Authors: Martin Laimer, MD, MD, Johann Bauer, MD, MD, Dedee F Murrell, MD Section Editor: Jennifer L Hand, MD Deputy Editor: Rosamaria Corona, MD, DSc Contributor Contribu tor Disc losures
All topics topics are updated as as new evidence evidence becomes becomes available available and our peer review process is process is complete. Literature re vie w current through: Sep through: Sep 2017. | This topic last update d: Jun d: Jun 21, 2017. INTRODUCTION — INTRODUCTION — Epidermolysis bullosa (EB) encompa encomp asses a clinically and genetically heterogeneous 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 involving at least 18 genes encoding structural proteins within keratin inter mediate mediate filaments, focal adhesions, desmoso me cell junctions, and hemidesmosome hemidesmosome attachment at tachment complexes, complexes, which form the intraepider int raepidermal mal adhesion and dermoepidermal anchoring complex within the t he basement membrane membrane zone (BM ( BMZ) Z) of the t he skin and a nd mucosae ( figure 1) 1) [1-3 [1-3]. ]. The T he molecular molecular aberrations interfere with the functional and st ructural ructural integrity of the BMZ (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 [ 3] and leads to cell and tissue dehiscence. 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) alteration of protein expression, expression, results in considerable genetic heterogeneity with complex genotype-phenotype correlations. Apart from the primary primary structural-functional defect, secondary secondary epigenetic factors (eg, differentially regulated expression of a host of other genes involved in the maintenance and function of this microenvironment, induction of inflammatory cascades) and environmental factors further contribute to the highly variable phenotype of EB [ 4,5 4,5]. ]. The epidemiology, pathogenesis, and clinical features of EB are discussed in this topic. The diagnosis and management of EB are discussed separately. (See "Diagnosis of epidermolysis bullosa" and bullosa" and "Overview of the management of epidermolysis bullosa" .) EPIDEMIOLOGY — EPIDEMIOLOGY — The most reliable figures on prevalence and incidence of epidermolysis bullosa (EB) are derived from the National EB Registry (NEBR), which collected cross-sectional and longitudinal longitudinal data on about a bout 3300 EB patients in the United States from 1986 through 2002 [ 6-8 6-8]. ]. Over a 16-year period (1986 through 2002), the 2002), the prevalence of EB was estimated to be approximately 11 per million and the incidenc incidence e approximately appro ximately 20 per million live births [8 [ 8]. Over the same period, the incidence rates of EB by subtype were approximately eight per million live births for EB simplex, three per million live births for junctional EB, two per million live births for dominant dystrophic EB, and three per million live births for recessive dystrophic EB. Data from the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) report an incidence rate of 3.6 per million per year for junctional EB over the period 2007 to 2011 2011 [9 [ 9]. Data from the Australasian EB Registry provided a prevalence estimate of 10 cases per million live births [ 10 10]. ]. Prevalence rates ranging from 15 to 32 cases per million have been estimated in the UK [ 11-13 11-13]. ]. NOMENCLATURE AND CLASSIFICATION OF EB — EB — In 2013, a revised nomenclature and classification system of EB have been proposed [ 14 14]. ]. The new classification includes the new clinical phenotypes and gene mutations that have been described since the 2008 consensus classification
[1]. The "onion skin approach" — 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) 1) [1 [1]. Based upon the level of skin cleavage, EB is classified into four major groups: ●
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Epidermolysis bullosa simplex (EBS) – Intraepidermal Intraepider mal cleavage plane, within the t he basal keratinocytes (basal EBS) or above the level of basal keratinocytes (suprabasal 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 syndrome – Multiple cleavage planes (intraepidermal, intralamina lucida, or sublamina densa)
In the next step, EB is classified based upon phenotypic features, such as distribution (eg, localized or generalized), severity, and presence of extracutaneous involvement. The patient's family history may suggest the mode of inheritance. The final classification of EB into specific subtypes 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".) bullosa" .) EPIDERMOLYSIS BULLOSA SIMPLEX Overview — Overview — Epidermolysis bullosa simplex (EBS) (EBS) is the t he most common common type of EB, accounting for 75 to 85 percent of all cases of EB in Western countries [ 15 15]. ]. In the vast majority of cases, EBS is caused by mutations in the keratin genes, resulting in the formation of a cleavage plane at the level of the basal keratinocytes. Rare variants are associated with mutations in genes encoding other structural proteins of the basal membrane zone, including desmoplakin, plakophilin-1, plakoglobin, integrins A6 and B4, type XVII collagen, plectin, transglutaminase 5, and dystonin ( figure 1) 1) [16 [16]. ]. EBS is almost always inherited in an autosomal dominant fashion, but rare autosomal recessive forms have been reported [15,17-20 [15,17-20]. ]. EBS is characterized by trauma- or friction-induced skin blistering with localized or disseminated anatomic distribution. The most common subtypes of EBS are: ●
EBS, EBS, localiz local ized ed (formerly ( formerly known as EBS Weber-Cockayne)
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EBS, EBS, generalized ge neralized severe (form (for merly known known as EBS Dow Dowling-Meara) ling-Meara)
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EBS, generalized intermediate (includes the type formerly known as EBS Koebner)
Rare variants include suprabasal EBS, recessive EBS, EBS associated with pyloric atresia, EBS with mottled pigmentation, EBS associated with muscular dystrophy, and EBS of Ogna. The pattern of inheritance, gene mutations, and clinical features of EBS variants are summarized in the table ( table 1).
Pathogenesis — In most cases, EBS is caused by dominant negative missense mutations in KRT5 and KRT14 genes (table 1), encoding keratins that are mainly expressed in the basal keratinocytes [21]. Rarely, EBS may be caused by autosomal recessive inheritance of either one of these genes (more often KRT14) [22,23]. Three cases of digenic inheritance (ie, combined mutations in KRT5 and KRT14-) have also been reported [ 24-26]. Genotype-phenotype analyses revealed that mutations affecting conserved areas at the beginning (Nterminal 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 [ 3,27-30] and are associated with a severe disruption of the cytoskeleton, epidermal fragility to friction forces, and phenotype. 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 phenotype [ 15,17]. Some keratin mutations may affect cytoskeletal dynamics or interfere with normal post-translational keratin modifications [31]. 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 [ 32,33]. Mutations in the PLEC1 gene that encodes plectin (a hemidesmosomal protein expressed in various tissues, including gastrointestinal epithelia and striated muscle) are associated with autosomal recessive EBS with muscular dystrophy and EBS with pyloric atresia ( table 1) [34,35]. Many plectin mutations cluster in exon 31 that encodes the rod domain. Plectin mutations are also associated with the autosomal dominant EBS of Ogna [ 36], a lethal form of EBS [37], and an autosomal recessive EBS form (with acral, later generalized blistering) without extracutaneous involvement [ 38]. Mutations affecting structural components of desmosomes, adhesion contacts, or proteins involved in the terminal differentiation within the upper epidermis are associated with suprabasal EBS ( table 1): ●
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Acantholytic EBS (includes variants formerly termed lethal acantholytic EBS and lethal congenital EBS) is associated with loss-of-function mutations in the DSP and JUP genes, encoding the desmosomal proteins desmoplakin and plakoglobin [ 39]. DSP mutations lead to the truncation of the keratin-binding tail domain of desmoplakin, resulting in impaired attachment or connection between the keratin intermediate filaments and the desmosomal inner dense plaque in all layers of the epidermis. Skin fragility syndromes are autosomal recessive disorders caused by loss-of-function or compound heterozygous mutations in the PKP1, DSP , or JUP genes, encoding the desmosomal proteins plakophilin-1, desmoplakin, and plakoglobin, respectively [ 40-47]. Plakoglobin and desmoplakin are desmosomal proteins that are pan-epidermal, whereas plakophilin-1 is expressed mainly in the suprabasal epidermis. 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 [48,49]. Mutant KLHL24 was associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts due to keratin 14 excessive ubiquitination and degradation.
Clinical presentation EBS, localized — Localized EBS, formerly known as Weber-Cockayne EBS, is the mildest and most common form of EB. Localized EBS presents between infancy and the third decade with traumaor friction-induced blistering mainly limited to the palms and soles ( picture 1A-D) [50]. 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 heal without scarring or milia. Discrete or focal calluses are common, especially in adults. EBS, generalized seve re — Generalized severe EBS, formerly known as Dowling-Meara EBS, is the most severe form of EBS. It presents at birth with disseminated trauma or friction-induced blistering. Grouped blisters with an arcuate, "herpetiform" arrangement may appear spontaneously on the trunk, upper limbs, or neck (picture 1C-D). 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, nail shedding, and hair loss (telogen effluvium). Erosions usually heal without scarring, but postinflammatory hypo- or hyperpigmentation are common; milia and atrophy may occur, mainly in infancy rather than later in life. Generalized 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 [51]. EBS, generalized intermediate — Generalized intermediate EBS, formerly known as Koebner EBS, includes all forms of generalized EBS other than the severe (Dowling-Meara) subtype [ 1]. Blistering starts at birth or during early infancy, is generally mild, and particularly involves the hands, feet, and extremities. Development of hair, teeth and nails is normal. Lesions often heal with postinflammatory dyspigmentation; atrophy and milia may occur, although less frequently than in the generalized severe form. Unusual variants Suprabasal EBS — In suprabasal EBS, intact blisters are hardly observed, due to the thin, and therefore fragile, blister roofs. Erosions or impaired keratinization with increased desquamation and palmoplantar keratoderma are usually seen ( table 1). The severity of the clinical manifestations and extracutaneous involvement varies among subtypes. Other v ariants — Other unusual variants of EBS include EBS with mottled pigmentation, EBS with muscular dystrophy, EBS with pyloric atresia, autosomal recessive EBS, and EBS Ogna and are summarized in the table (table 1) [52,53]. 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. Genotypic and phenotypic variants of JEB include ( table 2) [14]: Generalized JEB subtypes: ●
JEB, generalized severe (formerly known as JEB, Herlitz)
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JEB, generalized intermediate (formerly known as generalized non-Herlitz or generalized, other)
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JEB with pyloric atresia
Localized JEB subtypes:
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JEB, localized (hands, feet, elbows, knees)
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JEB inversa
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JEB, laryngo-onycho-cutaneous syndrome
Pathogenesis — Most cases of generalized severe JEB (formerly Herlitz) and generalized intermediate JEB (formerly non-Herlitz) are caused by autosomal recessive mutations in the LAMA3, LAMB3, or LAMC2 genes encoding the alpha-3, beta-3, and gamma-2 subunits of laminin-332, respectively (table 2). 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 [54-57]. Approximately 80 percent of mutations occur in the LAMB3 gene, which harbors a number of recurrent mutations, such as R635X [58]. In generalized 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 results in biallelic complete loss of laminin-332 and a severe phenotype. The majority of generalized intermediate JEB cases is 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 biological activity that results in mild or moderate generalized intermediate phenotypes. The remaining generalized 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 [1,58,59]. Most mutations are nonsense or insertion/deletion mutations causing premature chain termination. Type XVII collagen is mainly expressed in hemidesmosomes but is also present in extracutaneous tissues such as the eye and the central nervous system [ 60,61]. However, in these JEB cases the clinical manifestations are mainly limited to the skin, hair, and mucous membranes and generally do not involve other organs as in other forms of JEB. Up to 30 percent of patients with generalized intermediate JEB due to mutations in COL17A1 or LAMB3 present with the "revertant mosaicism" phenomenon, also called "natural gene therapy" [62,63]. 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 [ 64,65]. Revertant mosaicism may explain milder than expected phenotypes in some patients with generalized 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. The JEB variant 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 in JEB-PA 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 missense mutations have been identified in association with milder disease [66,67].
Homozygous mutations in the ITGA3 gene encoding the transmembrane integrin receptor subunit integrin alpha-3 have been reported in three patients with a new form of epidermolysis bullosa, JEB with respiratory and renal involvement, characterized by mild skin fragility but fatal multiorgan involvement with congenital nephrotic syndrome and interstitial lung disease [ 16]. The structural abnormalities detected in these patients (eg, subepidermal multi-layer 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 [ 68]. These observations indicate that integrin alpha-3 is indispensable for epidermal cell adhesion and basement-membrane organization. Mutations of the LAMA3A gene, encoding the laminin alpha-3a polypeptide, a component of the laminin-332 heterotrimer, are associated with the laryngo-onycho-cutaneous (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, LOC syndrome can be caused by other mutations in exon 39 [69-71]. 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) [ 72-75]. This phenomenon has to be taken into account for accurate genetic counseling. (See "Genetics: Glossary of terms".) Clinical presentation JEB, generalized seve re — Generalized severe JEB (former JEB, Herlitz) presents with generalized, often extensive mucocutaneous blistering at birth ( picture 2A-E) and is associated with early lethality despite aggressive therapeutic interventions. 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 hypo- or mottled pigmentation and, rarely, EB nevi. (See 'Epidermolysis bullosa nevi' below.) Exuberant granulation tissue presenting as moist, red, friable plaques ( picture 3) around the mouth, central face, or nose is pathognomonic of severe generalized JEB [ 76]. Other areas involved include the upper back, 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 2E). 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 [ 77]. 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 occur spontaneously or follow episodes of coughing, crying, or upper respiratory tract infection [78]. Symptoms associated with laryngotracheal stenosis, such as chronic hoarseness, weak cry, or inspiratory stridor, are seen in up to 50 percent of patients with generalized severe JEB and are ominous signs [79]. Partial or complete occlusion of the upper airways may occur in the generalized subtypes of JEB within the first year of life [ 78]. 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 generalized severe JEB [80]. 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 generalized 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 [ 81,82]. 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 generalized JEB in whom the diagnosis was based upon the complete absence of functional laminin-332 in immunofluorescence antigen mapping and DNA analyses [ 10,83]. Sepsis, failure to thrive, and respiratory failure are the major causes of death. JEB, generalized intermediate — Generalized intermediate JEB (former JEB, non-Herlitz) encompasses a group of rare, less severe forms of JEB, initially described in patients presenting with a generalized severe JEB phenotype who survived to adulthood [ 84,85]. The disease was formerly termed "generalized atrophic benign epidermolysis bullosa" (GABEB) [ 86,87]. Several variants of generalized intermediate JEB have been recognized ( table 2) [14]. In infants and children, generalized intermediate JEB may be clinically indistinguishable from other forms of generalized EB (picture 4) [86]. In adults, it is characterized by serous or hemorrhagic blisters predominantly located in sites exposed to friction, trauma, or heat ( picture 5A-B) [88]. 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 [1,86,87]. 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 6), dental enamel hypoplasia and caries, and EB nevi. Involvement of mucous membranes may occur in infancy and early childhood and, in contrast to generalized severe JEB, is usually moderate and without scarring. However, tracheolaryngeal stenosis, esophageal webs and strictures, and urogenital complications have been reported [ 89,90]. Generalized intermediate JEB is associated with a substantial risk of death during infancy [ 81]. Patients surviving into adulthood have an increased risk of developing squamous cell carcinoma [91,92].
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 'Pathogenesis' below.) The 2013 consensus classification [ 14] recognizes one major dominant (DDEB) and two major recessive (RDEB) subtypes of DEB and several rare dominant or recessive subtypes ( table 4). 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. 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. More than 600 distinct mutations in the COL7A1 gene have been identified in DEB [93-98]. Although a few mutations are recurrent in some populations due to the founder effect, most families carry unique mutations ("private mutations") [99]. In autosomal dominant DEB (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 [93]. Less frequently, deletions and splice-junction mutations have been identified. 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. In generalized severe recessive DEB (RDEB, formerly called Hallopeau-Siemens type) nonsense mutations, deletions, insertions, or splice site mutations with frame shift of translation typically result in premature termination codons [100]. 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 milder 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 [101]. 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 of type VII collagen were demonstrated to cause RDEB inversa, which predominantly involves the intertriginous areas [102,103]. Clinical presentation — Clinical hallmarks of DEB are skin fragility, blistering, scarring, nail changes, and milia formation (picture 7A-E). Since collagen VII is expressed also 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 "nail-only" dominant DEB, in which patients
have only dystrophic toe nails, 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). The three major clinical subtypes of DEB are: ●
DDEB, generalized
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RDEB, generalized severe (formerly named RDEB, Hallopeau–Siemens type)
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RDEB, generalized intermediate (formerly named RDEB, other)
Uncommon variants of dominant and recessive DEB are summarized in the table ( table 4). DDEB, ge neralized — In generalized dominant DEB (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 that becomes less noticeable with age. RDEB, generalized severe — Generalized severe recessive DEB (RDEB), formerly known as Hallopeau-Siemens type, 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 [104]. Pseudosyndactyly due to repeated blistering and scarring on hands and feet is a clinical hallmark of recessive dystrophic EB. 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 8). Contractures of hands and feet begin to develop as early as in the first year of life [ 105]. 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 scarring ( table 3). Dystrophic teeth, 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. Severe generalized RDEB patients have an extremely high risk of developing squamous cell carcinomas, which is the leading cause of death in this group [ 106]. (See 'Skin cancer' below.) RDEB, generalized intermediate — In generalized intermediate RDEB, blistering is less severe and mutilating deformities are generally missing. The clinical picture is variable. 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 recessive DEB, severe generalized, but are less extensive. The risk of squamous cell carcinomas is elevated [106]. Rare subtypes — Rare, localized subtypes of both dominant and recessive DEB include inverse, pretibial, pruriginosa, and nail-only forms ( table 4). Pretibial DEB presents in adolescence or adulthood with fragile blisters and erosions that are often overshadowed by pruritic, lichenified plaques [107]. DEB pruriginosa is also a late-onset variant of dominant, or occasionally recessive, dystrophic EB. Intense pruritus on a background of inherited skin fragility leads to skin signs resembling hypertrophic lichen planus or prurigo nodularis [ 108].
KINDLER SYNDROME Overview — Kindler syndrome (KS) is a distinct type of autosomal recessive epidermolysis bullosa characterized by skin blistering, photosensitivity, progressive poikiloderma (a combination of skin atrophy, telangiectasia, and dyspigmentation), and extensive skin atrophy [ 1,109]. KS is caused by loss-of-function mutations in the FERMT1 gene, encoding the focal adhesion protein fermitin family homolog 1, also called kindlin-1. Pathogenesis — KS is caused by mutations in the FERMT1 gene, encoding the fermitin family homolog 1 protein (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) [110-113]. About 40 different pathogenic mutations have been identified in KS, including frameshift, splice site, large deletion mutations, and gene rearrangements following homologous unequal crossing over [ 114117]. 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 epithelialmesenchymal signaling via these complexes [ 109,118-122]. KS 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 [123,124]. 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 [ 121,125,126]. Clinical presentation — Kindler syndrome (KS) presents at birth or in early infancy with traumainduced skin blistering that predominantly involves acral sites and heals with atrophic changes [ 109]. In late childhood, blistering generally subsides and gives 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 KS develop variable degrees of photosensitivity. Mucosal involvement tends to increase with age. Gingivitis and periodontitis are common findings. Esophageal or genitourinary stenoses, gastrointestinal symptoms, including constipation and colitis, have also been reported. Patients with KS have an increased risk of nonmelanoma skin cancer during adulthood [127]. EXTRACUTANEOUS MANIFESTATIONS — Index genes involved in the pathogenesis of epidermolysis bullosa (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 [ 78]. Complications may also involve other organs and systems, such as the heart and musculoskeletal system [ 105]. EB should thus be considered a multisystem disease associated with significant morbidity and mortality. The extracutaneous manifestations and complications of EB are summarized in the table ( table 3). Nail and hair — Nail abnormalities are a feature of most EB subtypes ( table 3), since antigenic expression of basement membrane zone (BMZ) components in the normal matrix, nail bed, proximal nail fold, and hyponychium is similar to that of normal skin [ 128]. 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) [ 129]. Nail
abnormalities may precede skin blistering as in late-onset JEB and pretibial dystrophic epidermolysis bullosa (DEB) or be an isolated finding as in "nails-only" dominant dystrophic epidermolysis bullosa (DDEB) [130]. 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 [ 130-133]. The expression of BMZ components in the anagen hair follicles of the human scalp is similar to that of the interfollicular epidermis [134]. 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 addition, absence of or abnormal BMZ 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 3). Eye — Ocular involvement is frequent in patients with JEB or recessive DEB [ 135,136]. Symptoms range from mild conjunctival irritation to severe cicatrization of eyelids, cornea, or conjunctiva and progressive visual impairment ( table 3). Corneal blisters and erosions are the most common ocular findings and have been reported in approximately 50 percent of patients with generalized severe JEB and 70 percent of patients with severe generalized DEB [ 136]. Oral cavity — The oral manifestations of EB include soft tissue and dental abnormalities ( table 3) [105]. Intraoral blisters and superficial erosions are common in all EB patients, although they are usually minimal in those with 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: ●
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Poor oral hygiene due to painful peri- 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
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Frequent feeding with high-calorie, cariogenic soft diets
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Malnutrition
Gastrointestinal tract — In patients with JEB, recessive DEB, or Kindler syndrome, any portion of the gastrointestinal tract may be injured [ 78]. Gastrointestinal manifestations include esophageal strictures, gastroesophageal reflux, rectal tears, anal fissures and stenosis, and constipation ( table 3). 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 recessive DEB, esophageal strictures develop in early childhood and more than 50 percent of patients report symptoms by the age of 10. Genitourinary tract — Complications of the genitourinary tract are reported in approximately 30 percent of patients with JEB or recessive DEB ( table 3) [137]. 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 [138].
COMPLICATIONS Malnutrition and anemia — In patients with epidermolysis bullosa (EB), several factors contribute to severe nutritional compromise, including: ●
Feeding difficulties due to oropharyngeal involvement, esophageal narrowing, dysphagia, and poor swallowing coordination
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Moderate to severe malabsorption due to recurrent mucosal lesions of the small intestine
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High energy consumption from accelerated skin turnover, wound healing, and natural growth
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Hypercatabolic state from chronic inflammation and infection
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Transcutaneous loss of nutrients
Malnutrition may result in refractory anemia, hypoalbuminemia, failure to thrive, and delayed puberty with secondary hypogonadism [ 139]. 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 [ 140]. 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 [ 105]. Blood transfusion may be necessary. Infection — Skin infection is common in all subtypes of epidermolysis bullosa and may have an exacerbating role in patients with severe generalized subtypes, such as recessive dystrophic EB and junctional EB Herlitz [141]. 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 junctional and recessive dystrophic EB. 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 (SCC) of the skin is a frequent complication and the leading cause of death of several subtypes of EB. The risk is highest for recessive dystrophic epidermolysis bullosa (RDEB) (picture 9A-B) [105]. SCC 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 US National EB Registry (NEBR) on 3280 consecutive patients with EB indicate that in patients with severe generalized RDEB the risk of developing SCC by age 55 is greater than 90 percent [106]. 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 reduced activity of natural killer cells [142]. Cultured cancer-associated fibroblasts from RDEB patients have been shown to 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 [143]. These observations suggest that the matrix composition in RDEB skin may form a permissive environment for tumor development [ 144]. The presence of flagellated bacteria may be an additional promoting factor in the development of SCC in RDEB tissue [145] Basal cell carcinoma (BCC) occurs with increased frequency in patients with generalized severe epidermolysis bullosa simplex (EBS) (Dowling-Meara), with estimated cumulative risks of 8 percent, 25 percent, and 44 percent by ages 40, 50, and 55, respectively [ 106]. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma", section on 'Epidermolysis bullosa' .) Patients with generalized 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 [106]. 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 generalized severe (Dowling-Meara) subtype [146]. Epidermolysis bullosa ne vi — EB nevi are large, eruptive, asymmetrical, often irregularly pigmented and highly dynamic melanocytic lesions that develop in patients with all EB variants [147,148]. EB nevi appear gradually in infancy or adolescence as black to brown stippled maculae (picture 10); sometimes, they display explosive growth over months, with frequent appearance of small satellite lesions (picture 11). 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 12A-B) [149]. Spontaneous disappearance of EB nevi may occur [ 150]. EB nevi typically arise in sites of previous bullae or erosions, often with a darker rim at the confines of the preceding vesiculation ( picture 13), suggesting that repetitive disruption of the basement membrane primes local nevus cell nests or single melanocytes to break senescence and undergo proliferation [148,150,151]. 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 [148,152]. 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 14) [153]. 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 EB simplex [ 154]. 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 [146,154]. SUMMARY
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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. (See 'Introduction' above.) Four major types of EB are recognized, based upon the ultrastructural level of blister formation within the epidermal basal membrane zone (BMZ): simplex, junctional, dystrophic, and Kindler syndrome (figure 1). (See 'Nomenclature and classification of EB' above.) Epidermolysis bullosa simplex (EBS) (table 1) is the most common type of EB and is characterized by localized or generalized trauma-induced skin blistering that heals without scarring. 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 'Pathogenesis' above and 'Clinical presentation' above.) Junctional epidermolysis bullosa (JEB) ( table 2) is characterized by blistering of the skin and mucosae that heal with scarring. Most cases of generalized severe JEB (JEB-Herlitz) are caused by autosomal recessive mutations in the LAMA3, LAMB3, and LAMC2 genes encoding laminin332, resulting in tissue cleavage in the lamina lucida of the BMZ. Generalized severe JEB presents with extensive mucocutaneous blistering at birth and is associated with early lethality (picture 2A-E). Generalized intermediate JEB (JEB-non Herlitz) is caused by mutations predominantly affecting COL17A1 (encoding type XVII collagen) and shows a generally milder course. (See 'Pathogenesis' above and 'Clinical presentation' above.) Dystrophic epidermolysis bullosa (DEB) ( table 4) is characterized by blistering of the skin and mucosae that heal with scarring and milia ( picture 7E). 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 BMZ. In severe recessive DEB, blistering starts at birth. Pseudosyndactyly, mitten deformity, esophageal strictures, oral and ocular involvement, and squamous cell carcinoma are frequent and early complications. (See 'Pathogenesis' above and 'Clinical presentation' above.) Kindler syndrome (KS) is an autosomal recessive EB type characterized by skin blistering, photosensitivity, progressive poikiloderma, and extensive skin atrophy ( table 5). KS 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 BMZ zone. KS presents at birth or in early infancy with trauma-induced skin blistering that predominantly involves the acral sites and heals with atrophic changes. (See 'Pathogenesis' above and 'Clinical presentation' above.) Extracutaneous manifestations common to all severe subtypes of EB include ( table 3): hair and nail abnormalities; intraoral blistering and scarring and dental abnormalities; esophageal strictures; and genitourinary abnormalities. 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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