DISEASE CARD

Definition

Epidermolysis bullosa simplex (EBS) is the most common type of EB (up to 80% of all EB cases) and characterized by skin blistering following minor trauma such as gentle pressure or friction due to cleavage at the epidermal level of the skin. Within EBS 14 different subtypes are distinguished. The three main subtypes (localized, intermediate, severe) account for 60-70% of all EBS cases. Most types are due to mutations in the keratin genes KRT5 and KRT14, leading to a cleavage at the epidermal level of the skin. Common is an autosomal dominant inheritance, rarely autosomal recessive inheritance occurs.¹

^{Author: Prof. Dr. Johann Bauer}

Clinical Description

EBS subtypes are characterized by trauma or friction induced skin blistering with either localized or generalized distribution. Blistering usually happens at the basal cell layer of the epidermis. Onset of the disease is commonly at birth or shortly after birth, except for localized subtypes, who may not develop blistering until late childhood or early adulthood. Localized variants, the most frequent subtypes, can present with a very subtle phenotype and thus may be underdiagnosed. Unless there is a secondary infection, erosions usually heal without scarring, but may leave post inflammatory hypo-/hyperpigmentation. Additional clinical features like nail dystrophy, nail shedding and alopecia, are uncommon within the EBS group. Mucosal involvement is rarely seen. High ambient temperatures or sweating (summer) are frequently aggravating factors.²

Intermediate EBS (previously EBS Köbner) is characterized by non-herpetiform mechanically induced blistering and erosions involving the entire skin surface, especially on hands, feet and extremities. Symptoms may be present at birth and tend to spare the palms and soles, which makes this rather mild EBS subtype distinguishable from EBS-localized patients. Milia, scarring, and nail dystrophy may occur, but less frequent when compared to EBS severe patients. Rarely, intraoral blistering manifests as the only extracutaneous finding.²

Severe EBS (previously EBS Dowling Meara) is a generalized form of EBS with trauma-/friction- induced blister formation on the entire skin surface from early on. It is usually associated with a high morbidity (especially if extracutaneous involvement is present) and in rare cases may even result in death during infancy (due to infection, malnutrition, respiratory compromise). Typically for this type is the rather spontaneous occurrence of small blisters arranged in a grouped or arc-like configuration (herpetiform), similar to herpes-simplex like lesions, which explains the originally name “EB-herpetiformis”.³ Lesions heal without scarring but usually lead to postinflammatory hypo- and hyperpigmentation, milia formation as well as atrophy. This type is clinically most severe during childhood and ameliorates with increasing age. By late childhood, many EBS-severe patients develop hyperkeratosis on the palms and soles, which may disappear partially with mid- to late adulthood.⁴ Nail dystrophy and oral involvement is frequent, but tracheolaryngeal complications, that are common in other more severe EB types, are only seen rarely in severe EBS.^{2, 5}

EBS-localized (previously EBS Weber-Cockayne) is characterized by blister formation primarily on the palms and soles, although any other skin area also develops blisters if sufficiently traumatized. Onset is usually during late infancy or early childhood. The occurrence of milia, scarring, and nail dystrophy is very rare. Occasional intraoral erosions or blisters are rare and usually occur only during infancy. In some patients focal palmoplantar keratoderma may occur by adulthood.²

EBS clinical subtypes^{1, 6}

^{* most common EBS subtypes}

Pathogenesis

EBS is usually caused by dominant negative missense mutations in KRT5 and KRT14 genes that are mostly expressed in the basal epidermal layer. The rate of de-novo mutation is approximately 30%. Normal keratin 5 and keratin 14 form the intermediate keratin filament network that is linked to the desmosomes and hemidesmosomes, which are essential for cell–cell and cell–basal lamina adhesion, respectively.⁷

Phenotype-genotype analysis revealed that mutations affecting conserved areas at the beginning (N-terminal end-domain) and end (C-terminal end-domain) of the central alpha-helical rod segment of keratin molecules are usually associated with a more severe disruption of cytoskeleton and clinical phenotype probably due to an inhibited end to end aggregation of keratin filaments. Mutations affecting less conserved areas, like the head or tail domain commonly cause a milder phenotype, although many exceptions from this rule have also been reported.^8-10 Disease severity is further influenced by homozygosity (severe manifestations) or heterozygosity (milder manifestations) of the genetic defect as well as the kind of point mutation.

Ultrastructural findings in EBS are cell vacuolization, keratin filament clumping, cytolysis and blister formation as well as an overexpression of chemokines and matrix degrading enzymes.^{11, 12} Decreased mechanical resistance to cell deformation, excessive apoptotic activity, possibly induced by keratin clumps, and up-regulation of the inflammatory response have been implicated in the pathogenesis of the disease and represent novel therapeutic targets. In in vitro experiments, the involvement of IL-1 β-induced stress pathways has been shown. ^{12, 13}

Phenotypic improvement with age in some EBS variants has been described. Possible mechanisms are compensatory overexpression of keratins such as KRT15, somatic genetic events (revertant mosaicism), and the influence of silent sequence alterations on phenotypic manifestations of the EBS causing mutations. ^{8, 14}

Rare genetic variants:

• Missense or nonsense mutations mostly in KRT14, rarely in KRT5, resulting in loss of gene function rather than a dominant negative effect and cause recessive forms of EBS.
• Mutations in DST gene, encoding an epithelial isoform of dystonin has been associated with autosomal recessive EBS. DST encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1 (BPAG1-e). The mutation leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduces labeling for plectin, the β4 integrin subunit, and for type XVII collagen.¹⁵
• Several distinct variants of EBS are due to mutated PLEC gene that encodes plectin. The hemidesmosomal protein is expressed in various tissues, including gastrointestinal epithelia and stratified muscle. Within skeletal muscle, it localizes to sacrolemma and Z-lines, thus participating in formation of the intermyofibrillar-desmin cytoskeleton ¹⁶. Mutations in the PLEC gene may cause EBS with muscular dystrophy (EBS-MD). The aberrant plectin is implicated to affect plasma membrane-cytoskeletal interactions in skin and muscle, thereby leading to epidermal blistering and muscle weakness. Many plectin mutations cluster in exon 31 that encodes the rod domain¹⁷. Mutations outside of exon 31 may account for EBS with pyloric atresia (EBS-PA) and blister formation within basal keratinocytes. The phenotypic differences between EBS-MD and EBS-PA are suggested to result from distinct pathogenic pathways of plectin mutations. In mutations within exon 31, the residual expression of the rodless isoform, as detected in some EBS-MD patients, may be the reason for milder skin manifestations compared to EBS-PA, yet being associated with late-onset muscle dystrophy.^{17, 18}
• Mutations in PLEC1a (alternative first exon of the PLEC gene) may cause EBS without muscular dystrophy, as plectin 1a isoform is not expressed in muscular tissue. ^{1, 19}
• Mutations in the KLHL24 gene, encoding kelch-like protein 24, cause disruption of intermediate filaments in keratinocytes and fibloblasts as keratin 14 is being excessively degraded. This genotype has been linked to a distinct skin-fragility phenotype with skin cleavage within basal keratinocytes. ^{20, 21}
• Frameshift mutations in exon 9 of keratin gene KRT5 (c.1649delG, c.1637del4, and c.1638_1641del-CATGA, c.1650delC) are indicative of EBS-migratory circinate.^{22, 23}
• Dominant negative mutations in the KRT5 gene may cause EBS with mottled pigmentation that is strongly associated with a missense mutation (p.P25L) affecting the KRT5 head domain. This aberration is suggested to impair melanin granule aggregation and keratin filament function by interfering with post-translational processing. Other data, however, suggest the same phenotype to result from other mutations in KRT5 and KRT14 or unrelated genes like plectin.^{24, 25}

• A few cases of EBS, linked to pathogenic mutations in two typical JEB genes (ITGB4 or COL17A1), associated with disruption of the cytoplasmic domains of the respective proteins, have been reported.
• Mutations in CD151 gene, coding for tetraspanin 24, have been associated with a phenotype of mild skin fragility, poikiloderma alopecia and nail dystrophy, resembling Kindler syndrome. Several extracutaneous manifestations have been reported in those patients like nephropathy, esophageal stenosis, stenosis of the lacrimal duct as well as sensorineural deafness.

Diagnosis

Whenever possible, laboratory diagnosis should be performed in a specialized EB centre.

To determine the level of skin cleavage, immunomapping or transmission electron microscopy of skin biopsies (4-6mm) is recommended. The immunomapping has diagnostic accuracy similar to transmission electron microscopy, with the advantage of simple and fast execution and reading. The splitting of the skin occurs in or just above the basal layer (intra-epidermal), and fluorescence deposition on the blister floor (dermal side) is seen with all antigenic markers (bullous pemphigoid antigen, laminin, collagens IV and VII). Electron microscopy may identify anomalies of keratin intermediate filaments.

In parallel, blood sampling for the extraction of genomic DNA is recommended. Genetic testing is the gold standard since it provides a definite diagnosis and classification of the major EB type and in many cases the subtype. It also enables genetic counselilng and DNA-based prenatal testing. A next-generation sequencing (NGS) EB-gene panel is the method of choice as it encompasses all known pathogenic EB genes and shows good sequencing coverage. In addition, Sanger sequencing may be performed if the target gene is known and of small size, or to detect familial and recurrent genetic variants. Immunofluorescence findings and genetic analysis provide complementary information that enables precise and fast diagnosis but also prediction of consequences of novel sequence variants and genotype-phenotype correlations. The vast majority of EB cases can be genetically characterized with these methods. ¹

Treatment

There is no cure for EB. Wound care as well as early recognition and treatment of complications (e.g. skin infections) remain the mainstays of management.

General measures: Prevention of blister formation in everyday life, e.g., by choosing appropriate foot wear and wide clothing without raised seams or labels as well as padding of trauma-exposed sites, should be routinely implemented. If palmar or plantar hyperkeratosis is present, regular debridement and/or keratinolytics will help reducing walking pain and preventing fissuring and infection under the thickened skin. Occurrence of pain should be regularly assessed and adequately treated, e.g. for mild pain with non-opioid analgesics, for moderate to severe pain with opioid analgesics and for chronic pain with tricyclic antidepressnats and non-pharmacologic practices. Management of pruritus is frequently challenging and includes pharmacologic interventions, topical emollients and psychological therapies like relaxation training, biofeedback or distraction. As oral involvement can occur, children should be referred to the dentist before the teeth erupt and preventative measures applied (e.g. oral hygiene, fluoride). Nutritional status should be checked and special diets, if needed, introduced. Especially neonates with severe EBS may require enteral nutrition support. Physical therapy must be started early in life, in particular in EBS with muscular dystrophy.^{26, 27}

Wound care: Large blisters can cause pain and should be carefully opened (e.g. with a sterile needle), in order to release the pressure from surrounding tissue. The blister roof can be left in place for a better healing. However, when it has been removed, special non adhesive dressings are needed to reduce the risk of wound infections and pain. The choice of the dressing should consider the wound characteristics (site, exudate, critical colonization/infection), size, patient age, patient/parent preferences). Low-level laser therapy may be helpful for accelerating cutaneous wound healing. Adhesive dressings or tapes must be avoided as they can induce blistering.²⁶

Systemic antibiotics, that cover common pathogens, may be needed if tissue infection (especially lymphadenopathy, malaise, fever) occurs.

Treatment with botulinum toxin during summer season showed ameliorating effects, due to reduction of hyperhidrosis.^{28, 29} The anti-inflammatory drug Diacerein has been tested in a pilot study with EBS-generalized severe patients and showed promising effects. ³⁰ mTOR inhibitor therapy has shown some effectiveness in case reports.³¹

References

^{1. Has C, Fischer J. Inherited epidermolysis bullosa: New diagnostics and new clinical phenotypes. Exp Dermatol. 2019;28(10):1146-1152.}

^{2. Fine JD. Inherited epidermolysis bullosa. Orphanet J Rare Dis. 2010;5:12.}

^{3. Dowling GB, Meara RH. Epidermolysis bullosa resembling juvenile dermatitis herpetiformis. Br J Dermatol. 1954;66(4):139-143.}

^{4. Livingston RJ, Sybert VP, Smith LT, Dale BA, Presland RB, Stephens K. Expression of a truncated keratin 5 may contribute to severe palmar--plantar hyperkeratosis in epidermolysis bullosa simplex patients. J Invest Dermatol. 2001;116(6):970-974.}

^{5. Fine J-D, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. Journal of the American Academy of Dermatology. 2009;61(3):367-384.}

^{6. Has C, Bauer JW, Bodemer C, et al. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. 2020;183(4):614-627.}

^{7. Pfendner EG, Sadowski SG, Uitto J. Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. J Invest Dermatol. 2005;125(2):239-243.}

^{8. Schuilenga-Hut PH, Vlies P, Jonkman MF, Waanders E, Buys CH, Scheffer H. Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations. Hum Mutat. 2003;21(4):447.}

^{9. Hu ZL, Smith L, Martins S, Bonifas JM, Chen H, Epstein EH, Jr. Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex--increased severity of disease in a homozygote.J Invest Dermatol. 1997;109(3):360-364.}

^{10. Jerábková B, Marek J, Bucková H, et al. Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure. Br J Dermatol. 2010;162(5):1004-1013.}

^{11. Uitto J, Richard G, McGrath JA. Diseases of epidermal keratins and their linker proteins. Exp Cell Res. 2007;313(10):1995-2009.}

^{12. Lettner T, Lang R, Klausegger A, Hainzl S, Bauer JW, Wally V. MMP-9 and CXCL8/IL-8 are potential therapeutic targets in epidermolysis bullosa simplex. PLoS One. 2013;8(7):e70123.}

^{13. Wally V, Lettner T, Peking P, et al. The pathogenetic role of IL-1β in severe epidermolysis bullosa simplex. J Invest Dermatol. 2013;133(7):1901-1903.}

^{14. Yasukawa K, Sawamura D, McMillan JR, Nakamura H, Shimizu H. Dominant and recessive compound heterozygous mutations in epidermolysis bullosa simplex demonstrate the role of the stutter region in keratin intermediate filament assembly. J Biol Chem. 2002;277(26):23670-23674.}

^{15. Ganani D, Malovitski K, Sarig O, Gat A, Sprecher E. Epidermolysis bullosa simplex due to bi-allelic DST mutations: Case series and review of the literature. 2021;38(2):436-441.}

^{16. Smith FJ, Eady RA, Leigh IM, et al. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet. 1996;13(4):450-457}

^{17. Bauer JW, Rouan F, Kofler B, et al. A compound heterozygous one amino-acid insertion/nonsense mutation in the plectin gene causes epidermolysis bullosa simplex with plectin deficiency. Am J Pathol. 2001;158(2):617-625.}

^{18. Nakamura H, Sawamura D, Goto M, et al. Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). J Mol Diagn. 2005;7(1):28-35.}

^{19. Gostyńska KB, Nijenhuis M, Lemmink H, et al. Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex. Hum Mol Genet. 2015;24(11):3155-3162.}

^{20. Lee JYW, Liu L, Hsu CK, et al. Mutations in KLHL24 Add to the Molecular Heterogeneity of Epidermolysis Bullosa Simplex. J Invest Dermatol. 2017;137(6):1378-1380.}

^{21. Lin Z, Li S, Feng C, et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.Nat Genet. 2016;48(12):1508-1516}

^{22. Kumagai Y, Umegaki-Arao N, Sasaki T, et al. Distinct phenotype of epidermolysis bullosa simplex with infantile migratory circinate erythema due to frameshift mutations in the V2 domain of KRT5. J Eur Acad Dermatol Venereol. 2017;31(5):e241-e243.}

^{23. Yalici-Armagan B, Kabacam S, Taskiran ZE, Gököz Ö, Utine GE, Ersoy-Evans S. A novel mutation of keratin 5 in epidermolysis bullosa simplex with migratory circinate erythema. Pediatr Dermatol. 2020;37(2):358-361.}

^{24. Echeverría-García B, Vicente A, Hernández Á, et al. Epidermolysis bullosa simplex with mottled pigmentation: a family report and review. Pediatr Dermatol. 2013;30(6):e125-131.}

^{25. Nagai H, Oiso N, Tomida S, et al. Epidermolysis bullosa simplex with mottled pigmentation with noncicatricial alopecia: identification of a recurrent p.P25L mutation in KRT5 in four affected family members. Br J Dermatol. 2016;174(3):633-635.}

^{26. Has C, El Hachem M. Practical management of epidermolysis bullosa: consensus clinical position statement from the European Reference Network for Rare Skin Diseases. 2021;35(12):2349-2360.}

^{27. Marro M, De Smet S, Caldari D, Lambe C, Leclerc-Mercier S, Chiaverini C. Gastrostomy for infants with severe epidermolysis bullosa simplex in neonatal intensive care. 2021;16(1):271.}

^{28. Holahan HM, Farah RS, Ferguson NN, Paller AS, Legler AA. Treatment of symptomatic epidermolysis bullosa simplex with botulinum toxin in a pediatric patient. JAAD Case Rep. 2016;2(3):259-260.}

^{29. Swartling C, Karlqvist M, Hymnelius K, Weis J, Vahlquist A. Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita. Br J Dermatol. 2010;163(5):1072-1076.}

^{30. Wally V, Hovnanian A, Ly J, et al. Diacerein orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized, placebo-controlled, double-blind clinical trial. J Am Acad Dermatol. 2018;78(5):892-901.e897}

^{31. Lee GH, Lekwuttikarn R, Tafoya E, Martin M, Sarin KY, Teng JM. Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex. J Invest Dermatol. 2021.}

Prof. Johann Bauer, MBA

Professor of Dermatology

University Hospital of the Paracelsus Medical University Salzburg, Austria 

Head of the EB Research Unit, EB House Austria, Salzburg

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