DiagnosisClinical DiagnosisThe 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).TestingSkin biopsy. Immunofluorescence antigenic mapping is the sine qua non for the diagnosis of EBS because of its rapid turnaround time and high sensitivity and specificity [Yiasemides et al 2006].Transmission electron microscopic examination may also be used to identify keratin intermediate filament clumping and further delineate the classification of EBS Dowling-Meara (EBS-DM) [Bergman et al 2007]. To insure the most accurate diagnosis, the leading edge of a fresh blister induced by mechanical friction should be biopsied. The healing in older blisters may obscure the diagnostic morphology.In all cases of EBS, splitting is observed within or just above the basal cell layer of the skin. In EBS-DM, the keratin intermediate filaments (also called tonofilaments) are clumped, a finding that serves as a distinguishing feature [Bergman et al 2007].
In most cases of EBS, diagnosis using immunofluorescent microscopy is made by mapping the blister. Antibodies to keratin 5 or keratin 14 and other dermal-epidermal junction antigens (typically laminin 332 and type VII collagen) show localization of stained epitopes to the blister floor. Note: Routine histology (light microscopy) suggests the diagnosis of EB but is an inadequate and unacceptable test for accurately diagnosing the EB type and subtype. Molecular Genetic TestingGene. The two genes in which mutation is currently known to cause the most common forms of EBS are KRT5 and KRT14.Evidence for further locus heterogeneity. Because only approximately 75% of individuals with biopsy-proven EBS have identifiable mutations in KRT5 or KRT14, it is possible that mutations in another as-yet unidentified gene are also causative [Yasukawa et al 2006, Rugg et al 2007, Bolling et al 2011]. Note: One individual with EBS caused by mutations in DST, encoding dystonin, has been reported [Groves et al 2010].Clinical testingSequence analysisSequence analysis is performed first in KRT5 and KRT14 regions in which a high percentage of mutations are known to occur; it may be targeted on the basis of the individual's clinical presentation.
Sequence analysis of the remaining KRT5 and KRT14 exons may be performed if a mutation is not identified in the initially tested gene regions.
Mutation detection rate in individuals with biopsy-diagnosed EBS is 75% [Yasukawa et al 2006, Rugg et al 2007].Table 1. Summary of Molecular Genetic Testing Used in Epidermolysis Bullosa SimplexView in own windowGene SymbolTest MethodEBS Subtype Mutations DetectedMutation Detection Frequency ^{1, 2Test AvailabilityKRT5 and KRT14Sequence analysis EBS-locKRT5 and KRT14 sequence variants 375% 4ClinicalEBS-gen-nonDM EBS-DMEBS-MPKRT5 p.Pro25Leu 90%-95% 5, 6, 7KRT14 p.Met119Thr2%-5% 81. The ability of the test method used to detect a mutation that is present in the indicated gene2. In individuals with biopsy-diagnosed EBS3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. Yasukawa et al [2006], Rugg et al [2007], Bolling et al [2011]5. Horiguchi et al [2005] describe a second mutation associated with EBS-MP.6. Shurman et al [2006]7. Pascucci et al [2006]8. Harel et al [2006] describe a KRT14 mutation associated with EBS-MP.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandA 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) DisordersKRT5. 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 HistoryThe most common forms of epidermolysis bullosa simplex (EBS) are subdivided into clinical phenotypes — EBS, localized (EBS-loc) (previously known as EBS, Weber-Cockayne type); EBS, generalized (EBS-gen-nonDM) (previously known as EBS, Koebner type); EBS Dowling-Meara (EBS-DM); and EBS-with mottled pigmentation (EBS-MP) — based primarily on dermatologic and histopathologic findings. Although it is now recognized that these phenotypes are part of a continuum with overlapping features, it is reasonable to continue to think of EBS in terms of the phenotypes in order to provide affected individuals with information about the expected clinical course. The clinical features of these disorders are summarized in Table 2.Table 2. Diagnostic Clinical Features of the Four Most Common Subtypes of EBS View in own windowEBS SubtypeLocalizedGeneralized, non-Dowling-MearaMottled PigmentationDowling-MearaAge of Onset Infancy, usually by 12-18 monthsBirth/infancyBirth/infancyBirthClinicalFeatureBlisters DistributionUsually limited to hands, feet; can occur at sites of repeated trauma (e.g., belt line)GeneralizedGeneralizedGeneralizedGrouped (herpetiform)NoNoSometimesYesMucosalRareOccasionallyOccasionallyOftenHyperkeratosis of palms and soles (keratoderma)OccasionallyOccasionallyCommon, focalCommon, progressiveNail involvementOccasionallyOccasionallyOccasionallyCommonMiliaRareOccasionallyUnknownCommonHyper/ HypopigmentationNoCan occurAlwaysCommonEBS, 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 CorrelationsA moderate correlation exists between the EBS phenotypes and the functional domain of either KRT5 or KRT14 in which the mutation is located [reviewed in Irvine & McLean 2003, Müller et al 2006]:Mutations in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc.Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen-nonDM.Mutations in the beginning of the 1A or the end of the 2B segments of the rod domain of KRT5 and beginning of the 1A or 2B segments of the rod domain of KRT5 and KRT14 are typical in EBS-DM.The p.Pro25Leu and c.1649delG mutations in KRT5 are associated with EBS-MP. Two mutations are described in KRT14 [see Harel et al 2006, Arin et al 2010]Autosomal dominant mutations cause signs in heterozygotes by acting in a dominant-negative manner; that is, in the process of keratin filament assembly the abnormal protein produced by the mutated allele interferes with the normal protein produced by the normal allele. In two different highly consanguineous families with autosomal dominant EBS, offspring homozygous for a missense mutation have been reported. In one case, a KRT5 allele was fully dominant and in the second a KRT14 allele was partially dominant [Hu et al 1997].Autosomal recessive KRT5 and KRT14 mutations are those that cause symptoms only in homozygotes. In the few reported cases of autosomal recessive EBS, the causal mutations are usually null alleles that produce no gene product. Typically, heterozygotes are unaffected because 50% of the normal keratin product is adequate to stabilize the skin, although reports of related autosomal dominant disorders caused by null alleles in KRT5 and KRT14 resulting in haploinsufficiency have also been reported [Betz et al 2006, Lugassy et al 2006, Liao et al 2007, Sprecher et al 2007] (see Genetically Related Disorders).The proportion of KRT5 and KRT14 mutations producing each phenotype are outlined in Table 3. Clinical overlap between EBS-K and EBS-DM is substantial; thus, much of the molecular genetic data have been lumped in the literature and the proportions presented in the table are necessarily imprecise. In addition, predominance of mutations in KRT5 or KRT14 may be population specific [Abu Sa'd et al 2006, Yasukawa et al 2006, Rugg et al 2007].Table 3. Molecular Basis of EBS Types Caused by KRT5 and KRT14 MutationsView in own windowPhenotype% of all EBS InheritanceSeverityProportion of KRT5 MutationsProportion of KRT14 MutationsEBS-loc 60%ADMild<50%>50%<1%AREBS-gen-nonDM 15%ADModerate-severe<50%>50%EBS-DM 25%<50%>50%EBS-MP <1%95% ¹ 5%All EBS 100%50%50%In 25% of EBS mutations in KRT5 and/or KRT14 could not be demonstrated [Bolling et al 2010]1. Hamada et al [2004], Horiguchi et al [2005]

Differential DiagnosisAccording to the current classification system, the four major types of epidermolysis bullosa (EB), caused by mutations in 14 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome [Fine et al 2008]. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis. The four major types of EB share easy fragility of the skin (and mucosa in many cases), manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring — especially in young children and neonates — may not be established or significant enough to allow identification of EB type; thus, skin biopsy is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators.Post-inflammatory changes, such as those seen in EBS-DM, are often mistaken for scarring or mottled pigmentation. Scarring can occur in simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface. Congenital absence of the skin can be seen in any of the four major types of EB and is not a discriminating diagnostic feature.Corneal erosions, esophageal strictures, and nail and tooth enamel involvement may indicate either DEB or JEB. In milder cases, scarring (especially of the dorsal hands and feet) suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB.In almost all cases, a fresh biopsy from a newly induced blister stained by indirect immunofluorescence for the critical dermal-epidermal protein components is necessary to establish the type of EB by determining the cleavage plane and the presence/absence of these protein components and their distribution.Other subtypes of EB simplex (EBS). The current classification system divides EBS into two subtypes based on the location of blistering in the epidermis. In the suprabasal forms of EBS, blistering occurs above the basal keratinocytes. The suprabasal forms of EBS are extremely rare and include: EBS superficialis; EBS, plakophilin-1 deficiency (also called ectodermal dysplasia/skin fragility syndrome); and EBS, lethal acantholytic. EBS, plakophilin-1 deficiency is characterized by mild skin fragility associated with perioral cracking and cheilitis, hypotrichosis or alopecia, and a painful and fissured palmoplantar keratoderma; it is caused by loss-of-function mutations in PKP1 (for review, see McGrath & Mellerio [2010]). EBS, lethal acantholytic is caused by mutations in the tail region of DSP which encodes desmoplakin [Jonkman et al 2005, Bolling et al 2010, Hobbs et al 2010]. Affected neonates present with progressive erosions without blistering, alopecia, and loss of nails. Death within the first days after birth secondary to profound fluid and electrolyte imbalance is common. In the basal forms of EBS, blistering occurs within the basal keratinocytes. The four most common subtypes of basal EBS are the subject of this GeneReview. Junctional EB (JEB). Separation occurs through the lamina lucida, or junction of dermis and epidermis, resulting in nonscarring blistering. Because atrophy may develop over time, the term "atrophicans" has been used in Europe to describe individuals with some forms of JEB.Broad classification of JEB includes JEB-Herlitz (typically lethal in the first year of life), JEB-non-Herlitz, and JEB with pyloric atresia. Mutations in the genes that encode the subunits of laminin-332 (formerly called laminin 5) (LAMA3, LAMC2, LAMB3) and type 17 collagen (COL17A1) are causative. JEB with pyloric atresia has been associated with α₆β₄ integrin and plectin mutations (see EB with pyloric atresia).The distinction between JEB-Herlitz and JEB-non-Herlitz caused by mutations in LAMA3, LAMC2, or LAMB3 is based on severity and survival past the first year of life. JEB-non-Herlitz caused by mutations in COL17A1 (formerly termed generalized atrophic benign epidermolysis bullosa [GABEB]) usually has a much better prognosis than JEB caused by mutations in LAMA3, LAMC2, or LAMB3; however, it can be lethal in neonates.Dystrophic EB (DEB). The blister forms below the basement membrane, in the superficial dermis. The basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Mutations in COL7A1, the gene encoding type VII collagen, have been demonstrated in DEB, both dominant and recessive:The designation Bart syndrome [OMIM 132000] is not used in the current classification of EB. Bart characterized a kindred with congenital absence of the skin on the lower legs and feet, nonscarring blistering of the skin and oral mucosa, and nail abnormalities. Genetic studies of the original kindred identified dominant mutations in COL7A1 [Christiano et al 1996], and some consider Bart syndrome to be most often, but not exclusively, a manifestation of dominant DEB. However, congenital absence of skin can be seen in all forms in EB and may not be a distinguishing feature of any particular form of EB.EB caused by mutations in PLEC1. Mutations in PLEC1, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause a cleavage in the basal keratinocyte layer; hence, they could be considered to cause EBS. However, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia, and the rare EB-Ogna) are more complex:EB with muscular dystrophy [OMIM 226670]. Some individuals with EB resulting from PLEC1 mutations develop muscular dystrophy either in childhood or later in life [Smith et al 1996, Shimizu et al 1999, Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005a]. Within basal keratinocytes, plectin is localized to the inner plaques of the hemidesmosomes, which are hypoplastic and show poor association with keratin filaments. Electron microscopy of skin biopsies reveals a plane of cleavage (level of separation) within the bottom layer of the basal keratinocytes, just above the hemidesmosomes. Inheritance is autosomal recessive.EB with pyloric atresia [OMIM 226730]. In several US and Japanese families, EB with pyloric atresia is associated with premature termination mutations in PLEC1 and the genes encoding alpha 6 integrin (ITGA6) and beta 4 integrin (ITGB4) [Nakamura et al 2005, Pfendner & Uitto 2005]. Disease course is severe and usually lethal in the neonatal period. Inheritance is autosomal recessive.EB-Ogna [OMIM 131950], observed in one Norwegian and one German family, is caused by a site-specific missense mutation within the rod domain of PLEC1 [Koss-Harnes et al 2002]. In these cases, transmission electron microscopy of a skin biopsy identified the cleavage plane to be just above the inner plates of the hemidesmosomes in the deep basal cell cytoplasm. Immunofluorescence staining of a skin biopsy showed reduced and/or patchy plectin staining. Inheritance is autosomal dominant.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).EBS, localizedEBS, Dowling-Meara typeEBS, other generalizedEBS with mottled pigmentation

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsSupportive 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 ManifestationsTwenty 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 ComplicationsInfection 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.SurveillanceSurveillance for infection and proper wound healing is indicated.Agents/Circumstances to AvoidExcessive 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 RiskSee 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 InvestigationProposed 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.OtherThe use of corticosteroids and vitamin E in treating EBS has been reported anecdotally; no rigorous clinical trials have been undertaken.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKRT512q13​.13Keratin, type II cytoskeletal 5Human Intermediate Filament Database KRT5
KRT5 homepage - Mendelian genesKRT5KRT1417q21​.2Keratin, type I cytoskeletal 14Human Intermediate Filament Database KRT14
KRT14 homepage - Mendelian genesKRT14Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Epidermolysis Bullosa Simplex (View All in OMIM) View in own window 131760EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE 131800EPIDERMOLYSIS BULLOSA SIMPLEX, LOCALIZED 131900EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED 131960EPIDERMOLYSIS BULLOSA SIMPLEX WITH MOTTLED PIGMENTATION; EBS-MP 148040KERATIN 5; KRT5 148066KERATIN 14; KRT14 601001EPIDERMOLYSIS BULLOSA SIMPLEX, AUTOSOMAL RECESSIVEMolecular Genetic PathogenesisKRT5 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].KRT5Normal allelic variants. The cDNA comprises 2,164 bp in eight exons. Genomic length is estimated at approximately 6 kb.Pathologic allelic variants. Mutations in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Mutations in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen-nonDM. Mutations in the beginning of the 1A segment or the end of the 2B segment of the rod domain of KRT5 and KRT14 are typical in EBS-DM.The KRT5 recurrent missense mutation p.Glu477Lys, along with the KRT14 recurrent mutations p.Arg125Cys, p.Arg125His, and p.Asn123Ser (see Table 5) are thought to account for approximately 70% of cases of EBS-DM [Stephens et al 1997, Pfendner et al 2005b].The KRT5 missense mutation p.Pro25Leu [Moog et al 1999] accounts for 90%-95% of identified mutations in EBS-MP. The KRT5 mutation c.1649delG is also responsible for a mottled pigmentation phenotype [Horiguchi et al 2005]. The KRT14 mutation p.Met119Thr (Table 5) was also recently described as associated with the EBS-MP phenotype [Harel et al 2006].Although a formal possibility, homozygosity for null KRT5 alleles has not been reported. Whether this genotype results in autosomal recessive EBS-gen-nonDM is unknown. An autosomal recessive missense mutation has been described [Indelman et al 2005]. (For more information, see Table A.)Table 4. Selected KRT5 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹)Reference Sequencesc.74C>Tp.Pro25Leu
(Pro24Leu)NM_000424​.3
NP_000415​.2c.1649delGp.Gly550Alafs*77 ^{2c.1429G>Ap.Glu477LysSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Asterisk indicates translation extended downstream of the normal translation termination codon.Normal gene product. KRT5 (keratin, type II cytoskeletal 5), a protein of 590 amino acidsAbnormal gene product. UnknownKRT14Normal allelic variants. The cDNA comprises 1,377 bp in eight exons. Genomic length is approximately 4.5 kb.Pathologic allelic variants. Mutations in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. Mutations in the 1A or 2B segments of the rod domain are typical for EBS- gen-nonDM. Mutations at a hot spot at codon 125 (p.Arg125Cys and p.Arg125His) have been identified as causal in approximately 50% of individuals with EBS-DM. In rare consanguineous families, homozygosity for null KRT14 alleles is associated with autosomal recessive inheritance of EBS- gen-nonDM. (For more information, see Table A.)Table 5. Selected KRT14 Pathologic Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.256T>Cp.Met119ThrNM_000526​.4
NP_000517​.2c.368A>Gp.Asn123Serc.373C>Tp.Arg125Cysc.374G>Ap.Arg125HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. KRT14 (keratin, type I, cytoskeletal 14), a protein of 472 amino acidsAbnormal gene product. Missense mutations give rise to abnormal gene products that may not assemble correctly into functional keratin intermediate filaments. The type and position of the amino acid change determines the degree of compromise and thus the severity of the disease. KRT14 null mutations may give rise to a less severe phenotype than certain missense mutations [Sorensen et al 2003, Smith et al 2004b].}