 |
|
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Epidermolysis bullosa simplex (EBS) is characterized by skin fragility that results in nonscarring blisters caused by little or no trauma. Four clinical subtypes of EBS range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. In EBS, Weber-Cockayne type (EBS-WC), blisters are rarely present 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, Koebner type (EBS-K), blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-WC, but generally milder than in EBS, Dowling-Meara type (EBS-DM). In EBS with mottled pigmentation (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-WC 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 transmission electron microscopic examination that reveals splitting within or just above the basal cell layer of the skin or on immunohistochemistry using appropriate fluorescent antibodies. All four forms of EBS are caused by mutation in either KRT5 or KRT14. Molecular genetic testing of KRT5 and KRT14 detects mutations in 75%-90% of individuals with biopsy-diagnosed EBS-K, EBS-DM, and EBS-WC, and 90%-95% of mutations in those with EBS-MP. Such testing is clinically available.
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 dressing, 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®) can reduce blistering in some individuals with EBS-DM. 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 with 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 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 gene mutation. For autosomal dominant EBS, the chance that an affected person will pass the disease-causing mutation to each child is 50%. For autosomal dominant EBS, prenatal testing is possible for pregnancies at increased risk if the disease-causing mutation has been identified in an affected family member.
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 are nonscarring. 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 positive family history who have blisters on the palms and soles only.
Skin biopsy. Immunofluorescent antibody/antigen mapping is the sine qua non for the diagnosis of EBS because of its rapid turnaround time and high sensitivity and specifity [Yiasemides et al 2006].
Transmission electron microscopic examination may also be used to identify tonofilament clumping and further delineate the classification of EBS Dowling-Meara (EBS-DM) [Bergman et al 2007]. (The leading edge of a mechanically induced blister with some normal adjacent skin should be biopsied as older blisters undergo change that 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, EBS-DM, the tonofilaments (also called keratin filaments) are clumped, a finding that serves as a distinguishing feature [Bergman et al 2007].
In the rare cases of autosomal recessive EBS, tonofilaments are absent from basal keratinocytes.
Abnormal or absent staining with antibodies to keratin 5 or keratin 14, coupled with normal staining for other antigens (e.g., laminin and type VII collagen) and the localization of stained epitopes relative to the blister cavity confirm the diagnosis of EBS. (When keratin 5 or keratin 14 staining is positive, the diagnosis is made by “mapping the blister,” i.e., keratin 5 or keratin 14 and the other antigens are present on the blister floor.)
Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of EBS.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. The two genes currently known to be associated with EBS are KRT5 and KRT14.
Other loci. Because only 75%-90% 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].
Clinical testing
Sequence analysis. Sequence analysis is performed first in the KRT5 and KRT14 gene regions in which a high percentage of mutations are known to occur and 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 70%-90% [Yasukawa et al 2006, Rugg et al 2007].
Table 1 summarizes molecular genetic testing for this disorder.
| Gene Symbol | Test Method | EBS Subtype | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|---|---|
| KRT5 and KRT14 | Sequence analysis | EBS-WC | KRT5 and KRT14 sequence variants | 70%-90% 2 | Clinical
 |
| EBS-K | |||||
| EBS-DM | |||||
| EBS-MP | KRT5 p.Pro25Leu | 90%-95%3, 4, 5 | |||
| KRT14 p.Met119Thr | 2%-5% 6 |
1. In individuals with biopsy-diagnosed EBS
3. Horiguchi et al [2005] describe a second mutation associated with EBS-MP.
6. 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.
To confirm the diagnosis in a proband
A skin biopsy 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 1,5,7) and KRT14 (exons 1,4,6) 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 for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
KRT5. Dowling-Degos disease (DDD), characterized by progressive and disfiguring reticulate hyperpigmentation of the flexures, is caused by KRT5 loss-of-function mutations [Betz et al 2006, Liao et al 2007]. Galli-Galli disease, a variant of DDD that exhibits the same hyperpigmentation pattern accompanied by acantholytic lesions, is also caused by KRT5 loss-of-function mutations [Sprecher et al 2007]. Inheritance is autosomal dominant.
KRT14. Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are phenotypically similar ectodermal dysplasia syndromes characterized by complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. Inheritance is autosomal dominant. Heterozygous nonsense or frameshift KRT14 mutations have been identified in five families, indicating that KRT14 haploinsufficiency may be causative [Lugassy et al 2006]. However, another family has been reported with a frameshift mutation that results in the EBS-DM phenotype and some amelioration with age [Titeux et al 2006].
Before the molecular basis of epidermolysis bullosa simplex (EBS) was understood, EBS was subdivided into clinical phenotypes — EBS, Weber-Cockayne type (EBS-WC); EBS, Koebner type (EBS-K); EBS, Dowling-Meara type (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.
| EBS Subtype | Weber-Cockayne | Koebner | Mottled Pigmentation | Dowling-Meara | ||
|---|---|---|---|---|---|---|
| Age of Onset | Usually ~12-18 months | Birth/infancy | Birth/infancy | Birth | ||
| ClinicalFeature | Blisters | Distribution | Usually limited to hands, feet; can occur at sites of repeated trauma (e.g., belt line) | Generalized | Generalized | Generalized |
| Grouped (herpetiform) | No | No | Sometimes | Yes | ||
| Hemorrhagic | Rare | Occasionally | Unknown | Yes | ||
| Mucosal | Rare | Occasionally | Occasionally | Often | ||
| Progressive pyperkeratosis of palms and soles | Occasionally | Occasionally | Yes | Yes | ||
| Nail involvement | Occasionally | Occasionally | Variable | Common | ||
| Milia | Rare | Occasionally | Unknown | Common | ||
| Hyper/ Hypopigmentation | No | Can occur | Always | Common | ||
EBS, Weber-Cockayne type (EBS-WC). Blisters are rarely present at birth. The first episodes may occur on the knees and shins with crawling or on the feet at approximately age 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-WC 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; affected individuals have developed blisters 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 (as is true for all forms of EBS except EBS-DM) 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, Koebner type (EBS-K). Blisters may be present at birth or develop within the first few months of life. EBS-K is distinguished from EBS-WC by its more widespread involvement and from EBS-DM by absence of clumped tonofilaments in basal keratinocytes on electron microscopy. In general, EBS-K is milder than EBS-DM, but clinical overlap is high. Similarly, mild EBS-K can be misdiagnosed as EBS-WC. Branches of one large pedigree were reported separately as EBS-K and EBS-WC, reflecting the heterogeneity in severity even within families. As all the EBS 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 EBS-DM. Over time, progressive, reticulate brown pigmentation interspersed with hypopigmented spots, different from post-inflammatory hyperpigmentation and hypopigmentation, develops 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 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. Widespread and severe blistering and/or multiple grouped clumps of small blisters (whose resemblance to the blisters of juvenile dermatitis herpetiformis gave the disorder one of its names) are typical. Hemorrhagic blisters are common. The mucosa can be involved; this usually resolves with age.
Improvement occurs during mid- to late childhood and blistering may be a minimal component of the disorder in adult life. Unlike other forms of epidermolysis bullosa (EB), the Dowling-Meara variant appears to improve with heat or warmth in some individuals. Spontaneous prolonged clearing with fevers has been reported.
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 and milia, typically thought to be limited to dystrophic disease, 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.
Cancer risk. Squamous cell carcinoma is not usually associated with EBS.
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-WC.
Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-K.
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.
Autosomal dominant mutations cause signs in heterozygotes by acting in a dominant negative manner, i.e., 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, Liao et al 2007, Lugassy et al 2006, Sprecher et al 2007] [see Genetically Related Disorders].
The proportion of KRT5 and KRT14 mutations producing each phenotype are outlined in the following table. 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 Table 3 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].
| Phenotype | % of all EBS | Inheritance | Severity | Proportion of KRT5 Mutations | Proportion of KRT14 Mutations |
|---|---|---|---|---|---|
| EBS-WC | 60% | AD | Mild | >50% | >50% |
| <1% | AR | ||||
| EBS-K | 15% | AD | Moderate-severe | <50% | >50% |
| EBS-DM | 25% | <50% | >50% | ||
| EBS-MP | <1% | 95% 1 | 5% | ||
| All EBS | 100% | 50% | 50% |
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 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 prevalence of EBS is uncertain; estimates range from 1:30,000 to 1:50,000. EBS-WC is most prevalent as it does not result in neonatal death and interferes least with fitness. EBS-DM and EBS-K 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 the birth rates during 1952-1989, of 1:56,000 for all types of EB [Horn et al 1997].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The three major types of epidermolysis bullosa (EB), caused by mutations in ten different genes, are EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB). Although agreement exists as to diagnostic criteria for some types of EB, the validity of rarer subtypes and their diagnostic criteria are disputed. For excellent clinical reviews, see Gedde-Dahl [1971] and Fine's Revised Classification System [Fine et al 2000].
The three major types of EB share easy fragility of the skin, 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, 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 diagnosis. A positive Nikolsky sign (blistering of uninvolved skin after rubbing) 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 also 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 three 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 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 basement membrane 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.
Junctional EB (JEB). Separation occurs above the basement membrane of the dermis within the lamina lucida of the dermal-epidermal junction, 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 lethal (or Herlitz) JEB and nonlethal (non-Herlitz) JEB, based on severity and survival past the first years of life. Generalized atrophic benign epidermolysis bullosa (GABEB) historically has been ascribed to COL17A1 mutations, but the phenotype overlaps significantly with non-Herlitz JEB.
Mutations in the genes that encode the subunits of laminin 5 (LAMA3, LAMC2, LAMB3) and type 17 collagen (COL17A1) are causative. EB with pyloric atresia has been associated with α6 β4 integrin and plectin mutations (see EB with pyloric atresia below).
Dystrophic EB (EBD). The blister forms below the basement membrane. 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 some forms of DEB, both dominant and recessive:
Bart syndrome [OMIM 132000], characterized by congenital absence of the skin on the lower legs and feet, nonscarring blistering of the skin and oral mucosa, and nail abnormalities, was originally reported as a subtype of EBS; however, demonstration of decreased anchoring fibrils and mutations in COL7A1 in one family led to recategorization as DEB. Some consider Bart syndrome to be most often, but not exclusively, a manifestation of dominant DEB, but the absence of skin on the legs can be seen in all forms in EB and may not be a distinguishing feature of any particular form.
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 lowest 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 and controversial EBS 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.
Note: Pulkkinen & Uitto [1999] proposed that EB with muscular dystrophy and EB with pyloric atresia be considered "hemidesmosomal JEB" because the involved proteins are located in the hemidesmosomes.
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.
To establish the extent of disease in an individual diagnosed with epidermolysis bullosa simplex (EBS), evaluation of the sites of blister formation, including oral and esophageal blisters and erosions, is recommended.
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 not strip 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 JEB and RDEB, 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.
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.
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.
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.
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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
If a pregnancy is known to be affected with any form of EB, caesarean delivery may reduce the trauma to the skin during delivery.
The use of corticosteroids and vitamin E in treating EBS has been reported anecdotally; no rigorous clinical trials have been undertaken.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Epidermolysis bullosa simplex (EBS) is usually inherited in an autosomal dominant manner, but in rare cases it can be inherited in an autosomal recessive manner.
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
The risk to the sibs of the proband depends on the genetic status of the parents.
If a parent is affected, the risk is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the disease-causing mutation 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 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 found to be affected, his or her family members are at risk.
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 testing is possible once the mutations have been identified in the family.
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 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, clarification of carrier status, 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 who are carriers of autosomal recessive EBS.
DNA banking. 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 disease will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
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 15-18 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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| KRT14 | 17q12-q21 | Keratin, type I cytoskeletal 14 |
| KRT5 | 12q13 | Keratin, type II cytoskeletal 5 |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 131760 | EPIDERMOLYSIS BULLOSA HERPETIFORMIS, DOWLING-MEARA TYPE |
| 131800 | EPIDERMOLYSIS BULLOSA OF HANDS AND FEET |
| 131900 | EPIDERMOLYSIS BULLOSA SIMPLEX, KOEBNER TYPE; EBS2 |
| 131960 | EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION; EBS-MP |
| 148040 | KERATIN 5; KRT5 |
| 148066 | KERATIN 14; KRT14 |
| 601001 | EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| KRT14 | 3861 (MIM No. 148066) | KRT14 |
| KRT5 | 3852 (MIM No. 148040) | KRT5 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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 to be 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-WC. Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-K. Mutations in the beginning of the 1A or the end of the 2B segments 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-K is unknown. An autosomal recessive missense mutation has been described [Indelman et al 2005]. (For more information, see Genomic Databases table above.)
| DNA Nucleotide Change | Protein Amino Acid Change (Alias 1) | Reference Sequence |
|---|---|---|
| c.74C>T | p.Pro25Leu (Pro24Leu) | NM_000424.3NP_000415.2 |
| c.1649delG | p.Gly550Alafs*77 2 | |
| c.1429G>A | p.Glu477Lys |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
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 8 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-WC. Mutations in the 1A or 2B segments of the rod domain are typical for EBS-K. 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-K. (For more information, see Genomic Databases table.)
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
|---|---|---|
| c.256T>C | p.Met119Thr | NM_000526.3NP_000517.2 |
| c.368A>G | p.Asn123Ser | |
| c.373C>T | p.Arg125Cys | |
| c.374G>A | p.Arg125His |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
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].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
DEBRA International
www.debra-international.org
DEBRA of America
(Dystrophic Epidermolysis Bullosa Research Association of America)
5 West 36th Street Room 404
New York NY 10018
Phone: 866-DEBRA76 (866-332-7276); 212-868-1573
Fax: 212-868-9296
Email: staff@debra.org
www.debra.org
DEBRA-UK
DebRA House
13 Wellington Business Park Dukes Ride
Crowthorne Berkshire RG45 6LS
United Kingdom
Phone: 44 01344 771961
Email: DebRA@DebRA.org.uk
www.debra.org.uk
National Library of Medicine Genetics Home Reference
Epidermolysis bullosa simplex
Medline Plus
Epidermolysis bullosa
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
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)
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
