Version August 2024
INTRODUCTION — Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous inherited skin fragility disorder characterized by disruption of the skin's structure at the dermoepidermal junction or in the basal layer of the epidermis, resulting in increased cutaneous vulnerability to mechanical stress [1]. Depending on the specific genetic defect and its molecular sequelae, clinical hallmarks include blisters, wounds, and scars following minor trauma. Wounds may present as acute, chronic, open (ie, not healing within six weeks), or recurrent (with repetitive blistering, healing, and subsequent reopening) [2].
EB, and particularly its more severe variants, carries a considerable societal burden that affects patients, caregivers, and health care providers [3-7].
The epidemiology, pathogenesis, and clinical features of EB are discussed in this topic. The diagnosis and management of EB and Kindler epidermolysis bullosa (KEB) are discussed separately.
●(See "Diagnosis of epidermolysis bullosa".)
●(See "Overview of the management of epidermolysis bullosa".)
●(See "Kindler epidermolysis bullosa".)
EPIDEMIOLOGY
●United States – In the United States, the most reliable figures on the incidence and prevalence of EB are derived from the National Epidermolysis Bullosa Registry (NEBR), which collected cross-sectional and longitudinal data on approximately 3300 patients with EB from 1986 through 2002 [8,9]. Over a 16-year period (1986 through 2002), the incidence of EB was estimated to be approximately 20 per million live births, and the prevalence was estimated to be approximately 11 per million population [9]. Over the same period, the incidence rates of EB by subtype were approximately 7.9 per million live births for epidermolysis bullosa simplex (EBS), 2.7 per million live births for junctional epidermolysis bullosa (JEB), 2.1 per million live births for dominant dystrophic epidermolysis bullosa (DDEB), and 3.1 per million live births for recessive dystrophic epidermolysis bullosa (RDEB).
Data from the Dystrophic Epidermolysis Bullosa Research Association of America (DEBRA) show an incidence rate of 3.6 per million live births per year for JEB over the period from 2007 to 2011 [9,10].
●Australia and New Zealand – Data from the Australasian Epidermolysis Bullosa Registry (2006 to 2008) provided a prevalence estimate of 10 cases per million population [11].
●Europe – Prevalence rates ranging from 15 to 35 cases per million have been estimated in the United Kingdom [12]. The estimated EB prevalence in France was 12.7 cases per million [13]. Higher incidence and prevalence rates have been reported in the Netherlands. Based on data from the Dutch Epidermolysis Bullosa Registry between 1988 and 2018, the incidence and point prevalence of EB were 41.3 per million live births and 22.4 per million population, respectively [14]. Likewise, epidemiologic data from Germany indicate an overall EB incidence of 45 per million live births and a prevalence of 54 per million for all EB types [15].
OVERVIEW OF PATHOGENESIS — EB is caused by variants in several genes encoding structural proteins within keratin intermediate filaments, focal adhesions, desmosome cell junctions, and hemidesmosome attachment complexes. These structures form the intraepidermal adhesion and dermoepidermal anchoring complexes within the basement membrane zone of the skin and mucosae (figure 1) [16-19]. The molecular aberrations interfere with the functional and structural integrity of the basement membrane zone (a highly specialized interface between epithelial cells and the underlying matrix) that is crucial for cell adhesion, proliferation, and differentiation; tissue repair; barrier function; and leads to cell and tissue dehiscence [2,18,20].
The variant type (biallelic versus monoallelic), number (monogenic, digenic inheritance), and location within the gene or gene segment, as well as the spectrum of associated quantitative (absence, reduction) or qualitative (gradual loss of function) alterations of protein expression, result in considerable genetic heterogeneity with complex genotype-phenotype correlations. For example, variants in the same gene may be inherited in an autosomal dominant or recessive manner and result in different phenotypes (eg, dystrophic EB), while variants in different genes, with either dominant or recessive inheritance, may underlie similar phenotypes (eg, epidermolysis bullosa simplex [EBS]).
Apart from the primary structural-functional defect, other genetic, epigenetic, and nongenetic factors further contribute to the highly variable phenotype of EB, including [1,21-25]:
●Gene variants in cis (within the same allele) that alter gene expression, postzygotic or revertant mosaicism, variants in genes whose products modulate or influence EB-associated proteins
●Differentially regulated expression of other genes involved in the maintenance and function of the skin microenvironment, induction of inflammatory cascades, and immune-mediated complications [26-28]
●Socioeconomic and environmental factors
Advanced molecular profiling techniques and methodologies (eg, next-generation sequencing panels encompassing EB-related genes and genes implicated in other skin fragility syndromes, whole exome/genome sequencing, homozygosity mapping) have been established to allow improvement in early confirmation of diagnosis, precise subcategorization, more accurate prognostication, inclusion in clinical trials, and precision medicine [29-34].
NOMENCLATURE AND CLASSIFICATION — In 2020, a revised nomenclature and classification system of EB was proposed [1]. This classification defines classical EB as the prototype of genetic disorders with skin fragility and classifies other disorders with skin fragility as separate entities in a group called "EB-related disorders" (table 1).
●EB – The revised classification (table 2) is based on the so-called "onion skin" approach [16] and involves a stepwise process that combines immunofluorescence/ultrastructural data, clinical phenotype, and genetic/molecular data.
•First step – The first diagnostic step in the classification of the patient with EB involves the identification of the level of blister formation, usually by immunofluorescence antigen mapping and/or transmission electron microscopy (figure 1). Based on the level of skin cleavage, EB is classified into four major groups (table 2):
-Epidermolysis bullosa simplex (EBS) – Intraepidermal cleavage plane within the basal layer of keratinocytes (basal EBS)
-Junctional epidermolysis bullosa (JEB) – Cleavage plane within the lamina lucida of the dermoepidermal junction
-Dystrophic epidermolysis bullosa (DEB) – Cleavage plane below the lamina densa, within the upper papillary dermis at level of anchoring fibrils
-Kindler epidermolysis bullosa (KEB) – Multiple cleavage planes (intraepidermal, intralamina lucida, or sublamina densa)
•Second step – The second step of EB classification is based on the consideration of phenotypic characteristics, such as lesion distribution (eg, localized versus generalized), severity, and presence of extracutaneous involvement. Of note, EB is a clinically heterogenous disease with a broad range of phenotypes showing considerable inter- and intraindividual variability in the different stages of life. Moreover, patient-related and environmental factors may further modify the clinical presentation and natural history [1].
•Third step – The third and final step involves the identification of the defective protein and the inheritance pattern. This may initially involve immunofluorescence staining with panels of specific monoclonal antibodies directed against epidermal antigens/structural proteins and components of the dermoepidermal junction. Whenever possible, the identification of the gene involved and specific variant should be performed by molecular genetic analysis. (See "Diagnosis of epidermolysis bullosa".)
●EB-related disorders – In EB-related disorders (table 1), including peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility, blisters are lacking or minimal due to the very superficial skin cleavage [1]. Moreover, some syndromic variants of EB-related disorders present with primary manifestations in other organs or systems, such as the gastrointestinal tract, urogenital tract, myocardium, ear, and skeletal muscle [1].
EPIDERMOLYSIS BULLOSA SIMPLEX
Classification — Epidermolysis bullosa simplex (EBS) is the most common type of EB. In Western countries, EBS accounts for 75 to 85 percent (or even more) of all cases of EB, as mild cases often remain underdiagnosed [35]. The subtypes of EBS, based on gene involved, inheritance pattern, severity, and phenotype, are summarized in the table (table 3). The most common subtypes are:
●Localized EBS (previously Weber-Cockayne)
●Intermediate EBS (previously EBS generalized intermediate, EBS Köbner)
●Severe EBS (previously EBS generalized severe, EBS Dowling-Meara)
Genetics and molecular pathogenesis
●Gene variants – Pathogenic variants in at least seven distinct genes (table 3) have been associated with EBS. However, the vast majority of cases are caused by monoallelic negative missense variants in KRT5 and KRT14, which encode keratins that are mainly expressed in the basal keratinocytes [36-38].
Rare subtypes are associated with variants in genes encoding structural proteins of the basal membrane zone, including integrin beta-4 and type XVII collagen (figure 1) [39-41].
●Inheritance patterns – In most cases, EBS is inherited in an autosomal dominant manner. The rate of de novo mutations is high (approximately 30 percent) [36,42,43]. Rarely, EBS may be inherited in an autosomal recessive manner due to biallelic variants in KRT5 or, more often, KRT14 [44-48].
Semidominant inheritance, variable penetrance, and digenic occurrence of pathogenic variants in both KRT5 and KRT14 have been reported [49-51]. Large, intragenic KRT5 mutations have additionally been implicated in some unsolved cases of EBS [52].
●Molecular pathogenesis – Pathogenic variants in KRT14 and KRT5 affecting conserved areas at the beginning (N-terminal end-domain) or end (C-terminal end-domain) of the central alpha-helical rod segment of keratin molecules inhibit the end-to-end assembly of keratin filaments (heterodimerization of keratin 5 and 14 polypeptides), resulting in the collapse of the cytoskeleton into cytoplasmic protein aggregates [53-58]. Such aggregates lead to keratinocyte fragility to minimal friction trauma and cytolysis and are characteristic of the most severe forms of EBS.
Variants affecting less conserved areas, such as the head or tail domain, result in an impaired, but still possible, partial filament formation and are associated with a milder (localized) phenotype [35,59]. Some keratin mutations may affect cytoskeletal dynamics or interfere with normal post-translational keratin modifications [60]. The disease severity is also influenced by homozygosity (severe phenotype) or heterozygosity (milder phenotype) of the genetic defect and by the type of point mutation [61,62].
Variants in the PLEC gene, which encodes plectin (a hemidesmosomal protein expressed in various tissues, including gastrointestinal epithelia and striated muscle), are associated with muscular dystrophy in intermediate EBS and with pyloric atresia in severe EBS (table 3) [63,64]. Many plectin mutations cluster in exon 31, which encodes the rod domain. Plectin mutations are also associated with the autosomal dominant intermediate EBS with PLEC pathogenic variants (formerly type Ogna) [65].
Variants in the translation initiation codon of KLHL24, encoding kelch-like protein 24, have been found in individuals with a distinct skin fragility phenotype and skin cleavage within basal keratinocytes [66-68]. Mutant KLHL24 is associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts due to keratin 14 excessive ubiquitination and degradation.
Clinical features — EBS is characterized by blistering, erosions, and crusts in the most superficial (epidermal) layer of the skin following frictional trauma, with localized or disseminated, anatomic distribution. The spectrum of clinical severity is broad, ranging from minor blistering on feet to extracutaneous involvement and lethal outcome [69].
Localized epidermolysis bullosa simplex — Localized EBS (previously Weber-Cockayne EBS) is the mildest and most common form of EB. Localized EBS presents between infancy and the third decade of life with trauma- or friction-induced blistering mainly limited to the palms and soles (picture 1A-D) [70]. In very young children, blisters on the knees associated with crawling are also common. An associated palmoplantar hyperhidrosis is common. Blistering or ulceration of the oral mucosa may develop in infants, sometimes triggered by trauma from bottle feeding, and usually resolves with increasing age. Hair and teeth are likely normal; nail dystrophy, if present, is generally mild.
Blisters generally heal without scarring or milia. Discrete or focal calluses are common, especially in adults.
Intermediate epidermolysis bullosa simplex — In patients with intermediate EBS (previously EBS generalized intermediate, EBS Köbner), blistering starts at birth or during early infancy; is generally mild; and particularly involves the hands, feet, and extremities. Development of hair and teeth is normal, but nails may be thick or dystrophic.
Lesions often heal with postinflammatory hyperpigmentation. Atrophy and milia may occur, although less frequently than in severe EBS.
Severe epidermolysis bullosa simplex — Severe EBS (previously EBS generalized severe, EBS Dowling-Meara) presents at birth with disseminated, trauma- or friction-induced blistering. Grouped blisters with an arcuate, "herpetiform" arrangement may spontaneously appear on the trunk, upper limbs, or neck (picture 2A-B). Involvement of the oral mucosa is common. Hyperkeratosis of the palms and soles appears during infancy and can progress over time to confluent keratoderma. Additional clinical features include nail dystrophy and nail shedding.
Extracutaneous manifestations may be severe (eg, laryngeal stenosis) and result in increased mortality due to infection, malnutrition, and respiratory failure [71].
Erosions usually heal without scarring, but postinflammatory hypo- or hyperpigmentation are common. Milia and atrophy may occur, mainly in infancy.
Severe EBS tends to improve with age. High ambient temperatures or sweating (eg, during summer) are exacerbating factors.
Rare and unusual variants — Rare and unusual variants of EBS are clinically heterogeneous and include syndromic disorders. The gene mutations, inheritance pattern, and clinical manifestations of these rare variants are summarized in the table (table 3).
JUNCTIONAL EPIDERMOLYSIS BULLOSA
Classification — Junctional epidermolysis bullosa (JEB) encompasses a group of autosomal recessive disorders characterized by blistering of the skin and mucosae that heal with scarring. The classification of JEB, based on gene involved, inheritance pattern, severity, and phenotype, is summarized in the table (table 4). The two major JEB subtypes are:
●Severe JEB (previously JEB generalized severe, Herlitz)
●Intermediate JEB (previously JEB generalized intermediate, non-Herlitz)
There are several rare subtypes that are clinically and genetically heterogeneous or are part of syndromic disorders.
Genetics and molecular pathogenesis
●Gene variants – Most cases of JEB are caused by biallelic variants in one of the three genes (LAMA3, LAMB3, and LAMC2) encoding the subunit chains of laminin 332, an essential component of the basement membrane zone (table 4) [72]. Approximately 80 percent of mutations occur in LAMB3, which harbors a number of recurrent variants, such as R635X [73].
Rare JEB subtypes are associated with variants in COL17A1, ITGA6, ITGB4, or ITGA3, encoding the hemidesmosomal proteins collagen XVII, integrin alpha-6, integrin beta-4, and integrin beta-3, respectively.
●Inheritance patterns – In nearly all cases, JEB is inherited in an autosomal recessive manner. However, unusual inheritance patterns have been described, including cases associated with autosomal dominant variants in ITGB4 and COL17A1 [74,75] or uniparental isodisomy (inheritance of two identical copies of one parental chromosome) with reduction to homozygosity [76-79]. Compound heterozygosity (two different pathogenic mutations in the same gene that together are sufficient to manifest a recessive phenotype) is also reported [79]. (See "Genetics: Glossary of terms".)
●Molecular pathogenesis
•Severe JEB – Laminin 332 is expressed in embryonal and adult tissues, including amnion; embryonic cartilage; enamel-forming matrix; cornea; dermoepidermal junction; and the basement membrane zone of kidney (glomeruli and tubuli), lung (alveoli, bronchioli, and bronchi), and small intestine epithelium [80]. In the skin, laminin 332 is synthetized by the basal keratinocytes and is an essential component of the epidermal basement membrane.
Homozygous or compound heterozygous null variants within the LAM genes generate premature termination codons that lead to accelerated nonsense-mediated messenger ribonucleic acid (mRNA) decay or truncated, unstable, nonfunctional proteins sensitive to proteolytic degradation. The absence of any of the three laminin subunits (alpha-3, beta-3 and gamma-2) prevents the assembly and secretion of functional trimeric laminin 332 [81]. The complete loss of laminin 332 leads to tissue separation along the lamina lucida of the epidermal basement membrane in the skin and mucosae, resulting in a severe phenotype usually associated with early lethality.
Intermediate JEB – The majority of intermediate JEB cases are caused by missense variants or in-frame deletions in the laminin 332 genes, leading to a reduced expression of aberrant laminin 332 due to defective triple helix formation, decreased thermal stability, and intracellular accumulation. The abnormal laminin 332 retains a residual biologic activity, resulting in mild or moderate, generalized intermediate phenotypes. Observations in patients with JEB suggest that as little as 5 to 10 percent of residual protein, even if truncated and partially functional, significantly alleviates the phenotype [81,82]. Molecular mechanisms that may allow the expression of truncated, but partially functional, proteins include alternative modulation of splicing, spontaneous readthrough of premature termination codons, or skipping of exons containing premature termination codons [83-86].
The remaining intermediate JEB cases are caused by pathogenic variants in the COL17A1 gene, encoding the hemidesmosomal protein collagen XVII, also known as bullous pemphigoid antigen 180 (BP180) or BPAG2 [16,73,86]. Most variants are nonsense or insertion/deletion variants causing premature chain termination. Rarely, biallelic loss-of-function variants can result in severe JEB phenotypes.
Type XVII collagen is mainly expressed in hemidesmosomes but is also present in extracutaneous tissues, such as the eye and the central nervous system [87,88]. However, in these JEB cases, the clinical manifestations are mainly limited to the skin, hair, teeth, and mucous membranes and generally do not involve other organs (as in other forms of JEB).
•Revertant mosaicism – Up to 30 percent of patients with intermediate JEB due to variants in COL17A1 or LAMB3 present with the "revertant mosaicism" phenomenon (also called "natural gene therapy") [89-91]. This phenomenon occurs when a pathogenic germline variant is locally corrected by a spontaneous genetic event in a somatic cell, including intragenic crossover, second-site mutation, mitotic gene conversion, or true back mutation [92,93]. Revertant mosaicism may explain milder than expected phenotypes in some patients with intermediate JEB. These patients present at birth or later in life with skin areas that are typically darker than affected areas and do not blister.
●JEB subtypes with extracutaneous organ involvement
•JEB with pyloric atresia – In most cases, JEB with pyloric atresia is caused by pathogenic variants in the genes ITGB4 and ITGA6, encoding the hemidesmosomal protein alpha-6 beta-4 integrin [94]. The level of tissue separation is just above the plasma membrane. A total lack of functional alpha-6 beta-4 integrin due to variants generating premature termination codons in both alleles is associated with severe skin fragility and early mortality. However, more subtle (eg, missense) variants with residual protein expression have been identified in association with milder disease [95,96].
•ILNEB – Biallelic variants in the ITGA3 gene, encoding the transmembrane integrin receptor subunit integrin alpha-3, have been reported in a new form of EB: interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB), which is characterized by mild skin fragility but fatal multiorgan involvement occurring in infancy or early childhood [39]. Cases with missense mutations show a milder course, with survival to late childhood or adulthood [97,98]. The structural abnormalities detected in these patients (eg, subepidermal multilayer blistering with lamina densa located in the blister floor with intact hemidesmosomes and cell fragments) are similar to those described in integrin alpha-3 knockout mice [99]. These observations indicate that integrin alpha-3 is indispensable for epidermal cell adhesion and basement membrane organization.
•JEB-LOC syndrome – Pathogenic variants in LAMA3A are associated with junctional epidermolysis bullosa-laryngo-onycho-cutaneous (JEB-LOC) syndrome, a distinct subtype of localized JEB seen in families from the Punjab region of Pakistan and India. The affected individuals are generally homozygous for the recessive frameshift variant 151insG in LAMA3A on chromosome 18q11.2. However, a JEB-LOC phenotype can be caused by other variants in exon 39 of LAMA3A as well as LAMA3 [100-102]. Homozygous LAMB3 variants determined by autozygosity mapping were found to underlie JEB-LOC syndrome in a patient initially diagnosed with LAMA3A aberration [32].
Clinical features — JEB comprises two major subtypes: severe JEB (previously JEB generalized severe, Herlitz) and intermediate JEB (previously JEB generalized intermediate, non-Herlitz). In addition, there are several rare JEB subtypes that are clinically and genetically heterogeneous, including syndromic disorders (table 4) [1].
Severe junctional epidermolysis bullosa — Severe JEB (formerly JEB generalized severe, Herlitz JEB) may present as clinically mild at birth, but it rapidly progresses with generalized, often extensive, mucocutaneous blistering (picture 3A-E) associated with early lethality. Blisters and erosions may occur in all stratified, squamous, epithelial tissues, including the conjunctival, oral, gastrointestinal, respiratory, and genitourinary mucosae.
●Cutaneous findings – Exuberant granulation tissue presenting as moist, red, friable plaques (picture 4) around the mouth, central face, or nose is pathognomonic of severe JEB [103]. Other areas involved include the upper back, ears, axillary vaults, and nail folds. Periorificial vegetations can cause luminal occlusion and may mimic squamous cell carcinoma clinically.
Lesions secondary to repeated trauma include atrophic scarring, webbing (scar formation between fingers or toes), contractures (typically in the axillary vaults), and milia. Pigmentary abnormalities include hypopigmentation, mottled pigmentation, and, rarely, EB nevi. (See 'Epidermolysis bullosa nevi' below.)
Onychodystrophy with onychogryphosis (thickened, yellowish, longitudinally grooved, markedly curved nail plates) or absence of nails (anonychia) due to atrophy and scarring of the nail bed and matrix are common findings (picture 3E).
Uncommon cutaneous features include localized or diffuse scarring alopecia; palmoplantar keratoderma; and areas of congenital absence of the skin (aplasia cutis congenita) presenting as smooth, red, well-demarcated, depressed patches on hands, feet, wrists, or ankles.
●Mucosal lesions – Blisters and erosions may occur in all stratified, squamous, epithelial tissues, including the conjunctival, oral, gastrointestinal, respiratory, and genitourinary mucosae. Strictures and obstructions resulting from healing of mucosal lesions are associated with significant morbidity and mortality (table 4). (See 'Extracutaneous manifestations' below.)
●Dental abnormalities – Enamel hypoplasia due to mutated structural proteins interfering with dental histomorphogenesis is a characteristic feature of intraoral disease in all JEB subtypes [104]. Excessive pitting and furrowing of the tooth surfaces create areas that are difficult to clean and favor microbial growth and substrate retention, which cause dental caries. In addition, the thin enamel provides decreased resistance to the development and progression of caries.
●Upper airway involvement – Upper airway injury may spontaneously occur or follow episodes of coughing, crying, or upper respiratory tract infection [105]. Symptoms associated with laryngotracheal stenosis, such as chronic hoarseness, weak cry, or inspiratory stridor, are seen in up to 50 percent of patients with severe JEB and are ominous signs [106]. Partial or complete occlusion of the upper airways may occur in the generalized subtypes of JEB within the first year of life [105]. The risk of upper airway obstruction decreases in later childhood, probably because of the age-related increase in the luminal diameter of airways.
●Urologic involvement – Urologic complications may occur in patients with severe JEB [107]. Urethral meatal stenosis and urinary retention have been reported in approximately 10 percent of patients. Less frequent complications include hydronephrosis and bladder hypertrophy.
Intermediate junctional epidermolysis bullosa — Intermediate JEB (formerly JEB generalized intermediate, non-Herlitz JEB) encompasses a group of rare, less severe forms of JEB initially described in patients presenting with a severe JEB phenotype who survived to adulthood. Several variants of intermediate JEB have been recognized (table 4) [1].
In infants and children, intermediate JEB may be clinically indistinguishable from other forms of generalized EB, although development of chronic granulation tissue is usually absent (picture 5) [108]. In adults, it is characterized by serous or hemorrhagic blisters predominantly located in sites exposed to friction, trauma, or heat (picture 6A-B) [109]. Lesions may progress to form superficial or deep ulcers, crusted lesions, and fissures. Recurrent blistering and healing results in skin atrophy with poikilodermatous appearance; pigmentary disturbances; and faint, stellate scars [16,108,110]. Sometimes, a mild disease early in life may evolve to a severe phenotype in adults or vice versa.
Additional clinical features include a permanent, diffuse, but incomplete alopecia that becomes apparent by the end of the first or second decade; dystrophic or absent nails (picture 7); dental enamel hypoplasia and caries; and EB nevi. Involvement of mucous membranes may occur in infancy and early childhood and, in contrast to severe JEB, is usually moderate and without scarring. However, tracheolaryngeal stenosis, esophageal webs and strictures, and urogenital complications have been reported [111,112].
Prognosis — The risk of death among children with severe JEB is estimated to be approximately 45 percent by age 1 and 60 percent by age 15. These estimates are based upon data from the United States National Epidermolysis Bullosa Registry (NEBR), which included cases diagnosed by nonmolecular tests from 1986 through 2002 [113,114]. In contrast, mortality rates of up to 100 percent, with most deaths occurring in the first two years of life, have been reported among children with severe JEB in whom the diagnosis was based upon the complete absence of functional laminin 332 in immunofluorescence antigen mapping and deoxyribonucleic acid (DNA) analyses [11,115]. Sepsis, failure to thrive, and respiratory failure are the major causes of death.
Intermediate JEB is associated with a substantial risk of death during infancy [113]. Patients surviving into adulthood have an increased risk of developing squamous cell carcinoma [116,117].
DYSTROPHIC EPIDERMOLYSIS BULLOSA
Classification — Dystrophic epidermolysis bullosa (DEB) is characterized by blistering of the skin and mucosal membranes that heal with scarring. The 2020 consensus classification recognizes four major subtypes and several rare dominant or recessive subtypes of DEB (table 5) [1]. The major DEB subtypes are:
●Localized dominant dystrophic epidermolysis bullosa (DDEB; previously encompassing nails only, pretibial, and acral DDEB)
●Intermediate DDEB (previously known as generalized DDEB)
●Intermediate recessive dystrophic epidermolysis bullosa (RDEB; previously known as RDEB generalized intermediate, non-Hallopeau-Siemens RDEB)
●Severe RDEB (previously RDEB generalized severe, Hallopeau-Siemens RDEB)
RDEB is more severe than dominant disease subtypes; however, there is a considerable phenotypic overlap among all types.
Genetics and molecular pathogenesis
●Gene variants and inheritance patterns − All DEB subtypes are caused by variants in the COL7A1 gene on chromosome 3p21.31, encoding the alpha-1 chain of type VII collagen (table 5). More than 600 distinct variants in the COL7A1 gene have been identified in DEB [118-123]. Although a few variants are recurrent in some populations due to the founder effect, most families carry unique variants ("private variants") [29]. DEB can be inherited in a dominant or recessive manner. RDEB is generally more severe than DDEB, although there is considerable phenotypic overlap between subtypes, and RDEB may present with a milder phenotype in some cases.
●Molecular pathogenesis − Collagen VII is the main constituent of the anchoring fibrils, which are located below the basal lamina at the dermoepidermal basement membrane zone and anchor the epidermal basement membrane to the dermis. Cleavage in DEB occurs just beneath the lamina densa in the most superficial portion of the dermis, corresponding to the level of anchoring fibrils (figure 1).
•In DDEB, the predominant type of variant is a missense variant resulting in a glycine substitution within the triple helical domain of the pro-alpha-chain of type VII collagen [118]. Notably, there is a considerable clinical variability among individuals bearing the same glycine substitution, even within the same family. Less frequently, deletions and splice-junction variants have been identified [124]. Both the mutated and the wild-type allele are expressed in DDEB, so some anchoring fibrils are functionally intact, accounting for the relatively mild phenotype. In rare cases, the skin symptoms may be transient, with improvement in the first years of life, reflecting in-frame skipping of exons with specific glycine substitutions [125-127].
•In severe RDEB, nonsense variants, deletions, insertions, or splice-site variants with frame shift of translation typically result in premature termination codons [128]. Homozygosity or compound heterozygosity for premature termination codon variants in COL7A1 result in null alleles and complete absence of anchoring fibrils, as visualized by transmission electron microscopy and by negative or severely reduced immunofluorescence for type VII collagen epitopes. Complete absence of anchoring fibrils is associated with extreme skin fragility, extensive scarring, joint contractures and deformity, severe mucosal involvement, malnutrition, and growth retardation. (See 'Severe recessive dystrophic epidermolysis bullosa' below.)
•In intermediate forms of RDEB, different variants (eg, missense or splice-site variants) and allelic combinations (eg, a premature termination codon variant on one allele and a missense variant or in-frame deletion on the other) result in defective collagen VII synthesis and structurally abnormal anchoring fibrils [129]. In these patients, electron microscopy reveals anchoring fibrils morphologically altered or reduced in number, and immunofluorescence for collagen VII is positive but attenuated.
●Genotype-phenotype correlation – Genotype-phenotype correlation studies have helped in the understanding of the clinical diversity in RDEB. As an example, specific recessive arginine and glycine substitutions in the triple helix domain that affect the thermostability of type VII collagen were demonstrated to cause RDEB inversa, which predominantly involves the intertriginous areas [130,131].
Clinical features — Clinical hallmarks of DEB are skin fragility, blistering, scarring, nail changes, and milia formation in areas of healed blistering (picture 8A-E). Since collagen VII is also expressed in noncutaneous stratified epithelia, blistering can also occur in the mucosae.
The phenotypic spectrum of DEB ranges from the mildest, localized DDEB, in which patients may have only dystrophic toenails, to the most severe RDEB, in which there is generalized blistering and scarring leading to fusion of fingers and toes (ie, pseudosyndactyly or "mitten" deformity) (table 5) [132,133].
Intermediate dominant dystrophic epidermolysis bullosa — In intermediate DDEB, blistering starts at birth or soon after, predominantly in the skin overlying bony prominences (eg, the knees, ankles, and dorsa of the hands and feet). Mucosal involvement is rare, and teeth are normal. Blisters heal with scarring and milia. Nail dystrophy is probably the most important diagnostic feature, especially in adults, because most patients have only limited scarring, which becomes less noticeable with age.
Severe recessive dystrophic epidermolysis bullosa — Severe RDEB (formerly known as RDEB generalized severe, Hallopeau-Siemens RDEB) is the most severe form of DEB.
●Cutaneous findings – Blistering starts at birth, spontaneously or after the mildest trauma, particularly in skin areas exposed to repeated friction or mechanical trauma (eg, knees, elbows, hands, feet, back of the neck, shoulders, and over the spine). Occasionally, there is extensive denudation of a body area due to congenital absence of the skin. Healing occurs with scarring and milia [134].
Pseudosyndactyly due to repeated blistering and scarring on the hands and feet is a clinical hallmark of RDEB. It initially presents as partial fusion of the interdigital spaces due to proximal webbing and synechiae and is followed by progressive bridging and complete fusion of all of the individual digits in a cocoon-like, scarred mass ("mitten" deformity (picture 9)). Contractures of hands and feet begin to develop as early as the first year of life [135]. Proximal contractures may also occur, especially within the popliteal and antecubital fossae and axillary vaults. Scarring alopecia is common.
●Mucosal involvement – Oral, esophageal, anal, and ocular mucosae are also affected with erosions and mutilating scarring (table 5). Dystrophic teeth, restricted mouth opening, and decreased tongue mobility due to scarring promote severe caries and, together with esophageal strictures, lead to reduced food intake and nutritional deficiencies.
●Risk of cutaneous squamous cell carcinoma – Patients with severe RDEB have an extremely high risk of developing aggressive squamous cell carcinomas, which is the leading cause of death in this group [136]. (See 'Skin cancer' below.)
Intermediate recessive dystrophic epidermolysis bullosa — In intermediate RDEB, blistering is less severe and does not result in mutilating deformities. The clinical picture is variable (table 5). Some patients have widespread disease, whereas others present with blistering limited to the extremities. Skin lesions heal invariably with scars and milia. Oral, dental, nail, and hair manifestations are similar to those seen in severe RDEB but are less extensive. The risk of squamous cell carcinomas is elevated [136].
Rare subtypes — Rare subtypes of both DDEB and RDEB include (table 5):
●Localized DDEB – Localized DDEB presents in early childhood (acral) or later childhood/adulthood (pretibial) with predominantly fragile blisters and erosions that are often overshadowed by pruritic, lichenified plaques [137,138].
●RDEB inversa – RDEB inversa is characterized by blistering in the body flexures, trunk, and mucosa [130,131]. Patients have generalized blistering at birth and transition to a localized phenotype with involvement limited to the mucosa and/or body flexures by the age of four years [130].
●DEB pruriginosa – DEB pruriginosa is also a late-onset (childhood or later) variant of DDEB or, occasionally, RDEB [139]. Intense pruritus on a background of inherited skin fragility leads to skin signs resembling hypertrophic lichen planus or prurigo nodularis that are often prominent on the anterior shins [140].
KINDLER EPIDERMOLYSIS BULLOSA — Kindler epidermolysis bullosa (KEB) is a distinct type of EB characterized by skin blistering, photosensitivity, progressive poikiloderma (a combination of skin atrophy, telangiectasia, and dyspigmentation), and extensive skin atrophy [16,141]. KEB is caused by biallelic loss-of-function variants in the FERMT1 gene, encoding the focal adhesion protein fermitin family homolog 1 (FFH1; also called kindlin-1) (table 6) [142].
The pathogenesis, clinical manifestations, diagnosis, and pathogenesis of KEB are discussed separately. (See "Kindler epidermolysis bullosa".)
EXTRACUTANEOUS MANIFESTATIONS — The genes involved in the pathogenesis of EB are also partly expressed in other epithelial tissues and mesenchymal tissues, resulting in the occurrence of primary extracutaneous manifestations and relevant complications, especially in the severe forms of EB [105]. Complications may involve other organs and systems (eg, the heart and musculoskeletal system) [135]. EB should, therefore, be considered a multisystem disease associated with significant morbidity and mortality necessitating regular follow-up and surveillance. (See "Overview of the management of epidermolysis bullosa", section on 'Management of extracutaneous complications'.)
The extracutaneous manifestations and complications of EB are summarized in the table (table 7).
Nail and hair
●Nail abnormalities – Nail abnormalities are a feature of most EB subtypes since antigenic expression of basement membrane zone components in the normal matrix, nail bed, proximal nail fold, and hyponychium is similar to that of normal skin [143]. Nail involvement ranges from a mild cosmetic problem to a disabling condition (table 7).
Early nail dystrophy and loss correlate with disease severity and progression, particularly in junctional epidermolysis bullosa (JEB) and recessive dystrophic epidermolysis bullosa (RDEB) [144]. Nail abnormalities may precede skin blistering, as in late-onset JEB and in the pretibial variant of localized dystrophic epidermolysis bullosa (DEB) [138], or be an isolated finding, as in the acral "nails only" subtype of localized dominant dystrophic epidermolysis bullosa (DDEB) [145,146]. In the nails only DDEB variant, the involvement is often limited to the toenails and can be mild and easily overlooked. Moreover, nail involvement without blistering may be present for generations before a family member with DEB develops blisters in the skin [138,145-148].
●Hair abnormalities – The expression of basement membrane zone components in the anagen hair follicles of the human scalp is similar to that of the interfollicular epidermis [149]. Blistering of the scalp involving the lamina lucida and below, as in JEB and DEB, usually leads to cicatricial alopecia secondary to inflammation of the interfollicular epidermis and upper portion of the hair follicle in DEB and nonscarring alopecia due to stem cell insufficiency in JEB [150]. In addition, absence or abnormalities of basement membrane zone proteins in the hair follicle may increase hair fragility. The hair abnormalities and alopecia patterns associated with EB subtypes are summarized in the table (table 7).
Eye — Ocular involvement is frequent in patients with JEB or RDEB [151-153]. Symptoms range from mild conjunctival irritation to severe cicatrization of the eyelids, cornea, or conjunctiva and progressive visual impairment (table 7). Corneal blisters and erosions are the most common ocular findings and have been reported in approximately 50 percent of patients with severe JEB and 70 percent of patients with severe DEB [152,154].
Oral cavity — The oral manifestations of EB include soft tissue and dental abnormalities (table 7) [135,155]. Intraoral blisters and superficial erosions are common in all patients with EB, although they are usually minimal in those with epidermolysis bullosa simplex (EBS). Scarring and loss of normal architecture of intraoral soft tissues occur in most patients with JEB or DEB. Enamel hypoplasia with pitting and furrowing is a pathognomonic feature of all subtypes of JEB and predisposes to dental caries and tooth loss. Additional factors contributing to dental caries and premature tooth loss include:
●Poor oral hygiene due to painful perioral and intraoral blisters or erosions and impaired manual dexterity
●Altered soft tissue architecture with contractures (microstomia, ankyloglossia), abnormal tongue mobility, and obliteration of oral vestibules resulting in decreased food clearance
●Frequent feeding with high-calorie, cariogenic soft diets
●Malnutrition
Gastrointestinal tract — In patients with JEB, RDEB, or Kindler epidermolysis bullosa (KEB), any portion of the gastrointestinal tract may be injured [105]. Gastrointestinal manifestations include esophageal strictures, gastroesophageal reflux, protein-losing enteropathy, rectal tears, anal fissures and stenosis, and constipation (table 7). Esophageal strictures, resulting from recurrent mucosal blistering and scarring, are the most frequent and, often, the most disabling complication. The majority of strictures occur in the upper third of the esophagus, but they may arise anywhere, leading to progressive dysphagia initially with hard or bulky foods, then with softer foods, and eventually with liquids. In RDEB, esophageal strictures develop in early childhood, and more than 50 percent of patients report symptoms by the age of 10 [105].
Genitourinary tract — Complications of the genitourinary tract are reported in approximately 30 percent of patients with JEB or RDEB (table 7) [156]. Urethral meatal stenosis and recurrent vesiculation within the mucosa of the urethra, ureterovesical junction, and ureters may cause dysuria, hematuria, and urinary retention. Subsequently, bladder distention and hypertrophy, vesicoureteral reflux, hydroureter, and hydronephrosis may develop and, ultimately, lead to chronic renal failure if not treated [157].
COMPLICATIONS
Malnutrition and anemia — In patients with EB, several factors contribute to severe nutritional compromise, including:
●Feeding difficulties due to oropharyngeal involvement, esophageal narrowing, dysphagia, and poor swallowing coordination
●Moderate to severe malabsorption due to recurrent mucosal lesions of the small intestine
●High energy consumption from accelerated skin turnover, wound healing, and natural growth
●Hypercatabolic state from chronic inflammation and infection
●Transcutaneous loss of nutrients
Malnutrition may result in refractory anemia, hypoalbuminemia, failure to thrive, and delayed puberty with secondary hypogonadism [158]. Anemia is largely caused by iron deficiency resulting from reduced intake and absorption, blood loss from chronic skin and mucosal wounds, and loss of skin cells [159]. A chronic, inflammatory state additionally suppresses erythropoiesis [160]. Anemia has a significant impact on the general well-being, causing fatigue, breathlessness, reduced exercise tolerance, poor wound healing, and anorexia. Many patients with severe forms of EB maintain hemoglobin levels of <8 g/dL despite therapy with iron supplements [135]. Blood transfusion may be necessary.
Infection — Skin infection is common in all subtypes of EB and may have an exacerbating role in patients with severe subtypes of recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) [161,162]. Staphylococcus aureus and Streptococcus pyogenes are common infectious agents [163]. Gram-negative infections with Pseudomonas aeruginosa, Escherichia coli, or Proteus also occur [164]. Methicillin-resistant Staphylococcus aureus (MRSA) and ciprofloxacin-resistant Pseudomonas are frequently isolated from EB wounds.
Sepsis, in most cases arising from cutaneous infection, is a frequent cause of morbidity in children with JEB and RDEB. The use of intravenous lines and indwelling ports is also a significant source of septicemia in patients with EB due to chronically colonized or infected surrounding or overlying skin.
Skin cancer — Squamous cell carcinoma of the skin is a frequent complication and the leading cause of death of several subtypes of EB; the risk is highest for RDEB (picture 10A-B) [165,166]. Squamous cell carcinoma generally develops in early adulthood at sites of chronic wounds, regeneration, or scarring and shows an aggressive course, with high rates of recurrence and metastasis after surgical excision. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)
Data from the United States National Epidermolysis Bullosa Registry (NEBR) on 3280 consecutive patients with EB indicate that in patients with severe RDEB, the risk of developing squamous cell carcinoma by age 55 is greater than 90 percent [136]. Among these patients, the risk of death from metastatic disease by the same age is approximately 80 percent.
Suggested pathogenetic mechanisms include repetitive tissue stress and remodeling, growth activation of keratinocytes, polymorphisms of matrix metalloproteinases, or compromised immune surveillance with reduced activity of natural killer cells [165,167-169]. Cultured cancer-associated fibroblasts from patients with RDEB display a distinct gene expression profile compared with normal RDEB skin fibroblasts and cancer-associated fibroblasts from patients without RDEB, with most of the differentially expressed genes being involved in matrix and cell adhesion [170]. These observations suggest that the matrix composition in RDEB skin may form a permissive environment for tumor development and progression along injury-driven inflammation and tissue remodeling with fibrosis and increased stiffness [81,168,171]. The presence of flagellated bacteria may be an additional promoting factor in the development of squamous cell carcinoma in RDEB tissue [172].
Basal cell carcinoma occurs with increased frequency in patients with severe epidermolysis bullosa simplex (EBS), with estimated cumulative risks of 8, 25, and 44 percent by ages 40, 50, and 55, respectively [136]. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)
Patients with severe RDEB may be at increased risk of melanoma during childhood. Data from the NEBR indicate that these patients have a 2.5 percent cumulative risk of developing melanoma by age 12, similar to the lifetime risk of melanoma for the general American population [136]. In the NEBR, melanoma was also reported in 0.4 percent of patients with localized EBS and in 0.5 percent of those with generalized EBS, including the severe subtype [173].
Epidermolysis bullosa nevi — EB nevi are large, eruptive, asymmetrical, often irregularly pigmented and highly dynamic melanocytic lesions that develop in patients with all EB variants [174,175]. The random arrangement of proliferating melanocytic clones and secondary changes due to wound healing, scar formation, disruption of rete ridges, and neovascularization may account for the irregular appearance of EB nevi.
EB nevi appear gradually in infancy or adolescence as black to brown, stippled maculae (picture 11). Sometimes, they display explosive growth over months, with frequent appearance of small satellite lesions (picture 12).
EB nevi undergo maturation like most common acquired melanocytic nevi. They begin as flat, black to brown pigmented lesions and subsequently become intradermal and lose their pigment, presenting as papillomatous ("shagreen") nevi (picture 13A-B) [176]. Spontaneous disappearance of EB nevi may occur [177].
EB nevi typically arise in sites of previous bullae or erosions, often with a darker rim at the confines of the preceding vesiculation (picture 14), suggesting that repetitive disruption of the basement membrane primes local nevus cell nests or single melanocytes to break senescence and undergo proliferation [175,177,178]. An alternative pathogenetic hypothesis is that EB nevi originate from melanocytes or nevus cells, probably derived from incipient nevi or nests of nevus cells, that free-float in the fluid-filled cavity of an EB blister ("flocking bird melanocytes"), set down at random (often at the edge of the blister), and proliferate excessively in the microenvironment of epidermal regeneration [175,179].
Although EB nevi frequently manifest clinical, histologic, and dermoscopic features suggestive of melanoma (picture 15) [180], the course of EB nevi is usually benign. However, the malignant transformation of an EB nevus to invasive melanoma has been reported in one patient with EBS [181]. This observation suggests that clinicians should maintain a high index of suspicion for melanoma in examining pigmented, atypical lesions in patients with EB. Any significant change in a morphologically abnormal, pigmented lesion that arises in EB skin, regardless of the EB subtype, warrants a skin biopsy to exclude melanoma [173,181].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Epidermolysis bullosa".)
SUMMARY
●Definition and pathogenesis – Epidermolysis bullosa (EB) includes a group of rare inherited disorders characterized by marked mechanical fragility of epithelial tissues, with blistering and erosions following minor trauma. EB is caused by mutations in several genes encoding structural proteins that form the intraepidermal adhesion and dermoepidermal anchoring complexes within the basement membrane zone of the skin and mucosae (figure 1). (See 'Introduction' above and 'Overview of pathogenesis' above.)
●Classification – Four major types of EB are recognized based upon the ultrastructural level of blister formation within the epidermal basement membrane zone (figure 1): epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB), and Kindler epidermolysis bullosa (KEB) (table 2). (See 'Nomenclature and classification' above.)
●Epidermolysis bullosa simplex – EBS is the most common type of EB and is characterized by localized or generalized, trauma-induced skin blistering that heals without scarring (table 3). In most cases, EBS is caused by autosomal dominant mutations in the KRT5 and KRT14 genes encoding keratins, resulting in tissue cleavage at the level of the basal keratinocytes. (See 'Genetics and molecular pathogenesis' above and 'Clinical features' above.)
●Junctional epidermolysis bullosa – JEB is characterized by blistering of the skin and mucosae that heal with scarring (table 4). Most cases of severe JEB are caused by autosomal recessive mutations in the LAMA3, LAMB3, and LAMC2 genes, encoding laminin 332, resulting in tissue cleavage in the lamina lucida of the basement membrane zone. Severe JEB presents with extensive, mucocutaneous blistering at birth and is associated with early lethality (picture 3A-E). Intermediate JEB is caused by mutations predominantly affecting COL17A1, encoding type XVII collagen, and shows a generally milder course. (See 'Genetics and molecular pathogenesis' above and 'Clinical features' above.)
●Dystrophic epidermolysis bullosa – DEB is characterized by blistering of the skin and mucosae that heal with scarring and milia (table 5 and picture 8E). DEB is caused by autosomal dominant or recessive mutations in the COL7A1 gene, encoding the alpha-1 chain of type VII collagen, resulting in tissue cleavage below the lamina densa of the basement membrane zone. In severe recessive dystrophic epidermolysis bullosa (RDEB), blistering starts at birth. Pseudosyndactyly, mitten deformity, esophageal strictures, oral and ocular involvement, and squamous cell carcinoma are frequent and early complications. (See 'Genetics and molecular pathogenesis' above and 'Clinical features' above.)
●Kindler epidermolysis bullosa – KEB is a distinct type of EB characterized by skin blistering, photosensitivity, progressive poikiloderma, and extensive skin atrophy. KEB is caused by biallelic loss-of-function variants in the FERMT1 gene, encoding the focal adhesion protein fermitin family homolog 1 (FFH1) (table 6). KEB is discussed in detail separately. (See "Kindler epidermolysis bullosa".)
●Extracutaneous manifestations and complications – Extracutaneous manifestations common to all severe subtypes of EB include hair and nail abnormalities, intraoral blistering and scarring, dental abnormalities, esophageal strictures, and genitourinary abnormalities (table 7). Skin infections, sepsis, malnutrition, anemia, and squamous cell carcinoma are frequent complications and are associated with significant morbidity and mortality. (See 'Extracutaneous manifestations' above and 'Complications' above.)
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