Der Hautarzt

, Volume 65, Issue 6, pp 490–498

Multiple Facetten der genetisch bedingten Hautfragilität

Leitthema

Zusammenfassung

Die genetisch bedingte Hautfragilität umfasst eine Gruppe von heterogenen Erkrankungen, bezeichnet als Epidermolysis bullosa (EB), die mit Bildung von Blasen oder Erosionen nach mechanischer Belastung der Haut einhergehen. Das Spektrum der klinischen Manifestationen ist breit sowie auch der molekulare Hintergrund. Die Haut, aber auch Schleimhäute und andere Organe können mit betroffen sein. In der Praxis sehen wir häufig Patienten mit milder, genetisch bedingter Hautfragilität, die kaum medizinische Betreuung benötigen und oft unter- oder fehldiagnostiziert werden. Die klassischen, eher schweren Subtypen der EB werden meist molekulargenetisch diagnostiziert, um den Familien genetische Beratung und pränatale Diagnostik anbieten zu können. Diese Patienten werden in spezialisierten Zentren medizinisch interdisziplinär betreut. Neben der Wundbehandlung und der Patientenführung, die von der Prognose abhängig ist, untersuchen die Forscher neue gezielte Therapieoptionen. Die modernen Sequenzierungsmethoden ermöglichen die Identifikation neuer, seltener EB-Subtypen.

Schlüsselwörter

Blasen Erosionen Wunden Mutation Dermoepidermale Adhäsion 

The many facets of inherited skin fragility

Abstract

The inherited skin fragility encompasses a heterogeneous group of disorders, collectively designated as epidermolysis bullosa, characterized by recurrent mechanically induced blisters, erosions or wounds. The spectrum of clinical manifestations is broad, as well as the molecular background. Besides the skin, mucosal membranes and other organs can be affected. In real-world practice, patients with mild genetic skin fragility usually do not require medical care and often remain underdiagnosed. In contrast, the well-defined severe EB subtypes are recognized based on typical clinical features. The molecular diagnostics is usually performed in order to allow genetic counselling and prenatal diagnosis. Besides wound care and careful management of the disease complications, new experimental targeted therapies are being developed. New very rare forms of inherited skin fragility have been identified with modern sequencing methods.

Keywords

Blister Erosion Wound Mutation Dermal-epidermal adhesion 

Literatur

  1. 1.
    Fine JD, Eady RA, Bauer EA et al (2008) The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 58:931–950PubMedCrossRefGoogle Scholar
  2. 2.
    Fine JD, Bruckner-Tuderman L, Eady RA et al (2014) Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol [Epub ahead of print]Google Scholar
  3. 3.
    Has C, Bruckner-Tuderman L (2011) Epidermolysis bullosa: diagnosis and therapy. Hautarzt 62:82–90PubMedCrossRefGoogle Scholar
  4. 4.
    Akker PC van den, Jonkman MF, Rengaw T et al (2011) The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations. Hum Mutat 32(10):1100–1107PubMedCrossRefGoogle Scholar
  5. 5.
    Wertheim-Tysarowska K, Sobczynska-Tomaszewska A, Kowalewski C et al (2012) The COL7A1 mutation database. Hum Mutat 33:327–331PubMedCrossRefGoogle Scholar
  6. 6.
    Kiritsi D, Kern JS, Schumann H et al (2011) Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa. J Med Genet 48:450–457PubMedCrossRefGoogle Scholar
  7. 7.
    Bruckner-Tuderman L, Has C (2012) Molecular heterogeneity of blistering disorders: the paradigm of epidermolysis bullosa. J Invest Dermatol 132:E2–E5PubMedCrossRefGoogle Scholar
  8. 8.
    Siegel DH, Ashton GH, Penagos HG et al (2003) Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet 73:174–187PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Has C, Castiglia D, Rio M del et al (2011) Kindler syndrome: extension of FERMT1 mutational spectrum and natural history. Hum Mutat 32:1204–1212PubMedCrossRefGoogle Scholar
  10. 10.
    Groves RW, Liu L, Dopping-Hepenstal PJ et al (2010) A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol 130:1551–1557PubMedCrossRefGoogle Scholar
  11. 11.
    Liu L, Dopping-Hepenstal PJ, Lovell PA et al (2012) Autosomal recessive epidermolysis bullosa simplex due to loss of BPAG1-e expression. J Invest Dermatol 132:742–744PubMedCrossRefGoogle Scholar
  12. 12.
    McGrath JA, Stone KL, Begum R et al (2012) Germline mutation in EXPH5 implicates the Rab27B effector protein Slac2-b in inherited skin fragility. Am J Hum Genet 91:1115–1121PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Pigors M, Kiritsi D, Krumpelmann S et al (2011) Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity. Hum Mol Genet 20:1811–1819PubMedCrossRefGoogle Scholar
  14. 14.
    Jonkman MF, Pasmooij AM, Pasmans SG et al (2005) Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet 77:653–660PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Has C, Sparta G, Kiritsi D et al (2012) Integrin alpha3 mutations with kidney, lung, and skin disease. N Engl J Med 366:1508–1514PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Nicolaou N, Margadant C, Kevelam SH et al (2012) Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome. J Clin Invest 122:4375–4387PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kiritsi D, Cosgarea I, Franzke CW et al (2010) Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals. J Invest Dermatol 130:1741–1746PubMedCrossRefGoogle Scholar
  18. 18.
    Szczecinska W, Nesteruk D, Wertheim-Tysarowska K et al (2014) Underrecognition of acral peeling skin syndrome: 59 new cases with 15 novel mutations. Br J Dermatol [Epub ahead of print]Google Scholar
  19. 19.
    Hammami-Hauasli N, Raghunath M, Kuster W et al (1998) Transient bullous dermolysis of the newborn associated with compound heterozygosity for recessive and dominant COL7A1 mutations. J Invest Dermatol 111:1214–1219PubMedCrossRefGoogle Scholar
  20. 20.
    Shimizu H, Hammami-Hauasli N, Hatta N et al (1999) Compound heterozygosity for silent and dominant glycine substitution mutations in COL7A1 leads to a marked transient intracytoplasmic retention of procollagen VII and a moderately severe dystrophic epidermolysis bullosa phenotype. J Invest Dermatol 113:419–421PubMedCrossRefGoogle Scholar
  21. 21.
    Mellerio JE, Ashton GH, Mohammedi R et al (1999) Allelic heterogeneity of dominant and recessive COL7A1 mutations underlying epidermolysis bullosa pruriginosa. J Invest Dermatol 112:984–987PubMedCrossRefGoogle Scholar
  22. 22.
    Schumann H, Has C, Kohlhase J et al (2008) Dystrophic epidermolysis bullosa pruriginosa is not associated with frequent FLG gene mutations. Br J Dermatol 159:464–469PubMedCrossRefGoogle Scholar
  23. 23.
    Has C, Burger B, Volz A et al (2010) Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer. Dermatology 221:309–312PubMedCrossRefGoogle Scholar
  24. 24.
    Leverkus M, Ambach A, Hoefeld-Fegeler M et al (2011) Late-onset inversa recessive dystrophic epidermolysis bullosa caused by glycine substitutions in collagen type VII. Br J Dermatol 164:1104–1106PubMedCrossRefGoogle Scholar
  25. 25.
    Has C, Kiritsi D, Mellerio JE et al (2014) The missense mutation p.R1303Q in type XVII collagen underlies junctional epidermolysis bullosa resembling Kindler syndrome. J Invest Dermatol 134:845–849PubMedCrossRefGoogle Scholar
  26. 26.
    Pasmooij AM, Jonkman MF, Uitto J (2012) Revertant mosaicism in heritable skin diseases – mechanisms of natural gene therapy. Discovery Medicine 14:167–179PubMedGoogle Scholar
  27. 27.
    Jonkman MF, Scheffer H, Stulp R et al (1997) Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 88:543–551PubMedCrossRefGoogle Scholar
  28. 28.
    Kiritsi D, He Y, Pasmooij AM et al (2012) Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination. J Clin Invest 122:1742–1746PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Kiritsi D, Garcia M, Brander R et al (2014) Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa. J Invest Dermatol [Epub ahead of print]Google Scholar
  30. 30.
    Gostynski A, Pasmooij AM, Jonkman MF (2014) Successful therapeutic transplantation of revertant skin in epidermolysis bullosa. J Am Acad Dermatol 70:98–101PubMedCrossRefGoogle Scholar
  31. 31.
    Fine JD, Mellerio JE (2009) Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J Am Acad Dermatol 61:367–384 (quiz 385–386)PubMedCrossRefGoogle Scholar
  32. 32.
    Mavilio F, Pellegrini G, Ferrari S et al (2006) Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med 12:1397–1402PubMedCrossRefGoogle Scholar
  33. 33.
    Remington J, Wang X, Hou Y et al (2009) Injection of recombinant human type VII collagen corrects the disease phenotype in a murine model of dystrophic epidermolysis bullosa. Mol Ther 17:26–33PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Wagner JE, Ishida-Yamamoto A, McGrath JA et al (2010) Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med 363:629–639PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Atkinson SD, McGilligan VE, Liao H et al (2011) Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex. J Invest Dermatol 131:2079–2086PubMedCrossRefGoogle Scholar
  36. 36.
    Gostynski A, Llames S, Garcia M et al (2014) Long-term survival of type XVII collagen revertant cells in an animal model of revertant cell therapy. J Invest Dermatol 134:571–574PubMedCrossRefGoogle Scholar
  37. 37.
    Tolar J, McGrath JA, Xia L et al (2013) Patient-specific naturally gene-reverted induced pluripotent stem cells in recessive dystrophic epidermolysis bullosa. J Invest Dermatol [Epub ahead of print]Google Scholar
  38. 38.
    Tolar J, Xia L, Lees CJ et al (2013) Keratinocytes from induced pluripotent stem cells in junctional epidermolysis bullosa. J Invest Dermatol 133:562–565PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Tolar J, Xia L, Riddle MJ et al (2011) Induced pluripotent stem cells from individuals with recessive dystrophic epidermolysis bullosa. J Invest Dermatol 131:848–856PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Klinik für Dermatologie und VenerologieUniversitätsklinikum FreiburgFreiburgDeutschland

Personalised recommendations