Skip to main content
SpringerLink
Log in

Junctional Epidermolysis Bullosa, Generalized Intermediate Type

  • Chapter
  • First Online:
Blistering Diseases

  • 1355 Accesses

Abstract

Non-Herlitz junctional epidermolysis bullosa is characterized by localized or generalized blistering of the skin at the level of the lamina lucida, caused by mutations in one of the six genes coding for laminin-332, type XVII collagen, or integrin α[alpha]6β[beta]4. Characteristic is the loss of secondary hair, enamel hypoplasia, and the high incidence of revertant mosaicism. Junctional epidermolysis bullosa with pyloric atresia is caused by severe deficiency of integrin α6β4 and is usually lethal in infancy. Junctional epidermolysis bullosa of late onset is caused by recessive missense mutations in COL17A1 and is not usually associated with the loss of secondary hair, which is so typical in non-Herlitz disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BMZ:

Basement membrane zone

C17:

Type XVII collagen

DIF:

Direct immunofluorescence microscopy

IF:

Immunofluorescence antigen mapping

JEB:

Junctional epidermolysis bullosa

JEB-lo:

Junctional epidermolysis bullosa of late onset

JEB-gi:

Junctional epidermolysis bullosa, generalized intermediate type

JEB-PA:

Junctional epidermolysis bullosa with pyloric atresia

LM-332:

Laminin-332

α6β4:

Integrin α6β4

β4:

Integrin β4

References

  1. Aberdam D, Galliano MF, Vailly J, et al. Herlitz’s junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5). Nat Genet. 1994;6:299–304.

    Article  CAS  PubMed  Google Scholar 

  2. Kivirikko S, McGrath JA, Baudoin C, et al. A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa. Hum Mol Genet. 1995;4:959–62.

    Article  CAS  PubMed  Google Scholar 

  3. Pulkkinen L, Christiano AM, Gerecke D, et al. A homozygous nonsense mutation in the beta 3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa. Genomics. 1994;24:357–60.

    Article  CAS  PubMed  Google Scholar 

  4. Yuen WY, Lemmink HH, van Dijk-Bos KK, et al. Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence, and population carrier frequency in the Netherlands. Br J Dermatol. 2011;165:1314–22.

    Article  CAS  PubMed  Google Scholar 

  5. Jonkman MF, De Jong MC, Heeres K, et al. Generalized atrophic benign epidermolysis bullosa: either 180-kD bullous pemphigoid antigen (BP180) or laminin-5 is deficient. Arch Dermatol. 1996;132:145–50.

    Article  CAS  PubMed  Google Scholar 

  6. Yuen WY, Sinke RJ, Jonkman MF. ITGB4-associated junctional epidermolysis bullosa, type non-Herlitz: report of two new cases carrying two novel ITGB4 mutations. Br J Dermatol. 2013;168:432–4.

    Article  CAS  PubMed  Google Scholar 

  7. Schumann H, Hammami-Hauasli N, Pulkkinen L, et al. Three novel homozygous point mutations and a new polymorphism in the COL17A1 gene: relation to biological and clinical phenotypes of junctional epidermolysis bullosa. Am J Hum Genet. 1997;60:1344–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Mazzanti C, Gobello T, Posteraro P, et al. 180-kDa bullous pemphigoid antigen defective generalized atrophic benign epidermolysis bullosa: report of four cases with an unusually mild phenotype. Br J Dermatol. 1998;138:859–66.

    Article  CAS  PubMed  Google Scholar 

  9. Pulkkinen L, Rouan F, Bruckner-Tuderman L, et al. Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. Am J Hum Genet. 1998;63:1376–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Pasmooij AM, van Zalen S, Nijenhuis AM, et al. A very mild form of non-Herlitz junctional epidermolysis bullosa: BP180 rescue by outsplicing of mutated exon 30 coding for the COL15 domain. Exp Dermatol. 2004;13:125–8.

    Article  CAS  PubMed  Google Scholar 

  11. Pasmooij AM, Pas HH, Jansen GH, et al. Localized and generalized forms of blistering in junctional epidermolysis bullosa due to COL17A1 mutations in the Netherlands. Br J Dermatol. 2007;156:861–70.

    Article  CAS  PubMed  Google Scholar 

  12. Kiritsi D, Kern JS, Schumann H, et al. Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa. J Med Genet. 2011;48:450–7.

    Article  CAS  PubMed  Google Scholar 

  13. Vidal F, Aberdam D, Miquel C, et al. Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia. Nat Genet. 1995;10:229–34.

    Article  CAS  PubMed  Google Scholar 

  14. Pulkkinen L, Kimonis VE, Xu Y, et al. Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Hum Mol Genet. 1997;6:669–74.

    Article  CAS  PubMed  Google Scholar 

  15. Pulkkinen L, Uitto J. Hemidesmosomal variants of epidermolysis bullosa. Mutations in the alpha6beta4 integrin and the 180-kD bullous pemphigoid antigen/type XVII collagen genes. Exp Dermatol. 1998;7:46–64.

    Article  CAS  PubMed  Google Scholar 

  16. Mellerio JE, Pulkkinen L, McMillan JR, et al. Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. Br J Dermatol. 1998;139:862–71.

    Article  CAS  PubMed  Google Scholar 

  17. Nakano A, Pulkkinen L, Murrell D, et al. Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res. 2001;49:618–26.

    Article  CAS  PubMed  Google Scholar 

  18. Dang N, Klingberg S, Rubin AI, et al. Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome: three novel mutations and a review of the literature. Acta Derm Venereol. 2008;88:438–48.

    Article  CAS  PubMed  Google Scholar 

  19. Inoue M, Tamai K, Shimizu H, et al. A homozygous missense mutation in the cytoplasmic tail of beta4 integrin, G931D, that disrupts hemidesmosome assembly and underlies Non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J Invest Dermatol. 2000;114:1061–4.

    Article  CAS  PubMed  Google Scholar 

  20. Jonkman MF, de Jong MC, Heeres K, et al. 180-kD bullous pemphigoid antigen (BP180) is deficient in generalized atrophic benign epidermolysis bullosa. J Clin Invest. 1995;95:1345–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Haber RM, Hanna W. Epidermolysis bullosa progressiva. J Am Acad Dermatol. 1987;16:195–200.

    Article  CAS  PubMed  Google Scholar 

  22. McLean WH, Irvine AD, Hamill KJ, et al. An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Hum Mol Genet. 2003;12:2395–409.

    Article  CAS  PubMed  Google Scholar 

  23. Nakar S, Ingber A, Kremer I, et al. Late-onset localized junctional epidermolysis bullosa and mental retardation: a distinct autosomal recessive syndrome. Am J Med Genet. 1992;43:776–9.

    Article  CAS  PubMed  Google Scholar 

  24. Bircher AJ, Lang-Muritano M, Pfaltz M, Bruckner-Tuderman L. Epidermolysis bullosa junctionalis progressiva in three siblings. Br J Dermatol. 1993;128:429–35.

    Article  CAS  PubMed  Google Scholar 

  25. Stouthamer A, Nieboer C, van der Waal RI, Jonkman MF. Normal expression of the 19-DEJ-1 epitope in two siblings with late-onset junctional epidermolysis bullosa. Br J Dermatol. 2001;144:1054–7.

    Article  CAS  PubMed  Google Scholar 

  26. Yancey KB, Hintner H. Non-Herlitz junctional epidermolysis bullosa. Dermatol Clin. 2010;28:67–77.

    Article  CAS  PubMed  Google Scholar 

  27. Hashimoto I, Schnyder UW, Anton-Lamprecht I. Epidermolysis bullosa hereditaria with junctional blistering in an adult. Dermatologica. 1976;152:72–86.

    Article  CAS  PubMed  Google Scholar 

  28. Hintner H, Wolff K. Generalized atrophic benign epidermolysis bullosa. Arch Dermatol. 1982;118:375–84.

    Article  CAS  PubMed  Google Scholar 

  29. Jonkman MF, Pasmooij AM. Revertant mosaicism—patchwork in the skin. N Engl J Med. 2009;360:1680–2.

    Article  CAS  PubMed  Google Scholar 

  30. Pasmooij AM, Nijenhuis M, Brander R, Jonkman MF. Natural gene therapy may occur in all patients with generalized non-Herlitz junctional epidermolysis bullosa with COL17A1 mutations. J Invest Dermatol. 2012;132:1374–83.

    Article  CAS  PubMed  Google Scholar 

  31. Nakamura H, Sawamura D, Goto M, et al. Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta. Int J Mol Med. 2006;18:333–7.

    CAS  PubMed  Google Scholar 

  32. Almaani N, Liu L, Dopping-Hepenstal PJ, et al. Autosomal dominant junctional epidermolysis bullosa. Br J Dermatol. 2009;160:1094–7.

    Article  CAS  PubMed  Google Scholar 

  33. McGrath JA, Gatalica B, Li K, et al. Compound heterozygosity for a dominant glycine substitution and a recessive internal duplication mutation in the type XVII collagen gene results in junctional epidermolysis bullosa and abnormal dentition. Am J Pathol. 1996;148:1787–96.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Murrell DF, Pasmooij AM, Pas HH, et al. Retrospective diagnosis of fatal BP180-deficient non-Herlitz junctional epidermolysis bullosa suggested by immunofluorescence (IF) antigen-mapping of parental carriers bearing enamel defects. J Invest Dermatol. 2007;127:1772–5.

    CAS  PubMed  Google Scholar 

  35. Yuen WY, Pasmooij AM, Stellingsma C, Jonkman MF. Enamel defects in carriers of a novel LAMA3 mutation underlying epidermolysis bullosa. Acta Derm Venereol. 2012;92:695–6.

    Article  CAS  PubMed  Google Scholar 

  36. Yuen WY, Huizinga J, Jonkman MF. Punch grafting of chronic ulcers in patients with laminin-332 deficient non-Herlitz junctional epidermolysis bullosa. J Am Acad Dermatol. 2013;68:93–7.

    Article  PubMed  Google Scholar 

  37. Di Persio CM, Hodivala-Dilke KM, Jaenisch R, et al. Alpha3beta1 integrin is required for normal development of the epidermal basement membrane. J Cell Biol. 1997;137:729–42.

    Article  Google Scholar 

  38. Goldfinger LE, Stack MS, Jones JC. Processing of laminin-5 and its functional consequences: role of plasmin and tissue-type plasminogen activator. J Cell Biol. 1998;141:255–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Goldfinger LE, Hopkinson SB, de Hart GW, et al. The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately regulate wound healing in cultured epithelial cells and in the skin. J Cell Sci. 1999;112:2615–29.

    CAS  PubMed  Google Scholar 

  40. Gonzales M, Haan K, Baker SE, et al. A cell signal pathway involving laminin-5, alpha3beta1 integrin, and mitogen- activated protein kinase can regulate epithelial cell proliferation. Mol Biol Cell. 1999;10:259–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Nguyen BP, Gil SG, Carter WG. Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling. J Biol Chem. 2000;275:31896–907.

    Article  CAS  PubMed  Google Scholar 

  42. Nguyen BP, Ryan MC, Gil SG, Carter WG. Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion. Curr Opin Cell Biol. 2000;12:554–62.

    Article  CAS  PubMed  Google Scholar 

  43. Watt FM. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 2002;21:3919–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Hintermann E, Quaranta V. Epithelial cell motility on laminin-5: regulation by matrix assembly, proteolysis, integrins and erbB receptors. Matrix Biol. 2004;23:75–85.

    Article  CAS  PubMed  Google Scholar 

  45. Hamill KJ, McLean WH. The alpha-3 polypeptide chain of laminin 5: insight into wound healing responses from the study of genodermatoses. Clin Exp Dermatol. 2005;30:398–404.

    Article  CAS  PubMed  Google Scholar 

  46. Ghosh S, Brown R, Jones JC, et al. Urinary-type plasminogen activator (uPA) expression and uPA receptor localization are regulated by alpha 3beta 1 integrin in oral keratinocytes. J Biol Chem. 2000;275:23869–76.

    Article  CAS  PubMed  Google Scholar 

  47. Yuen WY, Jonkman MF. Risk of squamous cell carcinoma in junctional epidermolysis bullosa, non-Herlitz type: report of 7 cases and a review of the literature. J Am Acad Dermatol. 2011;65:780–9.

    Article  PubMed  Google Scholar 

  48. McGrath JA, Schofield OMV, Mayou BJ, et al. Epidermolysis bullosa complicated by squamous cell carcinoma: report of 10 cases. J Cutan Pathol. 1992;19:116–23.

    Article  CAS  PubMed  Google Scholar 

  49. Monk BE, Pembroke AC. Epidermolysis bullosa with squamous cell carcinoma. Clin Exp Dermatol. 1987;12:373–4.

    Article  CAS  PubMed  Google Scholar 

  50. Swensson O, Christophers E. Generalized atrophic benign epidermolysis bullosa in 2 siblings complicated by multiple squamous cell carcinomas. Arch Dermatol. 1998;134:199–203.

    Article  CAS  PubMed  Google Scholar 

  51. Mallipeddi R, Keane FM, McGrath JA, et al. Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa. J Eur Acad Dermatol Venereol. 2004;18:521–6.

    Article  CAS  PubMed  Google Scholar 

  52. Saxena A, Lee JB, Humphreys TR. Mohs micrographic surgery for squamous cell carcinoma associated with epidermolysis bullosa. Dermatol Surg. 2006;32:128–34.

    Article  CAS  PubMed  Google Scholar 

  53. Mohr EB, Lohmeyer JA, Mikhaimer NC, et al. Multiple squamous cell carcinomas in junctional epidermolysis bullosa: a surgical challenge. Dermatol Surg. 2008;34:1131–6.

    CAS  PubMed  Google Scholar 

  54. Parker SC, Schofield OMV, Black MM, Eady RAJ. Non-lethal junctional epidermolysis bullosa complicated by squamous cell carcinoma. In: Epidermolysis bullosa: a comprehensive review of classification management and laboratory studies. Crowthorne: Dystrophic Epidermolysis Bullosa Research Association; 1990. p. 103–6.

    Google Scholar 

  55. Weber F, Bauer JW, Sepp N, et al. Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa. Acta Derm Venereol. 2001;81:189–92.

    Article  CAS  PubMed  Google Scholar 

  56. Marinkovich MP. Tumour microenvironment: laminin 332 in squamous-cell carcinoma. Nat Rev Cancer. 2007;7:370–80.

    Article  CAS  PubMed  Google Scholar 

  57. Moriya Y, Niki T, Yamada T, et al. Increased expression of laminin-5 and its prognostic significance in lung adenocarcinomas of small size: an immunohistochemical analysis of 102 cases. Cancer. 2001;91:1129–41.

    Article  CAS  PubMed  Google Scholar 

  58. Nakayama M, Sato YI, Okamoto M, Hirohashi S. Increased expression of laminin-5 and its prognostic significance in hypopharyngeal cancer. Laryngoscope. 2004;114:1259–63.

    Article  CAS  PubMed  Google Scholar 

  59. Tani T, Lumme A, Linnala A, et al. Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane. Am J Pathol. 1997;151:1289–302.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Tsuruta D, Kobayashi H, Imanishi H, et al. Laminin-332-integrin interaction: a target for cancer therapy? Curr Med Chem. 2008;15:1968–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Varki R, Sadowski S, Pfendner E, Uitto J. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. J Med Genet. 2006;43:641–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Yuen WY, Pas HH, Sinke RJ, Jonkman MF. Junctional epidermolysis bullosa of late onset explained by mutations in COL17A1. Br J Dermatol. 2012;164:1280–4.

    Article  Google Scholar 

  63. Yiasemides E, Walton J, Marr P, et al. A comparative study between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis bullosa. Am J Dermatopathol. 2006;28:387–94.

    Article  PubMed  Google Scholar 

  64. Yuen WY. Junctional epidermolysis bullosa [Thesis]. Groningen: University of Groningen; 2012.

    Google Scholar 

  65. McGrath JA, Darling T, Gatalica B, et al. A homozygous deletion mutation in the gene encoding the 180-kDa bullous pemphigoid antigen (BPAG2) in a family with generalized atrophic benign epidermolysis bullosa. J Invest Dermatol. 1996;106:771–4.

    Article  CAS  PubMed  Google Scholar 

  66. Wu Y, Li G, Zhu X. A novel homozygous point mutation in the COL17A1 gene in a Chinese family with generalized atrophic benign epidermolysis bullosa. J Dermatol Sci. 2002;28:181–6.

    Article  CAS  PubMed  Google Scholar 

  67. Ruzzi L, Pas H, Posteraro P, Mazzanti C, et al. A homozygous nonsense mutation in type XVII collagen gene (COL17A1) uncovers an alternatively spliced mRNA accounting for an unusually mild form of non-Herlitz junctional epidermolysis bullosa. J Invest Dermatol. 2001;116:182–7.

    Article  CAS  PubMed  Google Scholar 

  68. Pohla-Gubo G, Cepeda-Valdes R, Hintner H. Immunofluorescence mapping for the diagnosis of epidermolysis bullosa. Dermatol Clin. 2010;28:201–10. vii.

    Article  CAS  PubMed  Google Scholar 

  69. Schofield OM, Fine JD, Verrando P, et al. GB3 monoclonal antibody for the diagnosis of junctional epidermolysis bullosa: results of a multicenter study. J Am Acad Dermatol. 1990;23:1078–83.

    Article  CAS  PubMed  Google Scholar 

  70. Yuen WY, Jonkman MF. Reply to: “Squamous cell carcinoma and junctional epidermolysis bullosa”. J Am Acad Dermatol. 2012;66:857–8.

    Article  Google Scholar 

  71. Frew JW, Dopping-Hepenstal PJ, McGrath JA. Categorizing immunoflourescence mapping in epidermolysis bullosa with pyloric atresia: use as a broad prognostic indicator. Australas J Dermatol. 2010;51:212–4.

    Article  PubMed  Google Scholar 

  72. Jonkman MF, Pas HH, Nijenhuis M, et al. Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa simplex. J Invest Dermatol. 2002;119:1275–81.

    Article  CAS  PubMed  Google Scholar 

  73. Castiglia D, Zambruno G. Molecular testing in epidermolysis bullosa. Dermatol Clin. 2010;28:223–9, vii–viii.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Center for Blistering Diseases, University of Groningen, Groningen, The Netherlands

    Marcel F. Jonkman MD, PhD

  2. Department of Dermatology, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    Jemima E. Mellerio BSc, MBBS, MD, FRCP

Authors
  1. Marcel F. Jonkman MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jemima E. Mellerio BSc, MBBS, MD, FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jemima E. Mellerio BSc, MBBS, MD, FRCP .

Editor information

Editors and Affiliations

  1. Department of Dermatology, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia

    Dédée F. Murrell

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Jonkman, M.F., Mellerio, J.E. (2015). Junctional Epidermolysis Bullosa, Generalized Intermediate Type. In: Murrell, D. (eds) Blistering Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-45698-9_37

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-45698-9_37

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-45697-2

  • Online ISBN: 978-3-662-45698-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation