Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib for Olmsted Syndrome
Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations
Question Can epidermal growth factor receptor transactivation be targeted with erlotinib, an epidermal growth factor receptor inhibitor, to treat palmoplantar keratoderma in patients with Olmsted syndrome caused by transient receptor potential vanilloid 3 (TRPV3) mutations?
Findings In this case report, 3 patients with severe and disabling Olmsted syndrome caused by TRPV3 mutations experienced remission of their palmoplantar keratoderma within less than 3 months of initiating therapy with erlotinib hydrochloride. Hyperkeratosis and pain disappeared, and remission was sustained with ongoing treatment without major adverse effects.
Meaning This study’s findings suggest that erlotinib targets the molecular pathogenesis of Olmsted syndrome caused by TRPV3 mutations and may be an effective treatment for painful hyperkeratosis of this genetic disorder.
Importance Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3 (TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation.
Objective To examine the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3 mutations.
Design, Setting, and Participants In this case series, 3 patients from 2 unrelated families who had TRPV3-mutation–associated PPK were treated with erlotinib from May 5, 2018, through May 13, 2019.
Main Outcomes and Measures Clinical follow-up included evaluation of PPK progression, pain and interventions for pain, as well as erlotinib dose adjustment based on treatment effect, plasma levels, and tolerance.
Results The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies. Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis. All patients experienced depression and did not engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared. All patients were able to touch the ground with their feet, wear shoes, and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the patients resumed social activities. These improvements were sustained across 12 months of treatment and follow-up. The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted.
Conclusions and Relevance The findings of this study report improvement of PPK in patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib. Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention.