Dermatology

Epidermolysis Bullosa Simplex (localized EBS; Weber-Cockayne; Dowling-Meara (EBS herpetiformis)

Epidermolysis bullosa simplex (EBS)

EBS subtype synonyms: localized EBS = EBS, Weber-Cockayne; EBS, Dowling-Meara (EBS herpetiformis)

Are You Confident of the Diagnosis?

Epidermolysis bullosa (EB) simplex, like all types of inherited epidermolysis bullosa, is characterized by the presence of mechanically fragile skin and recurrent blisters, erosions, and crusts. At least 17 subtypes of EBS have now been described, distinguished by differences in clinical phenotype (to include anatomic distribution of lesions, cutaneous morphology, extracutaneous findings, and overall severity), genetic mode of inheritance, ultrastructural level of skin cleavage and/or ultrastructural morphological features, and molecular basis of disease.

  • What to be alert for in the history

Although considerable overlap and exceptions exist, most patients with EBS can be clinically distinguished from junctional and dystrophic EB by the absence of widespread scarring of the skin, milia, marked nail dystrophy, and specific cutaneous and extracutaneous findings (ie, exuberant granulation tissue; pseudosyndactyly; esophageal strictures) that are more characteristic of junctional and dystrophic EB. It should be emphasized that some cutaneous and extracutaneous findings may not develop until at least age 1, and that most EB infants later subclassified as having a more localized disease subtype have generalized skin involvement during the first several months of life, making the use of these findings as surrogate diagnostic markers for subclassification very imprecise.

  • Characteristic findings on physical examination

The prototypic patient with localized EBS has blisters primarily on the palms and/or soles (Figure 1, Figure 2, Figure 3, Figure 4). Similarly, the prototypic findings in Dowling-Meara include grouped ("herpetiform") blisters or vesicles in arcuate, polycyclic, or serpiginous array in generalized distribution, and well as confluent keratodermas on the palms and soles. EBS with mottled pigmentation, as the name implies, is associated with the presence of small brown macules, usually on the trunk. The presence of specific extracutaneous manifestations or complications, for example pyloric atresia or muscular dystrophy, further defines distinct EBS subtypes.

Figure 1.

Epidermolysis bullosa simplex. Superficial blistering along the neck (Courtesy of Bryan Anderson, MD)

Figure 2.

Epidermolysis bullosa simplex. Close-up photo of the child's neck. (COurtesy of Bryan Anderson, MD)

Figure 3.

Epidermolysis bullosa simplex. Hemorrhagic bulla on the foot. (Courtesy of Bryan Anderson, MD)

Figure 4.

Epidermolysis bullosa simplex. Foot involvement. (Courtesy of Bryan Anderson, MD)

EBS is separated into two major subtypes, basal and suprabasal, based on the ultrastructural level in which blisters arise, either spontaneously or following minor mechanical traction to the skin. Nearly all patients have some form of basal EBS, characterized by blister formation within the basal keratinocytes.

Among the three major subtypes of basal EBS -- localized EBS, Dowling-Meara EBS, and generalized non-Dowling-Meara EBS -- only one of these, the Dowling-Meara variant, has a pathognomic ultrastructural feature, the presence of clumped tonofilaments within the basal keratinocyte, although this may be seen in only about two-thirds of specimens examined by electron microscopy. Although most EBS subtypes arise as the result of mutations within the genes encoding for either keratin 5 or keratin 14, it is very difficult to discern abnormal keratin filaments by standard immunohistochemical techniques.

Although there is some overlap among these three major basal EBS subtypes, there is reasonable genotype-phenotype correlation, based on the site within these keratin genes in which mutations arise. Other keratinocyte-associated genes, which when mutated result in specific EBS subtypes, include those encoding for plectin (EBS with muscular dystrophy; EBS with pyloric atresia; EBS, Ogna variant), plakophilin-1 (plakophilin deficiency), and desmoplakin (lethal acantholytic EB).

  • Expected results of diagnostic studies

The two gold standards for the diagnosis of EBS are antigenic immunofluorescence mapping and transmission electron microscopy, either of which allows documentation of intraepidermal blistering. Electron microscopy further permits visualization of clumped tonofilaments in Dowling-Meara EBS. Mutational analysis on blood or buccal mucosal samples will further confirm both the targeted gene and the site and type of mutation present. Given the number of genes that, when mutated, may produce EBS subtypes, mutational analysis is still pursued primarily for research purposes rather than for routine diagnosis.

  • Diagnosis confirmation

A number of different diseases may mimic EBS in infants, but there is little or no differential diagnosis by early childhood or adulthood. In the setting of neonatal blistering, in the absence of a positive family history of epidermolysis bullosa, the major differential diagnosis is neonatalherpes simplex infection. Additional diagnostic considerations in infants with blisters may include congenital porphyria, bullousmastocytosis, bullous impetigo, staphylococcal scalded skin syndrome, bullous congenital ichthyosiform erythroderma, ichthyosis bullosa of Siemens, acrodermatitis enteropathica, and pachyonychia congenita.

Who is at Risk for Developing this Disease?

EBS is an inherited disease. Most subtypes are autosomal dominant in transmission. Incomplete penetration, as well as spontaneous mutations, may be seen in EBS. Based on the experience of the National EB Registry, about two-thirds of all patients with inherited EB in the United States have some form of EBS, and of these, about two-thirds have localized EBS. The prevalence and incidence of localized and all EBS subtypes are 3.94 per million and 3.67 per one million live births, and 6.0 per million and 7.87 per one million live births, respectively.

What is the Cause of the Disease?

As discussed previously, mutations in any of at least 10 genes encoding for structural proteins within the epidermis result in intraepidermal mechanical fragility, blister formation, and an EBS phenotype. These mutations impair the structural integrity of specific keratinocyte structures (tonofilaments; desomosomes; attachment plaques overlying the hemidesmosomes), faciitating shearing of the basal keratinocyte following the application of minor traction to the skin.

Systemic Implications and Complications

Most EB subtypes are associated with little or no extracutaneous manifestations or complications, with the exception of mild intraoral blistering in infancy and early childhood, which may be seen in at least 30% of all EBS patients, regardless of severity of skin disease.

Tracheolaryngeal injury, leading to upper airway obstruction, may occur in rare patients with Dowling-Meara EBS, analogous to what is commonly seen in both major subtypes of junctional EB. Infants and children presenting with persistent hoarseness or early evidence of stridor need immediate evaluation and intervention by a pediatric otolaryngologist, since this complication, if untreated, may lead to sudden airway occlusion and death.

Growth retardation or failure to thrive may also occur in Dowling-Meara EBS, as may potentially life-threatening sepsis in infancy. Aggressive nutritional supplementation via gastrostomy placement may benefit those with the former complication.

One subtype of EBS (EBS with muscular dystrophy) is characterized by variably severe, progressive muscle weakness, beginning either at birth or later in childhood or adulthood. Another rare EBS subtype is associated with pyloric atresia, readily diagnosed radiographically within the first day or two of life. One extremely rare EBS subtype, lethal acantholytic EB, is reportedly invariably fatal.

Treatment Options

There are no specific therapies yet available for any type or subtype of inherited EB. As such, management revolves around prevention of blister formation and measures that may enhance wound healing, as well as surveillance and intervention for any extracutaneous complications that may occur.

As in the case of all other forms of EB, patients with EBS should avoid tight-fitting garments and shoes, and the latter should be sufficiently padded so as to minimize traction induced blistering of the soles. Air-conditioning can be particularly beneficial. Parents should educate their child's school about EB, so that accommodations can be made in the child's classroom and playground activities.

There have been a few case reports suggesting that there may be a causal association between hyperhidrosis and blistering of the palms and soles in patients with localized EBS. Astringents such as aluminum chloride have therefore been used in this setting, although there are no well-controlled published studies that have convincingly confirmed such an observation.

A small subset of infants and small children with Dowling-Meara EBS may develop tracheolaryngeal involvement identical to that seen in junctional EB. As such, any child with unexplained chronic hoarseness or stridor should be referred to a pediatric otolaryngologist for careful evaluation.

Although clinically significant growth retardation is uncommon in EBS, a nutritionist experienced with this disease should be consulted if there is any evidence of this complication.

Optimal Therapeutic Approach for this Disease

As noted above, the primary focus of dermatologic care in patients with EB simplex revolves around the prevention and treatment of wounds. Both the patient's dermatologist and primary care physician need to be constantly attuned to the possibility of an extracutaneous complication and, the patient should be then referred to the appropriate specialist for further evaluation and care.

As discussed elsewhere, priorities in surveillance should be based upon knowledge of the time during which each of the major extra extracutaneous complications may arise. Recommendations regarding the latter may be found in a recently published review article on this subject.

Patient Management

Patients with more generalized subtypes of EBS need long-term follow-up not only by a dermatologist experienced with this disease but also by a pediatrician or internist. A multidisciplinary team approach, including input from other medical specialists, as well as nutritionists, is optimal for the management of these particular patients, whereas patients with localized EBS oftentimes require little or no assistance from anyone, once the patient's parents become experienced in routine day-to-day wound care.

Unusual Clinical Scenarios to Consider in Patient Management

Rare patients with generalized subtypes of EBS may develop other extracutaneous complications, including keratitis and partial hand deformities. These are listed within the most recent consensus report on diagnosis and classification of EB.

Patients with Dowling-Meara EBS are at high risk of developing basal cell carcinomas during mid or late adulthood, but there is no increased risk of either squamous cell carcinoma or malignant melanoma.

What is the Evidence?

Fine, J-D, Bauer, EA, McGuire, J, Alan, Moshell. "Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Findings of the National Epidermolysis Bullosa Registry". Johns Hopkins University Press. 1999.

(Peer-reviewed monograph containing original data on the first 1700 patients sequentially enrolled in the National EB Registry project and the only published source of epidemiologic data on this unique patient cohort.)

Fine, JD. "Inherited epidermolysis bullosa (EB): incidence and prevalence: estimates from the National EB Registry". JAMA Dermatology. 2016.

(Final estimates on the incidence and prevalence of inherited EB in the United States, based on 16 years of data collection on 3271 patients by the National EB Registry.)

Fine, J-D, Johnson, LB, Weiner, M, Stein, A, Cash, S, DeLeoz, J. "Inherited epidermolysis bullosa (EB) and the risk of death from renal disease: Experience of the National EB Registry". Am J Kidney Dis. vol. 44. 2004. pp. 651-660.

(Sixteen years of data on the frequency and cumulative risk of death from renal failure among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Johnson, LB, Weiner, M, Stein, A, Cash, S, DeLeoz, J. "Eye involvement in inherited epidermolysis bullosa (EB) : experience of the National EB Registry". Am J Ophthalmol. vol. 138. 2004. pp. 254-62.

(Sixteen years of data on the frequency and cumulative risk of ocular complications among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Johnson, LB, Weiner, M, Stein, A, Cash, S, DeLeoz, J. "Pseudosyndactyly and musculoskeletal deformities in inherited epidermolysis bullosa (EB): experience of the National EB Registry, 1986-2002". J Hand Surg (British and European Volume). vol. 30B. 2005. pp. 14-22.

(Sixteen years of data on the frequency and cumulative risk of hand and foot complications among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Johnson, LB, Weiner, M, Suchindran, C. "Tracheolaryngeal complications of inherited epidermolysis bullosa: cumulative experience of the National EB Registry". Laryngoscope. vol. 117. 2007. pp. 1652-60.

(Sixteen years of data on the frequency and cumulative risk of tracheolaryngeal complications among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Johnson, LB, Weiner, M, Suchindran, C. "Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National EB Registry". J Ped Gastroenterol Nutr. vol. 46. 2008. pp. 147-58.

(Sixteen years of data on the frequency and cumulative risk of gastrointestinal complications among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Johnson, LB, Weiner, M, Suchindran, C. "Cause-specific risks of childhood death in inherited epidermolysis bullosa". J Pediatr. vol. 152. 2008. pp. 276-80.

(Sixteen years of data on the frequency and cumulative risk of cause-specific deaths among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Hall, M, Weiner, M, Li, K-P, Suchindran, C. "The risk of cardiomyopathy in inherited epidermolysis bullosa". Br J Dermatol. vol. 159. 2008. pp. 677-82.

(Sixteen years of data on the frequency and cumulative risk of cardiomyopathy among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Johnson, LB, Weiner, M, Li, K-P, Suchindran, C. "Inherited epidermolysis bullosa (EB) and the risk of life-threatening skin-derived cancers: experience of the National EB Registry, 1986-2006". J Am Acad Dermatol. vol. 60. 2009. pp. 203-11.

(Twenty years of data on the frequency and cumulative risk of first skin cancer and death from any skin cancer among the National EB Registry cohort, stratified by EB subtype.)

Fine, J-D, Eady, RAJ, Bauer, EA, Bauer, J, Bruckner-Tuderman, L, Heagerty, A. "The classification of inherited epidermolysis: report of the Third International Consensus Meeting on Diagnosis and Classification of EB". J Am Acad Dermatol. vol. 58. 2008. pp. 931-50.

(The most recent classification system for inherited EB, including summaries of clinical, ultrastructural, immunohistochemical, and molecular findings that are typically seen in each major EB subtype.)

Fine, JD, Mellerio, J. "Extracutaneous manifestations and complications of inherited epidermolysis bullosa. Part I. Epithelial associated tissues". J Am Acad Dermatol. vol. 61. 2009. pp. 367-84.

Fine, JD, Mellerio, J.o. "Extracutaneous manifestations and complications of inherited epidermolysis bullosa. Part II. Other organs". J Am Acad Dermatol. vol. 61. 2009. pp. 387-402.

(The above two review articles are focused on a critical review of the literature pertaining to extracutaneous complications arising in specific EB subtypes.)
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