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Epidermolysis Bullosa Simplex

, PhD and , MD.

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Initial Posting: ; Last Update: October 13, 2016.

Summary

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.

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.

GeneReview Scope

Epidermolysis Bullosa Simplex: Included Phenotypes
  • Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP)
  • Epidermolysis bullosa simplex, generalized severe (EBS-gen sev)
  • Epidermolysis bullosa simplex, localized (EBS-loc)
  • Epidermolysis bullosa simplex, generalized intermediate (EBS-gen intermed)

For synonyms and outdated names see Nomenclature.

Diagnosis

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 multi-gene panel, and more comprehensive genomic testing.

Serial single-gene testing

A multi-gene 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 over time. (2) Some multi-gene panels may include genes unrelated to the disorder of interest; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For more information on multi-gene panels click 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 multi-gene 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 more information on comprehensive genome sequencing click here.

Table 1.

Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex (EBS)

Gene 1Proportion of EBS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method 3
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
EXPH5Estimated at 1%-2%>90%Unknown 6
KRT5~37% 7~99% 8, 9Unknown 6
KRT14~37% 7~99% 8, 10Unknown 6
TGM5Estimated at 5%>90% 11Unknown 6
Other or unknown 12~19%NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

In individuals with biopsy-diagnosed EBS

4.

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

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available. However, deletion/duplication analysis is likely to have a low yield for these genes (see Establishing the Diagnosis).

7.

For further information on the proportion of each EBS subtype caused by pathogenic variants in KRT5 and KRT14, see Table 3.

8.
9.

Approximately 90%-95% of individuals with EBS-MP will have the p.Pro25Leu pathogenic variant in KRT5 [Pascucci et al 2006, Shurman et al 2006]. Horiguchi et al [2005] describe a second pathogenic variant associated with EBS-MP.

10.

Approximately 2%-5% of individuals with EMB-MP have a p.Met119Thr pathogenic variant in KRT14 [Harel et al 2006].

11.

A common founder variant in the catalytic domain, p.Gly113Cys, has been found in the European population.

12.

Because only approximately 75% of individuals with biopsy-proven EBS have identifiable heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14, it is possible that pathogenic variants in another as-yet unidentified gene are also causative [Yasukawa et al 2006, Rugg et al 2007, Bolling et al 2011]. Note: Two individuals with features of EBS caused by biallelic pathogenic variants in DST, encoding dystonin, have been reported [Groves et al 2010, Liu et al 2012]. More recent studies from the Netherlands identified a heterozygous pathogenic variant in PLEC in six of 16 individuals with biopsy-proven EBS who did not have a pathogenic variant detected in KRT5 or KRT14 [Bolling et al 2014].

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 Characteristics

Clinical Description

The most common forms of epidermolysis bullosa simplex (EBS) are subdivided into clinical phenotypes — EBS, localized (EBS-loc) (previously known as EBS, Weber-Cockayne type); EBS, generalized 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.

Table 2.

Diagnostic Clinical Features of the Four Most Common Subtypes of EBS

EBS SubtypeLocalizedGeneralized IntermediateMottled PigmentationGeneralized Severe
Age of onsetInfancy, usually by 12-18 monthsBirth/infancyBirth/infancyBirth
Clinical
feature
BlistersDistributionUsually limited to hands, feet; can occur at sites of repeated trauma (e.g., belt line)GeneralizedGeneralizedGeneralized
Grouped (herpetiform)NoNoSometimesYes
MucosalRareOccasionallyOccasionallyOften
Hyperkeratosis of palms & soles (keratoderma)OccasionallyOccasionallyCommon, focalCommon, progressive
Nail involvementOccasionallyOccasionallyOccasionallyCommon
MiliaRareOccasionallyUnknownCommon
Hyper/ hypopigmentationNoCan occurAlwaysCommon

EBS, Localized (EBS-loc)

Blisters begin in infancy and can present at birth; 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.

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, Generalized Intermediate (EBS-gen intermed)

Blisters may be present at birth or develop within the first few months of life. EBS-gen intermed is distinguished from EBS-loc by its more widespread involvement and from EBS-sev gen by absence of clumped keratin intermediate filaments in basal keratinocytes on electron microscopy (see Establishing the Diagnosis, Skin biopsy). In general, EBS-gen intermed is milder than EBS-sev gen, but clinical overlap is high. Similarly, mild EBS-gen intermed can be indistinguishable from EBS-loc. Branches of one large pedigree were reported separately as EBS-Koebner (now EBS-gen intermed) and EBS-Weber Cockayne (now EBS-loc), reflecting the variability in severity even within families.

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, Generalized Severe (EBS-gen sev)

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-gen sev 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.

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].

Table 3.

Molecular Basis of EBS Types Caused by EXPH5, KRT5, KRT14, and TGM5 Pathogenic Variants

Phenotype% of all EBSInheritanceSeverityProportion of Pathogenic Variants
EXPH5KRT5KRT14TGM5
EBS-loc60%ADMild1%-2%<47%>47%5%
<1%AR
EBS-gen intermed15%ADModerate-severeNI<50%>50%NI
EBS-gen sev25%NI<50%>50%NI
EBS-MP<1%<1% 194% 25%NI
All EBS100%1%-2%47%47%5%

In 25% of biopsy proven EBS, no pathogenic variant in KRT5 or KRT14 could be identified [Bolling et al 2010]; molecular genetic testing of EXPH5 and TGM5 was not performed in this study. Further studies from the Netherlands identified a heterozygous pathogenic variant in PLEC in six of 16 individuals with biopsy-proven EBS who did not have a pathogenic variant detected in KRT5 or KRT14 [Bolling et al 2014].

NI = no information

1.
2.

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).

Table 4.

Comparison of 2008 Nomenclature with Proposed “Onion Skin” Terminology: Representative Examples

Old Name (per 2008 recommendations)2014 Nomenclature
EBS, localizedEBS localized, normal keratin 5 and 14 staining, KRT5 or KRT14 pathogenic variant (specify type)
EBS, Dowling-MearaEBS generalized severe, normal keratin 5 and 14 staining, KRT5 or KRT14 pathogenic variant (specify type)
EBS, generalized otherEBS generalized intermediate, normal keratin 5 and 14 staining, KRT5 or KRT14 pathogenic variant (specify type)
EBM-MPEBS-MP, normal keratin 5 staining, KRT5 pathogenic variant (specify type)

EBS = epidermolysis bullosa simplex

MP = mottled pigmentation

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-gen sev and EBS-gen intermed 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. Horn and colleagues estimate a prevalence of 28.6 per million in Scotland, and prevalence estimates from other countries range from one to 28 per million [Horn et al 1997].

Differential Diagnosis

According to the 2014 classification system, the four major types of epidermolysis bullosa (EB), caused by pathogenic variants in 18 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome [Fine et al 2014]. 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, molecular genetic testing (or less commonly 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-sev gen, 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.

Other subtypes of EB simplex (EBS). The 2014 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 include: EBS superficialis; EBS acantholytic; and skin fragility syndromes resulting from deficiencies of desmoplakin, plakoglobin, or plakophilin.

  • Acantholytic EBS is caused by biallelic pathogenic variants in the tail region of DSP, which encodes desmoplakin [Jonkman et al 2005, Bolling et al 2010, Hobbs et al 2010]. Affected neonates present with progressive erosions without blistering, alopecia, or loss of nails. Death within the first days after birth secondary to profound fluid and electrolyte imbalance is common.
  • EBS-plakophilin (skin fragility-ectodermal dysplasia syndrome) 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 biallelic loss-of-function variants in PKP1 (for review, see McGrath & Mellerio [2010]).

In the basal forms of EBS, blistering occurs within the basal keratinocytes. The most common subtypes of basal EBS are the subject of this GeneReview. Other rare forms of basal EBS in the 2014 classification are: EBS, migratory circinate (EBS-migr); EBS with muscular dystrophy (EBS-MD); EBS with pyloric atresia (EBS-PA); EBS-Ogna (EBS-Og); and EBS, autosomal recessive-BP230 deficiency (EBS-AR BP230).

EB caused by pathogenic variants in PLEC. Biallelic and heterozygous pathogenic variants in PLEC, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause cleavage in the basal keratinocyte layer. Hence, these disorders are classified as EBS in the 2014 classification system. In most cases, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia) are more complex:

  • EB with muscular dystrophy (OMIM 226670). Some individuals with EB resulting from biallelic pathogenic variants in PLEC1 develop muscular dystrophy either in childhood or later in life [Smith et al 1996, Shimizu et al 1999, Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005a]. Within basal keratinocytes, plectin is localized to the inner plaques of the hemidesmosomes, which are hypoplastic and show poor association with keratin filaments. Electron microscopy of skin biopsies reveals a plane of cleavage (level of separation) within the bottom layer of the basal keratinocytes, just above the hemidesmosomes. Inheritance is autosomal recessive.
  • EB with pyloric atresia is associated with biallelic premature termination pathogenic variants in PLEC. An identical phenotype is seen in JEB with pyloric atresia caused by the genes encoding alpha 6 integrin (ITGA6) or 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) was originally described in one Norwegian and one German family and is caused by a heterozygous site-specific pathogenic missense variant within the rod domain of PLEC [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. More recent work by Bolling and colleagues [2014] in the Netherlands demonstrated that approximately 40% of individuals with biopsy-proven EBS who lack identifiable pathogenic variants in KRT5 or KRT14 have a heterozygous pathogenic variant in PLEC. This work suggests that mutation of PLEC1 may be more common than previously realized.

Junctional EB (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers, and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. The broad classification of JEB is divided into generalized and localized major subtypes with subordinate phenotypic subtypes. JEB, generalized includes: JEB, generalized severe (JEN-gen sev, formerly Herlitz JEB); JEN, generalized intermediate (JEB-gen intermed); JEN with pyloric atresia (JEB-PA); JEB-late onset (JEB-LO); and JEB with respiratory and renal involvement (JEB-RR). In JEB-gen sev, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB-gen intermed, the phenotype may be milder with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, and joint contractures. Biallelic pathogenic variants in one of the following four genes are known to cause JEB: LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%).

JEB with pyloric atresia has been associated with biallelic pathogenic variants in either α6β4 integrin or plectin (see EBS with pyloric atresia); inheritance is autosomal recessive.

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. Both heterozygous and biallelic pathogenic variants in COL7A1, the gene encoding type VII collagen, have been associated with DEB.

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, non-scarring blistering of the skin and oral mucosa, and nail abnormalities. Genetic studies of the original kindred identified heterozygous pathogenic variants in COL7A1 [Christiano et al 1996], and some consider Bart syndrome to be most often, but not exclusively, a manifestation of dominant DEB. However, congenital absence of skin can be seen in all forms in EB and may not be a distinguishing feature of any particular form of EB.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa simplex (EBS), the following evaluations are recommended:

  • Consultation with a dermatologist to evaluate the sites of blister formation, including oral mucosa
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing of open wounds, 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 bandages. 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 absorbs drainage, provides stability for the primary layer, and adds padding to allow more activity. Foam dressings and/or 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

In the following 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:

  • 20% aluminum chloride applied to palms and soles can reduce blister formation in some individuals with EBS, presumably by decreasing sweating.
  • 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.
  • In one study of a limited number of individuals with EBS-gen sev, 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-loc [Weiner et al 2004]. A recent study evaluated three months of oral erythromycin therapy in six children ages one to eight years with EBS-gen sev, and showed the medication was well tolerated and improved blistering in three children [Chiaverini et al 2015]. An anti-inflammatory mechanism, rather an anti-microbial mechanism, is proposed for the effect of antibiotics in the treatment of EBS.

Other. Use of keratolytics and softening agents such as urea 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-gen sev or EBS-gen intermed who have more severe involvement. Infants with significant oral disease may develop an aversion to eating by mouth, even after oral disease improves. The involvement of a feeding therapist in these cases is suggested.

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-gen sev. 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.

Many 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 fetus 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], induction of a compensating pathogenic variant [Smith et al 2004a], and use of pathogenic variant-specific siRNAs [Atkinson et al 2011]; 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) 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; in rare cases it can be inherited in an autosomal recessive manner.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

Sibs of a proband

Offspring of a proband. The offspring of an individual with autosomal recessive EBS are obligate heterozygotes for an EBS-related pathogenic variant.

Other family members. Each sib of a proband's parents is at a 50% risk of being having an EBS-related pathogenic variant.

Heterozygote (carrier) detection. Carrier testing for at-risk relatives requires prior identification of the EBS-related pathogenic variants in the family.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Many individuals diagnosed with KRT5 or KRT14-related EBS have an affected parent from whom they inherited a pathogenic variant.
  • EBS can also be caused by a de novo KRT5 or KRT14 pathogenic variant. Individuals with severe forms of autosomal dominant EBS usually have a de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported in the mother of a proband with EBS [Nagao-Watanabe et al 2004].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include taking a personal history and performing a physical examination if the history is suggestive.
  • 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. Many families include individuals with a history of "blistering" but are unaware that these individuals have EBS. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

Offspring of a proband

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

Related Genetic Counseling Issues

Establishing the mode of inheritance

Note: In families with an apparent de novo pathogenic variant, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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 of being heterozygous for an EBS-related pathogenic variant.

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

Prenatal Testing and Preimplantation Genetic Diagnosis

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

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
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • Medline Plus
  • EBCare Registry
    The EBCare Registry is a resource for individuals and families affected by all forms of epidermolysis bullosa (EB) and qualified researchers working on approved EB research projects.
    Phone: 866-332-7276
    Fax: 888-363-0790
    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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

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

131760EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE; EBSDM
131800EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED
131900EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED
131960EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION; EBSMP
148040KERATIN 5, TYPE II; KRT5
148066KERATIN 14, TYPE I; KRT14
601001EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVE 1; EBSB1
603805TRANSGLUTAMINASE 5; TGM5
609796PEELING SKIN SYNDROME 2; PSS2
612878EXOPHILIN 5; EXPH5
615028EPIDERMOLYSIS BULLOSA, NONSPECIFIC, AUTOSOMAL RECESSIVE; EBNS

Molecular Genetic Pathogenesis

KRT5 and KRT14 are expressed in the basal keratinocytes of the epidermis (the innermost layer), 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. TGM5 encodes the transglutaminase 5 enzyme, which is strongly expressed in the epidermal granular cells, where it crosslinks a variety of structural proteins in the terminal differentiation of the epidermis to form the cornified cell envelope (the outermost layer). EXPH5 encodes a RAB27b GTPase effector protein, exophilin-5, which is not a structural protein, but rather plays a role in cell membrane trafficking and vesicle formation.

Autosomal dominant (heterozygous) pathogenic variants in KRT5 and KRT14 cause clinical features by acting in a dominant-negative manner. Dominant-negative missense variants predominate and often 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]. In two different highly consanguineous families with autosomal dominant EBS, offspring homozygous for a pathogenic missense variant have been reported.

Autosomal recessive (biallelic) EXPH5 and KRT14, pathogenic variants are those that cause symptoms only in homozygotes or compound heterozygotes. In the few reported cases of autosomal recessive EBS caused by KRT14 and EXPH5 variants, the pathogenic variants are usually functionally null alleles that produce no gene product. Autosomal recessive pathogenic variants in TGM5 are often missense variants that affect the crosslinking capabilities of the enzyme. 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).

EXPH5

Gene structure. EXPH5 encodes up to 11 known splicing variants; the v1 variant, encoding the longest mRNA at 10208 bp (NM_015065), comprises six exons. (For more information, see Table A.)

Pathogenic variants. Fewer than ten pathogenic variants have been described throughout the gene; to date, all have been null variants. All known affected individuals that have been described are from the Middle East, where consanguinity is common.

Normal gene product. EXPH5 encodes the 1983-amino acid protein exophilin-5, a Rab27 effector protein. Rab proteins are members of the large Ras superfamily of monomeric G proteins. Rab GTPases regulate many key steps of cell membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. Rab GTPases control trafficking in endocytic and secretory pathways by recruiting proteins onto membrane surfaces that are involved in cargo collection, organelle motility, or vesicle docking at membranes. Exophilin-5 is involved in intracellular protein transport and exosome secretion [Ostrowski et al 2010].

Abnormal gene product. Electron microscopy of skin biopsies from affected individuals with truncating EXPH5 variants shows a disruption of the keratin filament architecture and more cortically disturbed F actin compared to controls. How the abnormal gene product causes this disruption is unknown.

KRT5

Gene structure. The cDNA comprises 2,164 bp in eight exons. Genomic length is estimated at approximately 6 kb. (For more information, see Table A.)

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

The KRT5 recurrent pathogenic missense variant p.Glu477Lys, along with the common KRT14 recurrent pathogenic variants are thought to account for approximately 70% of cases of EBS-gen sev [Stephens et al 1997, Pfendner et al 2005b].

The KRT5 pathogenic missense variant p.Pro25Leu [Moog et al 1999] accounts for 90%-95% of identified pathogenic variants in individuals with EBS-MP. The KRT5 pathogenic variant c.1649delG is also responsible for a mottled pigmentation phenotype [Horiguchi et al 2005].

Although a formal possibility, homozygosity for null KRT5 alleles has not been reported. Whether this genotype results in autosomal recessive EBS-gen intermed is unknown. An autosomal recessive pathogenic missense variant has been described [Indelman et al 2005].

In one family, an individual with biallelic KRT5 pathogenic variants had clinical features indistinguishable from those associated with heterozygous KRT5 pathogenic variants [Stephens et al 1995].

Table 5.

Pathogenic KRT5 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.74C>Tp.Pro25Leu
(Pro24Leu)
NM_000424​.3
NP_000415​.2
c.1649delGp.Gly550AlafsTer77 2
c.1429G>Ap.Glu477Lys

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

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

1.

Variant designation that does not conform to current naming conventions

2.

“Ter” indicates translation extended downstream of the normal translation termination codon.

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

Abnormal gene product. The mechanism of disease is dependent on the variant, but often gain-of-function variants result in protein that prevents proper association with the protein partner (krt5-krt14) and assembly of those associated dimers into bundles and fibers.

KRT14

Gene structure. The cDNA comprises 1,377 bp in eight exons. Genomic length is approximately 4.5 kb. (For more information, see Table A.)

Pathogenic variants. Pathogenic variants in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Pathogenic variants in the 1A or 2B segments of the rod domain are typical for EBS-gen intermed.

The KRT5 recurrent pathogenic missense variant along with the common KRT14 recurrent pathogenic variants p.Arg125Cys, p.Arg125His, and p.Asn123Ser are thought to account for approximately 70% of cases of EBS-gen sev [Stephens et al 1997, Pfendner et al 2005b]. The p.Arg125Cys and p.Arg125His hotspot pathogenic variants alone have been identified as causal in approximately 50% of individuals with EBS-gen sev (see Table 6).

In rare consanguineous families, biallelic pathogenic null KRT14 variants are associated with autosomal recessive inheritance of EBS-gen intermed.

The KRT14 pathogenic variant p.Met119Thr (Table 6) was recently described as associated with the EBS-MP phenotype [Harel et al 2006].

An individual with biallelic KRT14 pathogenic variants was more severely affected than relatives who had heterozygous KRT14 pathogenic variants [Hu et al 1997].

Table 6.

Pathogenic KRT14 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein 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 authors. GeneReviews staff have not independently verified the classification of variants.

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

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

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

TGM5

Gene structure. TGM5 encodes a 9411-bp cDNA with 13 exons and two major alternately spliced transcripts; the v2 form omits exon11. (For more information, see Table A.)

Benign variants. The p.Thr109Met variant has been shown to be benign and often segregates with the p.Gly113Cys pathogenic variant.

Pathogenic variants. A common founder variant, p.Gly113Cys has been found in the European population. TGM5 is a transglutaminase involved in crosslinking of the cornified epithelium; the p.Gly113Cys pathogenic variant (common in persons of northern European background) is found in the catalytic domain and abolishes crosslinking activity by TGM5 [Szczecinska et al 2014].

Table 7.

TGM5 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.326C>Tp.Thr109MetNM_201631​.1
Pathogenicc.337G>Tp.Gly113Cys

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

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

Normal gene product. The normal TGM5v1 (TGX) gene product has 720 amino acids including catalytic domain. TGM5 is a transglutaminase involved in crosslinking of the cornified epithelium (the outermost layer of the epidermis) which is particularly important in the terminal differentiation of the epidermis

Abnormal gene product. Null variants and variants that abolish the enzymatic activity or crosslinking function cause reduced crosslinking and altered stability and reduced barrier function of the cornified epithelium.

References

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Suggested Reading

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

Chapter Notes

Author History

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

Revision History

  • 13 October 2016 (ma) Comprehensive update posted live
  • 1 September 2011 (me) Comprehensive update posted live
  • 11 August 2008 (et) Comprehensive update posted live
  • 3 November 2005 (me) Comprehensive update posted to live Web site
  • 16 July 2003 (me) Comprehensive update posted to live Web site
  • 2 February 2001 (me) Comprehensive update posted to live Web site
  • 7 October 1998 (me) Review posted to live Web site
  • 13 February 1998 (vs) Original submission
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