Chapter 6 Mechanobullous disorders
1. What are the mechanobullous disorders?
This is a group of disorders, either inherited or acquired, that result in small blisters (vesicle) or large blisters (bulla) that form after trauma to the skin. The most common acquired lesion would be a typical blister that one can develop on a foot after the skin rubs on a shoe or boot. The most common inherited mechanobullous disorders are those that fall into the category of epidermolysis bullosa (EB). Vesicles and bullae develop in these individuals with very minor trauma. The remaining portion of this chapter will deal with EB and its complications.
2. Do all of the blisters that form in EB develop in the same layer of the skin?
No. Depending on the type of EB there are three basic levels of separation within the skin. The two basic layers of skin are the epidermis and dermis. The junction between these two layers contains important structural proteins and is called the dermal–epidermal junction (DEJ) (Fig. 6-1). Separation due to trauma may occur in any one of these three anatomic sites.
Figure 6-1. Layers of the skin with major sites of splitting in epidermolysis bullosa (EB).
(Courtesy of James E. Fitzpatrick, MD.)
Key Points: Heritable Blistering Disorders
1. Epidermolysis bullosa is an inherited group of disorders characterized by genetic defects of structural proteins needed for the normal attachment and integrity of the epidermis.
2. There are four major subtypes with different ultrastructural localization of the blister: EB simplex (epidermal cleavage plane), junctional EB (cleavage plane between epidermis and dermis), dystrophic EB (cleavage plane in superficial dermis), and Kindler’s syndrome (with a mixed split of both epidermis and dermis).
3. How is EB classified, and what are the major modes of inheritance?
In the past, there were three major categories of EB, depending on the level of the blister, and numerous subtypes within each category. In 2008, the Third International Consensus Meeting on Diagnosis and Classification of EB was published. In this manuscript, there was an attempt to simplify classification and eliminate misleading terms and acronyms. EB is now divided into four major categories:
4. Describe the clinical findings in EB simplex.
In the common localized variety, the presentation is that of easy blistering noted on the hands and feet. These individuals may go undiagnosed until they are placed in a situation that generates increased pressure to these surfaces, such as marching in the military (Fig. 6-2). The generalized form is also usually present at birth, but, on rare occasions, it may not appear until 6 to 12 months of age in areas of trauma. The affected areas generally heal without scarring. In the simplex forms, generally the skin is the only thing affected; however, in the more severe forms of generalized simplex, they can have oral mucosa involvement and, on rare occasions, have esophageal strictures. The good news is that in some of the severe forms of generalized simplex EB the blistering tends to improve as the child ages. This is true for both the intraoral and cutaneous lesions.
5. Is the cause of EB simplex known?
Yes. In the vast majority of cases simplex EB is due to a mutation in either keratin 5 or 14 (Fig. 6-3). Keratins are structural proteins within keratinocytes that give the keratinocytes their shape and size, similar to the frame in a house. Keratins 5 and 14 are expressed in the basal layer of the epidermis, which is why the split is in the epidermis in EB simplex. There are rare forms of EB simplex that involve other structural proteins within the epidermis, such as plakophilin, desmoplakin, plectin, and integrins. Of interest is the simplex form of EB involving the protein plectin. Plectin is also important in skeletal muscle and individuals affected by the plectin form of EB simplex develop muscular dystrophy, usually after puberty.
6. What are the clinical findings in junctional EB?
At birth, a few blisters may be present over areas of trauma, and it may be impossible to tell this type from EB simplex or the dystrophic type. However, infants may have oral erosions that are not found in EB simplex. Junctional EB includes localized variants that are not as involved and a severe generalized form (lethal) that typically results in death prior to the age of two (Fig. 6-4). As with EB simplex, blisters and erosions over areas of trauma are common. In contrast to those with EB simplex, children with the lethal form of JEB have prominent central facial erosions with hypergranulation tissue that is difficult to treat. They also have dental defects, nail dystrophy, and tracheal and bronchiolar involvement producing respiratory distress, which is often the cause of death. The other common cause of death in infants with the lethal JEB is sepsis.
7. Is the cause of junctional EB known?
Yes. The most common cause of JEB is a defect in a protein at the DEJ called laminin 5. Laminin 5 is very important in keeping the epidermis attached to the dermis; therefore the split in JEB is at the lamina lucida within the DEJ. Many of the mutations in the laminin 5 gene that result in the lethal form of JEB cause a stop codon, which results in early termination of transcription; so, very little laminin 5 is made. In the milder forms of JEB, having a laminin 5 mutation, the result is just an abnormal or truncated protein that still maintains some function. There are other rarer forms of JEB that can result from mutations to the genes that encode for either bullous pemphigoid antigen-2 (also referred to as type XVII collagen) or α6β4 integrin. Both proteins are found in the anchoring filaments at the DEJ. Of note, the form of JEB involving α6β4 integrin results in pyloric atresia in addition to blistering.
8. What are the clinical findings in dystrophic EB?
In the recessive form of this condition, hemorrhagic blisters are typically present at birth. The blistered areas heal with scarring that can lead to the loss of functional digits in the hands (Fig. 6-5). Oral and esophageal involvement causes feeding problems with resultant esophageal stricture. The teeth are malformed, and multifactorial anemia is common. The dominant form of the disease is less severe and tends to be more localized. Atrophic scarring is still the rule over affected areas. A unique dominant dystrophic form exists (transient bullous dermolysis in the newborn) that is only transient. The blistering tendency decreases with age.
Figure 6-5. Recessive dystrophic epidermolysis bullosa. Severe scarring resulting in loss of functional digits.
Das BB, Sahoo S: Dystrophic epidermolysis bullosa, J Perinatol 24:41–47, 2004.
9. Is the cause of dystrophic EB known?
The primary defect in dystrophic EB is an absent or structurally altered protein found in the dermis. This protein is type VII collagen, which makes up the anchoring fibrils that connect the basement membrane with the dermal collagen. Recently, mutations in the type VII collagen gene (COL7A1) located on the short arm of chromosome 3 have been found in families with both the autosomal dominant and autosomal recessive form of dystrophic EB.
10. What is Kindler’s syndrome?
Kindler’s syndrome was added as a subtype of EB, in 2008, with the release of the Third International Consensus Meeting on EB. Prior to this, it was considered a separate mechanobullous disease. Kindler’s syndrome is an autosomal recessive form of EB that is characterized by poikiloderma, blistering in areas of trauma, mucosal inflammation, and photosensitivity. Like some forms of EB simplex, the blistering in Kindler’s syndrome tends to improve with age. The cause of Kindler’s syndrome is a loss of function mutation in the FERMT1 gene. This mutation causes an alteration in the actin cytoskeleton-extracellular matrix and results in a variable plane of blister formation at or close to the DEJ. Because of the severe mucosal inflammation, patients with Kindler’s syndrome have significant dental issues as well as anal stenosis and phimosis.
Lai-Cheong JE, McGrath JA: Kindler syndrome, Dermatol Clin 28(1):119–124, 2010.
11. Can a definitive diagnosis of the various EB types be made on clinical presentation?
No. In newborns and infants, it is virtually impossible to tell these disorders apart. Several techniques can aid in establishing the correct diagnosis. One such technique is immunomapping, which involves the use of antibodies directed against known proteins located at specific sites in the skin. The patient’s skin is subjected to minor trauma followed by a biopsy. The specimen is then “mapped” with the locating antibodies (Fig. 6-6). This technique locates the actual level of the blister formation in the skin specimen and determines the major category of mechanobullous disorder (i.e., epidermal, junctional, or dystrophic). The diagnosis can be further refined by using monoclonal antibodies that are specific for the missing or altered proteins. At many institutions, where electron microscopy (EM) is available, the tissue is also examined under EM, which can add additional information in making the diagnosis of EB (Fig. 6-7).
12. Are there any treatments for the mechanobullous disorders?
There are no specific treatments for this group of disorders. The current standard of care for these infants is strict wound care and infection control. Nonadherent dressings and padding are used to help blister heal and decrease trauma to the skin. Bathing can be quite painful for these children, especially for those that have the more severe forms of EB. Adding one pound of pool salt to a full tub of water has been found to help alleviate the pain with bathing.
Figure 6-7. Electron microscopic study of an induced blister in EB simplex demonstrating a split (arrow) in the cytoplasm of the basilar keratinocyte.
(Courtesy of James E. Fitzpatrick, MD.)
When dealing with a newborn with suspected EB it is best to contact one of the national organizations that deals with EB, such as the Dystrophic EB Research Association (www.DebRA.org), which can provide both clinical as well as family support. In addition, one can contact one of the five large multidisciplinary EB clinics in North America (Stanford University, Stanford, CA; Children’s Hospital, Aurora, CO; Cincinatti Children’s Hospital, OH; Hospital for Sick Children, Toronto, Canada; and Columbia University, New York).
13. Are prenatal diagnostic techniques useful for this group of disorders?
Fetoscopy with fetal skin biopsy has been the primary method of prenatal diagnosis for EB and other inherited skin diseases. More recently, it has been found that fetal DNA can be obtained as early as 10 weeks estimated gestational age (EGA) from chorionic villi or 12 weeks EGA from amniotic fluid.
Fassihi H, Ashton GH, Denyer J, et al: Prenatal diagnosis of Herlitz junctional epidermolysis bullosa in nonidentical twins, Clin Exp Dermatol 30:180–182, 2005.
