852 Olmsted syndrome due to PERP mutations shows activation of the EGFR pathway and is improved by oral erlotinib

Olmsted syndrome (OS) is a rare genodermatosis classically characterized by painful bilateral and mutilating transgredient palmoplantar keratoderma (PPK) with periorificial and intertriginous keratotic plaques. It is most often caused by dominant mutations in the transient receptor potential vanilloid-3 (TRPV3)gene, but we recently identified truncating mutations in PERP, encoding a crucial component of desmosomes, as a cause of autosomal dominant OS. We previously reported that blocking EGFR transactivation with oral erlotinib resulted in a remarkable clinical improvement in patients with OS (TRPV3) or with Pachyonychia congenita (KRT6A, KRT16), both of which present with very painful PPK. The mechanisms leading to pain and PPK in OS caused by PERP mutations remain elusive. To gain further insight into OS-PERP pathogenesis, we studied the EGFR pathway and TRPV3 expression in OS-PERP calluses from a 4-year old child and a 28-year old adult. Here, we show a strong overexpression of EGFR ligands epiregulin, TGF-a and HB-EGF in lesional skin. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. The expression of calcium permeable channel TRPV3 was also significantly increased, suggesting a predominant role of the EGFR/TRPV3 signaling complex in OS-PERP. To counteract this biological cascade, we treated the 2 patients with oral erlotinib for 4 to 6 months. The treatment was well tolerated and led to a marked reduction of pain, ameliorated PPK with a major improvement of quality-of-life. Our study provides further evidence that pharmacological inhibition of EGFR can be a powerful strategy in PPK.