|Year : 2017 | Volume
| Issue : 4 | Page : 267-273
Inherited epidermolysis bullosa: A multisystem disease of skin and mucosae fragility
Guadalupe Maldonado-Colin, Carolina Hernández-Zepeda, Carola Durán-McKinster, María Teresa García-Romero
Department of Dermatology, National Institute of Pediatrics, Mexico City, Mexico
|Date of Web Publication||29-Sep-2017|
María Teresa García-Romero
National Institute of Pediatrics, Insurgentes Sur 3700c, Col. Insurgentes Cuicuilco, México DF 04530
Source of Support: None, Conflict of Interest: None
Epidermolysis bullosa (EB) is a blistering disorder that can be autosomic or dominantly inherited and has a wide spectrum of clinical presentations. The most recent classification divides EB into four basic subtypes: (1) EB simplex, (2) junctional EB, (3) dystrophic EB and (4) Kindler syndrome; depending on the level of the epidermal-dermal junction where the formation of blisters is present. With the use of immunohistochemistry and molecular biology, new mutation genes and proteins have been identified and more than thirty subtypes of EB have been described according to text phenotype, each affecting different key proteins for the structural integrity of the skin. The phenotype can be a mild one where blisters occur after minor trauma, but quality of life is preserved or a severe one with multisystemic manifestations affecting skin, mucous membranes, bones, joints, nutritional status, and cancer development leading to early death. We describe the clinical manifestations, diagnostic approach, and multidisciplinary management of EB subtypes.
Keywords: Blisters, epidermolysis bullosa, skin fragility
|How to cite this article:|
Maldonado-Colin G, Hernández-Zepeda C, Durán-McKinster C, García-Romero MT. Inherited epidermolysis bullosa: A multisystem disease of skin and mucosae fragility. Indian J Paediatr Dermatol 2017;18:267-73
|How to cite this URL:|
Maldonado-Colin G, Hernández-Zepeda C, Durán-McKinster C, García-Romero MT. Inherited epidermolysis bullosa: A multisystem disease of skin and mucosae fragility. Indian J Paediatr Dermatol [serial online] 2017 [cited 2019 Oct 20];18:267-73. Available from: http://www.ijpd.in/text.asp?2017/18/4/267/206076
| Introduction|| |
Epidermolysis bullosa (EB) is a genetic skin condition that results in fragility of the skin and mucous membranes with the subsequent formation of blisters after minor trauma or spontaneously. It is caused by specific mutations in one of at least 18 genes responsible for the production of proteins vital to the structural integrity of the skin. The affection and severity of EB is not only limited to the skin, thus, in the most severe clinical subtypes it also affects other organs and systems such as cardiovascular, gastrointestinal, eyes, bones and/or joints; resulting in limb mutilation, malnutrition, carcinomas, and other complications.
The classification, pathogenesis, and manifestations of EB depend on the mutation of specific proteins that play a role in the dermal-epidermal junction. Specific proteins and their location are observed, as well as the EB subtype that occurs when each of these proteins is dysfunctional or absent [Figure 1].
|Figure 1: Representation of the epidermis, dermo-epidermal junction and the proteins that play a role in its integrity. Epidermolysis bullosa simplex, junctional epidermolysis bullosa, dystrophic epidermolysis bullosa and Kindler syndrome|
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| Epidemiology|| |
EB is a rare disease; the incidence is approximately 1 in 50,000 live births, and the prevalence is 1:20,000–1:100,000 in the USA and Europe. Statistically, EB simplex (EBS) represents 92% of the total of EB cases, 5% are dystrophic EB (DEB), 1% are junctional EB (JEB), whereas the remaining 2% are still unclassified. The prevalence of the different forms of EBS has not been systematically studied, but the Dystrophic Epidermolysis Bullosa Research Alliance reports the prevalence of three variants: Weber-Cockayne in probably 10–20 per million, Köebner 2 per million and Dowling-Meara (DM) 5–10 per million.
The incidence of new cases for JEB is around 20 per million births, and there is scarce data to indicate the prevalence of DEB: in Norway, the prevalence of dominant DEB (DDEB) is calculated at 1.4 per million whereas in England is estimated in 3 per million.
| Classification and Clinical Manifestations of Subtypes of Epidermolysis Bullosa|| |
In 2008, during the Third International Consensus Meeting on Diagnosis and Classification of EB, a new classification was proposed with more than thirty subtypes. The subtypes are categorized according to the phenotypic characteristics, on the transmission mode which is identifiable by the specific gene involved and determined by means of immunohistochemical techniques and mutation analysis. Based on the place of formation of blisters, there are four major types: intraepidermal (EBS), in the dermal-epidermal junction (JEB), below the basement membrane zone (DEB), and with a mixed pattern (Kindler syndrome [KS]) in which the defect can occur at any of the 3 previously described sites [Table 1] and [Figure 1].,,,
|Table 1: Summary of clinical characteristics of the main subtypes of epidermolysis bullosa|
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Epidermolysis Bullosa Simplex
The level cleavage is mainly intraepidermal and inheritance is autosomal dominant. The major subtypes are suprabasal EBS and basal EBS, and the targeted proteins are transglutaminase 5, plakophilin 1, desmoplakin, plakoglobin, Keratins 5 and 14, plectin, exophilin 5, and bullous pemphigoid antigen 1 (BPA1). The localized form (also called Weber-Cockayne) is the most common, and usually presents in early childhood with blistering. Restricted to hands and feet that rarely scar, and EBS-DM (in which blisters are generalized as well but show a distinct “herpetiform” or clustered pattern). EBS-DM presents with generalized herpetiform blistering since birth. The majority of the EBS subtypes have a good prognosis and a normal quality of life. However, other subtypes like the lethal acantholytic EB and the plakophilin deficiency may lead to early death.,
Junctional Epidermolysis Bullosa
This type is associated with skin cleavage al the level of the lamina lucida and is generally autosomal recessively inherited. The major JEB subtypes are generalized JEB or localized JEB and the targeted proteins are laminina-332, collagen XVII, α6 β4 integrin, and α3 integrin subunit. Severe generalized JEB or Herlitz (JEB-H) is associated with absence of laminin-332 expression and is fatal in the 1st years of life. Babies often have large areas of erosion and granulation tissue around their periorificial areas and have involvement of ocular, tracheolaryngeal, gastrointestinal tract, and renal systems. Blisters tend to heal with scarring, and hair, nail, and enamel defects are common [Figure 2]. Babies with JEB-other than Herlitz-usually have a better prognosis, because they have reduced rather than absent expression of laminin-332, or reduced/absent type XVII collagen, or α6 β4 integrin.
|Figure 2: Deep, generalized erosions and granulation tissue secondary to blistering in a patient with junctional epidermolysis bullosa|
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Dystrophic Epidermolysis Bullosa
Patients with this subtype have reduced or even practically absent type VII collagen expression. The major subtypes are categorized by inheritance pattern: DDEB and the more severe, recessive DEB (RDEB).
Patients with DDEB present with blisters that occur on areas of trauma, resulting in scarring, milia formation, and loss of nails. DDEB may occasionally result in esophageal stenosis, but in general, patients have a good quality of life.
Patients with RDEB can have a generalized severe phenotype (Hallopeau–Siemens), caused by the complete loss of type VII expression  and present severe skin blistering, milia formation, dystrophic or absent nails and extracutaneous involvement. It is characterized by a high incidence of caries, malnutrition, growth retardation, and other complications such as esophageal stenosis, pseudosyndactyly, osteoporosis and a high risk of developing aggressive squamous cell carcinomas (SCC) and death related to EB [Figure 3].
|Figure 3: Atrophic scarring, blistering and erosions, and absence of nails with partial loss of digits in a patient with severe recessive dystrophic epidermolysis bullosa|
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The RDEB generalized intermediate phenotype (non-Hallopeau–Siemens), is also caused by an autosomal recessive mutation on COL7A1 which induces a partial loss of collagen VII expression. The onset is at birth usually, with a generalized distribution of blisters, milia and atrophic scarring; patients also have gastrointestinal manifestations like dysphagia and malnutrition, and can develop SCC but with a lower frequency.
KS is autosomic recessively inherited and is due to mutations in the gene FERMT1 (KIND1) that encodes the fermitin family homolog 1 (kindlin-1). The dermal-epidermal defect can occur at the epidermal level, at the lamina lucida or sublamina densa. Patients present high inducibility of blisters beginning on childhood that usually improves in adulthood. They also can present dystrophic or absent nails, acral keratoderma, poikiloderma [Figure 4] and photosensitivity. They can present extracutaneous involvement like increased frequency of caries, colitis, esophagitis and esophageal strictures and an increased risk for SCC after age 30, especially if the defect is below the dermal-epidermal junction.
|Figure 4: Kindler syndrome - Poikilodermic changes are observed as well as scars from previous blisters|
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| Diagnosis|| |
Making the diagnosis of a specific type of EB is challenging. It is based on the clinical presentation and family history. A newborn who presents with generalized erosions or bullae, the diagnosis of EB should be considered once other diseases have been ruled out. A detailed clinical history, and complete physical examination is mandatory; culturing samples from the lesions with Gram and Giemsa stains (bacterial infections), Tzank smears are useful when viral infection is suspected as well as direct exams with potassium hydroxide to rule out mycosis.
Diagnostic testing and classification in EB begins with the identification of a clean blister at the dermal-epidermal junction (or suprabasal in some types of EBS) by a histological exam [Figure 5]. The exact level of cleavage and the structural defect is identified via immunofluorescence antigen mapping (IFM) and/or transmission electron microscopy (EM) on preferably newly induced blisters.
|Figure 5: Characteristic histopathology of most forms of epidermolysis bullosa showing a clean blister at the level of the dermo-epidermal junction with no inflammatory infiltrate|
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The biopsy should be performed from healthy skin and should be rubbed with a soft object like an eraser for 2 min to induce the formation of a new blister. The skin sample should be placed in Michel solution.
Both EM and IFM allow determination of the exact level of skin cleavage in EB [Figure 2]. The primary advantage of EM is that it also permits visualization and semiquantitative assessment of specific structures, which are altered in number and/or appearance in selected EB subtypes.
IFM coupled with the use of specific monoclonal antibodies can provide considerable insight into not only the major type of EB present but also the structural protein that is most likely mutated, as well as the site of separation and/or blister formation. The primary antibodies that can be used for antigen mapping are raised against cytokeratin 5, cytokeratin 14, plectin, integrin α6 and β4, type XVII collagen (180-kD bullous pemphigoid antigen 2 or BPA2), laminin 332, laminin 5 with its 3 chains (α3, β3, and γ2) and type VII collagen.
To evaluate the stained samples it is useful to consider a scale of 1 a 4 according to the intensity of the antigen-antibody reaction, where (+) is doubtful fluorescence, (++) weak fluorescence (+++), moderate fluorescence and (++++) strong fluorescence.
| Management|| |
Currently, we do not have a cure for EB. Treatment is entirely supportive, focused on minimizing skin trauma, preventing infection, pain control, nutritional support and early identification and management of potential complications. In patients with more severe subtypes, treatment of common manifestations such as anemia, esophageal strictures, delayed puberty, osteoporosis, cardiomyopathy, and cutaneous SCCs are additional components of care.
The management of EB is based on several general principles: Prevention of skin damage or trauma; strict wound care with appropriate wound dressing; procure a good nutrition; detection for extracutaneous complications; and psychosocial support.
The skin should be well lubricated with Vaseline or other bland ointments and the infant should be maintained in cool, air conditioned environment as overheating can increase skin fragility.
Blisters are not self-limiting, and will enlarge if left intact. They are therefore, lanced with a sterile needle as soon as they appear. The roof is left on the blister for protection. Open wounds should be dressed with nonadherent materials and added padding is required to protect vulnerable areas.
The assessment of these patients is complicated, particularly because of the multisystemic complications, they can present and a multidisciplinary approach is key for their management.
Recurrent painful erosions and blisters are among the most severe complications arising in the external eye, most commonly in patients with generalized JEB and RDEB. Both may occur in early childhood and if untreated, may lead to scarring and progressive visual impairment.
Patients should be referred for ophthalmologic evaluation and treatment. Similarly, secondary corneal dryness should be treated with sterile ophthalmologic ointments or artificial tears, and ectropion formation should be evaluated for possible oculoplastic surgical revision. Topical corticosteroids are indicated in the ulceration phase.
Involvement of gastrointestinal tract is common in different subtypes of EB that result in severe nutritional compromise 12. The most severe gastrointestinal complication is esophageal stricturing, the presence of which may markedly impair the intake of nutrients. A subtype of JEB is defined during the newborn period by the presence of pyloric atresia (JEB with pyloric atresia).
Blistering of the oral, pharyngeal and esophageal mucosa is common, mostly in DEB, and that is why dysphagia is a common complication. Babies with EB require the softest available teats to ensure an easy feeding without the need for sucking vigorously; in the case of several blistering, a nasogastric tube is indicated. In older patients, it may be necessary to liquidize their diet, assuring a higher concentrate of protein, vitamins, minerals, and high content of fiber to avoid constipation problems. It is recommended to patients to take their food in small portions but more frequently during the day to minimize pain and fullness sensation and maximize intake. If recurrent or constant dysphagia is referred or a severe esophageal stenosis that cannot be dilated is documented, a gastrostomy is indicated.
Children with EB have increased caloric and protein needs due to the increased energy expenditure for wound healing 12. Maximizing nutrition is of vital importance to promote growth and development, optimize wound healing and improve quality of life.
A deficiency of Selenium has been associated with fatal dilated cardiomyopathy in patients with DEB, monitoring with echocardiogram is important to consider.
Since osteoporosis is frequently in these patients, supplemental calcium and Vitamin D is important and if symptomatic (bone pain, fractures), intravenous bisphosphonates are indicated.
Syndactyly of the fingers and toes from repeated scarring is one of the most debilitating sequelae of RDEB. Preventive wrapping of individual fingers with tension beginning in infancy is recommended in an attempt to preserve function for as long as possible.
Recurrent severe vesiculation within the lining of the urethra, the ureterovesical junction, and ureters may lead to hydronephrosis and consequently to chronic renal failure. Follow up of these patients requires urinalysis and taking blood pressure every 6 months. If these tests are abnormal, imaging of the renal tract and/or functional tests of renal function may be indicated.
Patients with EB experience constantly great deal of pain at any age, so is important to provide them with drugs that can minimize and control their pain such as paracetamol, codeine, dihydrocodeine, morphine, and amitriptyline, all having a very important impact in patients with chronic pain.
| Future Research Directions|| |
The prognosis of EB varies between subtypes, depending on the kind of mutation and the type of inheritance (either autosomal dominantly or recessively), and this could determine a normal life expectancy or high index of mortality. The most severe subtypes are RDEB and JEB, and thus, research for therapies is focused toward those. Recent approaches such as allogeneic cellular therapy, gene therapy, and protein therapy show promise and will probably be a more available option in the near future.
The prototype of cell therapy for a genetic disorder like this one is hematopoietic cell transplantation (HCT), which allows systemic and long-term distribution of donor cells in the recipient; however allogeneic cell therapy includes allogeneic fibroblasts, mesenchymal stromal cells and gene-corrected autologous epidermal stem cells.,,, Patients treated with HCT have not only displayed an increase in collagen VII deposition but also showed donor chimerism in the skin following transplant, which is very promising. However, for an allogeneic HCT to be done an antigen-matched donor is needed, and the process itself can be lethal; so an autologous transplant would be the preferred option. Multiple approaches to correct the COL7A1 gene have been used, including retroviral vectors or lentiviral vectors, and transduced cells were capable of producing functional collagen VII. Recently, genome-editing strategies using zinc-finger nucleases and transcription activator-like effector nucleases have demonstrated the ability to target specific sites in the genome and correct mutations without the potential risks associated with retroviral vectors.
Another option for future therapies in RDEB would be the use of cells derived from personalized induced pluripotent stem cells (iPS), which can differentiate into almost all cell types in the body. Skin cells isolated from patients with RDEB and JEB can be reprogrammed into iPS cells which then produce the absent protein.,
Protein therapy has demonstrated promising results as well, using collagen VII protein therapy in preclinical models of RDEB. Intradermal injections of collagen VII resulted in the stable incorporation into the basement membrane zone and correction of the phenotype in murine models., Collagen VII is soluble, which underlies the safety and efficacy of systemic infusions; but topical collagen VII has also improved the phenotype and accelerated wound healing in mice.,
The future involves better understanding the mechanisms underlying patient-specific therapies to achieve the best possible outcomes for patients with RDEB and JEB, and new approaches will be considered successful if they result in long-term improvement of daily lives but also reduction of the associated complications and risks of the disease.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]