Dystrophic Epidermolysis Bullosa

Synonyms: DEB, Epidermolysis Bullosa Dystrophica

Pfendner EG, Lucky AW.

Publication Details

Summary

Clinical characteristics.

Dystrophic epidermolysis bullosa (DEB) comprises two types based on inheritance pattern:

  • Recessive DEB, including severe generalized (RDEB-sev gen; formerly called Hallopeau-Siemens type [RDEB-HS]) and generalized other (RDEB-O; formerly called non-Hallopeau-Siemens type [RDEB-non-HS])
  • Dominant DEB (DDEB)

In RDEB-sev gen, blisters affecting the whole body may be present in the neonatal period. Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Consequently, severe nutritional deficiency and secondary problems are common. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, a hallmark of this disorder. The lifetime risk of aggressive squamous cell carcinoma is higher than 90%.

In contrast, the blistering in the less severe forms of RDEB-O may be localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without the severe, mutilating scarring seen in RDEB-sev gen.

In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB.

Diagnosis/testing.

The only gene in which mutation is known to cause DEB is COL7A1. Sequencing of exons 73, 74, and 75 of COL7A1 detects pathogenic variants in 75% of families with DDEB; sequencing of all coding exons detects pathogenic variants in about 95% of individuals with either DDEB or RDEB. In the absence of a confirmatory molecular diagnosis, examination of a skin biopsy by transmission electron microscopy (EM) and/or immunofluorescent (IF) antibody/antigen mapping can help to establish the diagnosis.

Management.

Treatment of manifestations: New blisters should be lanced, drained, and in most cases dressed with a non-adherent material, covered with padding for stability and protection, and secured with an elastic wrap for integrity. Infants and children with RDEB-sev gen and failure to thrive require attention to fluid and electrolyte balance and may require nutritional support, including feeding gastrostomy. Anemia is treated with iron supplements and transfusions as needed. Other nutritional supplements may include calcium, vitamin D, selenium, carnitine, and zinc. Occupational therapy may help prevent hand contractures. Surgical release of fingers often needs to be repeated.

Prevention of primary manifestations: Dressings and padding are needed to protect bony prominences from blister-inducing impact; if a fetus is known to be affected with any form of DEB, cesarean delivery may reduce trauma to the skin during delivery.

Prevention of secondary complications: The most common secondary complication is infection; treatment of chronic wound infection with both antibiotics and antiseptics is necessary.

Surveillance: Beginning in the second decade of life, biopsies of abnormal-appearing wounds that do not heal or have exuberant scar tissue are indicated for evidence of squamous cell carcinoma. Screening for deficiencies of iron, zinc, vitamin D, selenium, and carnitine should start after the first year of life. Routine echocardiograms are recommended to identify dilated cardiomyopathy and bone mineral density studies to identify osteoporosis.

Agents/circumstances to avoid: Activities/bandages that traumatize the skin; all adhesives.

Evaluation of relatives at risk: Evaluating an at-risk newborn for evidence of blistering is appropriate so that trauma to the skin can be avoided as much as possible.

Pregnancy management: Cesarean section is often recommended to avoid vaginal delivery in a fetus at risk.

Genetic counseling.

Dystrophic epidermolysis bullosa is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) manner. Molecular characterization of pathogenic variants is the only accurate method to determine mode of inheritance and recurrence risk; phenotype severity and EM/IF findings alone are not sufficient.

  • DDEB. About 70% of individuals diagnosed with DDEB are reported to have an affected parent. If a parent of a proband with DDEB is affected, the risk to the sibs is 50%. Each child of an individual with DDEB has a 50% chance of inheriting the pathogenic variant.
  • RDEB. Each sib of an affected individual whose parents are both carriers has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

GeneReview Scope

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Table

Recessive dystrophic epidermolysis bullosa (RDEB) Dominant dystrophic epidermolysis bullosa (DDEB)

Diagnosis

Suggestive Findings

The diagnosis of dystrophic epidermolysis bullosa (DEB) is suspected in individuals with the following clinical findings:

  • Fragility of the skin, manifest by blistering with little or no trauma, which heal with milia and scarring.
  • Blistering that:
    • May be present in the neonatal period
    • Can affect the whole body (most severe forms) or primarily the hands, feet, knees, and elbows (milder forms)
    • Can lead to mutilating pseudosyndactyly of the hands and feet (severe forms)
    • Can lead to oral and/or laryngeal scarring and webbing
    • Can lead to corneal erosions with resulting scarring leading to loss of vision
  • Dystrophic nails, especially toenails, or absent nails
  • Family history that is consistent with either an autosomal recessive or an autosomal dominant inheritance pattern

Note: (1) Dystrophic epidermolysis bullosa (DEB) is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB). Each type is further subdivided into multiple clinical subtypes (see Nomenclature). (2) Absence of a known family history of DEB does not preclude the diagnosis.

Establishing the Diagnosis

Because the clinical features of all types of epidermolysis bullosa overlap significantly, clinical diagnosis alone is unreliable. Molecular genetic testing of COL7A1 is usually required to establish the diagnosis, especially in infants (see Figure 1 and Table 1). If molecular genetic testing is not diagnostic, examination of a skin biopsy may be necessary.

Figure 1.

Figure 1.

Common findings of dystrophic epidermolysis bullosa: a,b: Scarring on knees and hands and dystrophic nails found in dominant DEB in an adult c: Aplasia cutis congenita in a newborn with recessive DEB d: Generalized blistering in a child with recessive (more...)

Note: Molecular genetic testing may also be used to establish the inheritance pattern in a particular family and to guide future reproductive decisions by enabling prenatal diagnosis for the affected fetus and family members (see Genetic Counseling). Some pathogenic variants in COL7A1 have been described in both recessive and dominant inheritance patterns [Almaani et al 2011].

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Single-gene testing. One strategy for the diagnosis of an individual suspected of having DEB is single-gene testing of COL7A1, beginning with sequence analysis.
    Note: For dominant DEB (DDEB):
    • Although sequencing of exons with a known founder variant(s) in individuals of certain ethnic backgrounds has been described in European populations, such an approach has not been fruitful in the US population, in which more than 700 pathogenic variants have been found in any of the 118 exons of COL7A1.
    • Targeted approaches that may be considered in European populations include sequence analysis of exons 73, 74, and 75 of COL7A1 (which detects ~75% of the dominant DEB-causing pathogenic variants) as a first step. De novo and recurrent pathogenic variants, especially p.Gly2043Arg and p.Gly2034Arg in exon 73, have been described.
    • If no pathogenic variant is identified in exons 73-75, sequencing of the remaining coding exons is performed.
    If no pathogenic variant is identified – or if only a single pathogenic variant is identified in an individual in whom recessive DEB is suspected – deletion/duplication analysis of COL7A1 can be considered next.
  • A multi-gene panel that includes COL7A1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of DEB. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For more information on comprehensive genome sequencing click here.
Table 1.

Table 1.

Summary of Molecular Genetic Testing Used in Dystrophic Epidermolysis Bullosa

Skin biopsy. Examination of a skin biopsy by transmission electron microscopy and/or immunofluorescent antibody/antigen mapping is one way to establish the diagnosis of DEB. However, sometimes, especially in milder forms of epidermolysis bullosa, indirect immunofluorescent studies are not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In such cases, electron microscopic examination of the skin biopsy must be performed to examine the basement membrane zone structures — in particular, to determine the number and morphology of anchoring fibrils and the presence and morphology of hemidesmosomes, anchoring filaments, and keratin intermediate filaments.

In DEB the blister forms below the basement membrane, which becomes attached to the blister roof, thus resulting in scarring when the blister heals.

Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of epidermolysis bullosa.

The biopsy should be taken from the leading edge of a fresh (<12 hours old) or a mechanically induced blister and should include some normal adjacent skin; older blisters undergo changes that may obscure the diagnostic morphology. Elliptic or shave excisions are often used. Although a punch biopsy can introduce confusing artifact, careful use of the punch can avoid loss of the epidermis.

Findings on transmission electron microscopy (TEM)

  • All DEB. Splitting is observed below the lamina densa of the basement membrane of the epidermis.
  • Recessive DEB (RDEB), severe generalized type. Anchoring fibrils are markedly reduced or absent.
  • Dominant DEB (DDEB) and RDEB-other
    • Anchoring fibrils may appear reduced in number and show altered morphology.
    • Intracellular retention of collagen VII can be observed in some individuals.
    • Collagen VII may be retained intracellularly within the basal keratinocytes instead of being transported to the basement membrane zone in some individuals who have transient blistering in the newborn period.

Findings on immunofluorescent antibody/antigen mapping

  • Staining of collagen VII using antibodies is diminished or absent. (In mild DEB, staining for collagen VII may appear normal, but cleavage planes in the form of vesicles or microvesicles can be observed below the lamina densa and below the collagen VII staining.)
  • Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) confirms the diagnosis of DEB.

Clinical Characteristics

Clinical Description

Before the molecular basis of dystrophic epidermolysis bullosa (DEB) was understood, types and subtypes were identified based primarily on clinical features, mode of inheritance, and the presence or absence of collagen VII and anchoring fibrils detected on skin biopsy. The current classification system is based on inheritance pattern (autosomal dominant DEB versus autosomal recessive DEB) and is further stratified by collagen VII staining and the specific COL7A1 pathogenic variant that is identified in a given affected individual (see Nomenclature) [Fine et al 2014]. For the purposes of this GeneReview the terms recessive DEB severe generalized (RDEB-sev gen), recessive DEB generalized other (RDEB-O) (which includes several further subtypes), and dominant DEB (DDEB) (which also includes further subtypes) have been retained and are discussed below.

Recessive DEB Severe Generalized (RDEB-sev gen)

In this classic severe form of RDEB, blisters are present at birth or become apparent in the neonatal period. Medical consequences of RDEB-sev gen have been recently reviewed [Fine & Mellerio 2009a, Fine & Mellerio 2009b, Murrell 2010].

Blisters can affect the whole body including the oral mucosa, the esophageal mucosa, and the corneas as early as the newborn period. Secondary infection is common.

Blistering continues throughout life with scarring that may lead to disfigurement. Scarring pseudosyndactyly of the hands and feet, a hallmark of this disorder, fuses the digits into "mitten" hands and feet with severe loss of function.

Oral involvement may lead to fusion of the tongue to the floor of the mouth (ankyloglossia) and progressive diminution of the size of the oral cavity and mouth opening (microstomia) which, along with poor dental hygiene and caries, impairs food intake [Serrano-Martínez et al 2003, De Benedittis et al 2004].

Esophageal erosions and esophageal webs and strictures can cause severe dysphagia with resultant poor nutrition [Castillo et al 2002, Azizkhan et al 2006]. Rarely, affected individuals can have esophageal disease with few or no skin manifestations [Zimmer et al 2002].

Anal erosions can cause severe constipation. Gastroesophageal reflux disease (GERD) is common.

Corneal erosions can lead to scarring and loss of vision [Matsumoto et al 2005].

The lifetime risk of aggressive squamous cell carcinoma (SCC) is greater than 90% with significant metastatic potential [Fine et al 2009]. SCC usually appears in the third decade but can appear as early as the second decade [Ayman et al 2002]. Affected individuals usually succumb to aggressive metastatic SCC.

Many individuals develop large irregular brown patches that histologically comprise collections of nevus cells and are called EB nevi [Lanschuetzer et al 2010]. No instances of melanoma arising in these nevi have been reported to date.

Malnutrition caused by poor intake and an increased nutritional demand for tissue healing can result in growth retardation and failure to thrive in young children and absent or delayed puberty in older children.

Anemia results from poor iron intake and the anemia of chronic disease with bone marrow suppression.

Osteopenia and osteoporosis, often with vitamin D deficiency, result from poor nutrition, lack of exposure to adequate sunlight, and especially inactivity.

Dilated cardiomyopathy has been reported in RDEB and can be fatal in some cases [Lara-Corrales et al 2010].

Urethral erosions, strictures, bladder dysfunction, and a variety of renal diseases can occur [Fine et al 2004].

Severe stress to the patient and family because of the complications of this disorder and the chronic pain endured by the most affected individuals often result in decreased quality of life and psychosocial disorders including anxiety, depression, and drug dependence and abuse in older persons [Frew & Murrell 2010].

Recessive DEB Generalized Other (RDEB-O)

Multiple clinical phenotypes make up the spectrum of RDEB, many of which are not severe. The phenotype may be mild, with mild blistering localized to hands, feet, knees, and elbows and dystrophic nails, or relatively more widespread including flexural areas and trunk, but without the severe, mutilating scarring seen in RDEB-sev gen.

In the less common variants there are distinct features:

  • RDEB inversa. Blistering and skin atrophy occurs on the trunk, neck, thighs, and legs while no changes are observed on the hands, feet, elbows, or knees. Otherwise, the phenotype resembles DEB types with blistering and resulting scarring. Blisters of the hands and feet may be present in infancy.
  • RDEB pretibial and pruriginosa often affect the shins. Pretibial blisters develop into prurigo-like hyperkeratotic lesions. The lesions occur predominantly on the pretibial areas, sparing the knees and other parts of the skin. Other findings include nail dystrophy, albopapuloid skin lesions, and hypertrophic scars without pretibial predominance.
  • RDEB generalized intermediate (RDEB-gen intermediate) exhibits wide-spread blistering with scarring, milia, and nevi. Pseudosyndactyly may occur along with oral lesions and damaged or absent nails. Growth retardation is possible but not as severe as with RDEB sev gen. Squamous cell carcinoma also develops in some affected individuals.
  • RDEB localized exhibits blistering with scarring which may be severe but is localized to the hands and feet. Other sites are not affected. The nails are often absent. Growth retardation and systemic illness are also absent. Squamous cell carcinoma has not been reported in individuals who have this subtype.
  • RDEB centripetalis (RDEB-CE) is apparent at birth and involves the hands, feet, and pretibial areas only. Nails are absent. Growth retardation and systemic illness have not been reported. Squamous cell carcinoma has not been reported in individuals with this subtype.
  • Bullous dermolysis of the newborn often has only transient blistering limited to the newborn period [Fassihi et al 2005].

Dominant DEB (DDEB)

In this milder form of DEB, blistering is often limited to the hands, feet, knees, and elbows. Blistering may be relatively benign but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and loss of nails may occur. In the mildest forms, dystrophic nails may be the only characteristic noted [Dharma et al 2001, Sato-Matsumura et al 2002, Tosti et al 2003]. Blistering in DDEB often improves somewhat with age, possibly as a result of reduced physical activity. The subtypes of DDEB resemble those of RDEB but may present with milder manifestations.

  • DDEB generalized (DDEB-gen) is a milder form of EB where a single pathogenic variant in COL7A1 results in a milder blistering disease affecting most sites of friction in infancy but which often resolves to less severe disease in adulthood. Blisters form with scarring and the nails are often absent. Other systems are generally unaffected and growth retardation and squamous cell carcinoma are rarely reported.
  • DDEB pretibial represents the same phenotype as RDEB pretibial (see above); however, heterozygous pathogenic variants in COL7A1 lead to an autosomal dominant pattern of inheritance.
  • DDEB pruriginosa represents the same phenotype as RDEB pruriginosa; however, heterozygous pathogenic variants in COL7A1 lead to an autosomal dominant pattern of inheritance.
  • DDEB localized nails only affects the nails, which are dystrophic and fragile. No skin findings are identified.

Genotype-Phenotype Correlations

Recessive DEB (RDEB)

Dominant DEB (DDEB). Most DDEB results from dominant-negative amino acid substitutions of glycine in the collagenous triple helical domain of collagen VII, although a few splice junction and other amino acid substitutions have been reported. Phenotypes may show intra- and interfamilial variability with the same pathogenic variant [Murata et al 2000, Vaccaro et al 2000, Mallipeddi et al 2003, Nakamura et al 2004, Wessagowit et al 2005].

Penetrance

Until recently, pathogenic variants in COL7A1 were considered to be 100% penetrant when family members were evaluated for mild features of the disease. However, in several families, an individual with DDEB and a known COL7A1 pathogenic variant had relatives with the same variant that had no signs of the disease. Penetrance therefore appears to be less than 100%, at least in DDEB [Almaani et al 2011; Pfendner, unpublished observation].

Anticipation

Anticipation is not a feature of DEB.

Nomenclature

Recessive DEB, severe generalized (RDEB-sev gen) was originally called Hallopeau-Siemens type (RDEB-HS).

Recessive DEB, generalized intermediate (RDEB gen intermed) and localized (RDEB -loc) were originally called non-Hallopeau-Siemens type (RDEB-non-HS).

The nomenclature for DEB has changed four times in the last fifteen years. The most recent classification system, referred to as the “onion skin” terminology, arose from the most recent international consensus meeting, the recommendations of which were published in June 2014 [Fine et al 2014]. This classification system starts by dividing DEB into the inheritance pattern followed by a histologic description of collagen VII staining, and then the specific COL7A1 pathogenic variant that has been described in the affected individual (see Table 2).

For information on the newest nomenclature recommendations that pertain to epidermolysis bullosa simplex and junctional epidermolysis bullosa, see Table 3 (pdf).

Table 2.

Table 2.

Comparison of 2008 Nomenclature with Proposed “Onion Skin” Terminology – Representative Examples

Prevalence

According to the National EB Registry, the incidence of all types of DEB is 6.5 per million live births in the US population.

  • Mild forms of DDEB are estimated at 2.9 per million but may be under-represented.
  • RDEB incidence is 0.4-0.6 per million live births.

The carrier frequency of RDEB in the US population has been calculated as one in 370 [Pfendner et al 2001].

Differential Diagnosis

The four major types of epidermolysis bullosa (EB) syndrome, caused by pathogenic variants in 20 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome. While agreement exists as to diagnostic criteria for some types of epidermolysis bullosa, the validity of rarer subtypes and their diagnostic criteria are disputed. See Murrell [2010] for excellent clinical reviews and Fine et al [2014] (full text; note especially Figure 1) for the revised classification system.

The four major types of EB share fragility of the skin, manifested by blistering and/or erosions with little or no trauma. A positive Nikolsky sign (blistering of uninvolved skin after rubbing) is common to all types of EB. No clinical findings are specific to a given type; thus, establishing the EB type requires further laboratory evaluation. Molecular genetic testing may be used to establish a diagnosis (see Establishing the Diagnosis). Alternatively, a fresh skin biopsy from a newly induced blister that is stained by indirect immunofluorescence for critical basement membrane protein components can be performed. The diagnosis is established by determining the cleavage plane and the presence/absence and distribution of these protein components. Electron microscopy is also diagnostic and often more useful in milder forms of EB.

Clinical examination is useful in determining the extent of blistering, the presence of oral and other mucous membrane lesions, and the presence and extent of scarring.

Limitations of the clinical findings in establishing the type of EB include the following:

  • In young children and neonates, the extent and severity of blistering and scarring may not be established or significant enough to allow identification of EB type.
  • Mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators.
  • Post-inflammatory changes such as those seen in EBS, Dowling-Meara type (EBS-DM) are often mistaken for scarring or mottled pigmentation.
  • Scarring can occur in EB simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface.
  • Congenital absence of the skin can be seen in any of the three major types of EB (i.e., EBS, JEB, DEB) and is not a discriminating diagnostic feature.

Clinical findings that tend to be specific for a single type of EB include the following:

  • Esophageal strictures and nail involvement suggest DEB.
  • Tooth enamel involvement suggests JEB.
  • Scarring and milia of the hands and feet in milder cases suggests DEB rather than EBS.
  • Pseudosyndactyly (mitten deformities) caused by scarring of the hands and feet in older children and adults usually suggests RDEB.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in nonscarring blisters caused by little or no trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 12 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are:

  • EBS, localized (EBS-loc; previously known as Weber-Cockayne type);
  • EBS, Dowling-Meara type (EBS-DM);
  • EBS, other generalized (EBS, gen-nonDM; previously known as Koebner type);
  • EBS-with mottled pigmentation (EBS-MP).

The phenotypes for these subtypes range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant.

In EBS, gen-non DM, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-DM.

In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-DM; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur.

In EBS-DM, onset is usually at birth; severity varies greatly, both within and among families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. EBS-DM appears to improve with warmth in some individuals. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-DM may interfere with feeding. Blistering can be severe enough to result in neonatal or infant death.

The four most common forms of EBS are caused by mutation of either KRT5 or KRT14. Molecular genetic testing of KRT5 and KRT14 detects pathogenic variants in approximately 75% of individuals with biopsy-diagnosed EBS-loc, EBS-DM, and EBS-gen-nonDM, and in 90%-95% of those with EBS-MP.

Rarer subtypes of EBS include:

Junctional EB (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers, and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. Broad classification of JEB includes Herlitz JEB (aka lethal) and non-Herlitz JEB (aka non-lethal). In Herlitz JEB, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In non-Herlitz JEB, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures. The four genes in which pathogenic variants are known to cause JEB are LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%).

Kindler syndrome. The classification of Fine et al [2014] identifies Kindler syndrome as a major type in the EB or bullous disorders. It is characterized by multiple cleavage planes; specifically epidermal, lamina lucida, and sub lamina densa. The presence of multiple cleavage planes is a characteristic that is unique to the mechanobullous disorders. The phenotype can be severe at birth but resolves later in life and includes poikiloderma and photosensitivity. Pathogenic variants in FERMT1 (Kindlin 1) have been demonstrated; inheritance is autosomal recessive [Jobard et al 2003, Siegel et al 2003].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dystrophic epidermolysis bullosa (DEB), evaluation of the sites of blister formation including oral and esophageal blisters and erosions is recommended. Clinical genetics consultation may also be considered.

Treatment of Manifestations

Skin. New blisters should be lanced and drained to prevent further spread from fluid pressure [Pope et al 2012].

Families must decide which of the many correct and effective methods of bandaging works best for them. In most cases, dressings for blisters involve three layers:

  • A primary non-adherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers may include any the following:
    • Ordinary Band-Aids®
    • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® gauze, Adaptic®, Xeroform®)
    • Non-stick products (e.g., Telfa® or N-terface®)
    • Silicone-based products without adhesive (e.g., Mepitel® or Mepilex®)
  • A secondary layer providing stability for the primary layer and adding padding to allow more activity. Rolls of gauze (e.g., Conform®, Kerlix®,) are commonly used.
  • A tertiary layer (usually with some elastic properties) that ensures the integrity of the dressing (e.g., Tubifast®, Coban® or elasticized tube-gauze of varying diameters such as Band Net®)

Various lubricants and antimicrobial agents such as topical antibiotics, silver, or honey are often added to the contact layer to prevent and treat infection and promote healing.

In infants and children with RDEB with more severe involvement, failure to thrive may be a problem, requiring additional nutritional support including a feeding gastrostomy when necessary to assure adequate caloric intake [Haynes et al 1996, Stehr et al 2008]. Esophageal strictures and webs can be dilated repeatedly to improve swallowing [Castillo et al 2002, Kay & Wyllie 2002, Azizkhan et al 2006].

Other. Fluid and electrolyte problems, which can be significant and even life-threatening in the neonatal period and in infants with widespread disease, require careful management.

Anemia is a chronic problem with RDEB and can be treated with oral or intravenous iron infusions and red blood cell transfusions.

Other nutritional deficiencies must also be addressed:

  • Calcium and vitamin D supplementation for osteopenia and osteoporosis
  • Selenium and carnitine replacement to help prevent dilated cardiomyopathy
  • Zinc replacement to enhance wound healing

Good prophylactic dental care is essential to insure the ability to eat and to allow for adequate caloric intake [Harris et al 2001].

Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation.

Occupational therapy may be helpful in preventing progressive hand contractures. Splinting of the hands can be problematic because of skin fragility. Surgical release of fingers by several methods has been described; it often needs to be performed repeatedly [Marín-Bertolín et al 1999, Glicenstein et al 2000].

Psychosocial support including social services and psychological counseling is essential.

Prevention of Primary Manifestations

Age-appropriate play involving activities that cause minimal trauma to the skin is encouraged.

Dressings and padding are needed to protect bony prominences from blister-inducing impact.

If a fetus is known to be affected with any form of DEB, cesarean delivery may reduce trauma to the skin during delivery.

Prevention of Secondary Complications

The most common secondary complication is infection. In addition to wound care, treatment of chronic infection of wounds is a challenge. Many affected individuals become infected with resistant bacteria, most often methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Both antibiotics and antiseptics need to be employed.

Surveillance

Because the lifetime risk of metastatic squamous cell carcinoma is greater than 90% in individuals with RDEB, surveillance in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal is essential. Frequent biopsies of suspicious lesions may be necessary followed by local excision.

Screening for anemia should be routine with complete blood counts and possibly measurement of serum iron concentration in order to provide iron supplementation when necessary.

Screening for zinc deficiency by measurement of serum zinc concentration should be routine in order to provide zinc supplementation when necessary to enhance wound healing.

Screening for predisposition to dilated cardiomyopathy secondary to selenium deficiency and carnitine deficiency is possible by measurement of serum concentrations of selenium and carnitine. Screening for dilated cardiomyopathy by transthoracic echocardiogram is also useful [Sidwell et al 2000]. No guidelines regarding the age at which such screening should begin have been established.

Screening with bone mineral density scanning may pick up early osteopenia and/or osteoporosis. No guidelines have been established regarding the age at which this should begin.

Agents/Circumstances to Avoid

Poorly fitting or coarse-textured clothing and footwear should be avoided as they can cause trauma.

In general, activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) should be avoided; affected individuals who are committed to participation in such activities should be encouraged to devise ways of protecting the skin.

Most persons with DEB cannot use ordinary medical tape or Band-Aids®.

Evaluation of Relatives at Risk

Evaluating an at-risk newborn for evidence of blistering is appropriate so that trauma to the skin can be avoided as much as possible.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Cesarean section is often recommended to avoid vaginal delivery in a fetus at risk.

Therapies Under Investigation

The use of mouse models for EB has enhanced molecular therapies for the treatment of EB by mimicking the EB phenotypes and facilitating testing of a number of therapeutic approaches including the following:

In addition, older approaches involving the use of viral vectors to transfer functional genes to cultured cells for transplant into humans are still being explored [Siprashvili et al 2010, Titeux et al 2010, Melo et al 2014].

  • A new approach using engineered transcription activator-like effector nucleases (TALEN) for precise genome editing results in integration of the desired sequence in the targeted gene and in non-coding regions, reducing the risk of integration mutagenesis.
  • TALENs were able to induce site-specific double-stranded DNA breaks (DSBs) leading to homology-directed repair (HDR) from an exogenous normal COL7A1 donor template. This resulted in mutation correction in COL7A1 in primary fibroblasts that were subsequently reprogrammed into inducible pluripotent stem cells and showed normal protein expression and deposition in an in vivo skin model [Osborn et al 2013].

Human trials for the treatment of EB that have just begun include the following:

  • Use of naturally occurring gene revertant pluropotent cells transplanted into individuals with RDEB [Tolar et al 2014]
  • Local grafting of skin cells in which the genetic pathogenic variants have been corrected for treatment of human JEB [De Luca et al 2009, De Rosa et al 2013]
  • Local grafting of revertant skin in the treatment of JEB [Gostyński et al 2014]
  • Cell transfer-based treatment for DEB [Ortiz-Urda et al 2003; A Lane, Stanford University, personal communication]. One person with JEB has had cell transfer treatment on the legs. A large Stanford University trial for DEB has begun and one one affected individual is reported to be doing well six months after grafting [Siprashvili et al 2014] (see ClinicalTrials.gov).
  • Intradermal injections of large quantities of recombinant collagen 7 protein grown in vitro has shown efficacy in a murine model [Remington et al 2009 Woodley et al 2013]. Human clinical trials are likely to be under way in the near future.
  • Intradermal injections of allogenic fibroblasts have reconstituted collagen 7 protein in the basement membrane. Although it appears that this “new” collagen 7 protein is identical to the mutated protein of the host, the increased quantities of collagen 7 seem to be clinically beneficial [Wong et al 2008]. A recent trial in Australia showed that both fibroblasts and a non-fibroblast-containing vehicle improved healing in RDEB [Venugopal et al 2013].
  • Bone marrow transplantation:
    • Systemic use of allogenic stem cells has been shown in a murine model to have a clinically beneficial effect on blistering [Tolar et al 2009]. Currently trials of bone marrow and/or umbilical-cord stem cell transplants, using either conventional myeloablative or reduced intensity conditioning, are underway in two centers in the USA. See Wagner et al [2010] and search ClinicalTrials.gov for details of the two EB trials at the University of Minnesota and Columbia University [Tolar & Wagner 2013, Liao et al 2014].
    • Replacement of missing collagen 7 protein in RDEB has been accomplished using local injections of bone-marrow-derived mesenchymal stem cells. The clinical effect of healing of chronic wounds was noted in two patients; however, it lasted only four months [Conget et al 2010].

Medical treatment of lesions suspicious for squamous cell carcinoma with agents such as topical imiquimod needs to be studied further.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dystrophic epidermolysis bullosa (DEB) is inherited in an autosomal dominant or autosomal recessive manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Approximately 70% of individuals diagnosed with dominant DEB (DDEB) are reported to have an affected parent and about 30% of probands may have the disorder as the result of a de novo COL7A1 pathogenic variant [Wessagowit et al 2001, Varki et al 2007]; however, these numbers may not reflect the true proportion of de novo pathogenic variants because of bias of ascertainment.
  • Maternal germline mosaicism has been reported [Cserhalmi-Friedman et al 2001].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing for the pathogenic variant found in the proband.

Note: (1) Although 70% of individuals diagnosed with DDEB have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. (2) If the parent is the individual in whom mutation first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low (~1 in 106) but greater than that of the general population because germline mosaicism has been reported [Cserhalmi-Friedman et al 1999, Cserhalmi-Friedman et al 2001].

Offspring of a proband. Each child of an individual with DDEB has a 50% chance of inheriting the COL7A1 pathogenic variant.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of a child with recessive dystrophic epidermolysis bullosa (RDEB) are obligate heterozygotes (i.e., carriers of one COL7A1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an individual with RDEB whose parents are both carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with RDEB are obligate heterozygotes (carriers) for a pathogenic variant in COL7A1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a COL7A1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the COL7A1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating a-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Determining the mode of inheritance in a simplex case (i.e., a single occurrence in a family). Molecular characterization of pathogenic variants is the only accurate method of determining mode of inheritance and recurrence risk. Seven individuals with a combination of a recessive pathogenic variant on one allele and a dominantly inherited amino acid substitution on the other allele have been reported, suggesting caution when predicting recurrence risk based on parental phenotype alone (i.e., without molecular genetic testing) [Varki et al 2007].

Phenotypic severity and EM/IF findings alone are not sufficient to determine mode of inheritance and recurrence risk, as phenotypic variability is extreme in recessive DEB [Hashimoto et al 1999, Vaccaro et al 2000, Mallipeddi et al 2003]. An individual with a mild phenotype and no family history may have either autosomal dominant or autosomal recessive DEB; numerous descriptions of the spectrum of phenotypes in RDEB document that some are very mild and mimic DDEB [Hashimoto et al 1999, Vaccaro et al 2000, Mallipeddi et al 2003, Varki et al 2007].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the COL7A1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for DEB are possible.

Fetoscopy. Electron microscopic evaluation of fetal skin biopsies obtained by fetoscopy is also diagnostic in DEB. Fetoscopy carries a greater risk to pregnancy than CVS or amniocentesis and is performed relatively late (18-20 weeks) in gestation. Prenatal diagnosis for DEB using fetoscopy is not currently available in the US but may be available in Europe.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • DebRA of America, Inc. (Dystrophic Epidermolysis Bullosa Research Association)
    16 East 41st Street
    3rd Floor
    New York NY 10017
    Phone: 866-332-7276 (toll-free); 212-868-1573
    Email: staff@debra.org
  • DebRA UK
    DebRA House
    13 Wellington Business Park
    Crowthorne Berkshire RG45 6LS
    United Kingdom
    Phone: +44 01344 771961
    Fax: +44 01344 762661
    Email: debra@debra.org.uk
  • My46 Trait Profile
  • EBCare Registry
    The EBCare Registry is a resource for individuals and families affected by all forms of epidermolysis bullosa (EB) and qualified researchers working on approved EB research projects.
    Phone: 866-332-7276
    Fax: 888-363-0790
    Email: coordinator@EBCare.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Table A.

Dystrophic Epidermolysis Bullosa: Genes and Databases

Table B.

Table B.

OMIM Entries for Dystrophic Epidermolysis Bullosa (View All in OMIM)

Molecular Genetic Pathogenesis

COL7A1 is expressed in the keratinocytes including the basal keratinocytes of the epidermis where the protein products are assembled into homotrimeric molecules with a helical triple collagen domain. The homotrimers then associate via disulfide bonds into homodimeric structures in the extracellular matrix below the lamina densa and form the anchoring fibrils that anchor the basement membrane to the underlying dermis. The anchoring fibrils are linked to the basement membrane through attachment to laminin 5 and the keratinocyte hemidesmosomes directly above. The intracellular keratin intermediate filament network is linked directly to the hemidesmosomes that anchor the keratinocytes to the basal lamina and to the desmosomes that lead to strong attachment of the keratinocytes to one another. These associations along with the network itself supply stability and resistance to stress that enable the keratinocytes to maintain their structural integrity during minor trauma and remain anchored to the basement membrane and dermis [Bruckner-Tuderman 1999].

Mutation of COL7A1 can lead to reduced resistance to minor trauma and the resulting blistering that is the hallmark of DEB. The type of pathogenic variant, the biochemical properties of the substituted amino acid, and its location in the protein determine the severity of the blistering phenotype (see Genotype-Phenotype Correlations) and inheritance pattern. Pathogenic missense variants predominate in autosomal dominant forms of DEB and may affect the ability of the collagen VII to assemble into a triple helix (its secondary structure) and to form the intracellular network. Null variants predominate in autosomal recessive forms of DEB, and the absence of functional collagen VII and resulting absence of anchoring fibrils lead to the most severe forms of DEB. Intrafamilial phenotypic variability in dominant DEB suggests that other factors can affect the resistance of the cells to friction [Anton-Lamprecht & Gedde-Dahl 2002, Ortiz-Urda et al 2005].

Individuals with recessive DEB, severe generalized (RDEB-sev gen; formerly known as Hallopeau-Siemens type [RDEB-HS]) have a greater-than-90% lifetime risk of aggressive metastasizing squamous cell carcinoma. The reason for the elevated risk has not been clear until recently: Ortiz-Urda et al [2005] examined Ras-driven tumorigenesis in RDEB keratinocytes and found that cells lacking collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal non-collagenous domain NC1) were tumorigenic. Restoring NC1 expression restored tumorigenicity in collagen VII-deficient cells. They conclude that tumor-stroma interactions mediated by collagen VII promote neoplasia, and retention of NC1 sequences in a subset of individuals with RDEB may be a factor in their increased susceptibility to squamous cell carcinoma.

Gene structure. The normal cDNA comprises 9.2 kb with an open reading frame of 8,833 nucleotides encoding 2944 amino acids in 118 exons spanning 32 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Glycine substitution variants in the triple helical domain (especially in exons 73, 74, and 75) predominate (>75%) in DDEB. p.Gly2034Arg and p.Gly2043Arg are the most common DDEB-causing pathogenic variants, making up 50% of the dominant pathogenic variants reported in the largest US cohort [Varki et al 2007]. Glycine substitutions as well as other amino acid substitutions and splice junction variants outside of this region may also be found in dominant DEB; often, however, inheritance pattern cannot be predicted without determination of parental phenotype and corresponding genotype.

More than 700 recessive DEB-causing variants spanning the entire gene have been described for all forms of DEB [Ashton et al 1999, Mellerio et al 1999b, Whittock et al 1999, Gardella et al 2002a, Murata et al 2004, Sawamura et al 2005, Varki et al 2007]. Common pathogenic variants have been described in certain ethnic backgrounds – including c.497dupA [Ashton et al 1999, Gardella et al 2002a], c.2470dupG [Mellerio et al 1999b], c.1732C>T [Whittock et al 1999], c.3840delC [Whittock et al 1999], and c.4919delG [Whittock et al 1999] – and are recurrent in the US population. Each, however, accounts for no more than 1%-2% of the total number of pathogenic variants described. Null variants predominate in RDEB, though glycine substitutions and other amino acid substitutions have been described. Milder forms of RDEB are often caused by splice junction variants or other missense variants.

Table 4.

Table 4.

Selected COL7A1 Pathogenic Variants

Normal gene product. Collagen VII is a monomer of 2944 amino acids that associates into a homotrimer with a triple helical collagenous domain. The homotrimers then associate via disulfide bonds into homodimeric structures that form the anchoring fibrils.

Abnormal gene product. In dominant DEB, collagen VII with a glycine substitution in the collagenous domain may result in abnormal triple helical coiling and a partially nonfunctional protein product. These proteins may exhibit altered morphology on electron microscopy while immunofluorescent staining may be normal or slightly reduced in intensity, making diagnosis by immunofluorescent staining of a skin biopsy difficult unless a cleavage plane is present. In addition, in-frame exon skipping may serve to modulate disease severity in recessive disease and generate a partially functional gene product [McGrath et al 1999, Varki et al 2007].

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Chapter Notes

Author Notes

GeneDx Web site

Cincinnati Children’s Epidermolysis Bullosa Center Web site

Revision History

  • 26 February 2015 (me) Comprehensive update posted live
  • 4 November 2010 (me) Comprehensive update posted live
  • 4 October 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis
  • 21 September 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis
  • 17 October 2006 (cd) Revision: deletion/duplication analysis available on a clinical basis
  • 21 August 2006 (me) Review posted to live Web site
  • 27 December 2005 (ep) Original submission