Epidermolysis bullosa in Greece: the patients’ journey so far
Keywords:Hereditary epidermolysis bullosa, Immunofluorescence mapping, Molecular analysis, Mutations, Greece
Background: Hereditary epidermolysis bullosa (EB) represents a group of rare, inherited disorders with different penetrance patterns characterized by skin fragility and easy inducibility of blisters. Mucosal involvement of internal organs may occur. As no published data on EB in Greece exist, this study aimed to record demographics and clinical characteristics of EB patients. Another objective was to identify the associations among clinical characteristics of different types in connection with immunofluorescence mapping (IMF) findings and molecular analysis (MA) used for the laboratory diagnosis of the disease.
Methods: This is a descriptive study conducted at the outpatient clinic of rare diseases of Andreas Sygros Hospital, Athens, Greece from March 2012 until February 2015. Adults and children presenting with EB were enrolled. Patients underwent a thorough clinical and laboratory assessment. Specific laboratory analyses were performed in Rome and two sets of data based on IFM and MA were collected.
Results: In total, 41 patients were enrolled. Prevalence rate of EB was 0.024%. The most frequent type was dystrophic EB, as it affected 20 patients (48.8%). Twelve patients (29.3%) were diagnosed with EB simplex, 6 patients (14.6%) with Kindler syndrome and 3 (7.3%) with junctional EB. IFM was performed in 26 patients and MA in 8 patients. The concordance among clinical and laboratory diagnosis was 88.5%.
Conclusions: This study is the first report on hereditary EB in Greece. Since there is a lack in diagnostic management of EB, we would strongly encourage an effort to perform the required laboratory tests in Greece.
Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014;70(6):1103-26.
Intong LR, Murrell DF. Inherited epidermolysis bullosa: new diagnostic criteria and classification. Clin Dermatol. 2012;30(1):70-7.
Laimer M, Prodinger C, Bauer JW. Hereditary epidermolysis bullosa. J Dtsch Dermatol Ges. 2015;13(11):1125-33.
Murat-Sušić S, Husar K, Skerlev M, Marinović B, Babić I. Inherited epidermolysis bullosa - the spectrum of complications. Acta Dermatovenerol Croat. 2011;19(4):255-63.
Castiglia D, Posteraro P, Spirito F, Pinola M, Angelo C, Puddu P, et al. Novel mutations in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion, and deposition. J Invest Dermatol. 2001;117:731–9.
Posteraro P, Pascucci M, Colombi M, Barlati S, Giannetti A, Paradisi M, et al. Denaturing HPLC-based approach for detection of COL7A1 gene mutations causing dystrophic epidermolysis bullosa. Biochem Biophys Res Commun. 2005;338(3):1391-401.
Castiglia D, Zambruno G. Molecular testing in epidermolysis bullosa. Dermatol Clin. 2010;28(2):223-9.
Tadini G, Gualandri L,Colombi M, Paradisi M, Angelo C, Zambruno G, et al. The Italian registry of inherited epidermolysis bullosa. G Ital Dermatol Venereol. 2005;140(4):359-72.
Castori M, Floriddia G, De Luca N. Herlitz junctional epidermolysis bullosa: laminin-5 mutational profile and carrier frequency in the Italian population. Br J Dermatol. 2008;158(1):38-44.
Danescu S, Has C, Senila S, Ungureanu L, Cosgarea R. Epidemiology of inherited epidermolysis bullosa in Romania and genotype-phenotype correlations in patients with dystrophic epidermolysis bullosa. J Eur Acad Dermatol Venereol. 2015;29(5):899-903.
Pavicić Z, Kmet-Vizintin P, Kansky A, Dobrić I. Occurrence of hereditary bullous epidermolyses in Croatia. Pediatr Dermatol. 1990;7(2):108-10.
Meester I, Igoucheva O, Alexeev V, South A, Moreno-Treviño MG, Salas-Alanis JC. High concordance between clinical diagnosis of epidermolysis bullosa and immunofluorescence with a small, well-matched antibody panel. Australas J Dermatol 2018;59(1):73-6.
Shinkuma S, Natsuga K, NishieW, Shimizu H. Epidermolysis bullosa in Japan. Dermatol Clin. 2010;28(2):431-2.
Abahussein AA, al-Zayir AA, Mostafa WZ, Okoro AN. Epidermolysis bullosa in the Eastern Province of Saudi Arabia. Int J Dermatol. 1993;32(8):579-81.
Barzegar M, Asadi-Kani Z, Mozafari N, Vahidnezhad H, Kariminejad A, Toossi P. Using immunofluorescence (antigen) mapping in the diagnosis and classification of epidermolysis bullosa: a first report from Iran. Int J Dermatol. 2015;54(10):416-23.
Fine JD. Epidemiology of inherited epidermolysis bullosa based on incidence and prevalence estimates from the national epidermolysis bullosa registry. JAMA Dermatol. 2016;152(11):1231-8.
Yuen WY, Lemmink HH, van Dijk-Bos KK, Sinke RJ, Jonkman MF. Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier frequency in the Netherlands. Br J Dermatol. 2011;165(6):1314-22.
Kho YC, Rhodes LM, Robertson SJ, Su J, Varigos G, Robertson I, et al. Epidemiology of epidermolysis bullosa in the antipodes: the Australasian Epidermolysis Bullosa Registry with a focus on Herlitz junctional epidermolysis bullosa. Arch Dermatol. 2010;146(6):635-40.
Horn HM, Priestley GC, Eady RA, Tidman MJ. The prevalence of epidermolysis bullosa in Scotland. Br J Dermatol. 1997;136(4):560-4.
Hiremagalore R, Kubba A, Bansel S, Jerajani H. Immunofluorescence mapping in inherited epidermolysis bullosa: a study of 86 cases from India. Br J Dermatol. 2015;172(2):384-91.
Hernandez-Martín A, Aranegui B, Escámez MJ, de Lucas R, Vicente A, Rodríguez-Díaz E, et al. Prevalence of dystrophic epidermolysis bullosa in Spain: a population-based study using the 3-source capture-recapture method: evidence of a need for improvement in care. Actas Dermosifiliogr. 2013;104(10):890-6.
McKenna KE, Walsh MY, Bingham EA. Epidermolysis bullosa in Northern Ireland. Br J Dermatol. 1992;127(4):318-21.
Müller FB, Küster W, Wodecki K, Almeida H Jr, Bruckner-Tuderman L, Krieg T, et al. Novel and recurrent mutations in keratin KRT5 and KRT14 genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly. Hum Mutat. 2006;27(7):719-20.
Vahidnezhad H, Youssefian L, Saeidian AH, Mozafari N, Barzegar M, Sotoudeh S, et al. KRT5 and KRT14 Mutations in Epidermolysis Bullosa Simplex with Phenotypic Heterogeneity, and Evidence of Semidominant Inheritance in a Multiplex Family. J Invest Dermatol. 2016;136(9):1897-901.
Rugg EL, Horn HM, Smith FJ, Wilson NJ, Hill AJ, Magee GJ, et al. Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol. 2007;127(3):574-80.
Pfendner EG, Sadowski SG, Uitto J. Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. J Invest Dermatol. 2005;125(2):239-43.
Irvine AD, McKenna KE, Bingham A, Nevin NC, Hughes AE. A novel mutation in the helix termination peptide of keratin 5 causing epidermolysis bullosa simplex Dowling-Meara. J Invest Dermatol. 1997;109(6):815-6.
Wertheim-Tysarowska K, Sobczyńska-Tomaszewska A, Kowalewski C, Skroński M, Swięćkowski G, Kutkowska-Kaźmierczak A, et al. The COL7A1 mutation database. Hum Mutat. 2012;33(2):327-31.
Varki R, Sadowski S, Uitto J, Pfendner E. Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet. 2007;44(3):181–92.
Murata T, Masunaga T, Ishiko A, Shimizu H, Nishikawa T. Differences in recurrent COL7A1 mutations in dystrophic epidermolysis bullosa: ethnic-specific and worldwide recurrent mutations. Arch Dermatol Res. 2004;295(10):442-7.
Gardella R, Zoppi N, Zambruno G, Barlati S, Colombi M. Different phenotypes in recessive dystrophic epidermolysis bullosa patients sharing the same mutation in compound heterozygosity with two novel mutations in the type VII collagen gene. Br J Dermatol. 2002;147(3):450-7.
Gardella R, Castiglia D, Posteraro P, Bernardini S, Zoppi N, Paradisi M, et al. Genotype-phenotype correlation in italian patients with dystrophic epidermolysis bullosa. J Invest Dermatol. 2002;119(6):1456-62.
Murata T, Masunaga T, Shimizu H, Takizawa Y, Ishiko A, Hatta N, et al. Glycine substitution mutations by different amino acids in the same codon of COL7A1 lead to heterogeneous clinical phenotypes of dominant dystrophic epidermolysis bullosa. Arch Dermatol Res. 2000;292(10):477-81.
Tamai K, Murai T, Mayama M, Kon A, Nomura K, Sawamura D, et al. Recurrent COL7A1 mutations in Japanese patients with dystrophic epidermolysis bullosa: positional effects of premature termination codon mutations on clinical severity. Japanese Collaborative Study Group on Epidermolysis Bullosa. J Invest Dermatol. 1999;112(6):991-3.
Youssefian L, Vahidnezhad H, Barzegar M, Li Q, Sotoudeh S, Yazdanfar A, et al. The Kindler Syndrome: A Spectrum of FERMT1 Mutations in Iranian Families. J Investigative Dermatol. 2015;135(5):1447–50.
Has C, Castiglia D, del Rio M, Diez MG, Piccinni E, Kiritsi D, et al. Kindler syndrome: extension of FERMT1 mutational spectrum and natural history. Hum Mutat. 2011;32(11):1204-12.
Mansur AT, Elcioglu NH, Aydingöz IE, Akkaya AD, Serdar ZA, Herz C, et al. Novel and Recurrent KIND1 Mutations in Two Patients with Kindler Syndrome and Severe Mucosal Involvement. Acta Derm Venereol. 2007;87(6):563-5.
Burch JM, Fassihi H, Jones CA, Mengshol SC, Fitzpatrick JE, McGrath JA. Kindler syndrome: a new mutation and new diagnostic possibilities. Arch Dermatol. 2006;142(5):620–4.
Thomson MA, Ashton GH, McGrath JA, Eady RA, Moss C. Retrospective diagnosis of Kindler syndrome in a 37-year-old man. Clin Exp Dermatol. 2006;31(1):45-7.
Herz C, Aumailley M, Schulte C, Schlotzer-Schrehardt U, Bruckner-Tuderman L, Has C. Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes. J Biol Chem. 2006;281(47):36082–90.
Ashton GH, McLean WH, South AP, Oyama N, Smith FJ, Al-Suwaid R, et al. Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome. J Invest Dermatol. 2004;122(1):78–83.
Youssefian L, Vahidnezhad H, Uitto J. Kindler Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2016.