Papers of the Week

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma (PPK) for which there is no standard current treatment. PC is caused by dominant mutations in keratin 6A, 6B, 6C, 16, and 17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and PPK in PC remain elusive. Here, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1-EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. Abnormal late terminal keratinization was associated with elevated transglutaminase-1 (TG1) activity. Additionally, the Ca permeable channel TRPV3 was significantly increased in PC-lesional skin suggesting a predominant role of the TRPV3/EGFR signaling complex in PC. We hypothesized that this complex contributes to promoting TG1 activity and induces the expression and shedding of EGFR ligands. To counteract this biological cascade, we treated 3 PC patients with oral erlotinib for 6 to 8 months. The treatment was well tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of quality-of-life. Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC.