Cecilie Bredrup Department of Ophthalmology Haukeland University Hospital KELOIDS IN RTS - AND OTHER HEREDITARY SYNDROMES

 Proliferative fibrous growths resulting from excessive tissue response  Continuous growth invasively beyond the confines of the original wound  Histologically collagen fibers (type I and III) randomly orientated. Fibroblasts (cultured skin cells) show excessive extracellular matrix production and altered behavior  Treatment is difficult, recurrence is high KELOIDS

 Keloids occur in all ethnic groups but are more common in individuals with dark skin, most frequently in individuals aged years.  Most commonly chest, shoulders, upper back and ears  Puberty/pregnancy increased risk  Genetic predisposition plays a major role in keloid development (ethnicities, families, twins)  Pathogenesis remains largely unknown  Animal models limited value  A small number of congenital disorders also have keloids, RTS is the most frequent  Aesthetic disfigurement, impaired function due to restricted skin/joint mobility, pain and itching KELOIDS

 Non-targeted therapies  Surgery alone (70-100% recurrence)  In combination with laser, radiation pressure and laser ablation slightly improved  Corticosteroids at 4-6 weeks intervals (recurrence 10-30%)  Targeted therapies  Under development  Need for further understanding of how keloids develop TREATMENT OPTIONS

 Keloids in Rubinstein- Taybi syndrome: a clinical study  A.L. van de Kar, G. Houge, A.C. Shaw, D. de Jong, M.J. van Belzen, D.J.M. Peters and R.C.M. Hennekam  British Journal of Dermatology 2014 KELOIDS IN RTS

 24% of RTS patients develop keloids  50/50 men/women  Mean age first keloid 11.9 yrs  Ethnicity: predominantly white (Dutch and UK patients)  (Hardly) no family history  Patients with CREBBP mutations increased risk  Severe itching (89%)  Differences in behaviour (37%)  Pain, restriction in movement, infection, sleep problems KELOIDS IN RTS Van de Kar et al. 2014

 22/27 patients more than one keloid  Most located in the sternal area and the shoulder  Treatment limited value  Steroid injection (4)  Lotion (5)  Laser therapy (1)  Pressure therapy (1) KELOIDS IN RTS Copied from Van de Kar et al. 2014

RISK OF DISEASE AND HEREDITARY FACTORS  Complex diseases  Example: keloids kdaljf DNA Health Environment Economy Relationships Excercise Luck

MONOGENIC DISEASES CAN SOMETIMES BE USED AS MODELS FOR COMPLEX DISEASES

 3 billion base pairs  genes  We all have some gene variants not inherited from our parents  This is the case in most RTS patients DE NOVO MUTATIONS

HEREDITARY CONDITIONS WITH KELOID FORMATION USED AS A MODEL TO UNDERSTAND HOW KELOID FORMATION OCCURS (GENE 1-3 UNPUBLISHED) Gene 2 RTS Gene 3 Gene 1 KELOID formation RTS biobank: Raoul CM Hennekam & Dorien JM Peters

EXAMINE GENE EXPRESSION IN CULTURED RTS SKIN CELLS  2 CREBBP  1 EP300  1 unknown  Healthy skin  Border  Keloid  Compared to patients with mutations in Gene 1 and 2

 Currently examining Gene 1-3 and how this affects protein function.  Compare to gene expression dataset GENE 1-3

 Keloid is a frequent problem for RTS patients  Itching particularly problematic  Treatment difficult  We use RTS and 3 other hereditary conditions with keloid formation to try and unravel how keloid formation occur  This is an important step to try to improve treatment SUMMARY

 Raoul CM Hennekam  Dorien JM Peters  Gunnar Houge  Ove Bruland  Eyvind Rødahl  Hans Dauwerse  Linda Xu  Cecilie Bredrup KELOID TEAM