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 …

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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  • 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. 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. electron microscopy normal human skin
  • 4. EB simplexjunctional EBdystrophic EB
  • 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. IMPETIGO of the NEWBORN
  • 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. Diagnostical algorithm in neonatal bullous skin disease Skin biopsy Histology Direct immunofluorescence Antigen mapping Electron microscopy Blood sample Indirect immunofluorescence Mutation analysis
  • 9. FOR AN EXACT DIAGNOSIS A SKIN BIOPSY IS ALWAYS NECESSARY!BIOPSY FROM CLINICALLY NORMAL APPEARING SKIN – INNER ASPECT UPPER ARM
  • 10. EBS - Immunoperoxidase - type IV collagen
  • 11. „subepidermal“ blistering - EBJ PAS - Stain
  • 12. „subepidermal“ blistering - EBD H&E Stain
  • 13. electron microscopy normal human skin
  • 14. junctional eb
  • 15. dystrophic eb
  • 16. dystrophic eb
  • 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. Antigen mapping Ijunctional dermolytic
  • 19. Antigen mapping with anti-type IV collagen Determination of the level of split formation
  • 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. antigen mapping K14 - NHS
  • 22. antigen mapping K14 - EBS-K
  • 23. antigen mapping laminin 5 - NHS
  • 24. antigen mapping laminin 5 - EBJ-H
  • 25. heteroduplex analysis
  • 26. enzyme digestion
  • 27. mutation analysis
  • 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. eb simplex - WC
  • 30. eb simplex - K
  • 31. eb simplex - DM
  • 32. eb simplex - MD
  • 33. eb simplex - MD
  • 34. junctional eb - Herlitz
  • 35. junctional eb - Herlitzexuberant granulation tissue
  • 36. junctional eb – non Herlitz
  • 37. junctional eb – non Herlitz
  • 38. junctional eb – non Herlitz
  • 39. junctional eb – non Herlitz
  • 40. junctional eb – non Herlitz
  • 41. junctional eb – non Herlitz male pattern baldness
  • 42. dystrophic eb, dominant
  • 43. dystrophic eb, rezessive-HS
  • 44. dystrophic eb, rezessive-HS milia formation
  • 45. dystrophic eb, rezessive-HS pseudosyndactyly
  • 46. dystrophic eb, rezessive-HSpseudosyndactyly, contractures
  • 47. dystrophic eb, rezessive-HSpseudosyndactyly, contractures
  • 48. eb house austria asCENTRE OF EXPERTISEeb outpatient uniteb academyeb research
  • 49. MANAGEMENT OF PATIENTS WITH EB • Centre of expertise • Support group • University Department • Hospital • Dermatologist (specialist) • Family physician • Family • PATIENT
  • 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. 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. 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. Squamous cell carcinomas in RDEB - HS
  • 54. RDEB - HSLymph node metastasis
  • 55. EB and DENTAL PROBLEMS- Enamel defects: Results of the gene / protein defect odontogenesis- Caries (nutrition!)- Problematic oral hygiene
  • 56. EBJ - nHdental enamel defects, caries
  • 57. RDEB – HS, EBJ - nHmicrostomia, caries
  • 58. RDEB - HScaries, microstomia
  • 59. EBJ - nHcosmetically satisfiing crowns
  • 60. EBJ - nHpanoramic x-ray
  • 61. „at the dentist“sloughing of mucous membranes
  • 62. change of dressing
  • 63. WOUND HEALING – WOUND CARE- Wear cotton gloves- NON-ADHESIVE TAPE! (Binding, padded layers of dressing)- Place ointment in the eyes
  • 64. You can not prevent sloughing!
  • 65. cotton wool underneath blood pressure cuff
  • 66. No adhesive tape !
  • 67. wearing cotton gloves
  • 68. electrode attached with mepiform
  • 69. pseudosyndactyly, contractures
  • 70. change of dressingafter hand surgery
  • 71. change of dressingafter hand surgery
  • 72. splints
  • 73. splints
  • 74. The glove is well accepted
  • 75. a very special technique
  • 76. esophagus strictures
  • 77. RDEB - HSBouginage
  • 78. RDEB - HSskin erosion around gastrostomy button
  • 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. EB - Naevus EBJ non-H
  • 81. EBS-K1998 1999 2000
  • 82. EB – Naevi Pathogenesis EBJ non-H 1992
  • 83. EB - NaeviHistopathology HE S 100 Stain
  • 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. GENETIC COUNSELINGAutosomal rezessiver Erbgang: Autosomal dominanter Erbgang:z.B. in junktionaler Epidermolysis z.B. in dominanter dystrophenbullosa Herlitz Epidermolysis bullosa
  • 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. EB - ACADEMY• „Library“• Training (speakers from intern and extern)• Organization of congresses• Teledermatology: diagnosis; second opinion; training• EB Registry• .....
  • 88. visiting professor J.-D. Fine
  • 89. EB therapyTranssplicing
  • 90. SALZBURG – BOZEN - MODENAGene therapy for “butterfly children“
  • 91. EB – CLINET
  • 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. EB – CLINET
  • 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. 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. ~ 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. Cowden Syndrom Darier EKD fig.var. Mendes da CostaPTEN GENODERMATOSES ATP2A2 GJB3,GJB4 HAE PXE Cylindromas C1NH ABCC6 16q12-q13
  • 98. Recklinghausen tuberous sclerosis Netherton (Pringle ) NF1 TSC1, TSC2 SPINK 5Peutz Jeghers Ehlers-Danlos Pct STK11 Col UROD
  • 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. 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. EUROPEAN COMMISSION RARE DISEASE TASK FORCE ( HIGH LEVEL GROUP)EUROPEAN UNION COMMITTEEof EXPERTS on RARE DISEASES (EUCERD) Member Austria: H.Hintner
  • 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. Thank you!