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Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features

Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features
Literature review current through: Aug 2023.
This topic last updated: Feb 11, 2022.

INTRODUCTION — Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous, inherited skin fragility disorder characterized by structural anomalies that cause disruption 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, erosions, nonhealing ulceration, and scars following minor trauma.

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 — 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 EB patients from 1986 through 2002 [2-4]. 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 [4]. 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 2007 to 2011 [4,5].

Data from the Australasian Epidermolysis Bullosa Registry (2006 to 2008) provided a prevalence estimate of 10 cases per million population [6]. Prevalence rates ranging from 15 to 32 cases per million have been estimated in the United Kingdom [7-9].

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 [10].

OVERVIEW OF PATHOGENESIS — EB is caused by mutations involving several genes encoding structural proteins within keratin intermediate filaments, focal adhesions, desmosome cell junctions, and hemidesmosome attachment complexes, which form the intraepidermal adhesion and dermoepidermal anchoring complexes within the basement membrane zone of the skin and mucosae (figure 1) [11-14]. The molecular aberrations interfere with the functional and structural integrity of the basement membrane zone (which is a highly specialized interface between epithelial cells and the underlying matrix) that is crucial for cell adhesion, proliferation, and differentiation; tissue repair; and barrier function and leads to cell and tissue dehiscence [13].

Type (homozygosity versus heterozygosity), number (monogenic, digenic inheritance), and location of mutation(s) within the gene or gene segment, as well as the spectrum of subsequent 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, mutations in the same gene may be inherited in an autosomal dominant or recessive manner and result in different phenotypes, while mutations in different genes, with either dominant or recessive inheritance, may underlie similar phenotypes.

Apart from the primary structural-functional defect, other genetic, epigenetic, and nongenetic factors further contribute to the highly variable phenotype of EB, including [1,15,16]:

Gene variants in cis that change the expression of the corresponding allele, 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 and induction of inflammatory cascades

Socioeconomic and environmental factors

Against this background, 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 [17-22].

NOMENCLATURE AND CLASSIFICATION OF EPIDERMOLYSIS BULLOSA — In 2020, a revised nomenclature and classification system of EB was proposed [1]. This new 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 1A-B). In EB-related disorders, including peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility, blisters are lacking or are a minor part of the clinical presentation, owing 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].

The stepwise, "onion skin" approach — The first diagnostic step in the classification of the patient with EB involves the determination of the level of blister formation, usually by immunofluorescence antigen mapping and/or transmission electron microscopy (figure 1) [11].

Based upon the level of skin cleavage, EB is classified into four major groups (table 1A):

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)

The second step of EB classification is based upon phenotypic features, such as lesion distribution (eg, localized variants), severity, and presence of extracutaneous involvement.

It is important to consider, however, that EB is a clinically heterogenous disease with a broad range of phenotypes showing considerable inter- and intraindividual variability in the different stages of life and that patient-related and environmental factors may further modify its natural history [1].

In the third and final step, EB is classified into specific subtypes, which involves the identification of the defective protein by immunofluorescence staining with panels of specific monoclonal antibodies directed against epidermal antigens/structural proteins and components of the dermoepidermal junction and, whenever possible, the identification of the gene involved and specific mutation by mutational analysis. (See "Diagnosis of epidermolysis bullosa".)

EPIDERMOLYSIS BULLOSA SIMPLEX

Overview — Epidermolysis bullosa simplex (EBS) is the most common type of EB. In Western countries, this variant accounts for 75 to 85 percent of all cases of EB or even more, as mild cases often remain underdiagnosed [23]. Although mutations in at least seven distinct genes have been associated with EBS, the vast majority of cases harbor monoallelic mutations in the keratin genes KRT5 and KRT14, which result in the formation of a cleavage plane at the level of the basal keratinocytes (ie, intraepidermal) (table 2). Rare variants are associated with mutations in genes encoding structural proteins of the basal membrane zone, including integrin B4 and type XVII collagen, which disrupt the cytoplasmic domains of the respective proteins (figure 1) [24-26]. EBS is almost always inherited in an autosomal dominant fashion, but rare autosomal recessive forms have been reported [23,27-30].

EBS is characterized by trauma- or friction-induced, superficial skin blistering and erosions and crusts 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. The most common subtypes of EBS are:

Localized EBS (previously Weber-Cockayne)

Intermediate EBS (previously EBS generalized intermediate, EBS Köbner)

Severe EBS (previously EBS generalized severe, EBS Dowling-Meara)

The pattern of inheritance, gene mutations, and clinical features of EBS variants are summarized in the table (table 2).

Molecular pathogenesis — In most cases, EBS is caused by autosomal dominant negative missense mutations in KRT5 and KRT14, encoding keratins that are mainly expressed in the basal keratinocytes (table 2) [31]. The rate of de novo mutations is high (approximately 30 percent). Rarely, EBS may be caused by autosomal recessive inheritance of mutations in either one of these genes (more often KRT14) [32,33].

Semidominant inheritance, variable penetrance, and digenic occurrence (ie, combined mutations) of pathogenic variants in both KRT5 and KRT14 have also been reported [34-36]. Large, intragenic KRT5 mutations have additionally been implicated in some unsolved cases of EBS [37].

Genotype-phenotype analyses revealed that mutations 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 aggregation of keratin filaments (heterodimerization of keratin 5 and 14 polypeptides) and are associated with a profound disruption of the cytoskeleton, epidermal fragility to friction forces, and severe phenotype [13,38-41].

Mutations 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 [23,27]. Some keratin mutations may affect cytoskeletal dynamics or interfere with normal post-translational keratin modifications [42]. 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 [43,44].

Mutations in the PLEC gene, which encodes plectin (a hemidesmosomal protein expressed in various tissues, including gastrointestinal epithelia and striated muscle), are associated in intermediate EBS with muscular dystrophy and in severe EBS with pyloric atresia (table 2) [45,46]. 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) [47].

Mutations 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 [48-50]. Mutant KLHL24 was associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts due to keratin 14 excessive ubiquitination and degradation.

Clinical presentation

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) [51]. 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 normal; nail dystrophy is rare and 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.

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. Extracutaneous manifestations may be severe (eg, laryngeal stenosis) and result in increased mortality due to infection, malnutrition, and respiratory failure [52].

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 2).

JUNCTIONAL EPIDERMOLYSIS BULLOSA

Overview — Junctional epidermolysis bullosa (JEB) encompasses a group of autosomal recessive disorders characterized by blistering of the skin and mucosae that heal with scarring. In most cases, JEB is caused by autosomal recessive mutations in the laminin-332 genes, which result in a structural defect of the anchoring filaments located in the lamina lucida and superior lamina densa of the basal membrane zone. Rare variants of JEB are associated with mutations in the genes encoding the hemidesmosomal proteins collagen XVII, integrin alpha-6, and integrin beta-4.

JEB comprises two major subtypes:

Severe JEB (previously JEB generalized severe, Herlitz)

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 3) [1].

Molecular pathogenesis

Severe and intermediate junctional epidermolysis bullosa — Most cases of severe JEB and intermediate JEB are caused by autosomal recessive mutations in the LAMA3, LAMB3, or LAMC2 genes, encoding the alpha-3, beta-3, and gamma-2 subunit chains of laminin-332, respectively (table 3). The absence of any of the three laminin subunits prevents the assembly and secretion of functional trimeric laminin-332. 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 [53-56].

Approximately 80 percent of mutations occur in the LAMB3 gene, which harbors a number of recurrent mutations, such as R635X [57]. In severe JEB, homozygous or compound heterozygous null mutations within the LAM genes generate premature termination codons that lead to accelerated nonsense-mediated mRNA decay or truncated, unstable, nonfunctional proteins sensitive to proteolytic degradation. Any of these pathways result in biallelic complete loss of laminin-332 and a severe phenotype associated with early lethality.

The majority of intermediate JEB cases are caused by missense mutations 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 that results in mild or moderate, generalized intermediate phenotypes.

Observations in JEB patients suggest that as little as 5 to 10 percent of residual protein, even if truncated and partially functional, significantly alleviates the phenotype [58,59]. 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 [60-64].

The remaining intermediate JEB cases are caused by mutations in the COL17A1 gene, encoding the hemidesmosomal protein collagen XVII, also known as bullous pemphigoid antigen 180 (BP180) or BPAG2 [11,57,65]. Most mutations are nonsense or insertion/deletion mutations causing premature chain termination. Rarely, biallelic loss-of-function mutations 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 [66,67]. 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.

Up to 30 percent of patients with intermediate JEB due to mutations in COL17A1 or LAMB3 present with the "revertant mosaicism" phenomenon (also called "natural gene therapy") [68,69]. This phenomenon occurs when a causative germline mutation 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 [70,71]. 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.

Junctional epidermolysis bullosa variants with extracutaneous organ involvement — JEB variants with extracutaneous organ involvement include:

JEB with pyloric atresia – JEB with pyloric atresia is caused by mutations in the genes ITGB4 and ITGA6, encoding the hemidesmosomal protein alpha-6 beta-4 integrin. The level of tissue separation is just above the plasma membrane. A total lack of functional alpha-6 beta-4 integrin, due to mutations generating premature termination codons in both alleles, is associated with severe skin fragility and early mortality. However, more subtle (eg, missense) mutations with residual protein expression have been identified in association with milder disease [72,73].

JEB with interstitial lung disease and nephrotic syndrome – Homozygous mutations in the ITGA3 gene, encoding the transmembrane integrin receptor subunit integrin alpha-3, have been reported in a new form of EB, JEB with interstitial lung disease and nephrotic syndrome, which is characterized by mild skin fragility but fatal multiorgan involvement occurring in infancy or early childhood [24]. Cases with missense mutations show a milder course, with survival to late childhood. 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 [74]. These observations indicate that integrin alpha-3 is indispensable for epidermal cell adhesion and basement membrane organization.

JEB-laryngo-onycho-cutaneous (LOC) syndrome – Mutations of the LAMA3A gene, encoding the laminin alpha-3a polypeptide (a component of the laminin-332 heterotrimer), are associated with JEB-LOC syndrome, a distinct variant of localized JEB seen in families from the Punjab region of Pakistan and India. The affected individuals are generally homozygous for the recessive frameshift mutation 151insG in LAMA3A on chromosome 18q11.2. However, a JEB-LOC phenotype can be caused by other mutations in exon 39 of LAMA3A as well as LAMA3 [75-77]. In addition, homozygous LAMB3 mutations have been determined by autozygosity mapping to underlie LOC syndrome in a patient initially diagnosed with LAMA3A aberration [20].

Mutations causing JEB are generally inherited in an autosomal recessive pattern. However, unusual inheritance patterns have been described in some JEB patients, including autosomal dominant traits and uniparental isodisomy (inheritance of two identical copies of one parental chromosome) of chromosome 1 with reduction to homozygosity or compound heterozygosity (two different pathogenic mutations in the same gene that together are sufficient to manifest a recessive phenotype) [78-81] (see "Genetics: Glossary of terms"). The precise inheritance pattern must be taken into account for accurate genetic counseling.

Clinical presentation

Severe junctional epidermolysis bullosa — Severe JEB (formerly JEB generalized severe, Herlitz JEB) may present as clinically mild at birth, but in the first months of life, it rapidly progresses with generalized, often extensive, mucocutaneous blistering (picture 3A-E) associated with early lethality. Secondary lesions following repeated tissue 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.)

Exuberant granulation tissue presenting as moist, red, friable plaques (picture 4) around the mouth, central face, or nose is pathognomonic of severe JEB [82]. 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.

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.

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 3). (See 'Extracutaneous manifestations' below.)

Enamel hypoplasia, due to mutated structural proteins interfering with dental histomorphogenesis, is a characteristic feature of intraoral disease in all JEB subtypes [83]. Excessive pitting and furrowing of the tooth surfaces create areas that are difficult to clean and are ideal for 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 injury may spontaneously occur or follow episodes of coughing, crying, or upper respiratory tract infection [84]. 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 [85]. Partial or complete occlusion of the upper airways may occur in the generalized subtypes of JEB within the first year of life [84]. The risk of upper airway obstruction decreases in later childhood, probably because of the age-related increase in the luminal diameter of airways.

Urologic complications may occur in patients with severe JEB [86]. Urethral meatal stenosis and urinary retention have been reported in approximately 10 percent of patients. Less frequent complications include hydronephrosis and bladder hypertrophy.

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 [87,88]. 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 DNA analyses [6,89]. Sepsis, failure to thrive, and respiratory failure are the major causes of death.

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 [90,91]. The disease was formerly termed "generalized atrophic benign epidermolysis bullosa" [92,93]. Several variants of intermediate JEB have been recognized (table 3) [94].

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) [92]. In adults, it is characterized by serous or hemorrhagic blisters predominantly located in sites exposed to friction, trauma, or heat (picture 6A-B) [95]. 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 [11,92,93]. 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 [96,97].

Intermediate JEB is associated with a substantial risk of death during infancy [87]. Patients surviving into adulthood have an increased risk of developing squamous cell carcinoma [98,99].

DYSTROPHIC EPIDERMOLYSIS BULLOSA

Overview — Dystrophic epidermolysis bullosa (DEB) is characterized by blistering of the skin and mucosal membranes that heal with scarring. DEB is caused by mutations in the COL7A1 gene, encoding the alpha-1 chain of type VII collagen. Collagen VII is the main constituent of the anchoring fibrils located below the lamina densa of the epidermal basement membrane zone. DEB can be inherited in an autosomal dominant or recessive fashion. (See 'Molecular pathogenesis' below.)

The 2020 consensus classification recognizes four major subtypes and several rare, dominant or recessive subtypes of DEB (table 4) [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 variants; however, there is a considerable phenotypic overlap among all types.

Molecular pathogenesis — All DEB subtypes are caused by mutations in the COL7A1 gene on chromosome 3p21.31, coding for the alpha-1 chain of type VII collagen (table 4). 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).

More than 600 distinct mutations in the COL7A1 gene have been identified in DEB [100-105]. Although a few mutations are recurrent in some populations due to the founder effect, most families carry unique mutations ("private mutations") [17]:

In DDEB, the predominant type of mutation is a missense mutation resulting in a glycine substitution within the triple helical domain of the pro-alpha-chain of type VII collagen [100]. 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 mutations have been identified [106]. 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 [107-109].

In severe RDEB, nonsense mutations, deletions, insertions, or splice-site mutations with frame shift of translation typically result in premature termination codons [110]. Homozygosity or compound heterozygosity for premature termination codon mutations 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.

In intermediate forms of RDEB, different types of mutations (eg, missense or splice-site mutations) and allelic combinations (eg, a premature termination codon mutation on one allele and a missense mutation or in-frame deletion on the other) result in defective collagen VII synthesis and structurally abnormal anchoring fibrils [111]. 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 studies have helped in the understanding of the phenotype diversity in RDEB. As an example, specific recessive arginine and glycine substitutions in the triple helix domain implicated to affect the thermostability of type VII collagen were demonstrated to cause RDEB inversa, which predominantly involves the intertriginous areas [112,113].

Clinical presentation — 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 also occurs in the mucous membranes and upper third of the esophagus.

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 4).

Intermediate dominant dystrophic epidermolysis bullosa — In intermediate DDEB, blistering starts at birth or soon after, predominantly in the skin overlying bony prominences, such as 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. 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 [114].

Pseudosyndactyly due to repeated blistering and scarring on the hands and feet is a clinical hallmark of RDEB. Pseudosyndactyly 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 [115]. Proximal contractures may also occur, especially within the popliteal and antecubital fossae and axillary vaults. Scarring alopecia is common.

Oral, esophageal, anal, and ocular mucosae are also affected with erosions and mutilating scarring (table 4). Dystrophic teeth and restricted mouth opening and tongue mobility due to scarring promote severe caries and, together with esophageal strictures, lead to reduced food intake and nutritional deficiencies. 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 [116]. (See 'Skin cancer' below.)

Intermediate recessive dystrophic epidermolysis bullosa — In intermediate RDEB, blistering is less severe, and mutilating deformities are generally missing. The clinical picture is variable (table 4). 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 [116].

Rare subtypes — Rare, localized subtypes of both DDEB and RDEB include localized, inverse, and pruriginosa forms (table 4):

Localized DEB presents in early childhood (acral) or later childhood/adulthood (pretibial) with predominantly fragile blisters and erosions that are often overshadowed by pruritic, lichenified plaques [117].

RDEB inversa is characterized by blistering in the body flexures, trunk, and mucosa [112,113]. 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 [112]. 

DEB pruriginosa is also a late-onset (childhood or later) variant of DDEB or, occasionally, RDEB [118]. Intense pruritus on a background of inherited skin fragility leads to skin signs resembling hypertrophic lichen planus or prurigo nodularis [119].

KINDLER EPIDERMOLYSIS BULLOSA

Overview — Kindler epidermolysis bullosa (KEB) is a distinct type of autosomal recessive EB characterized by skin blistering, photosensitivity, progressive poikiloderma (a combination of skin atrophy, telangiectasia, and dyspigmentation), and extensive skin atrophy [11,120]. KEB is caused by loss-of-function mutations in the FERMT1 gene, encoding the focal adhesion protein fermitin family homolog 1 (FFH1; also called kindlin-1). KEB has been reported in approximately 250 individuals worldwide and is more common in isolated or consanguineous populations (table 5). (See "Kindler epidermolysis bullosa".)

Molecular pathogenesis — KEB is caused by mutations in the FERMT1 gene, encoding FFH1 (also referred to as kindlin-1), a focal adhesion protein predominantly expressed in skin basal keratinocytes, periodontal tissues, and colon. Kindlin-1 has a critical regulatory role in linking the actin cytoskeleton with the underlying extracellular matrix anchorage network and is implicated in the control of integrin activation (figure 1) [121-124].

Approximately 40 different pathogenic mutations have been identified in KEB, including frameshift, splice-site, large deletion mutations, and gene rearrangements following homologous unequal crossing over [125-128]. Loss-of-function mutations in FERMT1 lead to the disruption of the attachment of the actin cytoskeleton to focal adhesion junctions at the dermoepidermal junction and impaired epithelial-mesenchymal signaling via these complexes [120,129-133]. The KEB ultrastructural key features of thickening and reduplication of lamina densa may be related to repeated episodes of keratinocyte disadhesion and overcompensation by excessive matrix production and remodeling beneath the basement membrane [134,135]. Long-term FFH1 deficiency is also associated with an increased mucocutaneous cancer risk, suggesting that focal adhesions may have an important role in cell cycle control and cell survival, growth, signaling, and invasion [132,136,137].

Clinical presentation — KEB presents at birth or in early infancy with trauma-induced skin blistering that predominantly involves acral sites and heals with atrophic changes [120]. In late childhood, blistering and milia generally subside and give way to progressive poikiloderma and skin atrophy localized to sun-exposed areas, such as the dorsal aspect of the hands and feet. Most patients with KEB develop variable degrees of photosensitivity.

Mucosal involvement tends to increase with age. Gingivitis and periodontitis are common findings. Esophageal or genitourinary stenoses and gastrointestinal symptoms, including constipation and colitis, have also been reported. Patients with KEB have an increased risk of nonmelanoma skin cancer during adulthood [138]. (See "Kindler epidermolysis bullosa", section on 'Clinical manifestations and natural history'.)

EXTRACUTANEOUS MANIFESTATIONS — Index genes involved in the pathogenesis of EB are also partly expressed in other epithelial tissues and mesenchymal organs, resulting in the occurrence of primary extracutaneous manifestations and relevant complications, especially in the severe forms of EB [84]. Complications may also involve other organs and systems, such as the heart and musculoskeletal system [115]. EB should, therefore, be considered a multisystem disease associated with significant morbidity and mortality. The extracutaneous manifestations and complications of EB are summarized in the table (table 6).

Nail and hair — 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 [139]. Nail involvement ranges from a mild cosmetic problem to a disabling condition.

Early nail dystrophy and loss correlate with disease severity and progression, particularly in junctional epidermolysis bullosa (JEB) and recessive dystrophic epidermolysis bullosa (RDEB) [140]. Nail abnormalities may precede skin blistering, as in late-onset JEB and in the pretibial variant of localized dystrophic epidermolysis bullosa (DEB), or be an isolated finding, as in the acral "nails only" subtype of localized dominant dystrophic epidermolysis bullosa (DDEB) [141]. 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 DEB family member develops blisters in the skin [141-144].

The expression of basement membrane zone components in the anagen hair follicles of the human scalp is similar to that of the interfollicular epidermis [145]. 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 [146]. In addition, the absence of or abnormal 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 6).

Eye — Ocular involvement is frequent in patients with JEB or RDEB [147,148]. Symptoms range from mild, conjunctival irritation to severe cicatrization of eyelids, cornea, or conjunctiva and progressive visual impairment (table 6). 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 [148,149].

Oral cavity — The oral manifestations of EB include soft tissue and dental abnormalities (table 6) [115]. Intraoral blisters and superficial erosions are common in all EB patients, 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 KEB, any portion of the gastrointestinal tract may be injured [84]. Gastrointestinal manifestations include esophageal strictures, gastroesophageal reflux, rectal tears, anal fissures and stenosis, and constipation (table 6). 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 [84].

Genitourinary tract — Complications of the genitourinary tract are reported in approximately 30 percent of patients with JEB or RDEB (table 6) [150]. Urethral meatal stenosis and recurrent vesiculation within the mucosa of the urethra, ureterovesical junction, and ureters may cause dysuria 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 [151].

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 [152]. 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. A chronic, inflammatory state additionally suppresses erythropoiesis [153]. 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 [115]. 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) [154]. Staphylococcus aureus and Streptococcus pyogenes are common infectious agents. Gram-negative infections with Pseudomonas aeruginosa, Escherichia coli, or Proteus also occur. Methicillin-resistant S. aureus 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 EB patients, 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) [115]. 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 [116]. 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 [58,155-157]. Cultured cancer-associated fibroblasts from RDEB patients display a distinct gene expression profile compared with normal RDEB skin fibroblasts and cancer-associated fibroblasts from non-RDEB patients, with most of the differentially expressed genes being involved in matrix and cell adhesion [158]. 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 [58,159]. The presence of flagellated bacteria may be an additional promoting factor in the development of squamous cell carcinoma in RDEB tissue [160].

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 [116]. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma".)

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 [116]. In the NEBR, melanoma was also reported in 0.4 percent of patients with localized EBS and 0.5 percent of those with generalized EBS, including the severe subtype [161].

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 [162,163]. 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) [164]. Spontaneous disappearance of EB nevi may occur [165].

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 [163,165,166]. 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 [163,167].

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 frequently manifest clinical, histologic, and dermoscopic features suggestive of melanoma (picture 15) [168].

Although the state of chronic skin wounding and regeneration seems to promote carcinogenesis (see 'Skin cancer' above), 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 [169]. This observation suggests that clinicians should maintain a high index of suspicion for melanoma in examining pigmented, atypical lesions in EB patients. 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 [161,169].

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 1A). (See 'Nomenclature and classification of epidermolysis bullosa' 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 2). 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 'Molecular pathogenesis' above and 'Clinical presentation' above.)

Junctional epidermolysis bullosa – JEB is characterized by blistering of the skin and mucosae that heal with scarring (table 3). 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 'Molecular pathogenesis' above and 'Clinical presentation' above.)

Dystrophic epidermolysis bullosa – DEB is characterized by blistering of the skin and mucosae that heal with scarring and milia (table 4 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 'Molecular pathogenesis' above and 'Clinical presentation' above.)

Kindler epidermolysis bullosa – KEB is an autosomal recessive EB type characterized by skin blistering, photosensitivity, progressive poikiloderma, and extensive skin atrophy (table 5). KEB is caused by mutations in the FERMT1 gene, encoding the focal adhesion protein fermitin family homolog 1 (also called kindlin-1), resulting in tissue cleavage at variable levels in the basement membrane zone. KEB presents at birth or in early infancy with trauma-induced skin blistering that predominantly involves the acral sites and heals with atrophic changes. (See 'Molecular pathogenesis' above and 'Clinical presentation' above and "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 and dental abnormalities, esophageal strictures, and genitourinary abnormalities (table 6). 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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Topic 15449 Version 27.0

References

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