• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Epidermolysis Bullosa Simplex

Includes: Epidermolysis Bullosa Simplex with Mottled Pigmentation (EBS-MP); Epidermolysis Bullosa Simplex, Dowling-Meara Type (EBS-DM); Epidermolysis Bullosa Simplex, Localized (EBS-loc); Epidermolysis Bullosa Simplex, Other Generalized (EBS-gen-nonDM)

, 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.

Summary

Disease 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.

Diagnosis/testing. 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 in either KRT5 or KRT14. Molecular genetic testing of KRT5 and KRT14 detects mutations in approximately 75% of individuals with biopsy-diagnosed EBS-loc, EBS-DM, and EBS-gen-nonDM, and 90%-95% of mutations in those with EBS-MP.

Management. 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 mutations 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:

Diagnosis

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).

Testing

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 mutations in KRT5 or KRT14, it is possible that mutations 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 mutations 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 mutations 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 mutation is not identified in the initially tested gene regions.

    Mutation 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 SymbolTest MethodEBS Subtype Mutations DetectedMutation Detection Frequency 1, 2
KRT5 and KRT14Sequence analysis EBS-locKRT5 and KRT14 sequence variants 375% 4
EBS-gen-nonDM
EBS-DM
EBS-MPKRT5 p.Pro25Leu 90%-95% 5, 6, 7
KRT14 p.Met119Thr2%-5% 8

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

2. In individuals with biopsy-diagnosed EBS

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Yasukawa et al [2006], Rugg et al [2007], Bolling et al [2011]

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

6. Shurman et al [2006]

7. Pascucci et al [2006]

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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 mutations 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 disease-causing mutations in the family. Since autosomal recessive EBS-causing mutations may be found in any portion of KRT5 and KRT14, full gene sequencing of the affected relative is often required to identify the disease-causing mutation.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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 Onset Infancy, usually by 12-18 monthsBirth/infancyBirth/infancyBirth
Clinical
Feature
Blisters DistributionUsually limited to hands, feet; can occur at sites of repeated trauma (e.g., belt line)GeneralizedGeneralizedGeneralized
Grouped (herpetiform)NoNoSometimesYes
MucosalRareOccasionallyOccasionallyOften
Hyperkeratosis of palms and soles (keratoderma)OccasionallyOccasionallyCommon, focalCommon, progressive
Nail involvementOccasionallyOccasionallyOccasionallyCommon
MiliaRareOccasionallyUnknownCommon
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 mutation is located [reviewed in Irvine & McLean 2003, Müller et al 2006]:

  • Mutations in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc.
  • Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen-nonDM.
  • Mutations 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 mutations in KRT5 are associated with EBS-MP. Two mutations are described in KRT14 [see Harel et al 2006, Arin et al 2010]

Autosomal dominant mutations 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 mutated allele interferes with the normal protein produced by the normal allele. In two different highly consanguineous families with autosomal dominant EBS, offspring homozygous for a missense mutation 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 mutations are those that cause symptoms only in homozygotes. In the few reported cases of autosomal recessive EBS, the causal mutations 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 mutations 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, predominance of mutations 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 Mutations

Phenotype% of all EBS InheritanceSeverityProportion of KRT5 MutationsProportion of KRT14 Mutations
EBS-loc 60%ADMild<50%>50%
<1%AR
EBS-gen-nonDM 15%ADModerate-severe<50%>50%
EBS-DM 25%<50%>50%
EBS-MP <1%95% 1 5%
All EBS 100%50%50%

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

1. Hamada et al [2004], Horiguchi et al [2005]

Penetrance

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

Anticipation

Anticipation is not observed in EBS.

Nomenclature

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].

Prevalence

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 mutations 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 loss-of-function mutations in PKP1 (for review, see McGrath & Mellerio [2010]).
  • EBS, lethal acantholytic is caused by mutations 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. Mutations 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 mutations (see EB with pyloric atresia).

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

JEB-non-Herlitz caused by mutations in COL17A1 (formerly termed generalized atrophic benign epidermolysis bullosa [GABEB]) usually has a much better prognosis than JEB caused by mutations in 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. Mutations in COL7A1, the gene encoding type VII collagen, have been demonstrated in DEB, both dominant and recessive:

  • The designation Bart syndrome [OMIM 132000] 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 mutations 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 mutations in PLEC1. Mutations 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 226670]. Some individuals with EB resulting from PLEC1 mutations 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 [OMIM 226730]. In several US and Japanese families, EB with pyloric atresia is associated with premature termination mutations 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.
  • EB-Ogna [OMIM 131950], observed in one Norwegian and one German family, is caused by a site-specific missense mutation 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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

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 mutation [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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

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 gene mutation. The more severe forms of autosomal dominant EBS are usually caused by a de novo mutation 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

Offspring of a proband

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

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 mutant 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 mutant 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 disease-causing mutations 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 gene mutation) or autosomal recessive; a de novo dominant mutation 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal testing for pregnancies at increased risk for EBS is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

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
    Austria
    Phone: +43 1 876 40 30-0
    Fax: +43 1 876 40 30-30
    Email: office@debra-international.org
  • 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
    Email: staff@debra.org
  • DebRA UK
    DebRA House
    13 Wellington Business Park
    Crowthorne Berkshire RG45 6LS
    United Kingdom
    Phone: +44 01344 771961
    Fax: +44 01344 762661
    Email: debra@debra.org.uk
  • 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
    Email: coordinator@EBCare.org

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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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)

131760EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE
131800EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
131900EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
131960EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION; EBS-MP
148040KERATIN 5; KRT5
148066KERATIN 14; KRT14
601001EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1; EBSB1

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.

Mutations 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 mutation, the location of the mutation, 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 mutations 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].

KRT5

Normal allelic variants. The cDNA comprises 2,164 bp in eight exons. Genomic length is estimated at approximately 6 kb.

Pathologic allelic variants. Mutations in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen-nonDM. Mutations 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 mutation p.Glu477Lys, along with the KRT14 recurrent mutations 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 mutation p.Pro25Leu [Moog et al 1999] accounts for 90%-95% of identified mutations in EBS-MP. The KRT5 mutation c.1649delG is also responsible for a mottled pigmentation phenotype [Horiguchi et al 2005]. The KRT14 mutation 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 mutation has been described [Indelman et al 2005]. (For more information, see Table A.)

Table 4. Selected KRT5 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.74C>Tp.Pro25Leu
(Pro24Leu)
NM_000424​.3
NP_000415​.2
c.1649delGp.Gly550Alafs*77 2
c.1429G>Ap.Glu477Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). 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​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. 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

KRT14

Normal allelic variants. The cDNA comprises 1,377 bp in eight exons. Genomic length is approximately 4.5 kb.

Pathologic allelic variants. Mutations in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Mutations in the 1A or 2B segments of the rod domain are typical for EBS- gen-nonDM. Mutations 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 Pathologic Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.256T>Cp.Met119ThrNM_000526​.4
NP_000517​.2
c.368A>Gp.Asn123Ser
c.373C>Tp.Arg125Cys
c.374G>Ap.Arg125His

Note on variant classification: Variants listed in the table have been provided by the author(s). 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​.hgvs.org). 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. Missense mutations 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 mutations may give rise to a less severe phenotype than certain missense mutations [Sorensen et al 2003, Smith et al 2004b].

References

Literature Cited

  1. Abitbol RJ, Zhou LH. Treatment of epidermolysis bullosa simplex, Weber-Cockayne type, with botulinum toxin type A. Arch Dermatol. 2009;145:13–5. [PubMed: 19153338]
  2. Abu Sa'd J, Indelman M, Pfendner E, Falik-Zaccai TC, Mizrachi-Koren M, Shalev S, Ben Amitai D, Raas-Rothshild A, Adir-Shani A, Borochowitz ZU, Gershoni-Baruch R, Khayat M, Landau D, Richard G, Bergman R, Uitto J, Kanaan M, Sprecher E. Molecular epidemiology of hereditary epidermolysis bullosa in a Middle Eastern population. J Invest Dermatol. 2006;126:777–81. [PubMed: 16439963]
  3. Arin MJ, Grimberg G, Schumann H, De Almeida H, Chang YR, Tadini G, Kohlhase J, Krieg T, Bruckner-Tuderman L, Has C. Identification of novel and known KRT5 and KRT14 mutations in 53 patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. Br J Dermatol. 2010;162:1365–9. [PubMed: 20199538]
  4. Arin MJ, Roop DR. Inducible mouse models for inherited skin diseases: implications for skin gene therapy. Cells Tissues Organs. 2004;177:160–8. [PubMed: 15388990]
  5. Bergman R, Harel A, Sprecher E. Dyskeratosis as a histologic feature in epidermolysis bullosa simplex-Dowling Meara. J Am Acad Dermatol. 2007;57:463–6. [PubMed: 17707151]
  6. Betz RC, Planko L, Eigelshoven S, Hanneken S, Pasternack SM, Bussow H, Van Den Bogaert K, Wenzel J, Braun-Falco M, Rutten A, Rogers MA, Ruzicka T, Nöthen MM, Magin TM, Kruse R. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. 2006;78:510–9. [PMC free article: PMC1380294] [PubMed: 16465624]
  7. Bolling MC, Lemmink HH, Jansen GH, Jonkman MF. Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients. Br J Dermatol. 2011;164:637–44. [PubMed: 21375516]
  8. Bolling MC, Veenstra MJ, Jonkman MF, Diercks GF, Curry CJ, Fisher J, Pas HH, Bruckner AL. Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: expanding the phenotype and implications for desmoplakin function in skin and heart. Br J Dermatol. 2010;162:1388–94. [PubMed: 20302578]
  9. Charlesworth A, Gagnoux-Palacios L, Bonduelle M, Ortonne JP, De Raeve L, Meneguzzi G. Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. J Invest Dermatol. 2003;121:1344–8. [PubMed: 14675180]
  10. Christiano AM, Bart BJ, Epstein EH, Uitto J. Genetic basis of Bart's syndrome: a glycine substitution mutation in the type VII collagen gene. J Invest Dermatol. 1996;106:1340–2. [PubMed: 8752681]
  11. D'Alessandro M, Morley SM, Ogden PH, Liovic M, Porter RM, Lane EB. Functional improvement of mutant keratin cells on addition of desmin: an alternative approach to gene therapy for dominant diseases. Gene Ther. 2004;11:1290–5. [PubMed: 15215887]
  12. Fine JD, Bauer EA, McGuire J, Moshell A. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances and the Findings of the National Epidermolysis Registry. Baltimore, MD: Johns Hopkins University Press; 1999.
  13. Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, McGrath JA, Mellerio JE, Murrell DF, Shimizu H, Uitto J, Vahlquist A, Woodley D, Zambruno G. The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol. 2008;58:931–50. [PubMed: 18374450]
  14. Groves RW, Liu L, Dopping-Hepenstal PJ, Markus HS, Lovell PA, Ozoemena L, Lai-Cheong JE, Gawler J, Owaribe K, Hashimoto T, Mellerio JE, Mee JB, McGrath JA. A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol. 2010;130:1551–7. [PubMed: 20164846]
  15. Hamada T, Ishii N, Kawano Y, Takahashi Y, Inoue M, Yasumoto S, Hashimoto T. The P25L mutation in the KRT5 gene in a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol. 2004;150:609–11. [PubMed: 15030360]
  16. Hanneken S, Rütten A, Pasternack SM, Eigelshoven S, El Shabrawi-Caelen L, Wenzel J, Braun-Falco M, Ruzicka T, Nöthen MM, Kruse R, Betz RC. Systematic mutation screening of KRT5 supports the hypothesis that Galli-Galli disease is a variant of Dowling-Degos disease. Br J Dermatol. 2010;163:197–200. [PubMed: 20222933]
  17. Harel A, Bergman R, Indelman M, Sprecher E. Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14. J Invest Dermatol. 2006;126:1654–7. [PubMed: 16601668]
  18. Hobbs RP, Han SY, van der Zwaag PA, Bolling MC, Jongbloed JD, Jonkman MF, Getsios S, Paller AS, Green KJ. Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. J Invest Dermatol. 2010;130:2680–3. [PMC free article: PMC3061313] [PubMed: 20613772]
  19. Horiguchi Y, Sawamura D, Mori R, Nakamura H, Takahashi K, Shimizu H. Clinical heterogeneity of 1649delG mutation in the tail domain of keratin 5: a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. J Invest Dermatol. 2005;125:83–5. [PubMed: 15982306]
  20. Horn HM, Priestley GC, Eady RA, Tidman MJ. The prevalence of epidermolysis bullosa in Scotland. Br J Dermatol. 1997;136:560–4. [PubMed: 9155958]
  21. Hu ZL, Smith L, Martins S, Bonifas JM, Chen H, Epstein EH. Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex--increased severity of disease in a homozygote. J Invest Dermatol. 1997;109:360–4. [PubMed: 9284105]
  22. Indelman M, Bergman R, Sprecher E. A novel recessive missense mutation in KRT14 reveals striking phenotypic heterogeneity in epidermolysis bullosa simplex. J Invest Dermatol. 2005;124:272–4. [PubMed: 15654986]
  23. Irvine AD, McLean WH. The molecular genetics of the genodermatoses: progress to date and future directions. Br J Dermatol. 2003;148:1–13. [PubMed: 12534588]
  24. Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A, Pas HH. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet. 2005;77:653–60. [PMC free article: PMC1275614] [PubMed: 16175511]
  25. Koss-Harnes D, Hoyheim B, Anton-Lamprecht I, Gjesti A, Jorgensen RS, Jahnsen FL, Olaisen B, Wiche G, Gedde-Dahl T. A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol. 2002;118:87–93. [PubMed: 11851880]
  26. Koss-Harnes D, Hoyheim B, Jonkman MF, de Groot WP, de Weerdt CJ, Nikolic B, Wiche G, Gedde-Dahl T. Life-long course and molecular characterization of the original Dutch family with epidermolysis bullosa simplex with muscular dystrophy due to a homozygous novel plectin point mutation. Acta Derm Venereol. 2004;84:124–31. [PubMed: 15206692]
  27. Liao H, Zhao Y, Baty DU, McGrath JA, Mellerio JE, McLean WH. A heterozygous frameshift mutation in the V1 domain of keratin 5 in a family with Dowling-Degos disease. J Invest Dermatol. 2007;127:298–300. [PubMed: 16917491]
  28. Lugassy J, Itin P, Ishida-Yamamoto A, Holland K, Huson S, Geiger D, Hennies HC, Indelman M, Bercovich D, Uitto J, Bergman R, McGrath JA, Richard G, Sprecher E. Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet. 2006;79:724–30. [PMC free article: PMC1592572] [PubMed: 16960809]
  29. Lugassy J, McGrath JA, Itin P, Shemer R, Verbov J, Murphy HR, Ishida-Yamamoto A, Digiovanna JJ, Bercovich D, Karin N, Vitenshtein A, Uitto J, Bergman R, Richard G, Sprecher E. KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol. 2008;128:1517–24. [PubMed: 18049449]
  30. McGrath JA, Mellerio JE. Ectodermal dysplasia-skin fragility syndrome. Dermatol Clin. 2010;28:125–9. [PubMed: 19945625]
  31. Moog U, de Die-Smulders CE, Scheffer H, van der Vlies P, Henquet CJ, Jonkman MF. Epidermolysis bullosa simplex with mottled pigmentation: clinical aspects and confirmation of the P24L mutation in the KRT5 gene in further patients. Am J Med Genet. 1999;86:376–9. [PubMed: 10494094]
  32. Müller FB, Küster W, Wodecki K, Almeida H, Bruckner-Tuderman L, Krieg T, Korge BP, Arin MJ. Novel and recurrent mutations in keratin KRT5 and KRT14 genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly. Hum Mutat. 2006;27:719–20. [PubMed: 16786515]
  33. Nagao-Watanabe M, Fukao T, Matsui E, Kaneko H, Inoue R, Kawamoto N, Kasahara K, Nagai M, Ichiki Y, Kitajima Y, Kondo N. Identification of somatic and germline mosaicism for a keratin 5 mutation in epidermolysis bullosa simplex in a family of which the proband was previously regarded as a sporadic case. Clin Genet. 2004;66:236–8. [PubMed: 15324323]
  34. Nakamura H, Sawamura D, Goto M, Nakamura H, McMillan JR, Park S, Kono S, Hasegawa S, Paku S, Nakamura T, Ogiso Y, Shimizu H. Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). J Mol Diagn. 2005;7:28–35. [PMC free article: PMC1867514] [PubMed: 15681471]
  35. Neufeld-Kaiser W, Sybert VP. Is cyproheptadine effective in the treatment of subjects with epidermolysis bullosa simplex-Dowling-Meara? Arch Dermatol. 1997;133:251–2. [PubMed: 9041851]
  36. Pascucci M, Posteraro P, Pedicelli C, Provini A, Auricchio L, Paradisi M, Castiglia D. Epidermolysis bullosa simplex with mottled pigmentation due to de novo P25L mutation in keratin 5 in an Italian patient. Eur J Dermatol. 2006;16:620–2. [PubMed: 17229601]
  37. Pfendner E, Rouan F, Uitto J. Progress in epidermolysis bullosa: the phenotypic spectrum of plectin mutations. Exp Dermatol. 2005a;14:241–9. [PubMed: 15810881]
  38. Pfendner E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol. 2005;124:111–5. [PubMed: 15654962]
  39. Pfendner EG, Sadowski SG, Uitto J. Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. J Invest Dermatol. 2005b;125:239–43. [PubMed: 16098032]
  40. Rugg EL, Horn HM, Smith FJ, Wilson NJ, Hill AJ, Magee GJ, Shemanko CS, Baty DU, Tidman MJ, Lane EB. Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol. 2007;127:574–80. [PubMed: 17039244]
  41. Rugg EL, Leigh IM. The keratins and their disorders. Am J Med Genet C Semin Med Genet. 2004;131C:4–11. [PubMed: 15452838]
  42. Schara U, Tucke J, Mortier W, Nusslein T, Rouan F, Pfendner E, Zillikens D, Bruckner-Tuderman L, Uitto J, Wiche G, Schroder R. Severe mucous membrane involvement in epidermolysis bullosa simplex with muscular dystrophy due to a novel plectin gene mutation. Eur J Pediatr. 2004;163:218–22. [PubMed: 14963703]
  43. Shimizu H, Takizawa Y, Pulkkinen L, Murata S, Kawai M, Hachisuka H, Udono M, Uitto J, Nishikawa T. Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature. J Am Acad Dermatol. 1999;41:950–6. [PubMed: 10570379]
  44. Shurman D, Losi-Sasaki J, Grimwood R, Kivirikko S, Tichy E, Uitto J, Richard G. Epidermolysis Bullosa Simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date. Eur J Dermatol. 2006;16:132–5. [PubMed: 16581562]
  45. Smith FJ, Eady RA, Leigh IM, McMillan JR, Rugg EL, Kelsell DP, Bryant SP, Spurr NK, Geddes JF, Kirtschig G, Milana G, de Bono AG, Owaribe K, Wiche G, Pulkkinen L, Uitto J, McLean WH, Lane EB. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet. 1996;13:450–7. [PubMed: 8696340]
  46. Smith FJ, Morley SM, McLean WH. Novel mechanism of revertant mosaicism in Dowling-Meara epidermolysis bullosa simplex. J Invest Dermatol. 2004a;122:73–7. [PubMed: 14962092]
  47. Smith TA, Steinert PM, Parry DA. Modeling effects of mutations in coiled-coil structures: case study using epidermolysis bullosa simplex mutations in segment 1a of K5/K14 intermediate filaments. Proteins. 2004b;55:1043–52. [PubMed: 15146501]
  48. Sorensen CB, Andresen BS, Jensen UB, Jensen TG, Jensen PK, Gregersen N, Bolund L. Functional testing of keratin 14 mutant proteins associated with the three major subtypes of epidermolysis bullosa simplex. Exp Dermatol. 2003;12:472–9. [PubMed: 12930305]
  49. Sprecher E, Indelman M, Khamaysi Z, Lugassy J, Petronius D, Bergman R. Galli-Galli disease is an acantholytic variant of Dowling-Degos disease. Br J Dermatol. 2007;156:572–4. [PubMed: 17300252]
  50. Stephens K, Ehrlich P, Weaver M, Le R, Spencer A, Sybert VP. Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients. J Invest Dermatol. 1997;108:349–53. [PubMed: 9036937]
  51. Swartling C, Karlqvist M, Hymnelius K, Weis J, Vahlquist A. Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita. Br J Dermatol. 2010;163:1072–6. [PubMed: 20618323]
  52. Weiner M, Stein A, Cash S, de Leoz J, Fine JD. Tetracycline and epidermolysis bullosa simplex: a double-blind, placebo-controlled, crossover randomized clinical trial. Br J Dermatol. 2004;150:613–4. [PubMed: 15030362]
  53. Werner NS, Windoffer R, Strnad P, Grund C, Leube RE, Magin TM. Epidermolysis bullosa simplex-type mutations alter the dynamics of the keratin cytoskeleton and reveal a contribution of actin to the transport of keratin subunits. Mol Biol Cell. 2004;15:990–1002. [PMC free article: PMC363056] [PubMed: 14668478]
  54. Yasukawa K, Sawamura D, Goto M, Nakamura H, Jung SY, Kim SC, Shimizu H. Epidermolysis bullosa simplex in Japanese and Korean patients: genetic studies in 19 cases. Br J Dermatol. 2006;155:313–7. [PubMed: 16882168]
  55. Yiasemides E, Walton J, Marr P, Villanueva EV, Murrell DF. A comparative study between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis bullosa. Am J Dermatopathol. 2006;28:387–94. [PubMed: 17012912]

Suggested Reading

  1. Van Coster R, Pulkkinen L. Epidermolysis bullosa: The disease of the cutaneous basement membrane. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 222. Available online. Accessed 1-29-13.

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, Seattle (1998-2005)
Virginia P Sybert, MD; University of Washington, Seattle (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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1369PMID: 20301543
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...