Clinical characteristics.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some instances) that results in non-scarring blisters and erosions caused by minor mechanical trauma. EBS is distinguished from other types of epidermolysis bullosa (EB) or non-EB skin fragility syndromes by the location of the blistering in relation to the dermal-epidermal junction. In EBS, blistering occurs within basal keratinocytes. The severity of blistering ranges from limited to hands and feet to widespread involvement. Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation. Rare EBS subtypes have been associated with additional clinical features including pyloric atresia, muscular dystrophy, cardiomyopathy, and/or nephropathy.

Diagnosis/testing.

The diagnosis of EBS is established in a proband by: the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC; a heterozygous pathogenic variant in KLHL24; or biallelic pathogenic variants in CD151, DST, or EXPH5; and/or presence of characteristic findings on examination of a skin biopsy using transmission electron microscopy and/or immunofluorescent mapping.

Management.

Treatment of manifestations: Supportive care to protect the skin from blistering; use of dressings that will protect the skin and promote healing of wounds. Encourage activities that minimize trauma to the skin; appropriate footwear and physical therapy to preserve ambulation; lance and drain without unroofing new blisters. Dressings consist of three layers: a primary nonadherent contact layer; a secondary layer that provides stability, adds padding, and absorbs drainage; and a tertiary layer with elastic properties. Aluminum chloride (20%) applied to palms and soles can reduce sweating and therefore minimize blister formation in some individuals with EBS. In addition, botulinum toxin, cyproheptadine (Periactin^®), tetracycline, erythromycin, diacerein, sirolimus, apremilast, cannabidiol oil, and gentamicin have all been reported to be beneficial. Keratolytic agents for palmar and plantar hyperkeratosis may reduce skin thickening and cracking. Topical and/or systemic antibiotics or silver-impregnated dressings or gels can be used to treat skin infection or reduce bacteria colonization, thereby promoting wound healing. Identification and management of specific causes of pain and itching; management with a pain specialist as needed. Management of fluid and electrolyte imbalance in severely affected infants may be critical during the postnatal period. Nutritional support including vitamin and mineral supplementation, feeding via gastrostomy tube, guided feeding therapy, and Haberman feeder may be necessary for infants and children with oral manifestations of EBS. Iron supplementation for those with anemia as a result of chronic inflammation from blistering and wounding. Weight management and treatment of obesity in older individuals. Standard treatment for basal cell carcinomas in individuals with severe EBS. Psychosocial support when needed. Standard treatments for additional features reported in rare subtypes including pyloric atresia, muscular dystrophy, cardiomyopathy, and nephropathy.

Surveillance: Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs and symptoms of wound infection, as well as pruritus and pain. At each visit, assessment of hydration status, growth, nutrition, weight, motor development and mobility, and psychosocial well-being. Consider serum B-type natriuretic peptide (BNP) and creatinine kinase in those with EBS, intermediate with cardiomyopathy; serum renal function studies and urinalysis for those with nephropathy; and neurologic assessment for those with muscular dystrophy as needed.

Agents/circumstances to avoid: Excessive heat exposure may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin. Avoid adhesives from regular medical tapes or Band-Aids^®.

Genetic counseling.

EBS is typically inherited in an autosomal recessive or an autosomal dominant manner. Autosomal recessive EBS is associated with either biallelic loss-of-function variants in KRT5, KRT14, or PLEC or biallelic pathogenic variants in CD151, DST, or EXPH5. Autosomal dominant EBS is associated with either a heterozygous dominant-negative variant in KRT5, KRT14, or PLEC or a heterozygous pathogenic variant in KLHL24. In rare instances, EBS is caused by the presence of heterozygous pathogenic variants in both KRT5 and KRT14 and is inherited in a digenic manner.

• Autosomal recessive EBS. If both parents are known to be heterozygous for an EBS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Autosomal dominant EBS. In families with autosomal dominant inheritance, each child of an affected individual has a 50% chance of inheriting the pathogenic variant and (most likely) being affected with EBS (penetrance appears to be <100% for known heterozygous dominant-negative KRT5 and KRT14 variants).

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

Suggestive Findings

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 hyperpigmentation 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
• Natal teeth

Establishing the Diagnosis

The diagnosis of EBS is established in a proband with one or both of the following [Has et al 2020b]:

• Identification of a heterozygous dominant-negative or biallelic loss-of-function pathogenic (or likely pathogenic) variants in KRT5, KRT14, or PLEC; a heterozygous pathogenic (or likely pathogenic) variant involving KLHL24; or biallelic pathogenic (or likely pathogenic) variants involving CD151, DST, or EXPH5 by molecular genetic testing (See Table 1.)
• Characteristic findings on skin biopsy examined via immunofluorescent mapping (IFM) and/or transmission electron microscopy (TEM) (See Skin Biopsy.)

Note: (1) Both genetic testing and skin biopsy for IFM are often recommended to improve the sensitivity of the diagnostic tests. TEM may also be performed to assess for ultrastructural abnormalities in individuals with inconclusive genetic testing and IFM. (2) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of a variant(s) of uncertain significance does not establish or rule out the diagnosis of EBS.

Molecular testing approaches can include use of a multigene panel, single-gene testing, or comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Therefore, genetics consultation prior to testing is recommended.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with epidermolysis bullosa are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

In contrast to prior classification schemes, the most recent 2020 reclassification system distinguishes between EBS, defined by blistering within the basal keratinocytes, and other disorders with skin fragility that lack significant blistering as a result of superficial skin cleavage above the basal keratinocytes [Has et al 2020a].

The most common forms of EBS – localized EBS, intermediate EBS, severe EBS, and EBS with mottled pigmentation – are distinguished primarily on dermatologic, genetic, and histopathologic findings. The clinical features of these disorders are summarized in Table 2. Rare subtypes including several distinct syndromes have also been identified.

Phenotype Correlations by Gene

Genotype-Phenotype Correlations

Limited genotype-phenotype correlations have been reported. Digenic inheritance adds further complexity to genotype-phenotype associations observed in EBS [Padalon-Brauch et al 2012, Kim et al 2017, Yu et al 2020].

KRT5 and KRT14. A moderate correlation exists between the EBS phenotype and the functional domain of either KRT5 or KRT14 in which the pathogenic variant is located [Irvine & McLean 2003, Müller et al 2006, Coulombe et al 2009, Arin et al 2010]. Phenotypic expression can be highly variable; localized EBS, intermediate EBS, and severe EBS phenotypes have been reported in affected individuals from the same family [Deng et al 2011].

• Heterozygous pathogenic variants in the nonhelical head and linker segments (L1 and L2), and in the 1A segment of the rod domain are associated with localized EBS.
• Heterozygous pathogenic variants in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for intermediate EBS.
• Heterozygous 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 severe EBS. These domains are highly conserved and are thought to be critical to filament assembly.
• Heterozygous KRT5 variants p.Pro25Leu and c.1649delG and KRT14 variants p.Met119Thr and c.1117_1158dup are associated with EBS with mottled pigmentation [Harel et al 2006, Pascucci et al 2006, Shurman et al 2006, Arin et al 2010].
• In rare consanguineous families, biallelic KRT14 and KRT5 loss-of-function variants are associated with autosomal recessive inheritance of intermediate or severe EBS.

PLEC. Biallelic pathogenic variants within exon 31 of PLEC (which encodes for the rod domain of plectin) are associated with EBS, intermediate with muscular dystrophy, while biallelic pathogenic variants outside of exon 31 are associated with EBS, severe with pyloric atresia [Natsuga 2015].

Penetrance

Penetrance is 100% for biallelic KRT5 and KRT14 loss-of-function variants but appears to be less than 100% for heterozygous dominant-negative variants, as rare heterozygotes for dominant-negative variants are asymptomatic [Wertheim-Tysarowska et al 2016]. Heterozygous pathogenic variants in PLEC and KLHL24 and biallelic pathogenic variants in CD151, DST, EXPH5, and PLEC are presumed to be fully penetrant as asymptomatic individuals have not been reported to date.

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 five times in the last 20 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 2008a]. A new classification system was developed in 2014, referred to as the "onion skin" terminology, which considers the level of blistering, phenotypic characteristics including distribution and severity of cutaneous blisters and wounding, and associated gene [Fine et al 2014].

In February 2020, the most recent reclassification system for EB and other skin fragility disorders was published following the 2019 international consensus meeting [Has et al 2020a]. This 2020 consensus reclassification system incorporates genotype-phenotype associations and novel pathogenic variants identified in affected individuals (see Table 4).

Prevalence

The prevalence of EBS is uncertain; estimates from different countries range from 6:1,000,000 to 28.6:1,000,000 live births and vary by geographic location [Horn et al 1997, Pfendner et al 2001, Kho et al 2010, Petrof et al 2022]. One recent study among Dutch individuals estimated a prevalence of 11.9:1,000,000 [Baardman et al 2021]. Localized EBS is most common and the prevalence of localized EBS may be underestimated, as it does not cause significant morbidity and mortality, even in newborns, and many individuals may not be reported. Intermediate and severe EBS are rare, and EBS with mottled pigmentation is even rarer. The experience of the National Epidermolysis Bullosa Registry (NEBR) suggests that ascertainment is highly biased and incomplete, and that EBS likely remains underdiagnosed, particularly among individuals with mild clinical presentations [Has 2018a].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa simplex (EBS), the evaluations summarized in Table 8 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing of open wounds, and prevention and treatment of secondary infection are the mainstays of treatment.

Blistering. Encourage children to tailor physical activities to minimize trauma to the skin while staying active and engaging with peers in age-appropriate learning and social activities.

Lance and drain new blisters (without unroofing the 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. In noninfected wounds, a thin layer of simple, nonirritating moisturizer such as petrolatum may be applied either directly to the skin or to the primary nonadherent dressing prior to wound dressing. Topical antibiotics (e.g., gentamicin or mupirocin ointment) may also be applied as indicated.
• 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 cornstarch or Zeasorb^® to help absorb moisture and reduce friction on the skin, followed by a simple (i.e., one-layer) dressing [Lara-Corrales et al 2010, El Hachem et al 2014].

Newer generations of antimicrobial dressing with impregnated silver, iodine, gentian violet blue, or medical-grade honey may be used to reduce bacterial colonization and promote wound healing. However, these dressings are usually much more costly.

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:

• In some individuals with EBS, 20% aluminum chloride applied to palms and soles can reduce blister formation, presumably by decreasing sweating.
• Case reports and small studies 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 [Abitbol & Zhou 2009, Swartling et al 2010, Holahan et al 2016].
• In one study of a limited number of individuals with severe EBS, cyproheptadine (Periactin^®) reduced blistering. This may result from the anti-pruritic effect of the medication; the true mechanism is not clear [Neufeld-Kaiser & Sybert 1997].
• In another study, tetracycline reduced blister counts in two thirds of persons with localized EBS [Weiner et al 2004]. One study evaluated three months of oral erythromycin therapy in six children ages one to eight years with severe EBS, and showed that the medication was well tolerated and improved blistering in three children [Chiaverini et al 2015]. An anti-inflammatory mechanism, rather than an antimicrobial mechanism, is proposed for the effect of antibiotics in the treatment of EBS.
• In a clinical trial, topical diacerein cream reduced blister counts in 60% of individuals with severe EBS [Wally et al 2018]. In 17 children ages four to 12 years with severe EBS, 1% diacerein cream was applied once daily to skin areas with blisters and resulted in reduced blistering within treated areas. In vitro studies suggest that diacerein applied topically may reduce blister formation by downregulating the pro-inflammatory interleukin 1β pathway to subsequently stabilize keratin intermediate filament networks within basal keratinocytes.
• One pilot study of two individuals suggested that topical application of sirolimus, an mTOR inhibitor, may reduce plantar blistering and keratoderma and improve ambulation [Lee et al 2022]. These observed improvements may arise from regulation of key cytokines and pathways implicated in blister formation and inflammation.
• In a small pilot study of individuals with severe EBS, treatment with apremilast resulted in decreased blistering, potentially through the downregulation of Th17-associated inflammation [Castela et al 2019].
• A small case series noted anecdotal reductions in blistering and pain with walking, and increased speed of wound healing following treatment of affected areas with topical cannabidiol oil [Chelliah et al 2018]. These effects may be due to both the analgesic and anti-inflammatory effects of cannabinoids.
• A case report suggested that treatment with intravenous gentamicin may improve translational readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by PLEC truncating variants. Treatment with gentamicin resulted in increased plectin expression for several months, improvements in clinical outcomes including reduced mucosal erosions and blisters, and improved neuromuscular and respiratory functionality [Martínez-Santamaría et al 2022].

Hyperkeratosis. Use of moisturizers, keratolytics, and softening agents containing petrolatum, alpha hydroxy acid, and urea are often recommended for palmar and plantar hyperkeratoses to prevent skin thickening and cracking. In addition, soaking the hands and feet in saltwater helps soften hyperkeratosis, ease debridement of the thick skin, and promote penetration of skin emollients.

Infection. Treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful. Saltwater baths with and without acetic acid added may also reduce infections [Petersen et al 2015]. Diluted bleach water soak has become a common practice to reduce both colonization with Staphylococcus aureus and skin inflammation [Pope et al 2012].

Pain and itch. Effective management of pain and itch requires identifying and eliminating a specific cause, where possible (e.g., administration of antibiotics for pain or itch caused by an acute skin infection), as well as an overarching multimodal strategy that includes pharmacologic, physical, and psychosocial interventions to maintain daily function and quality of life [Goldschneider et al 2014, Bruckner et al 2015, Cohn & Teng 2016]. For individuals who require prescription analgesics, early referral to pain specialists for management including biofeedback therapy can be beneficial. Neurokinin-1 receptor antagonists are being studied for the treatment of itch in all types of EB (NCT03836001), as systemic antihistamines have not been shown to be effective.

Nutrition, dehydration, and electrolyte disturbances

• Management of dehydration and electrolyte disturbances
• Nutritional support including age-appropriate vitamin and mineral supplementation, and dietary modifications with nutrient-rich feeds. Gastrostomy tubes may be required to ensure adequate intake and to treat or prevent failure to thrive in neonates, infants, and children with intermediate EBS or severe EBS [Haynes 2010, Haynes et al 2012, Salera et al 2020, Marro et al 2021].
• Feeding modifications such as Haberman feeders to reduce trauma to the oral mucosa during breastfeeding, soft or pureed foods, and early involvement with a feeding therapist in those with oral aversion as a result of severe oral disease [Salera et al 2020]
• Iron supplementation should be considered in those with anemia due to chronic inflammation from ongoing blistering and wounding.

Excess weight gain and obesity in adolescents and adults with EBS. Weight management beginning in preadolescence is recommended to reduce the risk of obesity and associated conditions [Yerlett 2020].

Physical activity and mobility. Appropriate footwear is essential to preserve ambulation and mobility, including socks to wick moisture and reduce friction, orthotics and insoles, and supportive shoes [Khan et al 2020]. Tailored interventions including physical therapy and debridement of plantar keratoderma should also be considered.

Basal cell carcinoma in individuals with severe EBS is treated in the standard manner.

Decreased quality of life and other psychosocial considerations. Psychosocial support should be provided for reduced quality of life and significant psychosocial and economic challenges resulting from EBS, including feelings of anxiety, frustration, and depression, strained interpersonal relationships with family, financial burden due to the cost of wound dressing supplies and medications, reduced employment opportunities, and missed work days [Tabolli et al 2009, Williams et al 2011, Brun et al 2017, Martin et al 2019, Bruckner et al 2020, So et al 2022].

Standard treatment is indicated for other manifestations reported, including muscular dystrophy, pyloric atresia, cardiomyopathy, and nephropathy.

Surveillance

Agents/Circumstances to Avoid

Excessive heat and sweating may exacerbate blistering, wounding, 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; however, affected individuals who are determined to find ways to participate in these endeavors should be encouraged.

Many individuals with EBS cannot use medical tape or Band-Aids^® with adhesives.

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 EBS, cæsarean delivery may reduce the trauma to the skin during delivery. Vigorous rubbing of the infant after delivery should be avoided to reduce skin trauma. In pregnant mothers with EBS, vaginal delivery is not strictly contraindicated; early discussion of individual preferences and planning with a multidisciplinary care team including obstetricians, anesthesiologists, and neonatologists is recommended to ensure the safety and well-being of both the mother and baby [Greenblatt et al 2022].

Therapies Under Investigation

Proposed approaches for gene therapy in EBS include the use of CRISPR/Cas9-mediated DNA repair [Kocher et al 2017], TALEN-mediated DNA repair [Aushev et al 2017], viral vectors carrying corrected gene products to transduce keratinocytes [Petek et al 2010], RNA trans-splicing repair [Wally et al 2008, Peking et al 2019], addition of other functional proteins [D'Alessandro et al 2004], induction of a compensating pathogenic variant via revertant mosaicism [Smith et al 2004], and pathogenic variant-specific siRNAs [Atkinson et al 2011]. Systemic gentamicin may also induce PLEC readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by pathogenic nonsense variants (see Treatment of Manifestations) [Martínez-Santamaría et al 2022]. To date, however, no clinical trials of gene therapy for EBS have been completed. The recent development of a human induced pluripotent stem cell-derived keratinocyte model for EBS should facilitate further exploration of these therapeutic approaches [Coutier et al 2022].

Several clinical trials investigating new or repurposed therapeutics to reduce blistering, pain, and itch in EBS are ongoing, and novel computational methods leveraging transcriptome analysis may facilitate further identification of potential drug candidates for repurposing [Lee et al 2022]. Active clinical trials include investigations of topical TolaSure™ gel (NCT05062070) and Oleogel-S10 (NCT03068780), a birch bark extract, to improve wound healing; botulinum toxin injections to reduce sweating and improve clinical disease (NCT03453632); and oral serlopitant (NCT03836001), a neurokinin-1 inhibitor, to reduce itch.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

The use of vitamin E in treating EBS has been reported anecdotally [Sehgal & Sanyal 1972]. Topical steroids are often used for symptomatic relief as pruritus is common during wound healing. Poorly controlled excoriation may cause secondary trauma and repeated blistering. However, no rigorous clinical trials have been undertaken for these topical treatments.

Mode of Inheritance

Epidermolysis bullosa simplex (EBS) is typically inherited in an autosomal recessive or an autosomal dominant manner. Genetic counseling regarding risk to family members depends on accurate molecular diagnosis (i.e., identification of the causative pathogenic variant[s] in an affected family member) and confirmation of the mode of inheritance in each family.

Autosomal recessive EBS is associated with:

• Biallelic loss-of-function variants in KRT5, KRT14, or PLEC; and
• Biallelic pathogenic variants in CD151, DST, or EXPH5.

Autosomal dominant EBS is associated with:

• Heterozygous dominant-negative variants in KRT5, KRT14, or PLEC; and
• Heterozygous pathogenic variants in KLHL24.

In rare instances, EBS is caused by the presence of heterozygous pathogenic variants in both KRT5 and KRT14 and is inherited in a digenic manner (i.e., the presence of both the KRT5 and the KRT14 pathogenic variant is required for expression of the EBS phenotype) [Kim et al 2017, Yu et al 2020].

Note: Skin biopsy findings cannot be used to assess inheritance pattern.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an EBS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EBS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Typically, heterozygous parents of a child with autosomal recessive EBS are unaffected. (KRT5 and KRT14 pathogenic variants that cause autosomal recessive EBS are not currently known to be associated with the autosomal dominant disorders Dowling-Degos disease, Naegeli-Franceschetti-Jadassohn syndrome, and dermatopathia pigmentosa reticularis; see Genetically Related Disorders.)

Sibs of a proband

• If both parents are known to be heterozygous for an EBS-related pathogenic variant, each sib of an affected individual has at conception 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Typically, heterozygous sibs of a proband with autosomal recessive EBS are unaffected. (KRT5 and KRT14 pathogenic variants that cause autosomal recessive EBS are not currently known to be associated with the autosomal dominant disorders Dowling-Degos disease, Naegeli-Franceschetti-Jadassohn syndrome, and dermatopathia pigmentosa reticularis; see Genetically Related Disorders.)

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.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Individuals diagnosed with EBS caused by a heterozygous dominant-negative KRT5, KRT14, or PLEC variant or a heterozygous KLHL24 pathogenic variant may have an affected parent from whom they inherited a pathogenic variant.
• Some individuals diagnosed with autosomal dominant EBS have the disorder as the result of a de novo pathogenic variant. Individuals with severe forms of autosomal dominant EBS usually have a de novo pathogenic variant.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Nagao-Watanabe et al 2004, Chen et al 2022]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome and/or a milder phenotypic presentation in affected family members. 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. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Penetrance appears to be less than 100% for known heterozygous dominant-negative KRT5 and KRT14 variants (see Penetrance). Phenotypic expression can be highly variable; localized EBS, intermediate EBS, and severe EBS phenotypes have been reported in affected individuals from the same family (see Genotype-Phenotype Correlations).
  • Heterozygous dominant-negative variants in PLEC and heterozygous pathogenic variants in KLHL24 are presumed to be fully penetrant, as asymptomatic heterozygous individuals have not been reported to date.
• If the EBS-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Nagao-Watanabe et al 2004, Chen et al 2022].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with autosomal dominant EBS has a 50% chance of inheriting the EBS-related pathogenic variant.
• In the rare situation in which both parents have an autosomal dominant pathogenic variant in the same gene (e.g., in consanguineous unions), each child has a 75% chance of having at least one pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the EBS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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.

DST encodes the epidermal plakin protein BP230 (i.e., epithelial BPAG1, BPAG1-e), which facilitates dermal-epidermal adhesion through linkage of keratin intermediate filament networks and hemidesmosomes (for review, see Bouameur et al [2014]).

PLEC is widely expressed across a range of tissues including muscle, brain, cardiac, and stratified epithelium. Within the skin, three plectin isoforms are expressed to maintain mechanical integrity by linking keratin intermediate filament networks to intracellular desmosomes and hemidesmosomes. Plectin is highly versatile, and also binds to intermediate filaments within muscle and neural tissues, which may underlie the wide range of clinical phenotypes observed in PLEC-associated epidermolysis bullosa simplex (EBS) [Charlesworth et al 2013, Bouameur et al 2014, Kiritsi et al 2021].

Within the epidermis, CD151 expression is localized to hemidesmosomes and is thought to be critical for hemidesmosome formation and cell adhesion and signaling (for review, see [Vahidnezhad et al 2019c]. CD151 is also necessary for appropriate assembly of renal basement membranes, which may contribute to the syndromic presentation including protein-wasting nephropathy observed in individuals with CD151-associated EBS [Karamatic Crew et al 2004, Vahidnezhad et al 2018].

EBS may also be caused by pathogenic variants in nonstructural proteins. KLHL24 encodes for Kelch-like protein 24 (KLHL24), which is the receptor for a cullin-RING E3 ubiquitin ligase complex that regulates intermediate filament stability through turnover of keratin 14 (for review, see Has [2017] and Bolling & Jonkman [2019]). Pathogenic variants may cause skin fragility through increased ubiquitination and degradation of keratin 14 [Lin et al 2016], or impaired ability to promote keratin 14 degradation resulting in disorganized and fragmented intermediate filaments [He et al 2016].

EXPH5 encodes a RAB27b GTPase effector protein, exophilin-5, which plays a role in cell membrane trafficking and vesicle formation.

Dominant-negative missense variants in KRT5 and KRT14 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 2004, Werner et al 2004, Deng et al 2011].

Mechanism of disease causation. Pathogenic variants in genes encoding structural proteins (e.g., KRT5, KRT14, PLEC) are associated with dominant-negative or loss-of-function mechanisms. Pathogenic variants in nonstructural proteins may exhibit gain of function (e.g., KLHL24) or loss of function (e.g., EXPH5).

Author Notes

Stanford University Epidermolysis Bullosa Clinic

Stanford University Epidermolysis Bullosa Research

Author History

Anna L Bruckner, MD; University of Colorado School of Medicine (2008-2022)
Anne W Lucky, MD; Cincinnati Children's Hospital (2005-2008)
Ellen G Pfendner, PhD; GeneDx, Inc (2005-2022)
Jodi Y So, BA (2022-present)
Karen Stephens, PhD; University of Washington, Seattle (1998-2005)
Virginia P Sybert, MD; University of Washington, Seattle (1998-2005)
Joyce Teng, MD, PhD (2022-present)

Revision History

• 4 August 2022 (sw) Comprehensive update posted live
• 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 live
• 16 July 2003 (me) Comprehensive update posted live
• 2 February 2001 (me) Comprehensive update posted live
• 7 October 1998 (me) Review posted live
• 13 February 1998 (vs) Original submission

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