Clinical Update on Epidermolysis Bullosa 2006

1. Clinical Update on Epidermolysis Bullosa 2006 Anne W. Lucky, M.D. Professor of Dermatology and Pediatrics The Cincinnati Children’s EB Center The Cincinnati Children’s Hospital Cincinnati, Ohio USA

2. Epidermolysis Bullosa • Three major types: • Simplex (Epidermal) • Mutations of keratin 5 / 14 and plectin • Junctional (Basement Membrane) • Mutations of basement membrane proteins • Dystrophic (Dermal) • Mutations of type VII collagen • Some authors also include Hemidesmosomal • Revised classification in 2000 • Fine, JD et al, J Am Acad Dermatol 42: 1051-1066

3. EBS BP180 = BPAg2 = type XVII col JEB Laminin 5 has α3/β3/γ2 chains DEB Fine, JD et al, JAAD 2000; 43: 135-137

4. EB Clinical-Molecular Correlations From Pai, Am J Clin Derm 2002;3:371-380

5. EB Simplex (EBS) • Mutations in genes for • keratins (intermediate filaments) • plectin (hemidesmosome plaque) • Most are autosomal dominant • Subtypes of EBS: • Weber-Cockayne Keratin 5,14 • palms and soles • childhood or adult onset • Köbner Keratin 5,14 • generalized, at birth

6. EBS cont. • Dowling-Meara Keratin 5,14 • generalized, at birth, • herpetiform • hyperkeratosis • EBS + Muscular Dystrophy Plectin • Generalized EB • MD later in life • Some classify as EB HD

7. Junctional EB (JEB) • Lamina lucida defects of • anchoring filaments • hemidesmosomes • Most are autosomal recessive • Types: • JEB-H (Herlitz) Laminin 5 • Anchoring filament protein • Any of 3 chains (α3β3γ2) • Severe, generalized, granulation tissue • Lethal in < 2 years

8. JEB cont. • JEB-nH (Non-Herlitz) Laminin 5 • Variable severity Type XVII Col • Alopecia (BP 180) • Dental problems •  risk of squamous cell ca ? • JEB-PA (pyloric atresia) 64 Integrin • Either of 2 chains • Variable severity • + pyloric atresia • Some classify as EBHD • Bauer, JW, and Lanschuetzer, Clin Exp Derm 2003; 28:53-60.

9. Dystrophic EB • Dominant (DDEB) and Recessive (RDEB) • Many (>500) mutations identified in collagen VII gene (COL7A1) on 3p21 • Collagen VII is found in the • anchoring fibril • anchoring plaque

10. Dominant Dystrophic EB (DDEB) • DDEB • Wide spectrum of severity • Generally mild • May be generalized or severe at birth • Improves with age

11. RDEB • RDEB-nHS (non-Hallopeau-Siemens) • Less severe, variable • RDEB-HS (Hallopeau-Siemens) • Severe with • Esophageal strictures • Pseudosyndactyly • Anemia and failure to thrive • Dental problems • Risk for squamous cell carcinoma

12. RDEB Adolescence 19 Years Old Squamous Cell Carcinoma BK Amputation 20 Years Old Same patient Fatal Metastatic SCC

13. RDEB Variants 9 Year Old Boy Non-Hallepeau-Siemens Inverse involvement Pigmentary Abnormality

14. Father with DDEB Mother Asymptomatic with RDEB Mutation Child with one Mutation on Each Collagen 7 Allele Also has Deafness DEB Compound HeterozygoteDDEB and RDEB Mutations

15. EB: Diagnosis • Skin Biopsies • Routine histology • Electron microscopy • Immunofluorescence mapping of BM • Immunofluoroescence for specific proteins • Blood or skin • Genetic identification of the mutation

16. Recent Reviews • 1.Fine, JD et al, Revised classification system for inherited epidermolysis bullosa: report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Derm 2000;42:1051-1066. • 2.Fine,JD, McGrath,J, Eady, RA, Inherited epidermolysis bullosa comes into the new millennium. J Amer Acad Derm 2000; 43:135-137. • 3. Pai,S, Marinkovich,MP, Epidermolysis bullosa: new and emerging trends. Am J Clin Dermatol 2002;3:371-380. • 4. Fine, JD et al, Assessment of mobility, activities and pain in different subtypes of epidermolysis bullosa, Clin Exp Dermatol 2004; 29: 122-127

17. Recent Reviews cont. • 5. Devries,DT et al, Relative extent of skin involvement in inherited epidermolysis bullosa (EB): Composite regional anatomic diagrams based on the findings of the National Registry, 1986 to 2002, J Am Acad Dermatol 2004; 50: 572-581 • 6. Fine, JD, et al, Eye involvement in inherited epidermolysis bullosa: experience with the National Epidermolysis Bullosa Registry. Am J Ophthalmol 2004;138:254-262. • 7. Woodley, DT, Chen, M, Epidermolysis bullosa: then and now. J Am Acad Dermatol 2004; 51:Suppl1,S55-57. • 8. Ingen-Housz-Oro, S et al, Vitamin and trace metal levels in recessive dystrophic epidermolysis bullosa. J Eur Acad Dermatol Venerol 2004;18:649-53. • 9. McAllister, JC, Marinkovitch, P, Advances in inherited epidermolysis bullosa. Adv, Dermatol 2005;21:303-34

18. Recent Reviews cont. • 10. Uitto, J and Richard, G. Progress in Epidermolysis Bullosa: from eponyms to molecular genetic classification. Clin Dermatolol 2005;23:33-40. • 11. Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry,1986-2002. J Hand Surg (Br) 2005;30:14-22. • 12. Fine, JD et al. Impact of inherited epidermolysis bullosa on parental interpersonal relationships, marital status and family size. Br. J Dermatol.2005;152:1009-14 • 13. Fewtrell, MS et al, Bone mineralization in children with epidermolysis bullosa. Br J Dermatol 2006;154:959-62. • 14. Azizkhan, RG et al, Esophageal strictures in children with recessive dystrophic epidermolysis bullosa: an 11 year experience with fluoroscopically guided balloon dilatation. J Pediatr Surg 2006;41:55-60