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.

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.

Genetically Related (Allelic) Disorders

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, Hanneken et al 2010]. Inheritance is autosomal dominant.

EBS, migratory circinate (EBS-migr) is caused by mutations in KRT5.

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 mutations in the E1/V1-encoding region of KRT14 have been identified, indicating that KRT14 haploinsufficiency resulting in increased susceptibility of keratinocytes to pro-apoptotic signals is causative [Lugassy et al 2006, Lugassy et al 2008].

EBS, autosomal recessive (EBS-AR) is caused by autosomal recessive mutations in KRT14.

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.

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].

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].

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.

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

• The risk to the sibs of the proband depends on the genetic status of the parents.
• If a parent is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the 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 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.

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].

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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.

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