Австрийский центр буллезного эпидермолиза (EB House Austria)

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Материалы с I Евразийской Конференции по редким заболеваниям и редким лекарствам и III Всероссийской Конференции по редким заболеваниям и редко применяемым медицинским технологиям
«Дорога жизни».
21-23 июня 2012 года в гостиничном комплексе «Измайлово»

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Австрийский центр буллезного эпидермолиза (EB House Austria)

  1. 1. 1st Eurasean Conference on Rare Diseases and Orphan Products3rd All-Russian Conference for Rare Diseases and Rarely Used Medical Technologies EB House Austria H.Hintner Department of Dermatology Paracelsus Medical University Salzburg
  2. 2. EPIDERMOLYSIS BULLOSA DefinitionA group of rare hereditary skin diseases withcomplications in multiple organsMutations in the genes of structural proteinsof keratinocytes or of the dermo-epidermaljunction lead following minor trauma toblisters and erosions on skin and mucousmembranes
  3. 3. electron microscopy normal human skin
  4. 4. EB simplexjunctional EBdystrophic EB
  5. 5. PRESENT CLASSIFICATION of EB Major EB type Major EB subtype Proteins targeted for mutationEB simplex (EBS) EBS, Weber-Cockayne (EBS-WC) K5, K14 EBS, Koebner (EBS-K) K5, K14 EBS, Dowling-Meara (EBS-DM) K5, K14 EBS with muscular dystrophy (EBS-MD) plectin JEB, Herlitz (JEB-H) laminin-332Junctional EB (JEB) JEB, non-Herlitz (JEB-nH) laminin-332; type XVII collagen JEB with pyloric atresia (JEB-PA) 6 4 integrinDystrophic EB (DEB) dominant DEB (DDEB) type VII collagen recessive DEB, Hallopeau-Siemens type VII collagen (RDEB-HS) recessive dystrophic EB, non-Hallopeau- type VII collagen Siemens (RDEB-nHS)
  6. 6. IMPETIGO of the NEWBORN
  7. 7. Diagnostical algorithm in neonatal bullous skin diseaseStaining of lesion material Gram (fluid aspirate) Giemsa (scraping from base of blister) Tzanck (scraping from base of blister) KOH (preparation of blister roof)Bacterial, viral and fungal culturesPolymerase chain reactions
  8. 8. Diagnostical algorithm in neonatal bullous skin disease Skin biopsy Histology Direct immunofluorescence Antigen mapping Electron microscopy Blood sample Indirect immunofluorescence Mutation analysis
  9. 9. FOR AN EXACT DIAGNOSIS A SKIN BIOPSY IS ALWAYS NECESSARY!BIOPSY FROM CLINICALLY NORMAL APPEARING SKIN – INNER ASPECT UPPER ARM
  10. 10. EBS - Immunoperoxidase - type IV collagen
  11. 11. „subepidermal“ blistering - EBJ PAS - Stain
  12. 12. „subepidermal“ blistering - EBD H&E Stain
  13. 13. electron microscopy normal human skin
  14. 14. junctional eb
  15. 15. dystrophic eb
  16. 16. dystrophic eb
  17. 17. ANTIGEN MAPPING I- Determination of the level of split formation (junctional in lamina lucida vs. dystrophic below lamina densa)- Biopsy of a fresh blister or of clinically normal appearing skin- Immunofluorescence with, for example, anti- type IV collagen
  18. 18. Antigen mapping Ijunctional dermolytic
  19. 19. Antigen mapping with anti-type IV collagen Determination of the level of split formation
  20. 20. ANTIGEN MAPPING II- Biopsy of clinically normal appearing skin (inner aspect upper arm)- Immunofluorescence microscopy with a panel of antibodies against structural proteins of keratinocytes or the dermo- epidermal junction- Normal expression, reduction, lack of staining
  21. 21. antigen mapping K14 - NHS
  22. 22. antigen mapping K14 - EBS-K
  23. 23. antigen mapping laminin 5 - NHS
  24. 24. antigen mapping laminin 5 - EBJ-H
  25. 25. heteroduplex analysis
  26. 26. enzyme digestion
  27. 27. mutation analysis
  28. 28. PRESENT CLASSIFICATION of EB Major EB type Major EB subtype Proteins targeted for mutationEB simplex (EBS) EBS, Weber-Cockayne (EBS-WC) K5, K14 EBS, Koebner (EBS-K) K5, K14 EBS, Dowling-Meara (EBS-DM) K5, K14 EBS with muscular dystrophy (EBS-MD) plectin JEB, Herlitz (JEB-H) laminin-332Junctional EB (JEB) JEB, non-Herlitz (JEB-nH) laminin-332; type XVII collagen JEB with pyloric atresia (JEB-PA) 6 4 integrinDystrophic EB (DEB) dominant DEB (DDEB) type VII collagen recessive DEB, Hallopeau-Siemens type VII collagen (RDEB-HS) recessive dystrophic EB, non-Hallopeau- type VII collagen Siemens (RDEB-nHS)
  29. 29. eb simplex - WC
  30. 30. eb simplex - K
  31. 31. eb simplex - DM
  32. 32. eb simplex - MD
  33. 33. eb simplex - MD
  34. 34. junctional eb - Herlitz
  35. 35. junctional eb - Herlitzexuberant granulation tissue
  36. 36. junctional eb – non Herlitz
  37. 37. junctional eb – non Herlitz
  38. 38. junctional eb – non Herlitz
  39. 39. junctional eb – non Herlitz
  40. 40. junctional eb – non Herlitz
  41. 41. junctional eb – non Herlitz male pattern baldness
  42. 42. dystrophic eb, dominant
  43. 43. dystrophic eb, rezessive-HS
  44. 44. dystrophic eb, rezessive-HS milia formation
  45. 45. dystrophic eb, rezessive-HS pseudosyndactyly
  46. 46. dystrophic eb, rezessive-HSpseudosyndactyly, contractures
  47. 47. dystrophic eb, rezessive-HSpseudosyndactyly, contractures
  48. 48. eb house austria asCENTRE OF EXPERTISEeb outpatient uniteb academyeb research
  49. 49. MANAGEMENT OF PATIENTS WITH EB • Centre of expertise • Support group • University Department • Hospital • Dermatologist (specialist) • Family physician • Family • PATIENT
  50. 50. MANAGEMENT OF PATIENTS WITH EB• 2 EB – Physicians• 2 EB – Nurses• Group of experts from all fields of medicine= INTERDISCIPLINARY MANAGEMENT• Patient training (one week, with the family)• Routine visits or visit on demand• Recreation• .....
  51. 51. EPIDERMOLYSIS BULLOSACutaneous and extracutaneous complications- Squamous cell carcinomas- Dental problems- Wound healing problems- Pseudosyndactyly and contractures- Nutrition- Strictures- EB naevi- Prentatal and preimplantation diagnosis
  52. 52. EPIDERMOLYSIS BULLOSA and CANCER- Early (from 2nd decade on) multiple, highly aggressive squamous cell carcinomas that rapidly metastasize- RDEB-HS: 14a (0,8%); 20a (7,5%); 35a (67,8%); 40a (73,4%); 45a (80,2%) and 55a (90,1%)
  53. 53. Squamous cell carcinomas in RDEB - HS
  54. 54. RDEB - HSLymph node metastasis
  55. 55. EB and DENTAL PROBLEMS- Enamel defects: Results of the gene / protein defect odontogenesis- Caries (nutrition!)- Problematic oral hygiene
  56. 56. EBJ - nHdental enamel defects, caries
  57. 57. RDEB – HS, EBJ - nHmicrostomia, caries
  58. 58. RDEB - HScaries, microstomia
  59. 59. EBJ - nHcosmetically satisfiing crowns
  60. 60. EBJ - nHpanoramic x-ray
  61. 61. „at the dentist“sloughing of mucous membranes
  62. 62. change of dressing
  63. 63. WOUND HEALING – WOUND CARE- Wear cotton gloves- NON-ADHESIVE TAPE! (Binding, padded layers of dressing)- Place ointment in the eyes
  64. 64. You can not prevent sloughing!
  65. 65. cotton wool underneath blood pressure cuff
  66. 66. No adhesive tape !
  67. 67. wearing cotton gloves
  68. 68. electrode attached with mepiform
  69. 69. pseudosyndactyly, contractures
  70. 70. change of dressingafter hand surgery
  71. 71. change of dressingafter hand surgery
  72. 72. splints
  73. 73. splints
  74. 74. The glove is well accepted
  75. 75. a very special technique
  76. 76. esophagus strictures
  77. 77. RDEB - HSBouginage
  78. 78. RDEB - HSskin erosion around gastrostomy button
  79. 79. ABCD rule • A symmetry • B order irregularity • C olor variegation • D iameter > 6mm EB naevi are clinically highly suspective for melanoma!!!JEB-nHS
  80. 80. EB - Naevus EBJ non-H
  81. 81. EBS-K1998 1999 2000
  82. 82. EB – Naevi Pathogenesis EBJ non-H 1992
  83. 83. EB - NaeviHistopathology HE S 100 Stain
  84. 84. Ki-67 (400x) Pathogenesis • Free floating melanocytes spread within the blister cavityHMB-45 (1000x) • Settle down at random (edge of blister) • Proliferate independently in microenvironment of regeneration
  85. 85. GENETIC COUNSELINGAutosomal rezessiver Erbgang: Autosomal dominanter Erbgang:z.B. in junktionaler Epidermolysis z.B. in dominanter dystrophenbullosa Herlitz Epidermolysis bullosa
  86. 86. PRENATAL and PREIMPLANTATION Genetic DiagnosisHiva Fassihi, John Mc Grath, St.John‘s Institute of Dermatology, London• Fetal skin biopsy (1979); HE and electron microscopy; IF• Chorionic villus sampling and amniocentesis• Preiimplantation genetic diagnosis• Non - invasive, prenatal diagnosis (fetal DNA or cells in maternal circulation); fetal loss rate ~ 1 %
  87. 87. EB - ACADEMY• „Library“• Training (speakers from intern and extern)• Organization of congresses• Teledermatology: diagnosis; second opinion; training• EB Registry• .....
  88. 88. visiting professor J.-D. Fine
  89. 89. EB therapyTranssplicing
  90. 90. SALZBURG – BOZEN - MODENAGene therapy for “butterfly children“
  91. 91. EB – CLINET
  92. 92. CLINET• CEs und EB – Experts in 27 (28) EU – Member states• Exchange of information• Organisation of Cross Border Health Care Directive• Basis for clinical studies
  93. 93. EB – CLINET
  94. 94. Epidermolysis bullosa is a Rare = Orphan Disease • Incidence: 1 in 2000 individuals • Often life threatening and chronically debilitating with high complexity and enormous costs • 5000 to 8000 RD = 6% to 8% of the population • 27 to 36 million patients in the EU
  95. 95. Rare diseases in Dermatology are mostly: GENODERMATOSES Definition: Diagnosis, prevention and therapy of hereditary skin diseases, which are caused by mutations in genes encoding components of the skin, mucous membranes, hair and nails or of factors of the biogenetic maschinery for the production of those components.
  96. 96. ~ 400 Monogenetic Genodermatoses• Epidermolysis bullosa hereditaria - group• Hereditary disorders of keratinisation• Hereditary connective tissue diseases• Ectodermal dysplasias• Hereditary diseases of hair and nails• Hereditary pigmentary disorders• Hereditary metabolic diseases• Genodermatoses with benign tumors• Genodermatoses with malignant tumors• Others
  97. 97. Cowden Syndrom Darier EKD fig.var. Mendes da CostaPTEN GENODERMATOSES ATP2A2 GJB3,GJB4 HAE PXE Cylindromas C1NH ABCC6 16q12-q13
  98. 98. Recklinghausen tuberous sclerosis Netherton (Pringle ) NF1 TSC1, TSC2 SPINK 5Peutz Jeghers Ehlers-Danlos Pct STK11 Col UROD
  99. 99. Commission Communication 697 to the European Parliament, the Counsil, theEuropean Economic and Social Committeeand the Committee of the Regions on Rare Diseases: Europe‘s Challenges 11.11.2008Council Recommondation for European Action in the field of Rare Diseases 08.06.2009
  100. 100. DIRECTIVE (EC 2011/24/EU) OFTHE EUROPEAN PARLIAMENT and of the COUNCIL on the APPLICATION of PATIENT‘S RIGHTS in CROSS – BORDER HEALTH CARE 9.3.2011
  101. 101. EUROPEAN COMMISSION RARE DISEASE TASK FORCE ( HIGH LEVEL GROUP)EUROPEAN UNION COMMITTEEof EXPERTS on RARE DISEASES (EUCERD) Member Austria: H.Hintner
  102. 102. MUTATION vs. SINGLE NUCLEOTIDE POLYMORPHISM (SNP)Risk factors for diseases: $ 199.–Entire genome: 10.000.- $ (with disease) 40.000.- $ (normal persons)Company ILUMINA
  103. 103. Thank you!

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