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Inherited epidermolysis bullosa

Legaspi, Kristine N.M.a,b; Murrell, Dedee F.a,b

Journal of the Egyptian Women's Dermatologic Society: January 2014 - Volume 11 - Issue 1 - p 1–13
doi: 10.1097/01.EWX.0000437657.38804.96
Review article
Free

Epidermolysis bullosa (EB) comprises a group of inherited diseases that manifest with skin fragility leading to recurrent blistering. It is caused by mutations in any of the several genes that encode for structural proteins of the basement membrane zone. The abnormalities thereby result in various defects in basement membrane attachment. EB has been classified into four major types based on the ultrastructural location of the defect. Clinical manifestations vary depending on the type and subtype. In severe cases, extracutaneous involvement accompanies blistering. Immunofluorescence microscopy is considered the primary tool for diagnosis because of its increased availability worldwide and relative ease of use compared with electron microscopy. A specimen from a freshly induced blister is needed for proper diagnosis. Advances are being made in research to find a cure for this devastating disease. Until then, the best approach for managing this disease is with a multidisciplinary team, as multiple organs may be involved in some types of EB.

aDepartment of Dermatology, St George Hospital

bUniversity of New South Wales, Sydney, Australia

Correspondence to Dedee F. Murell, MA, BMBCh, FACD, MD, Department of Dermatology, St. George Hospital, Gray St., Sydney, NSW 2217, Australia Tel: +61 2 91132543; fax: +61 2 91132906; e-mail: d.murrell@unsw.edu.au

Received October 15, 2013

Accepted November 16, 2013

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Introduction

Inherited epidermolysis bullosa (EB) comprises a group of genodermatoses characterized by blister formation in response to minimal trauma. Blisters appear in both cutaneous and mucosal surfaces. All cases share the common feature of skin fragility and formation of painful blisters. However, the distribution of involvement, depth of blister formation, extracutaneous involvement, and severity of the blistering process are dependent on the underlying molecular defect and hence vary in the different types and subtypes. The latest report of the Third International Consensus Meeting on Diagnosis and Classification of EB has listed four major EB types: epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB), and Kindler syndrome (Table 1) 2. All types and subtypes of EB are rare 3. EB shows no geographic or racial predilection 4. Data from the study by Kho et al. 5 showed the highest recorded prevalence of EBS in Northern Ireland and Scotland, that of JEB in Sweden, and of DEB in Scotland. Advances in molecular genetics have enabled mutation screening and identification of known genes that encode structural proteins associated with the different EB subtypes 1. More than 1000 mutations on at least 14 structural genes have been documented 1–3. This article reviews the clinical manifestations of the major types of EB, as well as their evaluation, diagnosis, and management.

Table 1

Table 1

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Epidermolysis bullosa simplex

This type of EB is characterized by intraepidermal blistering. The cleavage plane is either in the basal or in the suprabasal layer. Defective genes associated with these diseases are those that encode for the proteins that are important components of keratin filaments and hemidesmosomes. These proteins are keratins 5 and 14, plectin, α6β4 integrin, plakophilin-1, plakoglobin, and desmoplakin. Most cases are inherited in an autosomal dominant manner except for the rarer subtype. EB is further subdivided into suprabasal and basal subtypes. EBS is further subdivided into a number of subtypes (Table 1). Blistering develops at birth or during early infancy. In most cases, there is a generalized distribution. An exception is EBS, which is localized only when acral areas are involved. Scarring and milia formation rarely occur. EBS superficialis is the only subtype in which atrophic scarring can occur. In some variants, patients develop focal keratoderma later in life. Hair and nails are invariably involved. Some subtypes may present with alopecia (lethal acantholytic EBS) and hypotrichosis (plakophilin deficiency). Presence of dystrophic or absent nails is common in EBS superficialis, lethal acantholytic EBS, and plakophilin deficiency. Blood-filled blistering is a common feature of EBS Ogna 1.

The overall prognosis for most EBS patients is good and they have a normal lifespan with adequate wound care. However, the less common, generally recessive, EBS subtypes carry the worst prognosis because of associated extracutaneous involvement and are associated with early death. The highest risk of death related to EB is seen in EBS with pyloric atresia, in EBS with muscular dystrophy, and in lethal acantholytic EBS (Fig. 1) 1.

Figure 1

Figure 1

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Junctional epidermolysis bullosa

The cleavage plane in all forms of JEB is at the level of the lamina lucida. JEB is associated with mutations in either one of the LAMA3, LAMB3, and LAMC2 gene 1, all of which encode for laminin-332; COL17A1, which encodes for type XVII collagen; or ITGA6 or ITGB4, which encode for α6β4 integrin. These mutations result in hemidesmosomal and sub-basal dense plate abnormalities. This group of diseases is inherited in an autosomal recessive manner with variable clinical phenotypes depending on molecular defects. JEB has two major subtypes: JEB Herlitz (JEB-H) and JEB other (JEB-O). Six distinct disease entities further constitute the JEB-O subtype (Table 1). Blistering starts at birth in all subtypes, except in the case of the late-onset type, which manifests during young adulthood or later. All JEBs will present with varying degrees of blistering, with the worst seen in JEB-H and JEB non-Herlitz-type generalized (Fig. 2) 1.

Figure 2

Figure 2

JEB-H is associated with the absence or severe reduction of laminin-332 expression and is often fatal 1. Besides the extensive blistering that heals with scarring and the formation of granulation tissue characteristically seen in periorificial areas, JEB-H is also associated with severe anemia, growth retardation, oral cavity abnormalities, ocular involvement, and laryngeal involvement. Patients with JEB-H also develop erosions in their gastrointestinal tract, genitourinary tract, and respiratory tracts. JEB-H is associated with high mortality within the first 2 years of life, with cumulative risk of death from all causes of 44.7% by 1 year of age, increasing to 61.8% by 15 years of age 6. The most common causes of death in JEB-H are failure to thrive, sepsis, and respiratory failure 6.

In JEB-O, laminin-332 is reduced or collagen XVII is either absent or reduced; hence, the course and prognosis depends on how severely affected the target protein is. Patients with mild phenotype (e.g. JEB non-Herlitz localized) will have limited disease and a normal lifespan, whereas other patients with severe disease (JEB non-Herlitz generalized) have an increased risk of death due to more extensive blistering and extracutaneous involvement. JEB with pyloric atresia is another form of severe disease under this subtype in which patients shortly after birth develop pyloric atresia and/or ureteral and renal abnormalities together with blister formation 1,5.

Laryngo-onychocutaneous syndrome/Shabbir’s syndrome is a new variant associated with mutations in the α-chain of laminin-332. Blisters and erosions at birth form predominantly on the face and neck. Early death with multiple organ involvement is common 1,2.

Milia formation is generally seen in different subtypes but is not a feature of late-onset JEB. Atrophic scarring, although present in most, is not seen in non-Herlitz-type JEB and late-onset JEB. Keratoderma is mostly absent. Presence of dystrophic or absent nails is a common feature in all subtypes. Enamel hypoplasia is a unifying feature in all forms of JEB (Fig. 3) 4.

Figure 3

Figure 3

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Dystrophic epidermolysis bullosa

Blistering in this type is the result of the split in the level of the sublamina densa. The defect in DEB is caused by mutations in the COL7A1 gene that codes for type VII collagen, an important component of anchoring fibrils. DEB can be inherited in an autosomal dominant (DDEB) or autosomal recessive (RDEB) fashion. In DDEB, anchoring fibrils may be normal or decreased in number, whereas in RDEB, anchoring fibrils are absent or rudimentary. As per the 2008 consensus there are currently six DDEB subtypes and seven RDEB subtypes (Table 1) 2. The 2008 consensus has recommended the use of the visually descriptive name of these subtypes rather than the name linked to the physicians who first described them 1.

Regardless of the mode of inheritance, patients present with either generalized or localized blistering manifesting either at birth or during infancy. In localized forms, the hands, feet, and nails are affected. There is one DEB subtype, however, that does not manifest with blistering on the skin but only presents with dystrophic nails; this subtype was termed DDEB nails only. Scarring and milium formation most often constitute the distinguishing feature of this type of EB. Lichen planus-like lesions may be seen in DDEB pretibial and RDEB pretibial. Albopapuloid lesions are variably present in DDEB generalized. Scalp abnormalities tend to present in generalized disease. In DEB pruriginosa, blistering is associated with severe pruritus. Extracutaneous involvement is common in subtypes with generalized involvement. Generalized severe RDEB carries the worst prognosis as it is associated with severe anemia, growth retardation, soft-tissue abnormalities, excessive dental caries, erosions in the gastrointestinal tract, ocular involvement, and pseudosyndactyly (Figs 4–6).

Figure 4

Figure 4

Figure 5

Figure 5

Figure 6

Figure 6

In the past, the most severe RDEB patients died in infancy as a result of sepsis and other complications arising from extensive blistering 7. At present, with improved infection control, wound care, and nutrition, patients can live through puberty into adulthood. Glomerulonephritis, renal amyloidosis, IgA nephropathy, chronic renal failure, cardiomyopathy, delayed puberty, and osteoporosis have also been reported as extracutaneous complications in these patients. After puberty, the most serious complication unique to generalized forms of RDEB is development of squamous cell carcinomas (SCCs) and less frequently malignant melanoma. RDEB-associated carcinomas are distinct from other cutaneous SCCs in that they are extremely aggressive with strong tendencies for invasion and metastases (Fig. 7) 7.

Figure 7

Figure 7

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Kindler syndrome

This disease has recently been proven as a result of a mutation in the gene, KIND1 coding for kindlin-1, which is a component of focal contacts in basal keratinocytes 8,9. Ultrastructurally, there is reduplication of the basement membrane, which is the most consistent feature seen. Because multiple cleavage planes typically seen within affected skin can be intraepidermal, junctional, or sublamina densa, it has been classified as a separate form of EB. It is inherited in an autosomal recessive manner 1. Patients present with generalized blistering at birth. Later during childhood, blistering improves and gives way to progressive poikiloderma predominantly in sun-exposed areas as well as to photosensitivity. These features are not seen in other types of EB, which is another reason why it should be distinguished from other types of EB. Nail changes and webbing of toes and fingers are also sometimes present (Fig. 8) 7. Extracutaneous involvement includes oral inflammation, esophageal or ureteral strictures, ectropion, esophagitis, colitis, and gingival hyperplasia 2,10–12. Mental retardation and bone abnormalities are also observed 1. Although not frequently observed, there is risk for the development of SCC, but no risk for melanoma and basal cell carcinoma, by age 30. Death related to Kindler syndrome is uncommon 1.

Figure 8

Figure 8

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Diagnosis

As the many different subtypes of EB, including the mild and severe variants, present with blistering at birth, with some variants having overlapping features, clinical diagnosis is unreliable, especially in the neonatal period. In conjunction with the clinical findings and family history, the diagnosis of EB type and subtype relies on biopsies of induced blisters analyzed using transmission electron microscopy (TEM) and immunofluorescence microscopy (IFM) 13.

Light microscopy with routine processing is not a reliable form of diagnosis for EB; however, it may rule out other differential diagnoses and may direct immunoflourescence if an autoimmune blistering disease is being considered 1.

Immunofluorescence mapping on a freshly induced blister is now recommended as the primary method of diagnosis 2. In this technique, cryopreserved EB skin specimens harvested from fresh blisters are treated with antibodies conjugated with fluorochromes (i.e. rhodamine or fluorescein). These sections are then examined under fluorescence light microscopy. IFM provides information as to the precise level of tissue separation and the relative expression and distribution of the various protein antigens at the basement membrane zone 14. These data should be ascertained before DNA mutational analyses can be pursued. In the majority of patients with EB, IFM allows for subtype classification and prognosis 4. IFM has been demonstrated to be as reliable diagnostically as TEM 15. Compared with TEM, IFM is relatively inexpensive and simple to perform, and the equipment, including a cryomicrotome and a fluorescence microscope, is much cheaper and easier to install 2. Another advantage of IFM is that tissues can be processed within only a few hours and the results are not affected by transport delays as the transport medium preserves tissue antigenicity for at least several weeks at room temperature. There are some cases, however, when IFM fails to provide the exact subtype diagnosis. This frequently occurs in the less severe DDEB subtype in which collagen VII is only slightly reduced and can have normal results with IFM. The overall success of IFM and EB-relevant monoclonal antibody studies is critically dependent on the experience of those who perform and interpret them, as false-negative staining may result from inadequate binding by secondary antibody, from apparent loss of antigenic staining due to use of outdated antibody preparations, or from batch-related differences in the intensity of antibody binding to tissue 2. Repeat biopsy for IFM and TEM as well as genetic testing may be considered when IFM fails to show a definitive diagnosis. The transport medium used for this test is either normal saline, if it can be delivered for processing within 24 h, or Michel’s medium, which can preserve target antigens for 24 h to 6 weeks until testing (Fig. 9).

Figure 9

Figure 9

In the past, TEM has been considered the gold standard in the diagnosis of EB as it allowed visualization of the skin ultrastructure, particularly the basement membrane zone. This method has been replaced by IFM as the primary method for diagnosis. TEM is impractical for use in routine clinical diagnosis as it requires expensive equipment and specialized expertise for specimen processing and interpretation, and is available in only a few laboratories worldwide. TEM uses beams of electrons focused by magnetic lenses to create a two-dimensional image with a resolution and magnification that is 1000 times greater than that of a light microscope 4. This allows direct visualization and provides morphologic and semiquantitative information of the important structures at the dermal–epidermal junction. TEM can be useful in identifying microsplits and subtle changes in the dermal–epidermal junction in mild EB variants in which IFM findings can be normal. It is the only technique that can identify patients with EBS-Dowling-Meara (EBS-DM) by visualizing the clumped keratin filaments within basal keratinocytes. Nevertheless, TEM continues to be an important tool when IFM fails to establish diagnosis, as well as in EB research. Specimens for TEM need to be fixed in glutaraldehyde for proper preparation (Fig. 10) 2.

Figure 10

Figure 10

Genetic testing is the ultimate means of determining the mode of inheritance and the precise site(s) and type(s) of molecular mutation present in a patient with EB 2. Currently, the cost and lack of widespread availability preclude it from being a first-line diagnostic test for EB 4.

Prenatal and preimplantation diagnosis is now possible for families with EB or for those at risk of having a child with EB. A crucial prerequisite for prenatal or preimplantation mutation analysis is the identification of the candidate gene in the affected family member(s), as well as identification of the exact mutation(s) 4.

More recently, numerous groups have demonstrated the successful prenatal diagnosis of EB using DNA isolated from chorionic villus samples taken at 10–12 weeks, or from amniotic fluid samples taken at 12–15 weeks’ gestation in at-risk pregnancies 16,17. In one report on 144 at-risk pregnancies, including families with EBS, JEB, JEB with pyloric atresia, and DEB, prenatal genetic testing on DNA from chorionic villi or amniotic fluid predicted postnatal EB diagnosis with greater than 98% accuracy 18. Prenatal diagnosis of EB through the assessment of fetal DNA in the maternal circulation is an area of active investigation 19. Although fetal cells have been detected as early as 4 weeks in the maternal circulation, their isolation is very difficult because of their low density. Successful implementation of this technique would allow for prenatal diagnosis of EB from a maternal blood sample at as early as 6–7 weeks 20.

For families at high risk for EB who wish to avoid termination of an established pregnancy, preimplantation genetic diagnosis is a newer option. This method uses in-vitro fertilization and involves testing of DNA extracted from the preimplanted embryo for mutations in the candidate gene 4. The embryo would only be implanted if testing reveals a normal or a carrier genotype. At present, the clinical pregnancy rate after this procedure is 25% per embryo transfer 21. Advances in molecular genetics, which have shortened the time for mutation detection, have improved success rates, and several successful unaffected pregnancies have been reported after preimplantation genetic diagnosis for JEB 22,23, RDEB 24, and EBS 25. Preimplantation genetic testing is a highly specialized procedure that is currently available in relatively few centers worldwide; however, continued technological progress will widen its availability and accessibility 4.

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Management

At present there is no known cure for EB. Until safe and effective corrective treatment is established and made widely available, the management of these patients remains guided by the prevention and treatment of complications that arise from fragility of the skin. As this debilitating disease affects several organ systems, a multidisciplinary team is required for complete care of EB patients. The ideal team would include a dermatologist, an EB nurse specialist, a gastroenterologist/nutrition specialist, a pain management specialist, physical and occupational therapist, geneticist, psychologist, and dentist. Several general principles may guide the management of EB.

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Prevention of skin trauma to avoid new blisters

The basic premise in preventing new lesions is modification of the home and work environment so as to minimize those external factors that might exacerbate the underlying genetic mechanical fragility of the skin 26,27. Overheating can increase skin fragility. Hence, EB patients benefit from being in a maintained cool air-conditioned environment 26,27.

In the neonatal period, prevention of new blisters is attempted by gentle handling of the infant, using loose-fitting clothing, padding bony prominences, and avoiding adhesives or direct rubbing (use patting instead) of the skin. Bland emollients should be applied to keep skin well lubricated. Babies with EB should be lifted by placing one hand beneath the child’s bottom and one hand behind the neck, rather than from under the arms, so as to minimize friction and blister development in this area 4.

In the hospital setting, all individuals involved in caring for a neonate with EB should be aware of the proper way of handling this patient. No tape or adhesives should be applied directly on the skin. Instead, nonstick wound dressings should be placed under pulse oximeter probes, EKG leads, and around intravenous sites. Patients should be gently lifted and not slid. There should be gauze or loose-fitting clothing under blood pressure cuffs or tourniquets. Tubes should be heavily lubricated first before being introduced into mucosal surfaces or before they come in contact with the skin. To prevent accidental injury to the skin, extra padding should be placed in beds and operating room tables. Patients with EB who may require surgery need to undergo special preoperative evaluation, preparation, and intraoperative management that will depend on the EB subtype. When appropriate precautions are taken, surgical procedures can be uneventful in children with EB 4. Perioperative guidelines for children with EB were thoroughly reviewed by Goldschneider et al.28.

Prophylactic wrapping is often used to prevent new blisters as infants grow older. However, during childhood it is impossible to prevent blister formation despite precautions 26,27.

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Meticulous wound care

The goal of wound care in EB is to promote healing and prevent further skin injury 27,29. Pain reduction is also extremely important 30. Intact blisters are painful and can spread; hence, they should be drained with a sterile needle. The blister’s roof should be left intact as it acts as the wound’s own natural dressing 26–31.

Mild soap and water should be used to routinely cleanse EB skin so as to avoid risk of allergic or irritant contact dermatitis from harsher materials. Regular cleansing reduces the skin’s bacterial count, preventing secondary infection within open erosions. There has been a lack of consensus among experts in the approach to bathing in patients with EB 31. Whereas some experts advocate bathing to soak off dressings and cleanse the skin, others use ‘dry’ dressing changes 32. Those that are against baths argue that baths make open wounds susceptible to infections, as wounds become exposed to contaminated and unclean water, which may contribute to the autoinoculation of microbes. There are, however, no convincing data to support this claim. One approach commonly taken that reduces such a risk is the use of very diluted bleach baths before the application of sterile dressings to affected skin sites (Figs 11 and 12) 31.

Figure 11

Figure 11

Figure 12

Figure 12

Dressings are a vital component of wound care in EB, and, although the ideal dressing is yet to be developed, there exist a variety of options that can be tailored to each individual patient and even to individual wounds, based on local availability, cost, relative efficacy, and personal preference 27,29. Nonadherent dressings are often preferred given the fragile nature of EB skin and to reduce the risk of infections. Dressings should be changed daily after gentle skin cleansing (Fig. 13) 4.

Figure 13

Figure 13

Wound contamination and colonization are very common in all subtypes of EB 33. Kingsley 34 considered bioburden in a wound as a continuum, in which contamination and colonization do not require treatment, but critical colonization and frank infection must be treated to allow wound healing. Because of the increased risk for bacterial resistance, topical antibiotic and antimicrobial dressings should be reserved for those wounds that are colonized with bacteria and fail to heal, referred to as ‘critically colonized’ 33. In some cases, topical antibiotics are used on a rotational basis in children with chronic and/or critically colonized wounds 4. Some experts recommend the use of silver-impregnated dressings or silver sulfadiazine cream, as is commonplace in the treatment of generalized second-degree burns, as both are highly antibacterial 31. However, systemic silver deposition (argyria) from prolonged percutaneous absorption has occurred in EB patients using silver sulfadiazine regularly, leading to permanent grayish discoloration of the skin and eyes 35,36. Medical-grade honey has been recently used in the care of EB wounds. Its antimicrobial property is due to its low pH, high osmolality, and ability to produce low hydrogen peroxide levels 37–39.

Systemic antibiotics are required for wounds with frank infection. The choice of antibiotic should be guided by culture. Purulent wounds may be irrigated with a variety of bacteriostatic or bactericidal solutions such as normal saline, dilute potassium permanganate, or 0.25% acetic acid 40. The use of antimicrobial emollient lotions such as benzalkonium chloride or chlorhexidine is also an option in selected cases 33.

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Maintenance of good nutrition to maximize growth and wound healing

Much of this altered growth is a result of impaired absorption of amino acids and other nutrients across damaged intestinal mucosal surfaces and the loss of blood and serum through open wounds on the skin, coupled with increased catabolism (analogous to what is observed in patients with severe cutaneous burns) and decreased oral intake [a reflection of the presence of painful lesions within the oral cavity and esophagus, structural alterations in either primary (as in JEB) or secondary (as in RDEB) teeth or their absence, and discomfort from severe constipation] 31. The risk of malnutrition is more prevalent in the severe forms of EB, most notably in RDEB-severe generalized and JEB-H, although it is also observed in children with EBS-DM, JEB non-Herlitz, and RDEB generalized other 41. These patients have also been shown to have protein and caloric deficiencies, as well as variable deficiency in several vitamins and/or micronutrients, including vitamins B6, B12, C, and D, as well as zinc and selenium 42,43. Anemia is usually multifactorial in these children, reflecting combinations of iron deficiency (through poor gastrointestinal absorption and increased loss of iron through the skin), decreased lifespan of erythrocytes, and other physiologic factors that contribute to the microcytic hypochromic anemia termed ‘anemia of chronic disease’ 10. As these patients age, many also develop osteoporosis and osteopenia. Maximizing nutrition is of vital importance for promoting growth and development, optimizing wound healing, and improving the quality of life 44.

Some children are able to take in sufficient calories and proteins by frequent oral feedings of nutritional supplements high in calories, protein, and micronutrients 45. For those unresponsive to high caloric oral feedings, gastrostomy placement and enteral feeding are the next option. Gastrostomy feedings have been shown to improve both growth and nutrition in EB patients 46. However, chronic nasogastric tube feeding is not part of the armamentarium of therapy in EB patients because of the risk of erosions arising within the nasopharynx or esophagus. Similarly, infusions of highly concentrated nutritional supplements through percutaneous indwelling catheters are not employed because of the risk of recurrent and potentially life-threatening septicemia, usually bacterial, in the setting of widespread nonhealing cutaneous wounds 31.

Growth charts must be closely monitored. A nutritionist or dietitian who is experienced with EB can help optimize the child’s nutritional status.

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Surveillance of extracutaneous complications

The extracutaneous features associated with the different subtypes of EB and their relative frequency were reviewed by Fine et al. 46. The most serious complication in EB, especially in RDEB, is the development of cutaneous derived SCC. Ninety percent are projected to develop at least one SCC and nearly 80% to die from metastatic SCC by 55 years, making it the leading cause of death in EB. Basal cell carcinoma arose almost exclusively in patients with generalized EBS-DM, with a 43.6% cumulative risk of occurrence by age 55. The cumulative risk for melanoma in those with generalized severe RDEB is 2.1% by age 12, although none of those tumors recurred following conventional excision 47. Hence, monitoring for cutaneous malignancies is vital especially in RDEB and generalized JEB. Dedicated skin checks are recommended every 3–6 months at 10 years of age, and at 3-month intervals on and after age 16 31. Serial digital photography can facilitate documentation of changing skin lesions. A body chart (available on the DebRA UK website at: http://www.debra.org.uk/) may also be useful in recording the progressive history of a patient’s SCC 48. Because of the development of erosions in gastrointestinal, respiratory, and genitourinary tracts, EB patients, particularly DEB, have the tendency to develop strictures that could be life threatening if undetected. Because of repeated scarring, pseudosyndactyly of the fingers and toes occurs. Pseudosyndactyly is the most debilitating sequelae of RDEB 4. Preventive wrapping of individual fingers with tension in the web space is recommended, beginning in infancy, in an attempt to preserve function for as long as possible. There is also variable ocular, endocrinologic, hematologic, renal, cardiac, and dental complications that need to be monitored. In our EB clinic, generalized RDEB and JEB patients are scheduled to be seen every 3 months by a multispecialty team with full skin examination and photography in an effort to detect SCCs early.

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Ongoing psychosocial support

As this devastating disease can isolate the affected individual and their respective families, ongoing psychosocial support is a vital part of management. Loss of self-esteem and worth, inability to cope, and severe depression have been documented in EB children and adults, especially in those with the more severe types in well-studied cohorts 49. Caring for an EB patient also takes a toll on the well-being of their caregivers, as much time and energy is required. The more severe the EB subtype, the more time, effort, and expense that go into his/her care, putting profound strain on their relationship with their partner, their workplace, their extended families, and even other children in the family who may feel an imbalance in the attention given to them and the affected child 49,50. Quality of life measurements should be incorporated in routine and continuing patient care 31. When properly validated, they can reflect disease severity and capture outcomes of therapeutic intervention 51. It is important that the medical team recognize psychosocial issues, as they can influence medical decision making. Good partnership between the patient, family, and medical staff is vital in providing optimal care given the nature of this disease.

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New or experimental therapies

Over the years, research in EB has been directed toward finding a way to correct the molecular defect. Although several approaches are promising, most still need further data to prove their safety and effectiveness in the clinical setting.

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Revertant mosaicism

Revertant mosaicism is a naturally occurring genetic phenomenon that results in the correction or rescue of a mutation 52. Revertant mosaicism is not rare and has been reported in genodermatoses such as EB 53, ichthyosis 54, and, most recently, in Kindler syndrome 55. It is believed to occur focally, leading to isolated patches of normal skin within predominantly affected (mutated) areas 31. The natural occurrence of reverted cells in vivo obviates the need for other methods of mutational correction, such as the use of potentially genotoxic retroviral vectors 54. Thus, the optimization of revertant mosaicism as natural gene therapy using the patient’s own naturally corrected cells has been the focus of translational research in recent times. If successful, the technique has the potential to significantly impact the treatment of many genetic diseases. One report of application of this revertant cell therapy was in a patient with proven revertant mosaic non-Herlitz JEB grafted with revertant autologous keratinocytes 56. Although the said procedure did not produce any functional improvement, as the graft had a low number of revertant cells (<3%), if it can be improved and modified it has the potential as future therapy for genodermatoses, not just in EB.

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Keratinocyte-corrected gene therapy

A number of laboratories have demonstrated that it is possible to functionally correct EB keratinocytes in vitro by insertion, facilitated by the use of retrovirus, of wild-type DNA encoding for the gene mutated in that specific EB subtype 31. In 2006, Mavillo et al.57 harvested keratinocytes from a patient with non-Herlitz JEB having a mutation within the LAMB3 gene, transduced those cells with a retroviral vector expressing LAMB3 cDNA, grew them into sheets, and then transferred them back to a small area of skin on this patient. Subsequent development of clinically and immunohistochemically normal human skin with over several years of follow-up of no further blistering was seen within the grafted site. However, to strengthen the evidence, additional patients have to be treated in this manner. This effort has been limited because of regulatory issues that have arisen in Europe regarding such therapy.

Although it holds some promise, there are technical and regulatory issues with gene therapy through ex-vivo correction of EB keratinocytes that need to be addressed before it becomes a practical and viable approach.

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Other potential molecular therapies

For autosomal dominant EB, its dominant-negative mutations require that the mutated gene be somehow turned off to allow cells to function normally. A variety of techniques have been explored in vitro, and include, but are not limited to, RNA interference, oligonucleotide-mediated gene correction, and antisense technology 58. Although intriguing, these techniques are associated with a number of inherent practical limitations, most notably efficiency 31.

Another novel molecular technique actively being explored in selected EB subtypes involves the use of spliceosome technology 58. However, there continue to be insufficient data on whether this long-term approach will be practical for application in the treatment of disease.

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Protein therapy

Research involving topical application or local or intravenous injection of purified type VII collagen has been performed in animal models of RDEB 59–61. Purified type VII collagen was injected into the mouse tail vein in one mouse model of RDEB, resulting in wild-type protein homing to the blistered sites, leading in wound healing 62. In a more recent conditional knockout mouse model, similar results were achieved, confirming the validity and potential utility of such a therapeutic approach 63. A phase I clinical trial is being organized at the University of Southern California to formally study the safety of local injections of purified collagen VII into chronic RDEB wounds 31.

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Fibroblast-based

Type VII collagen is expressed by both human skin keratinocytes and fibroblasts. Normal skin fibroblasts injected intradermally have been shown to increase the formation of type VII collagen and anchoring fibrils at the dermal–epidermal junction in mice 64. A pilot study has investigated the effect of intradermal injection of autologous and allogeneic fibroblasts in five RDEB patients who had reduced or absent type VII collagen expression. Autologous injections did not lead to any increase in type VII collagen in the skin in any of the five patients, which was expected, as those cells carry mutations in the COL7A1 gene. In contrast, allogeneic unrelated-donor cultured fibroblasts were shown to produce more type VII collagen compared with autologous fibroblasts. Partially functional mutant protein deposited along the dermal–epidermal junction in patients treated with autologous fibroblasts was associated with the presence of rudimentary-appearing anchoring fibrils 65. Recent studies suggest that a subclinical immunological mechanism may induce the synthesis of heparin-binding epidermal growth factor that then upregulates the synthesis and assembly of the patient’s own mutated type VII collagen following allogeneic fibroblast injection 66–68. Intriguingly, a recent randomized phase II trial by our group comparing allogeneic cultured fibroblast injections in transport solution to transport solution injections alone in paired chronic wounds found that placebo injections healed the wounds as quickly as did the active group, but both healed significantly faster than did uninjected chronic wounds 69.

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Stem cell therapy

Bone marrow stem cell therapy/transplantation

Recent studies have suggested that stem cells can be a source of cell types that contributes to the regeneration of disrupted skin in genetic skin diseases such as EB 70. Bone marrow-derived stem cells, in particular, may be induced to develop into skin cells, given the right conditions 71. The first clinical trial of allogeneic bone marrow transplantation involved seven children with RDEB 72. Improvement in wound healing and increased type VII collagen production were reported, with effects sustainable over 1 year of published follow-up after transplantation. However, two of the seven children died from complications arising from the traditional myeloablative procedures used before transplantation. Although such transplantation techniques may in the future play a significant clinical role in the treatment of RDEB, further modifications will be needed in order to improve the safety and efficacy of the procedure, before it will likely become routinely recommended by most EB experts. Strategies to lower morbidity and mortality through the use of a reduced-intensity conditioning regimen have been initiated by some groups 73. However, it is believed that even this may not completely avoid mismatch between graft and host, thus still allowing the development of graft-versus-host disease 59.

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Induced pluripotent stem cell therapy

Induced pluripotent stem cells (iPSCs) are patient-specific stem cells that have the capacity to differentiate into both hematopoietic and nonhematopoietic lineages 74. Salas-Alanis et al. 75 has suggested that the use of iPSCs combined with revertant mosaic cells could produce spontaneously corrected patient-specific autologous cells, which could then be used both as circulating cells and as skin grafts. This procedure offers the advantage of avoiding problems with the use of allogeneic products that are subject to immune reactivity from the host, the need for viral vectors, as well as induction of immunosuppression to prepare the host for the grafts. iPSC technology is in the preclinical trial stage 68,76.

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Mesenchymal stem cell therapy

Two RDEB patients in Chile have been treated with intralesional injections of mesenchymal stem cells, with reported improved wound healing within the treated sites 77.

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PTC read-through drugs

A novel class of drugs exists that can trick the body into ignoring certain stop codons that otherwise lead to premature cessation of gene translation (PTCs) and the generation of unstable foreshortened gene protein products 31. These drugs are already in clinical trials for Duchenne muscular dystrophy and cystic fibrosis 78,79. This class of drugs has great therapeutic potential for severe recessive forms of EB in which a high proportion of mutations are PTC mutations. The PTC 124 compound was reported to revert up to 100% of type VII collagen production in PTC-affected RDEB keratinocytes in preliminary work conducted by Chen, Woodley, and Bruckner-Tuderman, as presented at the DebRA International research conference EB 2009 in Vienna 59.

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Thymosin B4

Thymosin B4 is a purified protein found to promote enhanced healing in induced wounds in mice and normal volunteers. A multicenter double-blind randomized placebo-controlled phase I/II clinical trial has been recently completed, assessing both the safety and clinical efficacy of the application of this small-molecular-weight protein in the healing of selected wounds in RDEB patients 80. The results are currently being analyzed.

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Flightless antibody cream

Kopecki et al. 81–83 in Adelaide University have found that the signaling molecule called flightless-I (Flii-I) is upregulated in burns and chronic wounds. A study in patients with various forms of EB showed that Flii-I is upregulated in most forms of EB 31. A monoclonal antibody to Flii-I has been created that when topically administered to chronic wounds in a mouse model results in faster wound healing 84. This latter one, which is intriguing, may be eventually applicable to patients with EB, if proven to be clinically safe and effective in human wounds.

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Conclusion

EB is a complex disease best managed with a multidisciplinary team. As EB is associated with varied mutations leading to a variety of clinical phenotypes with different prognoses, proper identification of the specific subtype is ideal for guiding the patient and their caregivers. At present, there is still no cure, but advancement in research is paving the way.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

blistering disease; epidermolysis bullosa; inherited disease

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