Epidermolysis bul/osa hereditaria simplex Epidermolysis bulwsa hereditaria simpkx. Case report. N. I. Kihiczak, A. J. Papadopoulos, R. A. Schwartz and C. K. Janniger SUMMARY Blistering is a common childhood phenomenon. There is a group of heterogeneous, genetic mechanobullous diseases termed epidermolysis bullosa (EB) whose hallmark is blistering due to minor trauma or pressure. Some patients with EB may be limited in common extracurricular activities such as playing tennis or hiking, while others may be asymptomatic with occasional blistering. The level of vesiculation within the skin defines three major subtypes of EB: EB simplex, dystrophic EB and junctional EB. We describe a patient and review the simple type of epidermolysis bullosa (EBS), which has an incidence of approximately 10-30 cases per million. The incidence of EBS is most probably higher than the stated figure, due to underreporting of mild cases. The severity of EBS depends upon the type of underlying defect. Introduction Skin blistering is a relatively frequent manifestation in dermatological disorders of childhood. Blister forma- tion may be observed in infectious diseases such as im- petigo or primary varicella, in certain acquired immu- nological conditions such as linear IgA dermatosis or dermatitis herpetiformis Duhring and in hereditary diseases such as incontinentia pigmenti Bloch-Sulz- berger and heredita1y bullous epiclerrriolysis (EBs). EBs are subdivicled into three groups according to their pathogenetic mechanisms. Dystrophic epider- molysis bullosa (DEB) inclucles seriously disabling conclitions characterizecl by subepidermal blister forma- tion. Blisters commonly heal with scarring and milia far- mation. The pathogenesis of DEB has been attributecl to varying clegrees of faulty Type VII collagen, which results in deficient anchoring fibrils of the basement membrane zone. There are four major forms of DEB that make up the majority of cases. Rare variants, which usually procluce severe disease, also exist. The two autosomal dominant DEBs are the Cockayne-Touraine variant and the Pasini variant. The two autosomal rece- ssive forms of DEB are localized recessive DEB (RDEB) and generalizecl RDEB. RDEB is transmitted recessively and inlcucles a variable spectrum of clinical severity. The Hallopeau-Siemens variant, or HS-RDEB, is notable clue to its severely cleforming course. The clisease begins Case report 24 ------------- --------- -------- ---~Acta Dermatoven APA Vol 10, 2001, No 1 Case report Figure 1. An 18-month-old child with epidermolysis bullosa simplex (EBS), autosomal recessive type, with bullae on the distal tarsal aspect of the foot and a healing, open blister on the medial malleolus of the left foot. Figure 2. Child in Figure 1 with bullae and blisters at different stages of healing on the dorsal aspect of the right foot. Epiderrnolysis bul/osa hereditaria sirnplex at birth with generalized blistering, and severe scarring is the rule . Nails and teeth are also affected. These patients must be monitored for the formation of squamous cell carcinomas in areas of chronic erosions, which is a common occurrence in the second or third decade of patients affected with the Hallopeau-Siemens variant. Junctional EB UEB), which appears at birth, is histologically characterized by blister formation within the lamina lucida of the basement membrane zone. JEB is recessively inherited with a wide clinical spectrum. One important variant, termed Herlitz disease, is the most lethal variant of all the hereditary EBs; mortality may be as high as 40% in the first year of life. A gene- ralized blistering is evident at birth, and the development of periorificial involvement is quite characteristic. Nail, tooth and scalp involvement is common. Respiratory, gastrointestinal and urological epithelia are also affected in severe disease. JEB mitis and generalized atrophic benign EB (GABEB) are milder forms of JEB that also appear at birth. Survival past infancy is the rule. Another subtype of EB is characterized by intraepi- dermal blister formation, most commonly appearing in early infancy. This group of disorders is termed epider- molysis bullosa simplex, ar EBS. Many variants of EBS exist; the three most common variants are inherited in an autosomally dominant fashion. Ali subtypes are characterized by vesicle/ bullae formation secondary to friction; minor trauma or sweating combined with an increased body temperature. As a rule, healing of vesi- cles and bullae occurs w ithout scarring. The most co- mmon variant is EBS Weber-Cockayne (EBS-WC), or localized EBS. This is the mildest form of EBS and is limited to the palms and soles; the form may appear in early adolescence. The EBS-Koebner variant, or gene- ralized EBS, appears at birth or in early infancy. The most comrnon clinical presentation is acral involvement; healing occurs without scarring. EBS Dowling-Meara, or herpetiform EBS, appears at birth as a generalized blistering disorder. Oral involvement is common in this variant. We describe the case of a child whom we believe has a rare, recessive variant of EBS. Case report An 18-month-old white girl was evaluated for recu- rrent blister formation, mostly limited to acral areas. Figures 1 and 2. The parents stated that the blisters would develop into mild ulcerations, and then heal without scarring. The patient had no significant past medical history. There was no family history of blistering disorders, psoriasis or atopy. The child's parents were related as second cousins. The child had been given antibacterial ointments for denuded vesicles/bullae. A biopsy specimen was never done. Acta Dermatoven APA Vol 10, 2001, No 1 ----------------------------------- 27 Epidermolysis bul/osa hereditaria simplex On physical examination, a l x3 cm crusted erosion was evident on her right dorsal foot. The erosions had been large blisters, which were deroofed. Smaller erosions and a few small vesicles were noted on the fingers, bilaterally, and on her left elbow. Oral vesicles were not noted. Nails and teeth appeared normal. A relatively recent vesicle was biopsied from the patient's left elbow; the sample was sent far routine histological and electron microscopy (EM) examination. Mupirocin, an antimicrobial ointment, was provided far topical application on erosions. Avoidance of mechanical trauma or excessive heat was also stressed. The child returned three months later, with healing of most of the previous lesions and residual post- inflammatory hyperpigmentation. Some crusted ero- sions were noted on the dorsum of the hands and the fingers, which the parents stated were relatively new blisters that had denuded. Milia formation was also noted in these areas. Similar crusted erosions were also observed in the popliteal fossa, bilaterally, and on the dorsum of both feet. The patient returned on two more occasions. Hea- ling of bullae/ vesicles without scarring was noted on the dorsum of the hands/feet, fingers, left elbow and bilateral popliteal fossa. One new bulla was noted on the patient's left great toe. A biopsy specimen of a vesicle from the left elbow revealed a separation in the basal layer of the epidermis causing a bullous process. Electron microscopy confir- med the diagnosis of epidermolysis bullosa simplex (EBS) revealed by intraepidermal , midbasal cel! separation. Figure 3. Hemidesmosome and other BMZ structures were normal, essentially ruling out DEB and JEB. Ultrastructural examination did not reveal clumping of tonofilaments in basal keratinocytes, a characteristic finding of herpetiform EBS (EBS Dowling-Meara variant). Discussion EBS is a hereditary, noninflammatory cutaneous disorder that typically is transmitted as an autosomal dominant trait, commonly first seen at birth or in early infancy. Epidermolysis bullosa (EBS) has an incidence of approximately 10-30 cases per million (1-3). Severa! subtypes of EBS have been identified. The most co- mmon variants include generalized, or Koebner, EBS (EBS-K), localized, or Weber-Cockayne, EBS (EBS-WC), and herpetiformis, or Dowling-Meara, EBS (EBS-DM) ( 4,5). Each of these variants shares the common feature of autosomal dominant inheritance and mechanically fragile skin. Many more variants exist, with the majority being inherited as autosomal dominant traits. Rarer forms included autosomal recessive variants (6,7). The patient with EBS of any subtype typically has vesicles 28 or bullae secondary to minor trauma, sweating, friction, or increased temperature (Fig. 1, Fig. 2). The expre- ssion of EBS ranges from patients being asymptomatic, to minor acral blistering, to widespread, life-threatening erosions of the skin and mucous membranes with dental and nail deformities. Typically, the vesicles and bullae of EBS heal without scarring. Ultrastructural examination of skin biopsy specimens of a patient with suspected EBS enables differentiation of the different subtypes of EBS (8,9). This examination commonly reveals the separation of the epidermis from Figure 3. Electron microscopy demonstrating an intraepidermal blister with few inflammatory cells in an 18-month-old patient with EBS, autosomal recessive type. (The original specimen was stained with uranylacetate and lead citrate and magnified 5 x 103.) BC - basal celi, B - parts of a basal celi, M - mitochondrion, JJ - remenants of basement membrane Ca se report Acta Dermatoven APA Vol 10, 2001, No 1 Case report the dermis due to the fragility of basal cells with supra- basal clefts. These clefts progress into intraepidermal blisters which are devoid of inflammatory cells (Fig. 3) (10). A distinctive ultrastmctral finding in the Dowling- Meara variant ofEBS is clumping oftonofilaments within basal keratinocytes (11). This fragility is due to genetic defects of keratin 5 (K5) and keratin 14 (K14) , which are intermediate filaments expressed in the cytoskeleton of suprabasal keratinocytes (12,13) . Keratins are the intermediate filament proteins that join to form dimers and polymerize to form filaments, which are a main component of the epidermal cytoskeleton (14). Instead of forming fine threads, the mutated keratins 5 and 14 clump together, thus causing clefts in the keratinocytes; this is the etiology ofblister formation in EBS. Molecular biologists have detected various mutations in keratin 5 and 14 genes in EBS patients. Our patient has no family history of blistering dis- orders, which points away from an autosomal dominant inheritance. The consanguinity evident in the patient's family tree most likely points to a recessively inherited EBS. Less likely is the development of a spontaneous mutation in EBS-implicated genes. Diagnosis Diagnosis of EBS relies on a thorough history and physical examination. These patients typically have a history of spontaneous blister formation on the hands and feet from birth. Older patients develop blisters at sites subject to minor trauma. A biopsy specimen of perilesional skin, taken after slight mechanical provo- cation, may support a provisional diagnosis of EBS if histological evidence of intraepithelial tissue separation is evident. Tissue samples should be sent for further evaluation, including electron microscopy (Fig 3). Cha- racteristic suprabasilar, intraepidermal blistering is seen. Immunodiagnostic techniques, such as immunofluo- rescence microscopy, are also being used in many cen- CES Epidermolysis bul/osa hereditaria simplex ters. In patients with severe forms ofEBS, blood samples from family members should be attained for genetic analysis. Since it has been thought that the nature and location of the mutation may predict the severity ofEBS, such analysis is a means of screening family members for any defect in the genes for K5 and K14 (15). Treatment Treatment for patients affected with EBS is typically supportive and preventive, consisting of avoidance of trauma, wound management, nutritional support and infection control. Antiseptic baths, saline compresses and topical antibiotics are commonly used in order to provide relief and prevent secondaty infections in areas of blistering. Topical corticosteroids are also used; in principle, their mechanism of action slows down reepithelization. Tense blisters can also be evacuated for symptomatic relief. Patient education involves informing the patient of maintaining a cool environment, avoidance of trauma, and wearing loose, leather shoes. Genetic counseling is available for couples affected with EBS. Due to the continued research and localization of mutations in patients with various EBS subtypes, future therapies may eventually include protein replacement and/or gene therapy. Protein replacement encompasses the production of a defective protein by recombinant methods and topical application in a lotion, or cream, form. Gene therapy would deliver cultured keratinocy- tes , or stem cells, directly into patients with a specific gene defect. Murine EBS models hold great promise for future investigation of gene therapy and protein replacement techniques and eventual application to human patients (16-18). Acknowledgment We thank Cesar E. Fernandez and the New Jersey Medica! School Center for Electron Microscopy. l. Horn HM, Priestley GC, Eady RA, Tidman MJ. The prevalence of epidermolysis bullosa in Scotland. Br J Dermatol 136: 560-564, 1997. 2. Inaba Y, Kitamura K, Ogawa H et al. A study on the estimation of prevalence of epidermolysis bullosa in Japan. Nippon Hifuka Gakkai Zasshi 99: 1021-1026, 1989. 3. McKenna KE, Walsh MY, Bingham EA. Epidermolysis bullosa in Northern Ireland. Br] Dermatol 127: 318-321, 1992. 4. Muller FB, Kuster W, Bruckner-Tuderman Letal. Novel KS and K14 mutations in qerman patients with the Weber-Cockayne variant of epidermolysis bullosa simplex. J lnvest Dermatol 111: 900-902, 1998. 5. Combemale P, Kanitakis J. Epidermolysis bullosa simplex with mottled pigmentation. Case report and review of the literature. Dermatology (Basel) 189: 173-178, 1994. 6. Jonkman MF, Heeres K, Pas HH et al. Effects of keratin 14 ablation on the clinical and cellular phenotype in a kindred with recessive epidermolysis bullosa simplex.j lnvest Dermatol 107: 764-769, 1996. Acta Dermatoven APA Vol 10, 2001, No 1 ---------------------------- --- - - -- 29 Epidermolysis bul/osa hereditaria simplex AUTHORS' ADDRESSES 7. Batta K, Rugg EL, Wilson NJ et al. A keratin 14 žknockout' mutation in recessive epidermolysis bullosa simplex resulting in less severe disease. Br] Dermatol 143: 621-627, 2000. 8. Puddu P, Angelo C, Faraggiana Tet al. Epidermolysis bullosa of the Dowling-Meara type: clinical and ultrastructural findings in five patients. Pediatr Dermatol 13: 207-211, 1996. 9. D'Onghia FS, Rosina P, Barba A. Epidermolisi buli osa tli Dowling-Meara. ChronDermatol (Roma) 5: 547-552, 1995. 10. Metze D. Explaining clinical features and histopathologic finding by electron microscopy: epidermolysis bullosa simplex. De1matopathology: Practical and Conceptual 3: 232-233, 1997. 11. Pearson RW. Histopathologic and ultrastrucn1ral findings in certain genodermatoses. ClinDermatol 3: 143-174, 1985. 12. Hu ZL. Smith L, Martins S, et al. Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex - increased severity of disease in a homozygote.J Invest Dermatol 109: 360-364, 1997. 13. Horn HM, Tidman MJ. The clinical spectrum of epidermolysis bullosa simplex. Br J Dermatol 142: 468-472, 2000. 14. Galligan P, Listwan P, Siller GM et al. A novel mutation in the LIZ domain of keratin 5 in the Kobner variant of epidermolysis bullosa simplex.] Invest Dermatol l l l: 524-527, 1998. 15. Shemanko CS, Mellerio JE, Tidman MJ et al. Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis buli osa sin1plex caused by a mutation in the keratin 14 gene (KRTI 4) .] Invest Dermatol 111: 893-895, 1998. 16. Fuchs E. Genetic skin disorders of keratin.] Invest Dermatol 99: 671-674, 1992. 17. Fuchs E, Coulombe P, ChengJ et al. Genetic bases of epidermolysis bullosa simplex and epidermolytic hyperkeratosis.j Invest Dermatol 103: 25S-30S, 1994. 18. Troy TC, Turksen K. In vitro characteristics of early epidermal progenitors isolated from keratin 14 (KI 4)-deficient mice: insights into the role of keratin 17 in mouse keratinocytes.j Celi Physiol 180: 409- 421, 1999. Nadia L Kihiczak MD, Dermatology and Pediatrics, New Jersey Medical School, South OrangeAve 185. Newark 07103-2714, New Jersey Anthony J Papadopoulos MD, same address RobertA. Schwartz MD, MP.H, Professor and Chairman, same address Camila K. Janniger MD, same address Reprint requests to Dr. C. Janniger Case report 30 - ----- -------------------------- Acta Dermatoven APA Vol 10, 2001, No 1