Clinical characteristics.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in non-scarring blisters and erosions caused by minor mechanical trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 17 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, generalized intermediate (EBS-gen intermed; previously known as Koebner type)
• EBS-with mottled pigmentation (EBS-MP)
• EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type)

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 age 18 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 intermed, 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-gen sev.
• In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; 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-gen sev, onset is usually at birth; severity varies greatly, both among and within 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. 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-gen sev may interfere with feeding, especially in neonates and infants. Blistering can be severe enough to result in neonatal or infant death.

Diagnosis/testing.

The diagnosis of epidermolysis bullosa simplex (EBS) is established in a proband by the identification of biallelic pathogenic variants in EXPH5 or TGM5 or heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14 by molecular genetic testing; examination of a skin biopsy using immunofluorescence microscopy and transmission electron microscopy may be considered but can have limitations in the diagnosis of EBS.

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 of open wounds. Lance and drain new blisters. Dressings involve three layers: a primary nonadherent contact layer; a secondary layer providing stability, adding padding, and absorbing drainage; 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 with EBS. Cyproheptadine (Periactin^®), tetracycline, erythromycin, or botulimun toxin can reduce blistering in some individuals. Keratolytics and softening agents for palmar plantar hyperkeratosis may prevent tissue thickening and cracking.

Prevention of secondary complications: Monitor for wound infection; treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful. Nutritional support and feeding therapy may be necessary for infants and children with oral manifestations of EBS. Management of fluid and electrolyte problems in severely affected infants. 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. Avoid ordinary medical tape or Band-Aids^®.

Genetic counseling.

EBS caused by pathogenic variants in EXPH5 or TGM5 is inherited in an autosomal recessive manner. EBS caused by pathogenic variants in KRT5 or KRT14 is usually inherited in an autosomal dominant manner, but in rare families (especially those with consanguinity) it can be inherited in an autosomal recessive manner.

• In families with autosomal recessive inheritance, the parents of an affected child are obligate heterozygotes; at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a heterozygote.
• In families with autosomal dominant inheritance, each child of an affected individual has a 50% chance of inheriting the pathogenic variant and having EBS.

Molecular genetic testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known.

Suggestive Findings

The diagnosis of epidermolysis bullosa simplex (EBS) should be suspected in individuals with the following clinical findings:

• Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring
• Blistering that:
  • May be present in the neonatal period
  • Primarily affects the hands and feet but can affect the whole body
  • Occurs in annular or curvilinear groups or clusters
  • Can lead to progressive brown pigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life
  • Is associated with palmar and plantar hyperkeratosis that may be severe
• Nail dystrophy
• Milia
• Family history that is consistent with either an autosomal recessive or autosomal dominant inheritance pattern
  Note: Absence of a known family history of EBS does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of epidermolysis bullosa simplex (EBS) is best established in a proband by the identification of biallelic pathogenic variants in EXPH5 or TGM5 or heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14 by molecular genetic testing (see Table 1). Examination of a skin biopsy using immunofluorescence microscopy and transmission electron microscopy (see Skin biopsy below) may be considered but can have limitations in the diagnosis of EBS.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing

• Sequence analysis of KRT5 and KRT14 is performed first.
• If no pathogenic variants are found in KRT5 or KRT14 by sequence analysis, sequence analysis of EXPH5 and TGM5 should be considered next.
• If sequence analysis of EXPH5 and TGM5 reveals no or only one pathogenic variant, gene-targeted deletion/duplication analysis of EXPH5, KRT5, KRT14, and/or TGM5 may be considered. Note, however:
  • The majority of pathogenic variants in KRT5 and KRT14 are dominant-negative missense variants inherited in an autosomal dominant manner.
  • Loss-of-function variants in EXPH5, KRT5, KRT14, and TGM5 occur rarely and cause recessive disease.
  • No large deletion or duplication in EXPH5, KRT5, KRT14, or TGM5 has been reported.
  Therefore, a multigene panel or genomic testing may be higher yield than deletion/duplication analysis.

A multigene panel that includes EXPH5, KRT5, KRT14, TGM5 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes EXPH5, KRT5, KRT14, and TGM5) fails to confirm a diagnosis in an individual with features of EBS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Skin biopsy. Immunofluorescence antigenic mapping has been the sine qua non for the diagnosis of EBS because of its rapid turnaround time and high sensitivity and specificity [Yiasemides et al 2006]. However, advances in molecular genetic testing have lead clinicians to use genetic testing for diagnosis, as opposed to skin biopsy. Skin biopsy should still be considered in the evaluation of newborns with extensive blistering and erosions, in cases where the EB phenotype is not clear and a prompt diagnosis is needed, and when genetic testing is not available.

• Biopsy technique
  • To insure the most accurate diagnosis, the leading edge of a fresh blister induced by mechanical friction should be biopsied. The healing in non-induced intact blisters may obscure the morphology.
  • Induced blisters are typically analyzed by light microscopy, immunofluorescent microscopy, and transmission electron microscopy.
• Histology (light microscopy)
  • In all cases of EBS, splitting is observed within or above the basal cell layer of the skin. Routine histology suggests the diagnosis of EB but is an inadequate and unacceptable test for accurately diagnosing the EB type and subtype. It is most valuable to rule out other causes of blistering when the differential diagnosis is broad.
• Transmission electron microscopy
  • In cases of EBS caused by biallelic pathogenic variants in EXPH5, widened space between keratinocytes, aggregation of keratin filaments, and vesicles near the plasma membrane and nucleus have been reported [McGrath et al 2012].
  • In EBS-gen sev, the keratin intermediate filaments (also called tonofilaments) are clumped, a finding that serves as a distinguishing feature [Bergman et al 2007]. This finding is only seen using electron microscopy, making this study useful when the diagnosis of EBS-gen sev is suspected. The absence of keratin intermediate filaments is a distinguishing feature of autosomal recessive EBS caused by biallelic pathogenic variants in KRT14 (EBS-AR K14).
• Immunofluorescence microscopy
  • 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. This mapping pattern is specific to EBS but does not further delineate the EBS subtype. It also relies on the formation of a blister in the biopsy specimen. Thus, there is a risk in affected individuals with less severe disease that a blister may not be induced and the biopsy may be non-diagnostic.
  • Immunofluorescent microscopy can be helpful in the diagnosis of autosomal recessive forms of EBS, as the affected protein will be substantially reduced or absent. However, antibodies to exophilin 5 and transglutaminase 5 are not widely available, limiting the clinical utility of this study to the exceedingly rare forms of EBS-AR caused by biallelic pathogenic variants in KRT14.

Clinical Description

The most common forms of epidermolysis bullosa simplex (EBS) are subdivided into clinical phenotypes — EBS, localized (EBS-loc) (previously known as EBS, Weber-Cockayne type); EBS, generalized intermediate (EBS-gen intermed) (previously known as EBS, Koebner type); EBS-with mottled pigmentation (EBS-MP); and EBS, generalized severe (EBS-gen sev, previously known as EBS, Dowling-Meara) — 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.

Phenotype Correlations by Gene

The proportion of EXPH5, KRT5, KRT14, and TGM5 pathogenic variants responsible for each phenotype is shown in Table 3. Clinical overlap between EBS-gen intermed and EBS-gen sev 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 pathogenic variants in KRT5 or KRT14 may be population specific [Abu Sa'd et al 2006, Yasukawa et al 2006, Rugg et al 2007].

Genotype-Phenotype Correlations

EXPH5. Pathogenic variants in EXPH5 are rare, with only seven cases reported to date. All reported pathogenic variants resulting in EXPH5-related EBS are loss-of-function variants that can be located anywhere in the gene.

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

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

Penetrance

Penetrance is 100% for known heterozygous (autosomal dominant) and biallelic (autosomal recessive) KRT5 and KRT14 pathogenic variants. Penetrance is also 100% for known biallelic pathogenic variants in EXPH5 and TGM5. Disease severity may be influenced by other factors and may show intrafamilial variation [Indelman et al 2005].

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 nomenclature for EBS has changed four times in the last fifteen years. The eponyms EBS-Weber-Cockayne and EBS-Koebner were changed to EBS, localized and EBS-other generalized in the 2008 classification system [Fine et al 2008]. The most recent classification system, referred to as the "onion skin" terminology, arose from the most recent international consensus meeting, the recommendations of which were published in June 2014 [Fine et al 2014]. This classification system expands on the histologic description and specific pathogenic variants found in affected individuals (see Table 4).