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»

1. 1st Eurasean Conference on Rare Diseases and
Orphan Products
3rd 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
Definition
A group of rare hereditary skin diseases with
complications in multiple organs
Mutations in the genes of structural proteins
of keratinocytes or of the dermo-epidermal
junction lead following minor trauma to
blisters and erosions on skin and mucous
membranes

3. electron microscopy
normal human skin

4. EB simplex
junctional EB
dystrophic EB

5. PRESENT CLASSIFICATION of EB
Major EB type Major EB subtype Proteins targeted for mutation
EB 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-332
Junctional EB (JEB) JEB, non-Herlitz (JEB-nH) laminin-332; type XVII
collagen
JEB with pyloric atresia (JEB-PA) 6 4 integrin
Dystrophic 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 disease
Staining 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 cultures
Polymerase 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 I
junctional 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 mutation
EB 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-332
Junctional EB (JEB) JEB, non-Herlitz (JEB-nH) laminin-332; type XVII
collagen
JEB with pyloric atresia (JEB-PA) 6 4 integrin
Dystrophic 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 - Herlitz
exuberant 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-HS
pseudosyndactyly, contractures

47. dystrophic eb, rezessive-HS
pseudosyndactyly, contractures

48. eb house austria
as
CENTRE OF EXPERTISE
eb outpatient unit
eb academy
eb 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
• .....

52. EPIDERMOLYSIS BULLOSA
Cutaneous and extracutaneous complications
- Squamous cell carcinomas
- Dental problems
- Wound healing problems
- Pseudosyndactyly and contractures
- Nutrition
- Strictures
- EB naevi
- Prentatal and preimplantation diagnosis

53. 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%)

54. Squamous cell carcinomas in RDEB - HS

55. RDEB - HS
Lymph node metastasis

56. EB and DENTAL PROBLEMS
- Enamel defects:
Results of the gene / protein defect
odontogenesis
- Caries (nutrition!)
- Problematic oral hygiene

57. EBJ - nH
dental enamel defects, caries

58. RDEB – HS, EBJ - nH
microstomia, caries

59. RDEB - HS
caries, microstomia

60. EBJ - nH
cosmetically satisfiing crowns

61. EBJ - nH
panoramic x-ray

62. „at the dentist“
sloughing of mucous membranes

63. change of dressing

64. WOUND HEALING – WOUND
CARE
- Wear cotton gloves
- NON-ADHESIVE TAPE!
(Binding, padded layers of dressing)
- Place ointment in the eyes

65. You can not prevent sloughing!

66. cotton wool underneath blood pressure cuff

67. No adhesive tape !

68. wearing cotton gloves

69. electrode attached with mepiform

70. pseudosyndactyly, contractures

71. change of dressing
after hand surgery

72. change of dressing
after hand surgery

73. splints

74. splints

75. The glove is well accepted

76. a very special technique

77. esophagus strictures

78. RDEB - HS
Bouginage

79. RDEB - HS
skin erosion around gastrostomy button

80. ABCD rule
• A symmetry
• B order irregularity
• C olor variegation
• D iameter > 6mm
EB naevi are clinically
highly suspective for
melanoma!!!
JEB-nHS

81. EB - Naevus
EBJ non-H

82. EBS-K
1998 1999 2000

83. EB – Naevi Pathogenesis
EBJ non-H 1992

84. EB - Naevi
Histopathology HE
S 100 Stain

85. Ki-67 (400x)
Pathogenesis
• Free floating
melanocytes spread
within the blister
cavity
HMB-45 (1000x) • Settle down at
random (edge of
blister)
• Proliferate
independently in
microenvironment
of regeneration

86. GENETIC COUNSELING
Autosomal rezessiver Erbgang: Autosomal dominanter Erbgang:
z.B. in junktionaler Epidermolysis z.B. in dominanter dystrophen
bullosa Herlitz Epidermolysis bullosa

87. PRENATAL and PREIMPLANTATION Genetic
Diagnosis
Hiva 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 %

89. EB - ACADEMY
• „Library“
• Training (speakers from intern and extern)
• Organization of congresses
• Teledermatology: diagnosis; second opinion;
training
• EB Registry
• .....

90. visiting professor J.-D. Fine

91. EB therapy
Transsplicing

93. SALZBURG – BOZEN - MODENA
Gene therapy for “butterfly children“

94. EB – CLINET

95. 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

96. EB – CLINET

99. 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

100. 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.

101. ~ 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

102. Cowden Syndrom Darier EKD fig.var.
Mendes da Costa
PTEN
GENODERMATOSES ATP2A2 GJB3,GJB4
HAE PXE Cylindromas
C1NH ABCC6 16q12-q13

103. Recklinghausen tuberous sclerosis
Netherton
(Pringle )
NF1 TSC1, TSC2 SPINK 5
Peutz Jeghers Ehlers-Danlos
Pct
STK11 Col UROD

104. Commission Communication 697 to the
European Parliament, the Counsil, the
European Economic and Social Committee
and the Committee of the Regions on Rare
Diseases: Europe‘s Challenges
11.11.2008
Council Recommondation for European
Action in the field of Rare Diseases
08.06.2009

105. DIRECTIVE (EC 2011/24/EU) OF
THE EUROPEAN PARLIAMENT
and of the COUNCIL on the
APPLICATION of PATIENT‘S
RIGHTS in CROSS – BORDER
HEALTH CARE
9.3.2011

106. EUROPEAN COMMISSION RARE
DISEASE TASK FORCE ( HIGH
LEVEL GROUP)
EUROPEAN UNION COMMITTEE
of EXPERTS on RARE DISEASES
(EUCERD)
Member Austria: H.Hintner

107. MUTATION vs. SINGLE
NUCLEOTIDE POLYMORPHISM
(SNP)
Risk factors for diseases: $ 199.–
Entire genome: 10.000.- $ (with disease)
40.000.- $ (normal persons)
Company ILUMINA

108. Thank you!