder one of its names) are typical. Hemorrhagic blisters are common. The mucosa can be involved; this usually improves with age.

Decreased frequency of blistering occurs during mid- to late childhood and blistering may be a minimal component of the disorder in adult life.

Progressive hyperkeratosis (punctate or diffuse) of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy (thickened, deformed nails) is common. Both hyper- and hypopigmentation can occur, typically in areas of blistering. Mucosal involvement in EBS-DM may interfere with feeding. Laryngeal involvement, manifesting as a hoarseness, can also occur, but is not life threatening.

Cancer risk. Squamous cell carcinoma is not usually associated with EBS.

Genotype-Phenotype Correlations

A moderate correlation exists between the EBS phenotypes and the functional domain of either KRT5 or KRT14 in which the pathogenic variant is located [reviewed in Irvine & McLean 2003, Müller et al 2006]:

  • Pathogenic variants in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc.
  • Pathogenic variants in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen-nonDM.
  • Pathogenic variants in the beginning of the 1A or the end of the 2B segments of the rod domain of KRT5 and beginning of the 1A or 2B segments of the rod domain of KRT5 and KRT14 are typical in EBS-DM.
  • The p.Pro25Leu and c.1649delG pathogenic variants in KRT5 are associated with EBS-MP. Two pathogenic variants are described in KRT14 [see Harel et al 2006, Arin et al 2010]

Autosomal dominant pathogenic variants cause signs in heterozygotes by acting in a dominant-negative manner; that is, in the process of keratin filament assembly the abnormal protein produced by the pathogenic allele interferes with the normal protein produced by the benign allele. In two different highly consanguineous families with autosomal dominant EBS, offspring homozygous for a missense variant have been reported. In one case, a KRT5 allele was fully dominant and in the second a KRT14 allele was partially dominant [Hu et al 1997].

Autosomal recessive KRT5 and KRT14 pathogenic variants are those that cause symptoms only in homozygotes. In the few reported cases of autosomal recessive EBS, the causal variants are usually null alleles that produce no gene product. Typically, heterozygotes are unaffected because 50% of the normal keratin product is adequate to stabilize the skin, although reports of related autosomal dominant disorders caused by null alleles in KRT5 and KRT14 resulting in haploinsufficiency have also been reported [Betz et al 2006, Lugassy et al 2006, Liao et al 2007, Sprecher et al 2007] (see Genetically Related Disorders).

The proportion of KRT5 and KRT14 pathogenic variants producing each phenotype are outlined in Table 3. Clinical overlap between EBS-K and EBS-DM is substantial; thus, much of the molecular genetic data have been lumped in the literature and the proportions presented in the table are necessarily imprecise. In addition, the predominance of pathogenic variants in KRT5 or KRT14 may be population specific [Abu Sa'd et al 2006, Yasukawa et al 2006, Rugg et al 2007].

Table 3.

Molecular Basis of EBS Types Caused by KRT5 and KRT14 Pathogenic Variants

Phenotype% of all EBSInheritanceSeverityProportion of KRT5 Pathogenic VariantsProportion of KRT14 Pathogenic Variants
EBS-MP<1%95% 15%
All EBS100%50%50%

In 25% of EBS, variants in KRT5 and/or KRT14 could not be identified [Bolling et al 2010]



Penetrance is 100% for known autosomal dominant and autosomal recessive KRT5 and KRT14 pathogenic variants. Disease severity may be influenced by other factors and may show intrafamilial variation [Indelman et al 2005].


Anticipation is not observed in EBS.


In 1886, Koebner coined the term epidermolysis bullosa hereditaria. In the late nineteenth and early twentieth centuries, Brocq and Hallopeau coined the terms traumatic pemphigus, congenital traumatic blistering, and acantholysis bullosa; these terms are no longer in use [Fine et al 1999]. The eponyms EBS-Weber-Cockayne and EBS-Koebner were changed to EBS, localized and EBS-other generalized in the current classification system [Fine et al 2008].


The prevalence of EBS is uncertain; estimates range from 1:30,000 to 1:50,000. EBS-loc is most prevalent as it does not result in neonatal death and interferes least with fitness. EBS-DM and EBS-gen-nonDM are rare, and EBS-MP is even rarer.

The experience of the National Epidermolysis Bullosa Registry (NEBR) suggests that ascertainment is highly biased and incomplete. A review of the Health Surveillance Registry Cards for British Columbia (1952-1989) showed 27 individuals with EB in a population of approximately 3,000,000 for a prevalence approaching 1:100,000 and an incidence (based on birth rates from 1952 to 1989) of 1:56,000 for all types of EB [Horn et al 1997].

Differential Diagnosis

According to the current classification system, the four major types of epidermolysis bullosa (EB), caused by pathogenic variants in 14 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome [Fine et al 2008]. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis.

The four major types of EB share easy fragility of the skin (and mucosa in many cases), manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring — especially in young children and neonates — may not be established or significant enough to allow identification of EB type; thus, skin biopsy is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators.

Post-inflammatory changes, such as those seen in EBS-DM, are often mistaken for scarring or mottled pigmentation. Scarring can occur in simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface. Congenital absence of the skin can be seen in any of the four major types of EB and is not a discriminating diagnostic feature.

Corneal erosions, esophageal strictures, and nail and tooth enamel involvement may indicate either DEB or JEB. In milder cases, scarring (especially of the dorsal hands and feet) suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB.

In almost all cases, a fresh biopsy from a newly induced blister stained by indirect immunofluorescence for the critical dermal-epidermal protein components is necessary to establish the type of EB by determining the cleavage plane and the presence/absence of these protein components and their distribution.

Other subtypes of EB simplex (EBS). The current classification system divides EBS into two subtypes based on the location of blistering in the epidermis. In the suprabasal forms of EBS, blistering occurs above the basal keratinocytes. The suprabasal forms of EBS are extremely rare and include: EBS superficialis; EBS, plakophilin-1 deficiency (also called ectodermal dysplasia/skin fragility syndrome); and EBS, lethal acantholytic.

  • EBS, plakophilin-1 deficiency is characterized by mild skin fragility associated with perioral cracking and cheilitis, hypotrichosis or alopecia, and a painful and fissured palmoplantar keratoderma; it is caused by pathogenic loss-of-function variants in PKP1 (for review, see McGrath & Mellerio [2010]).
  • EBS, lethal acantholytic is caused by pathogenic variants in the tail region of DSP which encodes desmoplakin [Jonkman et al 2005, Bolling et al 2010, Hobbs et al 2010]. Affected neonates present with progressive erosions without blistering, alopecia, and loss of nails. Death within the first days after birth secondary to profound fluid and electrolyte imbalance is common.

In the basal forms of EBS, blistering occurs within the basal keratinocytes. The four most common subtypes of basal EBS are the subject of this GeneReview.

Junctional EB (JEB). Separation occurs through the lamina lucida, or junction of dermis and epidermis, resulting in nonscarring blistering. Because atrophy may develop over time, the term "atrophicans" has been used in Europe to describe individuals with some forms of JEB.

Broad classification of JEB includes JEB-Herlitz (typically lethal in the first year of life), JEB-non-Herlitz, and JEB with pyloric atresia. Pathogenic variants in the genes that encode the subunits of laminin-332 (formerly called laminin 5) (LAMA3, LAMC2, LAMB3) and type 17 collagen (COL17A1) are causative. JEB with pyloric atresia has been associated with α6β4 integrin and plectin pathogenic variants (see EB with pyloric atresia).

The distinction between JEB-Herlitz and JEB-non-Herlitz caused by mutation of LAMA3, LAMC2, or LAMB3 is based on severity and survival past the first year of life.

JEB-non-Herlitz caused by mutation of COL17A1 (formerly termed generalized atrophic benign epidermolysis bullosa [GABEB]) usually has a much better prognosis than JEB caused by mutation of LAMA3, LAMC2, or LAMB3; however, it can be lethal in neonates.

Dystrophic EB (DEB). The blister forms below the basement membrane, in the superficial dermis. The basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Pathogenic variants in COL7A1, the gene encoding type VII collagen, have been demonstrated in DEB, both dominant and recessive:

  • The designation Bart syndrome (OMIM) is not used in the current classification of EB. Bart characterized a kindred with congenital absence of the skin on the lower legs and feet, nonscarring blistering of the skin and oral mucosa, and nail abnormalities. Genetic studies of the original kindred identified dominant pathogenic variants in COL7A1 [Christiano et al 1996], and some consider Bart syndrome to be most often, but not exclusively, a manifestation of dominant DEB. However, congenital absence of skin can be seen in all forms in EB and may not be a distinguishing feature of any particular form of EB.

EB caused by mutation of PLEC1. Pathogenic variants in PLEC1, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause a cleavage in the basal keratinocyte layer; hence, they could be considered to cause EBS. However, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia, and the rare EB-Ogna) are more complex:

  • EB with muscular dystrophy (OMIM). Some individuals with EB resulting from mutation of PLEC1 develop muscular dystrophy either in childhood or later in life [Smith et al 1996, Shimizu et al 1999, Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005a]. Within basal keratinocytes, plectin is localized to the inner plaques of the hemidesmosomes, which are hypoplastic and show poor association with keratin filaments. Electron microscopy of skin biopsies reveals a plane of cleavage (level of separation) within the bottom layer of the basal keratinocytes, just above the hemidesmosomes. Inheritance is autosomal recessive.
  • EB with pyloric atresia. In several US and Japanese families, EB with pyloric atresia is associated with premature termination variants in PLEC1 and the genes encoding alpha 6 integrin (ITGA6) and beta 4 integrin (ITGB4) [Nakamura et al 2005, Pfendner & Uitto 2005]. Disease course is severe and usually lethal in the neonatal period. Inheritance is autosomal recessive.
  • EBS-Ogna (OMIM), observed in one Norwegian and one German family, is caused by a site-specific missense variant within the rod domain of PLEC1 [Koss-Harnes et al 2002]. In these cases, transmission electron microscopy of a skin biopsy identified the cleavage plane to be just above the inner plates of the hemidesmosomes in the deep basal cell cytoplasm. Immunofluorescence staining of a skin biopsy showed reduced and/or patchy plectin staining. Inheritance is autosomal dominant.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with epidermolysis bullosa simplex (EBS), evaluation of the sites of blister formation, including oral mucosa, is recommended.

Treatment of Manifestations

Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing, and prevention and treatment of secondary infection are the mainstays of EB treatment.

Encourage children to tailor their activities to minimize trauma to the skin while participating as much as possible in age-appropriate play.

Lance and drain new blisters to prevent further spread from fluid pressure.

Dressings usually involve three layers:

  • A primary nonadherent dressing that will adhere to the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers; some individuals with EBS can use ordinary band-aids. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® Gauze, Adaptic®, Xeroform). Nonstick products (e.g., Telfa or N-Terface®) or silicone-based products without adhesive (e.g., Mepitel® or Mepilex®) are also popular.
  • A secondary layer provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Kerlix®) are commonly used.
  • A tertiary layer, usually with some elastic properties, ensures the integrity of the dressing (e.g., Coban™ or elasticized tube gauze of varying diameters, such as BandNet®).

Note: Many individuals with EBS, in contrast to those with junctional EB and dystrophic EB, find that excessive bandaging may actually lead to more blistering, presumably as a result of increased heat and sweating. Such individuals may benefit from dusting the affected areas with corn starch to help absorb moisture and reduce friction on the skin, followed by a simple (i.e., one-layer) dressing.

Prevention of Primary Manifestations

Twenty percent aluminum chloride applied to palms and soles can reduce blister formation in some individuals with EBS, presumably by decreasing sweating.

In one study of a limited number of individuals with EBS-DM, cyproheptadine (Periactin®) reduced blistering. This may result from the anti-pruritic effect of the medication, but the true mechanism is not clear [Neufeld-Kaiser & Sybert 1997]. In another study, tetracycline reduced blister counts in two thirds of persons with EBS-WC [Weiner et al 2004]. In both studies, small sample sizes limit the statistical validity and generalizability of the results; however, given the lack of effective treatments for EBS, these potentially helpful treatments should be considered on a case-by-case basis.

A case report [Abitbol & Zhou 2009] and small study [Swartling et al 2010] suggest that injection of botulinum toxin into the feet is effective in reducing blistering and associated pain. The mechanism of action is unclear, but likely relates to reduction of sweating and subsequent maceration of the skin.

Use of keratolytics and softening agents for palmar plantar hyperkeratosis has some benefit in preventing tissue thickening and cracking. In addition, soaking the hands and feet in salt water helps soften hyperkeratosis and ease debridement of the thick skin.

Prevention of Secondary Complications

Infection is the most common secondary complication. Surveillance for wound infection is important and treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful.

Additional nutritional support may be required for failure to thrive in infants and children with EBS-DM or EBS-K who have more severe involvement.

Management of fluid and electrolyte problems is critical, as they can be significant and even life-threatening in the neonatal period and in infants with widespread disease.

Some children have delays or difficulty walking because of blistering and hyperkeratosis, especially in EBS-DM. Appropriate footwear and physical therapy are essential to preserve ambulation.


Surveillance for infection and proper wound healing is indicated.

Agents/Circumstances to Avoid

Excessive heat may exacerbate blistering and infection in EBS.

Poorly fitting or coarse-textured clothing and footwear can cause trauma and should be avoided.

Avoiding activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) can reduce skin damage, but affected individuals who are determined to find ways to participate in these endeavors should be encouraged.

Most individuals with EBS cannot use ordinary medical tape or band-aids.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

If a pregnancy is known to be affected with any form of EB, caesarean delivery may reduce the trauma to the skin during delivery.

Therapies Under Investigation

Proposed approaches to gene therapy for EBS include use of ribozymes, addition of other functional proteins [D'Alessandro et al 2004], and induction of a compensating variant [Smith et al 2004a]; no clinical trials have been carried out. The inducible mouse model for EBS should facilitate the development of these therapeutic approaches [Arin & Roop 2004].

Search for access to information on clinical studies for a wide range of diseases and conditions.


The use of corticosteroids and vitamin E in treating EBS has been reported anecdotally; no rigorous clinical trials have been undertaken.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Epidermolysis bullosa simplex (EBS) is usually inherited in an autosomal dominant manner; in rare cases it can be inherited in an autosomal recessive manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Many individuals diagnosed with EBS have an affected parent.
  • However, a proband with EBS may have the disorder as the result of a de novo pathogenic variant. The more severe forms of autosomal dominant EBS are usually caused by a de novo pathogenic variant for an autosomal dominant allele.
  • Recommendations for the evaluation of parents of a child with EBS and no known family history of EBS include a family and personal history and a physical examination if history is suggestive. Many families include individuals with a history of "blistering" but are unaware that they have EBS; evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If a parent is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the pathogenic variant cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been reported in the mother of a proband with EBS [Nagao-Watanabe et al 2004].

Offspring of a proband

  • Each child of an individual with EBS has a 50% chance of inheriting the pathogenic variant.
  • In the rare situation in which both parents have an autosomal dominant variant (e.g., in consanguineous unions), each child has a 75% chance of having at least one pathogenic variant.

Other family members of a proband

  • The risk to other family members depends on the genetic status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with EBS are obligate heterozygotes (carriers) for a pathogenic allele causing EBS.

Other family members of a proband. Each sib of a proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible once the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Establishing the mode of inheritance. The mode of inheritance in a given family is usually established by pedigree analysis. Inheritance of EBS in families in which only one child is affected could be either autosomal dominant (as the result of a de novo pathogenic variant) or autosomal recessive; a de novo dominant pathogenic variant is the more likely mode of inheritance. Furthermore, EBS inherited in an autosomal recessive manner can generally be distinguished from autosomal dominant EBS by immunohistochemistry.

Autosomal recessive inheritance of null alleles needs to be considered, especially if the parents are consanguineous. Autosomal recessive inheritance is suspected in (1) pedigrees showing consanguinity and affected sibs born to unaffected parents; and (2) individuals whose skin biopsy reveals absent tonofilaments in the basal cells or lack of staining with antibodies to either keratin 5 or keratin 14 (see Clinical Diagnosis).

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the KRT5 or KRT14 pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for EBS are possible options.

Fetoscopy. Electron microscopic evaluation of skin biopsies in utero is also diagnostic in EBS-DM, but the biopsy must be obtained by the procedure of fetoscopy. Fetoscopy carries a greater risk to pregnancy than CVS or amniocentesis and is performed relatively late (18-20 weeks) in gestation. It is not currently available in the US.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • DEBRA International
    Am Heumarkt 27/3
    Vienna 1030
    Phone: +43 1 876 40 30-0
    Fax: +43 1 876 40 30-30
  • DebRA of America, Inc. (Dystrophic Epidermolysis Bullosa Research Association)
    16 East 41st Street
    3rd Floor
    New York NY 10017
    Phone: 866-332-7276 (toll-free); 212-868-1573
  • DebRA UK
    DebRA House
    13 Wellington Business Park
    Crowthorne Berkshire RG45 6LS
    United Kingdom
    Phone: +44 01344 771961
    Fax: +44 01344 762661
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • Medline Plus
  • EBCare Registry
    The EBCare Registry is a resource for individuals and families affected by all forms of epidermolysis bullosa (EB) and qualified researchers working on approved EB research projects.
    Phone: 866-332-7276
    Fax: 888-363-0790

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Epidermolysis Bullosa Simplex: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Epidermolysis Bullosa Simplex (View All in OMIM)

148066KERATIN 14, TYPE I; KRT14

Molecular Genetic Pathogenesis

KRT5 and KRT14 are expressed in keratinocytes, including the basal keratinocytes of the epidermis, where their protein products form heterodimeric molecules that assemble into the intracellular keratin intermediate filament network. This network is linked directly to the hemidesmosomes that anchor the keratinocytes to the basal lamina and to the desmosomes, leading to strong attachment of the keratinocytes to one another. These associations along with the network itself supply stability and resistance to stress, enabling the keratinocytes to maintain their structural integrity during minor trauma.

Pathogenic variants in either KRT5 or KRT14 can lead to reduced resistance to minor trauma and the resulting blistering that is the hallmark of epidermolysis bullosa simplex (EBS). The type of variant, the location of the variant, and the biochemical properties of the substituted amino acid determine the severity of the blistering phenotype (see Genotype-Phenotype Correlations) and identify the inheritance pattern. Autosomal dominant missense variants predominate and may affect the ability of the keratin to associate with its keratin partner, its secondary structure, and its ability to form the intracellular network. Intrafamilial phenotypic variability exists, suggesting that other factors can affect the resistance of the cells to friction [Rugg & Leigh 2004, Smith et al 2004a, Werner et al 2004].


Gene structure. The cDNA comprises 2,164 bp in eight exons. Genomic length is estimated at approximately 6 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic variants in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Variants in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen-nonDM. Variants in the beginning of the 1A segment or the end of the 2B segment of the rod domain of KRT5 and KRT14 are typical in EBS-DM.

The KRT5 recurrent missense variant p.Glu477Lys, along with the KRT14 recurrent variants p.Arg125Cys, p.Arg125His, and p.Asn123Ser (see Table 5) are thought to account for approximately 70% of cases of EBS-DM [Stephens et al 1997, Pfendner et al 2005b].

The KRT5 missense variant p.Pro25Leu [Moog et al 1999] accounts for 90%-95% of identified pathogenic variants in EBS-MP. The KRT5 variant c.1649delG is also responsible for a mottled pigmentation phenotype [Horiguchi et al 2005]. The KRT14 variant p.Met119Thr (Table 5) was also recently described as associated with the EBS-MP phenotype [Harel et al 2006].

Although a formal possibility, homozygosity for null KRT5 alleles has not been reported. Whether this genotype results in autosomal recessive EBS-gen-nonDM is unknown. An autosomal recessive missense variant has been described [Indelman et al 2005]. (For more information, see Table A.)

Table 4.

Selected KRT5 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.1649delGp.Gly550AlafsTer77 2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Asterisk indicates translation extended downstream of the normal translation termination codon.

Normal gene product. KRT5 (keratin, type II cytoskeletal 5), a protein of 590 amino acids

Abnormal gene product. Unknown


Gene structure. The cDNA comprises 1,377 bp in eight exons. Genomic length is approximately 4.5 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic variants in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Variants in the 1A or 2B segments of the rod domain are typical for EBS- gen-nonDM. Variants at a hot spot at codon 125 (p.Arg125Cys and p.Arg125His) have been identified as causal in approximately 50% of individuals with EBS-DM. In rare consanguineous families, homozygosity for null KRT14 alleles is associated with autosomal recessive inheritance of EBS- gen-nonDM. (For more information, see Table A.)

Table 5.

Selected KRT14 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Normal gene product. KRT14 (keratin, type I, cytoskeletal 14), a protein of 472 amino acids

Abnormal gene product. Pathogenic missense variants give rise to abnormal gene products that may not assemble correctly into functional keratin intermediate filaments. The type and position of the amino acid change determines the degree of compromise and thus the severity of the disease. KRT14 null variants may give rise to a less severe phenotype than certain missense variants [Sørensen et al 2003, Smith et al 2004b].


Literature Cited

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Suggested Reading

  1. Van Coster R, Pulkkinen L. Epidermolysis bullosa: The disease of the cutaneous basement membrane. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 222. Available online.

Chapter Notes

Author History

Anna L Bruckner, MD (2008-present)
Anne W Lucky, MD; Cincinnati Children’s Hospital (2005-2008)
Ellen G Pfendner, PhD (2005-present)
Karen Stephens, PhD; University of Washington (1998-2005)
Virginia P Sybert, MD; University of Washington (1998-2005)

Revision History

  • 1 September 2011 (me) Comprehensive update posted live
  • 11 August 2008 (et) Comprehensive update posted live
  • 3 November 2005 (me) Comprehensive update posted to live Web site
  • 16 July 2003 (me) Comprehensive update posted to live Web site
  • 2 February 2001 (me) Comprehensive update posted to live Web site
  • 7 October 1998 (me) Review posted to live Web site
  • 13 February 1998 (vs) Original submission
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